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Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.
Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies. PMID:23523402
Volz, Asisa; Sutter, Gerd
Development of regional chemotherapies: feasibility, safety and efficacy in clinical use and preclinical studies
Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development.
Cai, Shuang; Bagby, Taryn R; Forrest, M Laird
Pig models of neurodegenerative disorders: Utilization in cell replacement-based preclinical safety and efficacy studies.
An important component for successful translation of cell replacement-based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large-scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (na�ve noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed. J. Comp. Neurol. 522:2784-2801, 2014. � 2014 Wiley Periodicals, Inc. PMID:24610493
Dolezalova, Dasa; Hruska-Plochan, Marian; Bjarkam, Carsten R; S�rensen, Jens Christian H; Cunningham, Miles; Weingarten, David; Ciacci, Joseph D; Juhas, Stefan; Juhasova, Jana; Motlik, Jan; Hefferan, Michael P; Hazel, Tom; Johe, Karl; Carromeu, Cassiano; Muotri, Alysson; Bui, Jack; Strnadel, Jan; Marsala, Martin
Nonindustry-Sponsored Preclinical Studies on Statins Yield Greater Efficacy Estimates Than Industry-Sponsored Studies: A Meta-Analysis
Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966�April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I2 statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (?1.99; 95% CI ?2.68, ?1.31) versus studies sponsored by industry (?0.73; 95% CI ?1.00, ?0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study.
Krauth, David; Anglemyer, Andrew; Philipps, Rose; Bero, Lisa
Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trials.
Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein ? 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R(2) = 0.11, P < 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R(2) = 0.89, P < 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models. PMID:24049060
van de Steeg, E; Kleemann, R; Jansen, H T; van Duyvenvoorde, W; Offerman, E H; Wortelboer, H M; Degroot, J
Spinal cord stimulation for heart failure: preclinical studies to determine optimal stimulation parameters for clinical efficacy.
Spinal cord stimulation with implantable devices has been used worldwide for decades to treat regional pain conditions and cardiac angina refractory to conventional therapies. Preclinical studies with spinal cord stimulation in experimental animal models of heart disease have described interesting effects on cardiac and autonomic nervous system physiology. In canine and porcine animals with failing hearts, spinal cord stimulation reverses left ventricular dilation and improves cardiac function, while suppressing the prevalence of cardiac arrhythmias. In this paper, we present further canine studies that determined the optimal site and intensity of spinal cord stimulation that produced the most robust and beneficial clinical response in heart failure animals. We then explore and discuss the clinically relevant aspects and potential impediments that may be encountered in translating spinal cord stimulation to human patients with advanced cardiac disease. PMID:24569871
Lopshire, John C; Zipes, Douglas P
Clinical attrition due to biased preclinical assessments of potential efficacy
Unless it is carefully controlled, bias often distorts the results of clinical trials, usually exaggerating the magnitude of true efficacy. For that reason, procedures to limit bias have been mandated by the FDA when assessing efficacy in clinical trials. The present review shows that the effects of bias in preclinical studies are at least as large as in clinical trials,
Mark D. Lindner
Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study
Purpose To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis. Methods Seven normally-sighted feline subjects were implanted for 96�143 days with a suprachoroidal electrode array and six were chronically stimulated for 70�105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue. Results All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11�15 k? during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses. Conclusions Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.
Nayagam, David A. X.; Williams, Richard A.; Allen, Penelope J.; Shivdasani, Mohit N.; Luu, Chi D.; Salinas-LaRosa, Cesar M.; Finch, Sue; Ayton, Lauren N.; Saunders, Alexia L.; McPhedran, Michelle; McGowan, Ceara; Villalobos, Joel; Fallon, James B.; Wise, Andrew K.; Yeoh, Jonathan; Xu, Jin; Feng, Helen; Millard, Rodney; McWade, Melanie; Thien, Patrick C.; Williams, Chris E.; Shepherd, Robert K.
Pasteurization of bone for tumour eradication prior to reimplantation - An in vitro & pre-clinical efficacy study
Background & objectives: In current era of limb-salvage therapy, pasteurization of bone sarcomas is receiving growing attention as a potential extracorporeal treatment and cost-effective alternative to allografts and radiation before surgical reimplantation. Detailed in vitro and in vivo pre-clinical study to evaluate efficacy of pasteurization to eradicate malignant cells has not been reported yet. The present study was carried out to assess the efficacy of pasteurization to kill tumour cells both in vitro and in vivo. Methods: Surgically resected specimens of osteosarcomas (n=4) were cut into equal halves and one section was pasteurized by heating at 60�C to 65�C for 40 min. Paired samples before and after pasteurization were studied in vitro for DNA ploidy, evaluation of histological change and elimination of mitotic activity. These tissues were transplanted in immune-deficient NOD-SCID mice to evaluate effect on tumour-generating ability, presence of human nuclei, osteopontin and cytokine/chemokines released in tumour-transplanted mice. Results: Non-pasteurized tumour samples had viable tumour cells which exhibited significant growth in culture, increased proliferative ability and clonogenic potential while respective pasteurized tumour tissues did not grow in culture and did not exhibit clonogenicity. Flow cytometry revealed that propidium iodide positive dead cells increased significantly (P< 0.01) post pasteurization. Seven of 12 non-pasteurized tumour transplanted mice demonstrated tumour-forming ability as against 0 of 12 in pasteurized tumour transplanted mice. Solid tumour xenografts exhibited strong expression of anti-human nuclei and osteopontin by immunohistochemistry as well as secretary human interluekin-6 (IL-6) while pasteurized mice failed to express these markers. Interpretation & conclusions: This study has provided a basis to establish pasteurization as being efficacious in ensuring tumour eradication from resected bone tumour specimens. Pasteurized tumour bearing bone can thus safely be used to reconstruct large defects after tumour resection.
Kode, Jyoti; Taur, Prasad; Gulia, Ashish; Jambhekar, Nirmala; Agarwal, Manish; Puri, Ajay
Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments
Background The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. Methods and Findings We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria�most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. Conclusions By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary
Henderson, Valerie C.; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M.; Hackam, Dan G.
Preclinical studies on the radioprotective efficacy and pharmacokinetics of subcutaneously administered amifostine.
The radioprotective effects and pharmacokinetics of subcutaneously (SC) administered amifostine have been investigated in animal studies. Studies in rats using a single dose of amifostine showed that SC administration gave protection from radiation-induced mucositis that is at least equivalent to that achieved by intravenous administration of the drug. These studies also indicate that tissue levels of the active metabolite WR-1065 correlated better with the radioprotective effects of amifostine than do plasma WR-1065 levels. Multiple-dose studies in rats show radioprotective effects equal to or greater than those obtained with intravenous dosing in the setting of fractionated irradiation. In addition, there is no evidence of drug accumulation in either normal or tumor tissue, with tumor WR-1065 levels peaking just above the limits of quantitation during treatment. Preliminary data from studies of SC amifostine in monkeys indicate a plasma pharmacokinetic profile similar to that reported earlier in humans. Tissue WR-1065 levels were higher at 30 minutes after SC dosing than they were after intravenous dosing and were comparable for the two routes at 60 minutes. PMID:12577236
Cassatt, David R; Fazenbaker, Christine A; Kifle, Gizachew; Bachy, Christine M
Preclinical efficacy spectrum and pharmacokinetics of ixabepilone
Purpose��Ixabepilone, a semisynthetic analog of natural epothilone B, was developed for use in cancer treatment. This study extends\\u000a previous findings regarding the efficacy of ixabepilone and its low susceptibility to tumor resistance mechanisms and describes\\u000a the pharmacokinetics of this new antineoplastic agent.\\u000a \\u000a \\u000a \\u000a Methods��The cytotoxicity of ixabepilone was assessed in vitro in breast, lung, and colon tumor cell lines and in
Francis Y. F. Lee; Richard Smykla; Kathy Johnston; Krista Menard; Kelly McGlinchey; Russell W. Peterson; Amy Wiebesiek; Gregory Vite; Craig R. Fairchild; Robert Kramer
Preclinical studies of low back pain
Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain.
In-Vivo Efficacy of Compliant 3D Nano-Composite in Critical-Size Bone Defect Repair: a Six Month Preclinical Study in Rabbit
Bone defects above critical size do not heal completely by itself and thus represent major clinical challenge to reconstructive surgery. Numerous bone substitutes have already been used to promote bone regeneration, however their use, particularly for critical-sized bone defects along with their long term in vivo safety and efficacy remains a concern. The present study was designed to obtain a complete healing of critical-size defect made in the proximal tibia of New Zealand White rabbit, using nano-hydroxyapatite/gelatin and chemically carboxymethylated chitin (n-HA/gel/CMC) scaffold construct. The bone-implant interfaces and defect site healing was evaluated for a period up to 25 weeks using radiography, micro-computed tomography, fluorescence labeling, and histology and compared with respective SHAM (empty contra lateral control). The viscoelastic porous scaffold construct allows easy surgical insertion and post-operatively facilitate oxygenation and angiogenesis. Radiography of defect treated with scaffold construct suggested expedited healing at defect edges and within the defect site, unlike confined healing at edges of the SHAM sites. The architecture indices analyzed by micro-computed tomography showed a significant increase in percentage of bone volume fraction, resulted in reconciled cortico-trabecular bone formation at n-HA/gel/CMC constructs treated site (15.2% to 52.7%) when compared with respective SHAM (10.2% to 31.8%). Histological examination and fluorescence labeling revealed that the uniformly interconnected porous surface of scaffold construct enhanced osteoblasts� activity and mineralization. These preclinical data suggest that, n-HA/gel/CMC construct exhibit stimulation of bone's innate regenerative capacity, thus underscoring their use in guided bone regeneration.
Sagar, Nitin; Pandey, Alok K.; Gurbani, Deepak; Khan, Kainat; Singh, Dhirendra; Chaudhari, Bhushan P.; Soni, Vivek P.; Chattopadhyay, Naibedya; Dhawan, Alok; Bellare, Jayesh R.
A Preclinical Study of the Safety and Efficacy of Occlusin Trade-Mark-Sign 500 Artificial Embolization Device in Sheep
Introduction: This study evaluated the safety, effectiveness, and biodegradation of a new embolic agent, Occlusin Trade-Mark-Sign 503 Artificial Embolization Device (OCL 503). The agent consists of biodegradable poly-lactic-co-glycolic acid microspheres (150-212 {mu}m) coated with type I bovine collagen and was compared with Embosphere{sup Registered-Sign} Microspheres (300-500 {mu}m) in this controlled study of uterine artery embolization (UAE) in sheep. Methods: Unilateral UAE was performed in 32 adult ewes randomly assigned. Vessels were embolized to effective stasis. The cohort was divided into four groups, which were sacrificed at 1, 3, 6, and 12 months. Results: Both agents were 100% effective in achieving stasis. At 6 months, all OCL 503-treated arteries were occluded, the microspheres degraded with time, and at 12 months all four animals examined demonstrated recanalization. OCL 503 was found in the untreated uterine artery in one animal with no other evidence of non target embolization. In the Embosphere-treated group, all vessels remained occluded and microspheres were detected in the contralateral uterine artery in 6 of 15 examined vessels and in 10 vaginal, 2 ovarian, and 1 vesical artery. No procedural-related complications were seen in either group. Conclusions: OCL 503 is as effective an embolic agent as Embosphere{sup Registered-Sign} Microspheres when embolizing ovine uterine arteries and resorbs with time, allowing recanalization of the treated arteries. No device-related issues or adverse events were observed.
Owen, Richard J., E-mail: firstname.lastname@example.com [University of Alberta, Radiology and Diagnostic Imaging, Walter C. Mackenzie Health Sciences Centre (Canada); Nation, Patrick N. [University of Alberta, Laboratory Medicine and Pathology, Walter C. Mackenzie Health Sciences Centre (Canada); Polakowski, Robert [BioLipids Inc (Canada); Biliske, Jennifer A. [University of Alberta, Biological Sciences, CW405, Biological Sciences Building (Canada); Tiege, Paul B. [University of Alberta, Lipid Products Research Alberta (LiPRA), 410 Agriculture/Forestry Centre (Canada); Griffith, Irwin J. [IMBiotechnologies Ltd (Canada)
Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)
Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441�1152 days) versus the placebo group (441 days, IQR 151�641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491�1531 days) versus the placebo group (466 days, IQR 236�710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.
Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P
Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.
Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.
Pre-clinical studies of toxin-specific nanobodies: evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming.
Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab'(2) based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of (99m)Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab'(2) product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab'(2) based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. PMID:22968189
Hmila, Issam; Cosyns, Bernard; Tounsi, Hayfa; Roosens, Bram; Caveliers, Vicky; Abderrazek, Rahma Ben; Boubaker, Samir; Muyldermans, Serge; El Ayeb, Mohamed; Bouhaouala-Zahar, Balkiss; Lahoutte, Tony
Pre-clinical studies of toxin-specific Nanobodies: Evidence of in vivo efficacy to prevent fatal disturbances provoked by scorpion envenoming
Scorpions represent a significant threat to humans and animals in various countries throughout the world. Recently, we introduced Nanobodies (Nbs) to combat more efficiently scorpion envenoming and demonstrated the performance of NbAahIF12 and NbAahII10 to neutralize scorpion toxins of Androctonus australis hector venom. A bispecific Nb construct (NbF12-10) comprising these two Nbs is far more protective than the classic Fab?{sub 2} based therapy and is the most efficient antivenom therapy against scorpion sting in preclinical studies. Now we investigate the biodistribution and pharmacokinetics of {sup 99m}Tc labeled Nbs by in vivo imaging in rodents and compared these data with those of the Fab?{sub 2} product (PAS). The pharmacodynamics of the Nbs was investigated in rats by in vivo echocardiography and it is shown that NbF12-10 prevents effectively the hemodynamic disturbances induced by a lethal dose of venom. Moreover, even a late injection of NbF12-10 restores the heart rate and brings the blood pressure to baseline values. Histology confirms that NbF12-10 prevents lung and heart lesions of treated mice after envenoming. In conjunction, in this preclinical study, we provide proof of concept that NbF12-10 prevents effectively the fatal disturbances induced by Androctonus venom, and that the Nanobody based therapeutic has a potential to substitute the classic Fab?{sub 2} based product as immunotherapeutic in scorpion envenoming. Further clinical study using larger cohorts of animals should be considered to confirm the full protecting potential of our NbF12-10. -- Highlights: ? Nanobody therapy prevents the hemodynamic disturbances induced by a lethal dose. ? Late injection of Nanobody restores hemodynamic parameters to baseline values. ? Nanobody therapy prevents lung and heart lesions of treated mice after envenoming. ? Labeled Nanobody and Fab�2 pharmacokinetics curves reach plateau in favour of Nanobody.
Hmila, Issam [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Cosyns, Bernard [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Tounsi, Hayfa [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Roosens, Bram; Caveliers, Vicky [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium); Abderrazek, Rahma Ben [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Boubaker, Samir [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Service d'Anatomo-Pathologie, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Muyldermans, Serge [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium) [Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussel (Belgium); Department of Structural Biology, VIB, Brussels (Belgium); El Ayeb, Mohamed [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia)] [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Bouhaouala-Zahar, Balkiss, E-mail: firstname.lastname@example.com [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia) [Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, 13 Place Pasteur, BP-74, 1002 Tunis (Tunisia); Facult� de M�decine de Tunis, Universit� de Tunis-El Manar (Tunisia); Lahoutte, Tony [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)] [Laboratory of In Vivo Cellular and Molecular Imaging, Vrije Universiteit Brussel (Belgium)
Ibandronate: pharmacology and preclinical studies.
Over the past three decades, changes to the chemical structures of the bisphosphonates have resulted in progressive improvements in their antiresorptive potencies. Ibandronate is a potent, nitrogen-containing bisphosphonate that possesses a tertiary nitrogen group on its R2 side chain and a hydroxyl group on its R1 side chain, which together confer one of the highest antiresorptive potencies of all bisphosphonates. In common with other nitrogen-containing bisphosphonates, ibandronate is a strong inhibitor of farnesyl pyrophosphate synthase, which probably accounts for its major effects on osteoclast activity. In addition, it binds strongly to hydroxyapatite. The pharmacological efficacy and safety of various continuous and intermittent regimens of ibandronate have been extensively investigated in experimental models of osteoporosis in several animal species, including rats, dogs, and monkeys. In ovariectomized (OVX) rats, intermittent (dosing interval 2, 4, and 6 weeks) and continuous ibandronate regimens provided equivalent results per total dose irrespective of the dosing regimen. Similar results were obtained in OVX dogs and monkeys. High doses of ibandronate many times those used therapeutically were well tolerated and did not impair bone quality or mineralization in rats. Moreover, bone mass, architecture, and strength were maintained or improved, and bone healing was not adversely affected in animal models, regardless of whether ibandronate was administered intermittently or daily. The findings from all these studies demonstrate the efficacy and safety of intermittent ibandronate regimens and support the development of such regimens for the clinical management of postmenopausal osteoporosis. PMID:16531132
Russell, R G G
Preclinical Studies of Amixicile, a Systemic Therapeutic Developed for Treatment of Clostridium difficile Infections That Also Shows Efficacy against Helicobacter pylori.
Amixicile shows efficacy in the treatment of Clostridium difficile infections (CDI) in a mouse model, with no recurrence of CDI. Since amixicile selectively inhibits the action of a B vitamin (thiamine pyrophosphate) cofactor of pyruvate:ferredoxin oxidoreductase (PFOR), it may both escape mutation-based drug resistance and spare beneficial probiotic gut bacteria that do not express this enzyme. Amixicile is a water-soluble derivative of nitazoxanide (NTZ), an antiparasitic therapeutic that also shows efficacy against CDI in humans. In comparative studies, amixicile showed no toxicity to hepatocytes at 200 ?M (NTZ was toxic above 10 ?M); was not metabolized by human, dog, or rat liver microsomes; showed equivalence or superiority to NTZ in cytochrome P450 assays; and did not activate efflux pumps (breast cancer resistance protein, P glycoprotein). A maximum dose (300 mg/kg) of amixicile given by the oral or intraperitoneal route was well tolerated by mice and rats. Plasma exposure (rats) based on the area under the plasma concentration-time curve was 79.3 h � ?g/ml (30 mg/kg dose) to 328 h � ?g/ml (100 mg/kg dose), the maximum concentration of the drug in serum was 20 ?g/ml, the time to the maximum concentration of the drug in serum was 0.5 to 1 h, and the half-life was 5.6 h. Amixicile did not concentrate in mouse feces or adversely affect gut populations of Bacteroides species, Firmicutes, segmented filamentous bacteria, or Lactobacillus species. Systemic bioavailability was demonstrated through eradication of Helicobacter pylori in a mouse infection model. In summary, the efficacy of amixicile in treating CDI and other infections, together with low toxicity, an absence of mutation-based drug resistance, and excellent drug metabolism and pharmacokinetic metrics, suggests a potential for broad application in the treatment of infections caused by PFOR-expressing microbial pathogens in addition to CDI. PMID:24890599
Hoffman, Paul S; Bruce, Alexandra M; Olekhnovich, Igor; Warren, Cirle A; Burgess, Stacey L; Hontecillas, Raquel; Viladomiu, Monica; Bassaganya-Riera, Josep; Guerrant, Richard L; Macdonald, Timothy L
Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib
Background & Aims Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Methods Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Results Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts. Conclusions Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.
Lachenmayer, Anja; Toffanin, Sara; Cabellos, Laia; Alsinet, Clara; Hoshida, Yujin; Villanueva, Augusto; Minguez, Beatriz; Tsai, Hung-Wen; Ward, Stephen C.; Thung, Swan; Friedman, Scott L.; Llovet, Josep M.
Efficacy and safety of mesenchymal stromal cells in preclinical models of acute lung injury: a systematic review protocol
Background Acute respiratory distress syndrome (ARDS) in humans is caused by an unchecked proinflammatory response that results in diffuse and severe lung injury, and it is associated with a mortality rate of 35 to 45%. Mesenchymal stromal cells (MSCs; �adult stem cells�) could represent a promising new therapy for this syndrome, since preclinical evidence suggests that MSCs may ameliorate lung injury. Prior to a human clinical trial, our aim is to conduct a systematic review to compare the efficacy and safety of MSC therapy versus controls in preclinical models of acute lung injury that mimic some aspects of the human ARDS. Methods/Design We will include comparative preclinical studies (randomized and non-randomized) of acute lung injury in which MSCs were administered and outcomes compared to animals given a vehicle control. The primary outcome will be death. Secondary outcomes will include the four key features of preclinical acute lung injury as defined by the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar capillary barrier, lung inflammatory response, and physiological dysfunction) and pathogen clearance for acute lung injury models that are caused by infection. Electronic searches of MEDLINE, Embase, BIOSIS Previews, and Web of Science will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias will be assessed using the Cochrane risk of bias tool, and individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Discussion The results of this systematic review will comprehensively summarize the safety and efficacy of MSC therapy in preclinical models of acute lung injury. Our results will help translational scientists and clinical trialists to determine whether sufficient evidence exists to perform a human clinical trial. These results may also guide future acute lung injury preclinical and clinical research.
Preclinical Studies of Raloxifene and Related Compounds
\\u000a The development of raloxifene (also know as keoxifene) for clinical use was based on a series of preclinical studies that\\u000a demonstrated it has a highly desirable tissue-specific activity. Results indicated that the therapeutic effects of raloxifene\\u000a (LY138481 HCl; LY156758) mimicked some of those of estrogen in ovariectomized animals by reducing bone loss and lowering serum\\u000a cholesterol levels. Conversely, in mammary
Robin Fuchs-Young
A Summary of Preclinical Topical Microbicide Rectal Safety and Efficacy Evaluations in a Pigtailed Macaque Model
Background There is widespread recognition of the potential promise of vaginal microbicides as a tool to combat global HIV/AIDS and STI epidemics, and candidate product development has maintained a rapid pace in recent years; however, rectal microbicide development has received less attention. As it is likely that commercial products developed for vaginal use will also be used rectally, there is a clear need to assess the safety and efficacy of candidate microbicide products specifically in the rectal compartment. Methods We have developed a standardized protocol for preclinical rectal safety and (chlamydial) efficacy assessment of topical microbicide candidates in a non-human primate model. We evaluated a total of twelve test compounds for rectal safety (via rectal pH, microflora, and rectal lavage) and one compound for efficacy against rectal chlamydial infection. Results In this paper, we describe our methods in detail and summarize our results, particularly noting the ability of our model to distinguish products with deleterious effects on the rectal environment. We also outline the specific criteria used to recommend products move into preclinical rectal efficacy trials or be recommended for reformulation to the product developer. In sum, we observed significant adverse effects in two products. The single product that underwent efficacy evaluation was not observed to be protective against rectal chlamydial infection. Conclusions A preclinical safety and efficacy model is critical to promoting rectal microbicide development, which will ultimately offer a significant opportunity for intervention in the global HIV/AIDS epidemic.
Patton, Dorothy L.; Sweeney, Yvonne T. Cosgrove; Paul, Kathleen J.
Drug-Eluting Stents in Preclinical Studies Updated Consensus Recommendations for Preclinical Evaluation
Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time.
Schwartz, Robert S.; Edelman, Elazer; Virmani, Renu; Carter, Andrew; Granada, Juan F.; Kaluza, Greg L.; Chronos, Nicolas A.F.; Robinson, Keith A.; Waksman, Ron; Weinberger, Judah; Wilson, Gregory J.; Wilensky, Robert L.
Seprafilm� adhesion barrier: (1) a review of preclinical, animal, and human investigational studies.
The aim of this study was to provide a single site resource for investigators, clinicians, and others seeking preclinical, animal, and human investigational studies concerning the postsurgical, anti-adhesion barrier Seprafilm� (Genzyme Corporation, Cambridge, MA). All published preclinical, animal, human extra-abdominal research as of July 2011 have been summarized and included in this document. Searches of Medline and EMBASE Drugs and Pharmaceuticals databases were conducted for original preclinical, animal, and human extra-abdominal studies involving Seprafilm. Preclinical, animal, and extra-abdominal human investigational studies are the study selection for this manuscript. Intraabdominal use is discussed in the accompanying manuscript. Data extraction includes systematic manuscript review. Summary of preclinical, animal, and extra-abdominal human investigational use of Seprafilm by surgical discipline were gathered for data synthesis. The clinical use of Seprafilm, which was approved by the FDA for intra-abdominal procedures, is supported by preclinical and animal studies relating to general surgical and obstetrical/gynecological applications. Findings from preclinical, animal, and human investigational studies at other sites throughout the body raises the potential for additional human clinical trials to assess efficacy and safety following surgical procedures at non-abdominal locations. PMID:22837732
Diamond, Michael P; Burns, Ellen L; Accomando, Beverly; Mian, Sadiqa; Holmdahl, Lena
Efficacy of oncolytic adenovirus expressing suicide genes and interleukin-12 in preclinical model of prostate cancer
Oncolytic adenovirus-mediated suicide gene therapy has been shown to improve local tumor control in preclinical tumor models and in the clinic. Although local tumor control is important, for most human cancers, new therapies must also target metastatic disease if they are to have an impact on survival. Here, we test the hypothesis that adding cytokine gene therapy to our multimodal platform improves both local and metastatic tumor control in a preclinical model of prostate cancer. An oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse interleukin-12 (IL-12) was generated. Relative to an adenovirus lacking IL-12 (Ad5-yCD/mutTKSR39rep), Ad5-yCD/mutTKSR39rep-mIL12 improved local and metastatic tumor control in the TRAMP-C2 prostate adenocarcinoma model, resulting in a significant increase in survival. Ad5-yCD/mutTKSR39rep-mIL12 resulted in high levels of IL-12 and interferon gamma in serum and tumor, increased natural killer (NK) and cytotoxic T-lymphocyte lytic activities, and the development of tumor-specific antitumor immunity. Immune cell depletion studies indicated that both the innate and adaptive arms of immunity were required for maximal Ad5-yCD/mutTKSR39rep-mIL12 activity. The results demonstrate that the addition of IL-12 significantly improves the efficacy of oncolytic adenovirus-mediated suicide gene therapy and provide the scientific basis for future trials targeting locally aggressive cancers.
Freytag, SO; Barton, KN; Zhang, Y
Pravafenix(�) is a fixed-dose combination of 40mg of pravastatin and 160mg of fenofibrate. The rationale behind the use of Pravafenix(�) is based on the increased residual cardiovascular risk observed in high risk patients with hypertriglyceridemia and/or low HDL cholesterol levels despite treatment with statins in monotherapy. In this article, we review the available evidence on the clinical efficacy of Pravafenix(�), which shows complementary benefits in the overall lipid profile of high risk patients with mixed dyslipidemia not controlled with 40-mg pravastatin or 20-mg simvastatin. PMID:25043542
Pedro-Botet, Juan; Flores-Le Roux, Juana A
Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data
Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and �developable� dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the �anticipation� of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for �AHD� demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus�. Methods to enhance prediction confidence such as in vitro�in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via �reverse pharmacology strategies� that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus� in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.
Lakshminarayana, Suresh B.; Hu, Wenyu; He, Handan
A review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy data?
Summary There is an urgent need for an improved TB vaccine. Vaccine development is hindered by the lack of immune correlates and uncertain predictive value of preclinical animal models. As data become available from human efficacy trials, there is an opportunity to evaluate the predictive value of the criteria used to select candidate vaccines. Here we review the efficacy in animal models of the MVA85A candidate vaccine in light of recent human efficacy data and propose refinements to the preclinical models with the aim of increasing their predictive value for human efficacy.
McShane, Helen; Williams, Ann
Preclinical Efficacy Testing for Stomach and Liver Cancers
Purpose Hollow fiber assays offer an early in vivo method of anticancer drug screening. The assays have been optimized for human cancers originating from the lung, breast, colon, ovary, and brain, but not from the stomach and liver. The current study focused on optimization of hollow fiber assays for gastric and hepatocellular carcinoma cell lines. Materials and Methods Gastric (SNU-16, SNU-484, SNU-668) and hepatocellular (HepG2, SK-Hep-1, Hep3B) carcinoma cell lines in hollow fibers were transplanted subcutaneously and intraperitoneally into mice, which were subsequently treated with a standard anticancer agent, paclitaxel. The hollow fiber activity of paclitaxel in each cell line was compared with the xenograft activity. Results Using optimized inoculation densities and schedules, treatment with paclitaxel was effective in gastric carcinoma cell lines, SNU-16 and SNU-484, but not in SNU-668. In the hollow fiber assays, paclitaxel was effective in hepatocellular carcinoma cell lines, HepG2 and SK-Hep-1, but not in Hep3B. Consistent with the results of the hollow fiber assay, SNU-16 and SNU-484, but not SNU-668, showed tumor regression, and HepG2 and SK-Hep-1, but not Hep3B, showed effective tumor responses following treatment with paclitaxel in xenograft models. When EW7197, a novel compound, and flavopiridol were tested in SNU-16 cells under optimized conditions, the hollow fiber activity showed good correlation with the xenograft activity of each compound. Conclusion Our protocols may be useful for screening candidate small molecules that may exhibit activity against stomach and liver cancers, both of which are common in Korea.
Park, Jun Won; Baek, Nam Suk; Lee, Seok Cheol; Oh, Su Jin; Jang, Seok Hoon; Kim, In Hoo
Student perception about efficacy of preclinical fixed prosthodontic training to facilitate smooth transition to clinical context
Background: Studies indicate that the initial transition period between preclinical and clinical phases are the most stressful. The students have experienced the difficulty in performing clinical procedures due to the vast difference in the clinical and preclinical setup. It is better to identify the particular skill found poorly correlated, enabling educators to address the concerns. We sought the opinion and suggestion from the beneficiary student on fixed prosthodontics steps difficult to practice in clinical setup at the initial stage, their suggestion to overcome these shortcomings was also sought. Aims: To determine the fixed prosthodontics skills difficult to perform in a transition period due to poor correlation between preclinical and clinical training from our focus group study on the student's perception, and their suggestion regarding alternative methods to improve the preclinical training. Materials and Methods: Focus groups in the study were the students involved in clinical practice of fixed partial denture procedure. A well-constructed Questionnaire, designed to evaluate the difficult clinical steps in a transitional period and suggestion to improve the existing preclinical training was distributed to all focus group students. The response to the questionnaire was based on the five-point Likert scale. Statistical Analysis Used: Medians, frequencies were used to assess their perception on preclinical training and suggestion. Results: A total of 97 students participated in the study, 88% response received during the survey. The clinical steps student felt difficult during a transition period from preclinical to clinical phase were positional variations of teeth (52.6%-63.9%), fluid control (48.5-67.1%), shade selection procedure (29.9%-50.5%), subgingival cervical finish line preparation (38.1-51.5%), and gingival retraction procedure. The students felt that the inclusion of problem-based learning, preclinical patient exposure, and better simulation will alleviate the stress during the transition period. Conclusions: This study highlighted the tooth preparation steps found difficult to practice in a transition period between preclinical and clinical phases. This study also obtained suggestions from the students for innovative upgradation of the course curricula.
Haralur, Satheesh B.; Al-Malki, Abdullah Edrees
Preclinical studies of alcohol binge drinking
Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans.
Crabbe, John C.; Harris, R. Adron; Koob, George F.
High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the ?-secretase inhibitor, RO4929097.
Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the ?-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation. PMID:21315665
He, Wei; Luistro, Leopoldo; Carvajal, Daisy; Smith, Melissa; Nevins, Tom; Yin, Xuefeng; Cai, James; Higgins, Brian; Kolinsky, Kenneth; Rizzo, Christine; Packman, Kathryn; Heimbrook, David; Boylan, John F
Intravital microscopy as a tool to study drug delivery in preclinical studies.
The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies. PMID:20933026
Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto
Novel Lignan and stilbenoid mixture shows anticarcinogenic efficacy in preclinical PC-3M-luc2 prostate cancer model.
Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid -rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ? 40 ?M concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ? 10 ?M concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7-73 ?M, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals. PMID:24699425
Yatkin, Emrah; Polari, Lauri; Laajala, Teemu D; Smeds, Annika; Eckerman, Christer; Holmbom, Bjarne; Saarinen, Niina M; Aittokallio, Tero; M�kel�, Sari I
Preclinical studies for induced pluripotent stem cell-based therapeutics.
Induced pluripotent stem cells (iPSCs) and their differentiated derivatives can potentially be applied to cell-based therapy for human diseases. The properties of iPSCs are being studied intensively both to understand the basic biology of pluripotency and cellular differentiation and to solve problems associated with therapeutic applications. Examples of specific preclinical applications summarized briefly in this minireview include the use of iPSCs to treat diseases of the liver, nervous system, eye, and heart and metabolic conditions such as diabetes. Early stage studies illustrate the potential of iPSC-derived cells and have identified several challenges that must be addressed before moving to clinical trials. These include rigorous quality control and efficient production of required cell populations, improvement of cell survival and engraftment, and development of technologies to monitor transplanted cell behavior for extended periods of time. Problems related to immune rejection, genetic instability, and tumorigenicity must be solved. Testing the efficacy of iPSC-based therapies requires further improvement of animal models precisely recapitulating human disease conditions. PMID:24362021
Harding, John; Mirochnitchenko, Oleg
JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials
The recent identification of somatic mutations such as JAK2V617F that deregulate Janus kinase (JAK)�signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy
A Pardanani
PTEN status mediates 2ME2 anti-tumor efficacy in preclinical glioblastoma models: role of HIF1? suppression.
Glioblastoma (GBM) is the most common brain cancer and is highly lethal in both adults and children. 2-methoxyestradiol (2ME2) is a microtubule inhibitor that potently inhibits HIF1?, GBM angiogenesis and tumor growth in preclinical models. In patients, 2ME2 exhibits low toxicity and promising but inconsistent efficacy. Given its preclinical potency and its tolerability in patients, we sought to determine whether 2ME2 therapy could be enhanced by addressing resistance via combination therapy, and with biomarkers to identify responsive glioma subgroups. We demonstrate that the PTEN-PI3K axis regulates HIF1? in glioma models. We utilized isogenic-pairs of glioma cell lines, deficient in PTEN or stably reconstituted with PTEN, to determine the role of PTEN in 2ME2 sensitivity in vitro and in vivo. Chou-Talalay synergy studies reveal significant synergy when a pan-PI3K inhibitor is combined with 2ME2. This synergistic activity was correlated with a synergistic suppression of HIF1? accumulation under hypoxic conditions in glioma models. In vivo, 2ME2 markedly inhibited tumor-induced angiogenesis and significantly reduced tumor growth only in a PTEN reconstituted GBM models in both subcutaneous and orthotopic intracranial mouse models. Collectively, these results: (1) suggest that PTEN status predicts sensitivity to 2ME2 and (2) justify exploration of 2ME2 combined with pan-PI3K inhibitors for the treatment of this intractable brain cancer. PMID:24162827
Muh, Carrie R; Joshi, Shweta; Singh, Alok R; Kesari, Santosh; Durden, Donald L; Makale, Milan T
Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma
Purpose: Sorafenib tosylate (sorafenib, BAY 43-9006, Nexavar�) is a multi-kinase inhibitor that targets tumor cell proliferation and angiogenesis. These studies evaluated the efficacy and tolerability of combinations of sorafenib plus agents used to treat non-small cell lung cancer (NSCLC) using preclinical models of that disease. Methods: Intravenous (iv) vinorelbine and interperitoneal (ip) cisplatin were administered intermittently (q4d�נ3) in combination with
Christopher A. Carter; Charles Chen; Cheryl Brink; Patrick Vincent; Yulia Y. Maxuitenko; Karen S. Gilbert; William R. Waud; Xiaomei Zhang
Preclinical in vivo efficacy of two 9-dihydrotaxane analogues against human and murine tumours.
Two 9-dihydrotaxane analogues were synthesised and tested for in vitro potency and in vivo efficacy against murine and human tumour xenografts in mice. The in vitro potency of 9-dihydrotaxol (9-DH-t) and 10-deacetyl-9-dihydrotaxol (10-DeAc-9-DH-t) was generally less than that of paclitaxel against human and murine tumour cells. However, both analogues were at least 20-fold more soluble than paclitaxel in water. The analogues yielded cure rates > or = 60% against human MX-1 solid tumour xenografts in mice, compared with a cure rate of 10% for mice treated with paclitaxel. Both of the analogues were more effective than paclitaxel for treatment of murine M109 solid tumour in mice. 10-DeAc-9-DH-t was as effective as paclitaxel against murine B16 ascites tumour, while 9-DH-t was less effective. Both 10-DeAc-9-DH-t and 9-DH-t were demonstrably less toxic than paclitaxel. At equal dosages 9-DH-t produced serum concentrations greater than paclitaxel, while 10-DeAc-9-DH-t yielded serum concentrations less than paclitaxel. However, the decrease in toxicity of 9-DH-t and 10-DeAc-9-DH-t allowed a 4-fold increase in daily dosage. These two 9-dihydrotaxane analogues yielded favourable preclinical data and demonstrated good potential for further development.
Alder, J. D.; Jarvis, K. P.; Marsh, K. C.; Klein, L. L.; Clement, J. J.
A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models.
DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies. PMID:24688048
Yin, Tinggui; Lallena, Maria J; Kreklau, Emiko L; Fales, Kevin R; Carballares, Santiago; Torrres, Raquel; Wishart, Graham N; Ajamie, Rose T; Cronier, Damien M; Iversen, Phillip W; Meier, Timothy I; Foreman, Robert T; Zeckner, Douglas; Sissons, Sean E; Halstead, Bart W; Lin, Aimee B; Donoho, Gregory P; Qian, Yuewei; Li, Shuyu; Wu, Song; Aggarwal, Amit; Ye, Xiang S; Starling, James J; Gaynor, Richard B; de Dios, Alfonso; Du, Jian
Preclinical pharmacology of alendronate
This brief review summarizes some of the preclinical findings of studies aimed at assessing the efficacy and safety of the aminobisphosphonate alendronate (ALN) in preventing or restoring the bone loss caused by calcium or estrogen deficiency. Mode of action studies show that ALN localizes at sites of bone resorption and inhibits osteoclastic activity. In secondary hyperparathyroidism caused by calcium-deficient diets
G. A. Rodan; J. G. Seedor; R. Balena
Preclinical Efficacy and Mechanisms of Mesenchymal Stem Cells in Animal Models of Autoimmune Diseases
Mesenchymal stem cells (MSCs) are present in diverse tissues and organs, including bone marrow, umbilical cord, adipose tissue, and placenta. MSCs can expand easily in vitro and have regenerative stem cell properties and potent immunoregulatory activity. They inhibit the functions of dendritic cells, B cells, and T cells, but enhance those of regulatory T cells by producing immunoregulatory molecules such as transforming growth factor-?, hepatic growth factors, prostaglandin E2, interleukin-10, indolamine 2,3-dioxygenase, nitric oxide, heme oxygenase-1, and human leukocyte antigen-G. These properties make MSCs promising therapeutic candidates for the treatment of autoimmune diseases. Here, we review the preclinical studies of MSCs in animal models for systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and experimental autoimmune encephalomyelitis, and summarize the underlying immunoregulatory mechanisms.
Lee, Hong Kyung; Lim, Sang Hee; Chung, In Sung; Park, Yunsoo; Park, Mi Jeong; Kim, Ju Young; Kim, Yong Guk; Hong, Jin Tae; Kim, Youngsoo
ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma.
Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor. Conventional treatment options include surgery and radiotherapy but there is no validated medical option. Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth. Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with VS. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays. Downstream signaling pathway activation was analyzed by phospho-MAPK arrays. Activated RTKs and downstream kinases were validated immunohistochemically in corresponding formalin-fixed, paraffin-embedded tissues. Phospho-RTK arrays and immunohistochemistry showed consistent overexpression and activation of EGFR family receptors and evidence of ERK1/2 downstream signaling was observed in all samples analyzed (n = 11). Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model. EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation. We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related VS. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model. Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway. PMID:20511180
Ammoun, Sylwia; Cunliffe, Clare H; Allen, Jeffrey C; Chiriboga, Luis; Giancotti, Filippo G; Zagzag, David; Hanemann, C Oliver; Karajannis, Matthias A
Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors
Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer.
Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.
Genetically engineered humanized mouse models for preclinical antibody studies.
The use of genetic engineering has vastly improved our capabilities to create animal models relevant in preclinical research. With the recent advances in gene-editing technologies, it is now possible to very rapidly create highly tunable mouse models as needs arise. Here, we provide an overview of genetic engineering methods, as well as the development of humanized neonatal Fc receptor (FcRn) models and their use for monoclonal antibody in vivo studies. PMID:24150980
Proetzel, Gabriele; Wiles, Michael V; Roopenian, Derry C
Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways
In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox
Shiekh Tanveer Ahmad; Wani Arjumand; Amlesh Seth; Sana Nafees; Summya Rashid; Nemat Ali; Sarwat Sultana
Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.
Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. PMID:19773430
Luistro, Leopoldo; He, Wei; Smith, Melissa; Packman, Kathryn; Vilenchik, Maria; Carvajal, Daisy; Roberts, John; Cai, James; Berkofsky-Fessler, Windy; Hilton, Holly; Linn, Michael; Flohr, Alexander; Jakob-R�tne, Roland; Jacobsen, Helmut; Glenn, Kelli; Heimbrook, David; Boylan, John F
Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line.
Melanoma is the most common malignant skin cancer, appears indestructible and is notoriously resistant to all current modalities of cancer treatment strategies. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, has shown to have radiosensitizing properties for a variety of cancers. Recently, we have shown that PTX exhibits antimetastatic and anti-angiogenic activities in B16F10 melanoma cells in vitro as well as in vivo. In the present study, we have demonstrated the anticancer and antimetastatic potential of PTX against A375 human melanoma cell line at sub-toxic doses. The results implicate that PTX at sub-toxic doses exhibited an inhibitory effect on the ability of cellular proliferation as shown by MTT and colony formation assay. It impedes migration and also induces apoptosis. A375 cells pretreated with PTX showed decrease in adhesion to both Matrigel and Collagen type IV. Further, Gelatin zymography result reveals that PTX treatment decreases the secretion of MMP2 and MMP9. Finally, PTX significantly inhibited A375 subcutaneous tumour xenograft growth without having any toxicity. Thus PTX at sub-toxic doses affected melanoma metastasis at multiple steps in vitro as well as tumour growth in vivo. These data demonstrate its antimetastatic potential and provide preclinical evidence for the development of PTX as a potential agent against metastatic melanoma. PMID:23089470
Kamran, Mohammed Zahid; Gude, Rajiv P
Exploring Polymeric Micelles for Improved Delivery of Anticancer Agents: Recent Developments in Preclinical Studies
As versatile drug delivery systems, polymeric micelles have demonstrated particular strength in solubilizing hydrophobic anticancer drugs while eliminating the use of toxic organic solvents and surfactants. However, the true promise of polymeric micelles as drug carriers for cancer therapy resides in their potential ability to preferentially elevate drug exposure in the tumor and achieve enhanced anticancer efficacy, which still remains to be fully exploited. Here, we review various micellar constructs that exhibit the enhanced permeation and retention effect in the tumor, the targeting ligands that potentiate the anticancer efficacy of micellar drugs, and the polyplex micelle systems suitable for the delivery of plasmid DNA and small interference RNA. Together, these preclinical studies in animal models help us further explore polymeric micelles as emerging drug carriers for targeted cancer therapy.
Tan, Chalet; Wang, Yingzhe; Fan, Wei
Pharmacological Intervention Studies Using Mouse Models of the Inflammatory Bowel Diseases: Translating Preclinical Data into New Drug Therapies
Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in well-controlled clinical trials is to identify the most relevant mouse models IBD and pharmacologic strategies that most closely mimic the clinical situation. To begin this process, we present a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies.
Koboziev, Iurii; Karlsson, Fridrik; Zhang, Songlin; Grisham, Matthew B.
Experimental design and efficient parameter estimation in preclinical pharmacokinetic studies.
Monte Carlo simulation technique used to evaluate the effect of the arrangement of concentrations on the efficiency of estimation of population pharmacokinetic parameters in the preclinical setting is described. Although the simulations were restricted to the one compartment model with intravenous bolus input, they provide the basis of discussing some structural aspects involved in designing a destructive ("quantic") preclinical population pharmacokinetic study with a fixed sample size as is usually the case in such studies. The efficiency of parameter estimation obtained with sampling strategies based on the three and four time point designs were evaluated in terms of the percent prediction error, design number, individual and joint confidence intervals coverage for parameter estimates approaches, and correlation analysis. The data sets contained random terms for both inter- and residual intra-animal variability. The results showed that the typical population parameter estimates for clearance and volume were efficiently (accurately and precisely) estimated for both designs, while interanimal variability (the only random effect parameter that could be estimated) was inefficiently (inaccurately and imprecisely) estimated with most sampling schedules of the two designs. The exact location of the third and fourth time point for the three and four time point designs, respectively, was not critical to the efficiency of overall estimation of all population parameters of the model. However, some individual population pharmacokinetic parameters were sensitive to the location of these times. PMID:7479560
Ette, E I; Howie, C A; Kelman, A W; Whiting, B
Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model
Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a
A Bozec; A Sudaka; J-L Fischel; M-C Brunstein; M-C Etienne-Grimaldi; G Milano
Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer.
Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC. PMID:24395797
Fahrenholtz, Cale D; Rick, Ferenc G; Garcia, Maria I; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L; Schally, Andrew V; Burnstein, Kerry L
Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer
Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists�MIA-602, MIA-606, and MIA-690�on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.
Fahrenholtz, Cale D.; Rick, Ferenc G.; Garcia, Maria I.; Zarandi, Marta; Cai, Ren-Zhi; Block, Norman L.; Schally, Andrew V.; Burnstein, Kerry L.
Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways.
In the present study, we have evaluated the chemopreventive potential of geraniol (GOH), an acyclic monoterpene alcohol against ferric nitrilotriacetate (Fe-NTA) induced renal oxidative stress and carcinogenesis in Wistar rats. Chronic treatment of Fe-NTA induced oxidative stress, inflammation and cellular proliferation in Wistar rats. The chemopreventive efficacy of GOH was studied in terms of xenobiotic metabolizing enzyme activities, LPO, redox status, serum toxicity markers and the expression of putative nephrotoxicity biomarker Kim-1, tumor suppressor gene P53, inflammation, cell proliferation and apoptosis related genes in the kidney tissue. Oral administration of GOH at doses of 100 and 200mg/kg b wt effectively suppressed renal oxidative stress and tumor incidence. Chemopreventive effects of GOH were associated with upregulation of xenobiotic metabolizing enzyme activities and down regulation of serum toxicity markers. GOH was able to down regulate expression of Kim-1, NF?B, PCNA, P53 along with induction of apoptosis. However, higher dose of GOH was more effective in modulating these multiple molecular targets both at transcriptional and protein level. These results provide a powerful evidence for the chemopreventive efficacy of GOH against renal carcinogenesis possibly by modulation of multiple molecular pathways. PMID:21907755
Ahmad, Shiekh Tanveer; Arjumand, Wani; Seth, Amlesh; Nafees, Sana; Rashid, Summya; Ali, Nemat; Sultana, Sarwat
Novel Epigenetic Target Therapy for Prostate Cancer: A Preclinical Study
Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2?-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.
Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina
Novel epigenetic target therapy for prostate cancer: a preclinical study.
Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours. PMID:24851905
Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina
Targeted agents: how to select the winners in preclinical and early clinical studies?
There has been a significant shift within oncology drug development away from empiric screening of cytotoxic compounds to the era of genomics and molecularly targeted agents. The drug development process is evolving with greater emphasis on proof-of-mechanism studies in both preclinical and early clinical development. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Task Force, established as a forum for academic and pharmaceutical leaders to discuss methodological issues in targeted anticancer therapy development, met in March 2010 to review what were the minimal data required to make appropriate decisions about moving new targeted cancer agents from late preclinical development into phase I and from phase I into phase II trials. A number of specific questions were posed, and responses to each developed through survey, literature review and discussion at the face to face meeting of the MDICT Task Force. Consensus emerged around the necessity to demonstrate proof-of-mechanism and obtain information on key pharmacokinetic aspects of drug behaviour in late preclinical and early clinical trials. However, controversy remains on the extent of in vivo anti-tumour efficacy required to support clinical development of targeted agents. A systematic review of the data in this area would be informative. Further, while objective response in phase I trials may be a favourable signal about the potential activity of a new agent, debate exists around the weight that should be placed on the observation of stable disease or functional imaging changes in driving drug development decisions in the absence of observing either responses or convincing pharmacodynamic data in phase I. MDICT made a number of recommendations that may aid in future development of targeted agents. PMID:22093946
Goodwin, Rachel; Giaccone, Giuseppe; Calvert, Hilary; Lobbezoo, Marinus; Eisenhauer, Elizabeth A
Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies.
Encapsulation of doxorubicin in polyethylene glycol-coated liposomes (Doxil/Caelyx [PLD]), was developed to enhance the safety and efficacy of conventional doxorubicin. The liposomes alter pharmacologic and pharmacokinetic parameters of conventional doxorubicin so that drug delivery to the tumor is enhanced while toxicity normally associated with conventional doxorubicin is decreased. In animals and humans, pharmacokinetic advantages of PLD include an increased area under the plasma concentration-time curve, longer distribution half-life, smaller volume of distribution, and reduced clearance. In preclinical models, PLD produced remission and cure against many cancers including tumors of the breast, lung, ovaries, prostate, colon, bladder, and pancreas, as well as lymphoma, sarcoma, and myeloma. It was also found to be effective as adjuvant therapy. In addition, it was found to cross the blood-brain barrier and induce remission in tumors of the central nervous system. Increased potency over conventional doxorubicin was observed and, in contrast to conventional doxorubicin, PLD was equally effective against low- and high-growth fraction tumors. The combination of PLD with vincristine or trastuzumab resulted in additive effects and possible synergy. PLD appeared to overcome multidrug resistance, possibly as the result of increased intracellular concentrations and an interaction between the liposome and P-glycoprotein function. On the basis of pharmacokinetic and preclinical studies, PLD, either alone or as part of combination therapy, has potential applications to treat a variety of cancers. PMID:15717736
Vail, David M; Amantea, Michael A; Colbern, Gail T; Martin, Francis J; Hilger, Ralf A; Working, Peter K
Role of self-efficacy and anxiety among pre-clinically disabled older adults when using compensatory strategies to complete daily tasks
Classic developmental theory suggests that aging is associated with using compensatory strategies to prolong independence. While compensatory strategies are typically considered positive adaptations, they also signify an early phase in the disablement process � commonly known as pre-clinical disability. To build a better understanding of psychological constructs related to these early signs of disability, we examined the contribution of self-efficacy and state anxiety on using compensatory strategies among pre-clinically disabled older adults. Compensatory strategies were observed during performance of daily activities in 257 pre-clinically disabled older adults (67.6 � 7.04), and self-efficacy and state anxiety were evaluated prior to performing each task. In univariate models, lower self-efficacy and higher anxiety were associated with more compensation (Spearman correlations: 0.15-0.48, p < 0.05). Multivariate logistic regression indicated that low self-efficacy [Odds Ratio (OR): 1.70; 95% Confidence Interval (CI): 1.40-2.08) and high anxiety (OR: 1.34; 95% CI: 1.10-1.63) were positively associated with using ? 6 compensatory strategies � a level signifying substantial compensation. When considered jointly with self-efficacy, the association with anxiety was reversed� higher anxiety demonstrated a lower likelihood of using compensation (OR: 0.70-0.73; 95% CI: 0.50-0.99). The addition of self-efficacy might remove the self-defeating cognitions characterizing anxiety allowing the remaining arousal component to appear beneficial. In conclusion, lower self-efficacy and higher anxiety are associated with using compensation to complete daily tasks among pre-clinically disabled older adults. Such psychological constructs may contribute to the use of compensatory strategies and represent future intervention targets to help reduce early signs of disability.
Higgins, Torrance J.; Janelle, Christopher M.; Naugle, Kelly M.; Knaggs, Jeffrey; Hoover, Brian M.; Marsiske, Michael; Manini, Todd M.
Characterization of Liposarcoma Cell Lines for Preclinical and Biological Studies
Liposarcoma cell lines represent in vitro models for studying disease mechanisms at the cellular level and for preclinical evaluation of novel drugs. To date there are a limited number of well-characterized models available. In this study, nine immortal liposarcoma cell lines were evaluated for tumor-forming ability, stem cell- and differentiation potential, and metastatic potential, with the aim to generate a well-characterized liposarcoma cell line panel. Detailed stem cell and differentiation marker analyses were also performed. Five of the liposarcoma cell lines were tumorigenic, forming tumors in mice. Interestingly, tumor-forming ability correlated with high proliferative capacity in vitro. All the cell lines underwent adipocytic differentiation, but the degree varied. Surprisingly, the expression of stem cell and differentiation markers did not correlate well with function. Overall, the panel contains cell lines suited for in vivo analyses (LPS141, SA-4, T778, SW872, and LISA-2), for testing novel drugs targeting cancer stem cells (LPS141) and for studying tumor progression and metastasis (T449 and T778).
Stratford, Eva W.; Castro, Russell; Daffinrud, Jeanette; Skarn, Magne; Lauvrak, Silje; Munthe, Else; Myklebost, Ola
Rodent Preclinical Models for Developing Novel Antiarthritic Molecules: Comparative Biology and Preferred Methods for Evaluating Efficacy
Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor.
Bolon, Brad; Stolina, Marina; King, Caroline; Middleton, Scot; Gasser, Jill; Zack, Debra; Feige, Ulrich
A crowdsourcing model for creating preclinical medical education study tools.
During their preclinical course work, medical students must memorize and recall substantial amounts of information. Recent trends in medical education emphasize collaboration through team-based learning. In the technology world, the trend toward collaboration has been characterized by the crowdsourcing movement. In 2011, the authors developed an innovative approach to team-based learning that combined students' use of flashcards to master large volumes of content with a crowdsourcing model, using a simple informatics system to enable those students to share in the effort of generating concise, high-yield study materials. The authors used Google Drive and developed a simple Java software program that enabled students to simultaneously access and edit sets of questions and answers in the form of flashcards. Through this crowdsourcing model, medical students in the class of 2014 at the Johns Hopkins University School of Medicine created a database of over 16,000 questions that corresponded to the Genes to Society basic science curriculum. An analysis of exam scores revealed that students in the class of 2014 outperformed those in the class of 2013, who did not have access to the flashcard system, and a survey of students demonstrated that users were generally satisfied with the system and found it a valuable study tool. In this article, the authors describe the development and implementation of their crowdsourcing model for creating study materials, emphasize its simplicity and user-friendliness, describe its impact on students' exam performance, and discuss how students in any educational discipline could implement a similar model of collaborative learning. PMID:23619061
Bow, Hansen C; Dattilo, Jonathan R; Jonas, Andrea M; Lehmann, Christoph U
Preclinical Studies of Signaling Pathways in a Mutant Mouse Model of Hormone-Refractory Prostate Cancer.
National Technical Information Service (NTIS)
We have been investigating targeted therapies for the treatment of advanced prostate cancer using a genetically engineered mouse model of the disease. Based on previous studies, we performed pre-clinical studies to examine the consequences of combinatoria...
C. Abate-Shen
Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.
King, Alastair J.; Arnone, Marc R.; Bleam, Maureen R.; Moss, Katherine G.; Yang, Jingsong; Fedorowicz, Kelly E.; Smitheman, Kimberly N.; Erhardt, Joseph A.; Hughes-Earle, Angela; Kane-Carson, Laurie S.; Sinnamon, Robert H.; Qi, Hongwei; Rheault, Tara R.; Uehling, David E.; Laquerre, Sylvie G.
Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions.
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor. PMID:23844038
King, Alastair J; Arnone, Marc R; Bleam, Maureen R; Moss, Katherine G; Yang, Jingsong; Fedorowicz, Kelly E; Smitheman, Kimberly N; Erhardt, Joseph A; Hughes-Earle, Angela; Kane-Carson, Laurie S; Sinnamon, Robert H; Qi, Hongwei; Rheault, Tara R; Uehling, David E; Laquerre, Sylvie G
Tracking the extramedullary PML-RAR?-positive cell reservoirs in a preclinical model: biomarker of long-term drug efficacy.
Using an acute promyelocytic leukemia (APL) preclinical model, we show that oncogene-specific PCR (Polymerase Chain Reaction)-based assays allow to evaluate the efficacy of immunotherapy combining all-trans retinoic acid (ATRA) and a DNA-based vaccine targeting the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR?) oncogene. Kaplan-Meier survival analysis according to the peripheral blood PML-RAR? normalized copy number (NCN) clearly shows that ATRA�+�DNA-treated mice with an NCN lower than 10 (43%) formed the group with a highly significant (p�<�0.0001) survival advantage. Furthermore, a PCR assay was used to assess various tissues and organs for the presence of PML-RAR?-positive cells in long-term survivors (n�=�15). As expected, the majority of mice (n�=�10) had no measurable tissue level of PML-RAR?. However, five mice showed a weak positive signal in both the brain and spleen (n�=�2), in the brain only (n�=�2) and in the spleen only (n�=�1). Thus tracking the oncogene-positive cells in long-term survivors reveals for the first time that extramedullary PML-RAR?-positive cell reservoirs such as the brain may persist and be involved in relapses. PMID:22906630
Pokorna, Katerina; Le Pogam, Carole; Chopin, Martine; Balitrand, Nicole; Reboul, Murielle; Cassinat, Bruno; Chomienne, Christine; Padua, Rose Ann; Pla, Marika
Mouse Model for the Preclinical Study of Metastatic Disease
The successful development of new cancer therapeutics requires reliable preclinical data that are obtained from mouse models for cancer. Human tumor xenografts, which require transplantation of human tumor cells into an immune compromised mouse, represent the current standard mouse model for cancer. Since the immune system plays an important role in tumor growth, progression and metastasis, the current standard mouse model is not ideal for accurate prediction of therapeutic effectiveness in patients.
Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma
The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.
Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio
Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis
Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies.
Wenzler, Tanja; Yang, Sihyung; Braissant, Olivier; Boykin, David W.; Brun, Reto
MRI biomarkers for evaluation of treatment efficacy in preclinical diabetic retinopathy
Introduction: One sober consequence of the current epidemic of diabetes mellitus is that an increasing number of people world-wide will partially or completely lose their sight to diabetic retinopathy. Clinically, the sight-threatening complications of diabetes are diagnosed and treated based on visible retinal lesions (e.g., dot-blot hemorrhages or retinal neovascularization). However, such anatomical microvascular lesions are slow to respond with treatment. Thus, there remains an urgent need for imaging biomarkers that are abnormal before retinal lesions are visibly apparent and are responsive to treatment. Areas covered: Here, the development of new MRI methods, such as manganese-enhanced MRI, for evaluating early diabetes-evoked retinal pathophysiology, and its usefulness in guiding new treatments for diabetic retinopathy are reviewed. Expert opinion: In diabetic retinopathy, not all important diagnostic and prognostic needs are well served by optical methods. In the absence of gross anatomy changes, critical times when drug intervention is most likely to be successful at reducing vision loss are missed by most light-based methods and thus provide little help in guiding diagnosis and treatment. For example, before clinical symptoms, is there an optimal time to intervene with drug therapy? Is a drug reaching its target? How does one assess optimal drug dose, schedule, and routes? How well do current experimental models mimic the clinical condition? As discussed herein, MRI is as an analytical tool for addressing these unmet needs. Future clinical applications of MRI can be envisioned such as in clinical trials to assess drug treatment efficacy, or as an adjunct approach to refine or clarify a difficult clinical case. New MRI-generated hypotheses about the pathogenesis of diabetic retinopathy and its treatment are discussed. In the coming years, a substantial growth in the development and application of MRI is expected to address relevant question in both the basic sciences and in the clinic.
Berkowitz, Bruce A; Bissig, David; Dutczak, Oliver; Corbett, Shannon; North, Rob; Roberts, Robin
High-Affinity CRF1 Receptor Antagonist NBI-34041: Preclinical and Clinical Data Suggest Safety and Efficacy in Attenuating Elevated Stress Response
There is an extensive evidence that corticotropin releasing factor (CRF) is hypersecreted in depression and anxiety, and blockade of CRF could have therapeutic benefit. We report preclinical data and the results of a clinical Phase I study with the novel nonpeptide CRF1 antagonist NBI-34041\\/SB723620. Preclinical data conducted with different cell lines expressing human CRF receptors and in Wistar and Sprague�Dawley
Marcus Ising; Ulrich S Zimmermann; Heike E K�nzel; Manfred Uhr; Alan C Foster; Susan M Learned-Coughlin; Florian Holsboer; Dimitri E Grigoriadis
A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety.
Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 � 14 ng/ml for inhibition of proliferation. The EC50 of 53 � 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases. PMID:24081989
Suchard, Suzanne J; Davis, Patricia M; Kansal, Selena; Stetsko, Dawn K; Brosius, Ruth; Tamura, James; Schneeweis, Lumelle; Bryson, James; Salcedo, Theodora; Wang, Haiqing; Yang, Zheng; Fleener, Catherine A; Ignatovich, Olga; Plummer, Christopher; Grant, Steven; Nadler, Steven G
Stem cell therapy for ischaemic stroke: translation from preclinical studies to clinical treatment.
No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke. PMID:23394533
Balami, Joyce S; Fricker, Rosemary A; Chen, Ruoli
Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study.
Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 ?g/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 ?g/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin. PMID:23686785
Eslin, Don; Lee, Chris; Sankpal, Umesh T; Maliakal, Pius; Sutphin, Robert M; Abraham, Liz; Basha, Riyaz
Dicycloplatin, a novel platinum analog in chemotherapy: synthesis of chinese pre-clinical and clinical profile and emerging mechanistic studies.
Dicycloplatin (DCP) has better solubility and stability than both cisplatin and carboplatin. Pre-clinical and phase I studies demonstrated significant antitumor activity and fewer adverse events than carboplatin. Phase II clinical trials in advanced non-small cell lung cancer found efficacy and safety of DCP-plus-paclitaxel comparable to carboplatin-plus-paclitaxel but better tolerability. This article summarizes and reviews pre-clinical and clinical data for dicycloplatin from the Chinese medical literature. We also report on new mechanistic findings in our laboratory in West Virginia, USA. Patient blood samples were collected for DCP-prototype determination by liquid chromatography mass spectrometry (LC-MS/MS). Molecular studies of ovarian cancer cells treated with DCP or cisplatin were carried out for gene-signature profiling using immunoblotting. Pharmacokinetic mass-spectrometry showed different spectrum profiles of DCP and carboplatin in plasma. Plasma concentration of DCP prototype was 17.1 ?g/ml 2h after administration, with a peak concentration of 26.9 ?g/ml at 0.5 h. Immunoblotting showed DCP-induced activation of DNA damage pathways, including double-phosphorylated checkpoint kinase 2 (CHK2) and breast cancer 1 (BRCA1) and triple-phosphorylated p53, compared to controls. Cisplatin produced a similar profile, with increased p53 protein. DCP and cisplatin activate DNA-damage response through similar pathways. DCP may be more soluble and stable, and better-tolerated. PMID:24403501
Yu, Jing Jie; Yang, Xuqing; Song, Qinhua; Mueller, Michael D; Remick, Scot C
Focused Ultrasound-Induced Blood-Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study
The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.
Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li
Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats.
Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund's adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations. PMID:24797666
Pravetoni, Marco; Vervacke, Jeffrey S; Distefano, Mark D; Tucker, Ashli M; Laudenbach, Megan; Pentel, Paul R
Effect of Currently Approved Carriers and Adjuvants on the Pre-Clinical Efficacy of a Conjugate Vaccine against Oxycodone in Mice and Rats
Vaccination against the highly abused prescription opioid oxycodone has shown pre-clinical efficacy for blocking oxycodone effects. The current study further evaluated a candidate vaccine composed of oxycodone derivatized at the C6 position (6OXY) conjugated to the native keyhole limpet hemocyanin (nKLH) carrier protein. To provide an oxycodone vaccine formulation suitable for human studies, we studied the effect of alternative carriers and adjuvants on the generation of oxycodone-specific serum antibody and B cell responses, and the effect of immunization on oxycodone distribution and oxycodone-induced antinociception in mice and rats. 6OXY conjugated to tetanus toxoid (TT) or a GMP grade KLH dimer (dKLH) was as effective as 6OXY conjugated to the nKLH decamer in mice and rats, while the 6OXY hapten conjugated to a TT-derived peptide was not effective in preventing oxycodone-induced antinociception in mice. Immunization with 6OXY-TT s.c. absorbed on alum adjuvant provided similar protection to 6OXY-TT administered i.p. with Freund�s adjuvant in rats. The toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) adjuvant, alone or in combination with alum, offered no advantage over alum alone for generating oxycodone-specific serum antibodies or 6OXY-specific antibody secreting B cells in mice vaccinated with 6OXY-nKLH or 6OXY-TT. The immunogenicity of oxycodone vaccines may be modulated by TLR4 signaling since responses to 6OXY-nKLH in alum were decreased in TLR4-deficient mice. These data suggest that TT, nKLH and dKLH carriers provide consistent 6OXY conjugate vaccine immunogenicity across species, strains and via different routes of administration, while adjuvant formulations may need to be tailored to individual immunogens or patient populations.
Pravetoni, Marco; Vervacke, Jeffrey S.; Distefano, Mark D.; Tucker, Ashli M.; Laudenbach, Megan; Pentel, Paul R.
Glycoengineered Pichia produced anti-HER2 is comparable to trastuzumab in preclinical study
Mammalian cell culture systems are used predominantly for the production of therapeutic monoclonal antibody (mAb) products. A number of alternative platforms, such as Pichia engineered with a humanized N-linked glycosylation pathway, have recently been developed for the production of mAbs. The glycosylation profiles of mAbs produced in glycoengineered Pichia are similar to those of mAbs produced in mammalian systems. This report presents for the first time the comprehensive characterization of an anti-human epidermal growth factor receptor 2 (HER2) mAb produced in glycoengineered Pichia, and a study comparing the anti-HER2 from Pichia, which had an amino acid sequence identical to trastuzumab, with trastuzumab. The comparative study covered a full spectrum of preclinical evaluation, including bioanalytical characterization, in vitro biological functions, in vivo anti-tumor efficacy and pharmacokinetics in both mice and non-human primates. Cell signaling and proliferation assays showed that anti-HER2 from Pichia had antagonist activities comparable to trastuzumab. However, Pichia-produced material showed a 5-fold increase in binding affinity to Fc?IIIA and significantly enhanced antibody dependent cell-mediated cytotoxicity (ADCC) activity, presumably due to the lack of fucose on N-glycans. In a breast cancer xenograft mouse model, anti-HER2 was comparable to trastuzumab in tumor growth inhibition. Furthermore, comparable pharmacokinetic profiles were observed for anti-HER2 and trastuzumab in both mice and cynomolgus monkeys. We conclude that glycoengineered Pichia provides an alternative production platform for therapeutic mAbs and may be of particular interest for production of antibodies for which ADCC is part of the clinical mechanism of action.
Zhang, Ningyan; Liu, Liming; Dumitru, Calin Dan; Cummings, Nga Rewa Houston; Cukan, Michael; Jiang, Youwei; Li, Yuan; Li, Fang; Mitchell, Teresa; Mallem, Muralidhar R; Ou, Yangsi; Patel, Rohan N; Vo, Kim; Wang, Hui; Burnina, Irina; Choi, Byung-Kwon; Huber, Hans; Stadheim, Terrance A
Exploratory Study of Factors Related to Educational Scores of First Preclinical Year Medical Students
ERIC Educational Resources Information Center
The relationships among the scores of major subjects taught in the first preclinical year of a Thai medical school, previous academic achievements, and daily life activities are rarely explored. We therefore performed an exploratory study identifying various factors possibly related to the educational scores of these medical students.�
Sitticharoon, Chantacha; Srisuma, Sorachai; Kanavitoon, Sawita; Summachiwakij, Sarawut
Plant-based medicines for anxiety disorders, part 2: a review of clinical studies with supporting preclinical evidence.
Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. Thus, our aim was to provide a comprehensive narrative review of plant-based medicines that have clinical and/or preclinical evidence of anxiolytic activity. We present the article in two parts. In part one, we reviewed herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In this current article (part two), we review herbal medicines for which there have been both preclinical and clinical investigations of anxiolytic activity. A search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) for English language papers using the search terms 'anxiety' OR 'anxiety disorder' OR 'generalized anxiety disorder' OR 'social phobia' OR 'post-traumatic stress disorder' OR 'panic disorder' OR 'agoraphobia' OR 'obsessive compulsive disorder' in combination with the search terms 'Herb*' OR 'Medicinal Plants' OR 'Botanical Medicine' OR 'Chinese herb*', in addition to individual herbal medicines. This search of the literature revealed 1,525 papers, of which 53 plants were included in the review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed here in part two), with the other 32 having solely preclinical evidence (reviewed in part one). Support for efficacy was found for chronic use (i.e. greater than one day) of the following herbs in treating a range of anxiety disorders in human clinical trials: Piper methysticum, Matricaria recutita, Ginkgo biloba, Scutellaria lateriflora, Silybum marianum, Passiflora incarnata, Withania somniferum, Galphimia glauca, Centella asiatica, Rhodiola rosea, Echinacea spp., Melissa officinalis and Echium amoenum. For several of the plants studied, conclusions need to be tempered due to methodological issues such as small sample sizes, brief intervention durations and non-replication. Current evidence does not support Hypericum perforatum or Valeriana spp. for any anxiety disorder. Acute anxiolytic activity was found for Centella asiatica, Salvia spp., Melissa officinalis, Passiflora incarnata and Citrus aurantium. Bacopa monnieri has shown anxiolytic effects in people with cognitive decline. The therapeutic application of psychotropic plant-based treatments for anxiety disorders is also discussed, specifically Psychotria viridis and Banisteriopsis caarti (ayahuasca), Psilocybe spp. and cannabidiol-enriched (low tetrahydrocannabinol (?(9)-THC)) Cannabis spp. PMID:23653088
Sarris, Jerome; McIntyre, Erica; Camfield, David A
Preclinical Safety and Efficacy Assessments of Dendrimer-Based (SPL7013) Microbicide Gel Formulations in a Nonhuman Primate Model
Three gel formulations (1%, 3%, and 5% (wt\\/wt)) of SPL7013, a dendrimer known to have antiviral (anti-human immunodeficiency virus and anti-herpes simplex virus) activities, completed a range of preclinical tests in the pigtailed macaque models for vaginally and rectally applied topical microbicide safety assessments. The vaginal safety profile of the 3% SPL7013 gel formulation was equal to that of the
D. L. Patton; Y. T. Cosgrove Sweeney; T. D. McCarthy; S. L. Hillier
Preclinical Toxicology Studies for New Drugs and Vaccines.
National Technical Information Service (NTIS)
During the reporting period, Two Week Oral Toxicity Studies of WR2425 11 and WR2694 10 in Rats, In Vitro Mutagenicity Tests of WR2425 11 and WR2694 10, Four Week Oral Toxicity Studies of WR2425 11 and WR2694 10 in Dogs, Thirteen Week Oral Toxicity Studies...
B. S. Levine
Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model
Background With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor. Methods In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography. Results Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field. Conclusions Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth.
A magnetic resonance (MR) compatible selective brain temperature manipulation system for preclinical study
There is overwhelming evidence that hypothermia can improve the outcome of an ischemic stroke. However, the most widely used systemic cooling method could lead to multiple side effects, while the incompatibility with magnetic resonance imaging of the present selective cooling methods highly limit their application in preclinical studies. In this study, we developed a magnetic resonance compatible selective brain temperature manipulation system for small animals, which can regulate brain temperature quickly and accurately for a desired period of time, while maintaining the normal body physiological conditions. This device was utilized to examine the relationship between T1 relaxation, cerebral blood flow, and temperature in brain tissue during magnetic resonance imaging of ischemic stroke. The results showed that this device can be an efficient brain temperature manipulation tool for preclinical studies needing local hypothermic or hyperthermic conditions.
Liu, Qingwei; Cai, Yu; Lin, Weili; Turner, Gregory H; An, Hongyu
From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development
The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited.
Preclinical studies of N3-O-toluyl-fluorouracil-loaded lipid-based nanosuspensions in H22-bearing mice
Purpose N3-O-toluyl-fluorouracil (TFU) is a potential antitumor prodrug of 5-fluorouracil (5-FU), but its poor solubility has limited its use in clinic. This study aimed to improve the bioavailability of TFU by preparing TFU-loaded lipid-based nanosuspensions (TFU-LNS) and perform a preclinical evaluation. Methods TFU-LNS were prepared through high-pressure homogenization and were lyophilized afterwards. For in vitro test, the physicochemical properties and cytotoxicity against HegG2 cells were conducted. For in vivo evaluation, the pharmacokinetics, tissue distribution, and antitumor efficacy were investigated in H22-bearing Kunming mice. Results TFU showed different degradability in four media; in particular, nearly all of it converted to an equimolar amount of 5-FU in blank plasma of Wistar rats. The lyophilized TFU-LNS had a mean particle size of 180.03�3.11 nm and zeta potential of ?8.02�1.43 mV and showed no discernible changes after storage at 4�C for 3 months. In the in vivo antitumor study, the antitumor efficacy of TFU-LNS was consistent with that of 5-FU injection. Furthermore, TFU-LNS released a lower concentration of 5-FU in heart and kidney throughout the tissue distribution studies. Conclusion TFU-LNS exhibited convincing antitumor activity and easy scale-up opportunity, which suggests that TFU-LNS might be a promising drug delivery system for cancer therapy.
Zhang, Juan; Li, Min; Liu, Zhihong; Wang, Lili; Liu, Yongjun; Zhang, Na
Preclinical Toxicology Studies of New Drugs and Vaccines.
National Technical Information Service (NTIS)
During the reporting period, Thirteen Week Oral Toxicity Studies of WR6026 with a Thirteen Week Recovery Period in dogs and rats, In Vitro Mutagenicity Tests of HI-6 Dichloride and an Acute Oral and intraperitoneal Toxicity Study of WR242511 and WR269410 ...
B. S. Levine
Toxicogenomics in drug discovery: from preclinical studies to clinical trials
Gene expression analysis applied to toxicology studies, also referred to as toxicogenomics, is rapidly being embraced by the pharmaceutical industry as a useful tool to identify safer drugs in a quicker, more cost-effective manner. Studies have already demonstrated the benefits of applying gene expression profiling towards drug safety evaluation, both for identifying mechanisms underlying toxicity, as well as for providing
Yi Yang; Eric A. G. Blomme; Jeffrey F. Waring
Curcumin nanoformulations: a review of pharmaceutical properties and preclinical studies and clinical data related to cancer treatment.
Curcumin, a natural yellow phenolic compound, is present in many kinds of herbs, particularly in Curcuma longa Linn. (turmeric). It is a natural antioxidant and has shown many pharmacological activities such as anti-inflammatory, anti-microbial, anti-cancer, and anti-Alzheimer in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, nephroprotective, cardioprotective, neuroprotective, hypoglycemic, antirheumatic, and antidiabetic activities and it also suppresses thrombosis and protects against myocardial infarction. Particularly, curcumin has demonstrated efficacy as an anticancer agent, but a limiting factor is its extremely low aqueous solubility which hampers its use as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. In this review, we summarize the recent works on the design and development of nano-sized delivery systems for curcumin, including liposomes, polymeric nanoparticles and micelles, conjugates, peptide carriers, cyclodextrins, solid dispersions, lipid nanoparticles and emulsions. Efficacy studies of curcumin nanoformulations using cancer cell lines and in vivo models as well as up-to-date human clinical trials are also discussed. PMID:24439402
Naksuriya, Ornchuma; Okonogi, Siriporn; Schiffelers, Raymond M; Hennink, Wim E
Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs.
National Technical Information Service (NTIS)
During the past year of the contract, a study was initiated to evaluate, in dogs, whether significant clinical or pharmacological interactions occur when single oral doses of the antimalarial drug WR238605 are given in combination with one of the followin...
P. Noker
Preclinical Studies on the Anti-Migraine Drug, Sumatriptan
Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT1 receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan�s precise clinical mode of action have focused on the human meningeal circulation and should lead to
P. P. A. Humphrey; W. Feniuk; A. S. Marriott; R. J. N. Tanner; M. R. Jackson; M. L. Tucker
Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies
Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti-vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and\\/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab\\/ A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or
Hans-Peter Gerber; Napoleone Ferrara
In Vitro Preclinical Evaluation Studies with the Echinocandin Antifungal MK-0991 (L-743,872)
The echinocandin MK-0991, formerly L-743,872, is a water-soluble lipopeptide that has been demonstrated in preclinical studies to have potent activity against Candida spp., Aspergillus fumigatus, and Pneumocystis carinii. An extensive in vitro biological evaluation of MK-0991 was performed to better define the potential activities of this novel compound. Susceptibility testing with MK-0991 against approximately 200 clinical isolates of Candida, Cryptococcus
Antisense Oligonucleotides: Insights from Preclinical Studies and Clinical Trials
\\u000a Since the first pioneering studies using antisense oligonucleotides (ASOs) in the late 1970s, thousands of publications followed,\\u000a demonstrating the remarkableness of antisense action and its enormous application spectrum. In 1998, Fomivirsen (Vitravene)\\u000a was the first, and to date the only ASO that gained approval by the US Food and Drug Administration (FDA) for intravitreous\\u000a treatment of cytomegalovirus-induced retinitis in patients
Doreen Kunze; Kai Kraemer; Susanne Fuessel
Developing a measurement tool for assessing physiotherapy students� self-efficacy: a pilot study
The aim of this research was to determine if self-efficacy can be correlated with prior academic achievement and whether self-efficacy can be an outcome measure of education. A self-efficacy instrument was developed and administered to physiotherapy students following completion of their pre-clinical theory experience. The questionnaire results completed by students regarding their self-efficacy were compared with their pre-clinical theory performance
Anne Jones; Lorraine Sheppard
Centpropazine is a new antidepressant with minimal anticholinergic effects in preclinical animal models. In this study centpropazine has been compared with imipramine in a double blind randomized multicentric study. A total of 159 patients of major depressive disorder (79 in centpropazine group and 80 in imipramine group) from four centres were included in this trial. Each patient was randomised to receive either centpropazine in a dose of 40 to 120 mg per day or imipramine in a dose of 50 to 150 mg per day for a period of six weeks. The antidepressant efficacy of centpropazine was comparable to imipramine but anticholinergic side effects were four times less than imipramine. This establishes centpropazine as an effective antidepressant with remarkably safer tolerability profile.
Srivastava, J.S.; Asthana, O.P.; Singh, H.; Agarwal, A.K.; Shah, L.P.; Sharma, K.C.; Gopinath, P.S.; Srimal, R.C.
Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies
Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.
Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies.
Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable. PMID:21943025
Shineman, Diana W; Basi, Guriqbal S; Bizon, Jennifer L; Colton, Carol A; Greenberg, Barry D; Hollister, Beth A; Lincecum, John; Leblanc, Gabrielle G; Lee, Linda Bobbi H; Luo, Feng; Morgan, Dave; Morse, Iva; Refolo, Lorenzo M; Riddell, David R; Scearce-Levie, Kimberly; Sweeney, Patrick; Yrj�nheikki, Juha; Fillit, Howard M
Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents
In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (�the nanomolar rule�). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed.
Wong, C. C.; Cheng, Ka-Wing
Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents.
In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses ("the nanomolar rule"). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed. PMID:22448039
Wong, C C; Cheng, Ka-Wing; Rigas, Basil
Review: green tea polyphenols in chemoprevention of prostate cancer: preclinical and clinical studies.
The prevention of prostate cancer (PCa) is a crucial medical challenge in developed countries. PCa remains surrounded by puzzles in spite of the considerable progress in research, diagnosis, and treatment. It is an ideal target for chemoprevention, as clinically significant PCa usually requires more than two decades for development. Green tea and its major constituent epigallocatechin gallate (EGCG) have been extensively studied as a potential treatment for a variety of diseases including cancer. In this review, we highlight the evidences of green tea polyphenols from preclinical and clinical studies in the chemoprevention/chemotherapy of PCa. PMID:20155624
Khan, Naghma; Adhami, Vaqar Mustafa; Mukhtar, Hasan
A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer.
Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules. PMID:24643470
Modjtahedi, Helmout; Cho, Byoung Chul; Michel, Martin C; Solca, Flavio
Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.
Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID:23436255
Sarris, Jerome; McIntyre, Erica; Camfield, David A
Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study
Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10?mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24?h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice.
Rivulgo, Virginia; Sparo, Monica; Ceci, Monica; Fumuso, Elida; Confalonieri, Alejandra; Sanchez Bruni, Sergio F.
Preclinical efficacy of the oncolytic measles virus expressing the sodium iodide symporter in iodine non-avid anaplastic thyroid cancer: a novel therapeutic agent allowing noninvasive imaging and radioiodine therapy.
Anaplastic thyroid cancer is an extremely aggressive disease resistant to radioiodine treatment because of loss of sodium iodide symporter (NIS) expression. To enhance prognosis of this fatal cancer, we validated the preclinical efficacy of measles virus (MV)-NIS, the vaccine strain of the oncolytic MV (MV-Edm), modified to include the NIS gene. Western blotting analysis confirmed that a panel of eight anaplastic thyroid cancer (ATC)-derived cell lines do not express NIS protein, but do express CD46, the MV receptor. In vitro cell death assays and in vivo xenograft studies demonstrate the oncolytic efficacy of MV-NIS in BHT-101 and KTC-3, ATC-derived cell lines. Radioactive iodine uptake along with single-photon emission computed tomography (SPECT)-computed tomography imaging of KTC-3 xenografts after (99)Tc(m) administration confirmed NIS expression in vitro and in vivo, respectively, after virus treatment. Adjuvant administration of RAI, to MV-NIS-treated KTC-3 tumors showed a trend for increased tumor cell killing. As current treatment for ATC is only palliative, and MV-NIS is currently Food and Drug Administration approved for human clinical trials in myeloma, our data indicate that targeting ATC with MV-NIS could prove to be a novel therapeutic strategy for effective treatment of iodine-resistant ATC and will expedite its testing in clinical trials for this aggressive disease. PMID:22790962
Reddi, H V; Madde, P; McDonough, S J; Trujillo, M A; Morris, J C; Myers, R M; Peng, K W; Russell, S J; McIver, B; Eberhardt, N L
Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model
Clinical benefit has been demonstrated in patients with head and neck tumours receiving an anti-epidermal growth factor receptor (EGFR) agent in combination with radiotherapy (RT). Recent preclinical and clinical studies suggest beneficial effects from combining anti-angiogenic drugs with RT. To investigate the effect of combining these approaches, we evaluated in vivo the anti-tumour efficacy of the anti-angiogenic compound bevacizumab, a highly specific monoclonal antibody directed against the vascular endothelial growth factor (VEGF), erlotinib, an EGFR tyrosine kinase inhibitor, and irradiation given alone and in combination. Investigations were performed using a VEGF-secreting human head and neck tumour cell line, CAL33, with a high EGFR content, injected as orthotopic xenografts into the mouth floor of nude mice. Three days after tumour cell injection, bevacizumab (5?mg?kg?1, 5 days a week, i.p.), erlotinib (100?mg?kg?1, 5 days a week, orally) and irradiation (6?Gy, 3 days a week) were administered alone and in combination for 10 days. As compared with the control, concomitant administration of drugs produced a marked and significant supra-additive decrease in tumour mass; the addition of irradiation almost completely abolished tumour growth. The drug association markedly reduced the number of metastatic nodes and the triple combination significantly reduced the total number of pathologically positive lymph nodes as compared with controls. The RT-induced proliferation, reflected by Ki67 labelling, was reduced to control level with the triple combination. Radiotherapy induced a strong and very significant increase in tumour angiogenesis, which was no longer observed when combined with erlotinib and bevacizumab. The efficacy of the combination of bevacizumab+erlotinib and RT may be of clinical importance in the management of head and neck cancer patients.
Bozec, A; Sudaka, A; Fischel, J-L; Brunstein, M-C; Etienne-Grimaldi, M-C; Milano, G
Advanced Pre-Clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity
Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non-human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticated research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey model (in vivo), when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course, and developmental stage at time of exposure (in vivo studies), serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.
Wang, Cheng
The Metabotropic Glutamate Receptor 4-Positive Allosteric Modulator VU0364770 Produces Efficacy Alone and in Combination with l-DOPA or an Adenosine 2A Antagonist in Preclinical Rodent Models of Parkinson's Disease
Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu4), including N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu4 PAMs exhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu4 in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu4 PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with l-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of l-DOPA, suggesting that mGlu4 PAMs may provide l-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu4 PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either l-DOPA or A2A antagonists.
Jones, Carrie K.; Bubser, Michael; Thompson, Analisa D.; Dickerson, Jonathan W.; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L.; Bridges, Thomas M.; Morrison, Ryan D.; Jadhav, Satyawan; Engers, Darren W.; Italiano, Kimberly; Bode, Jacob; Daniels, J. Scott; Lindsley, Craig W.; Hopkins, Corey R.; Conn, P. Jeffrey
Bioresorbable fracture fixation in orthopedics: a comprehensive review. Part I. Basic science and preclinical studies.
Metal alloys are currently the most popular materials for manufacture of fracture-fixation devices. Two major disadvantages of these materials are their extreme stiffness, which causes stress shielding of the underlying bone, and the necessity, in a significant number of cases, of removing metallic implants after fracture healing is complete. These shortcomings of metal alloys have led to the study of bioresorbable materials for use in fracture fixation. Currently, polylactic acid, polyglycolic acid, and polydioxanone implants are available to the orthopedic surgeon for the fixation of small cancellous bone fractures. Part I of this article provides an overview of the basic science of bioresorbable materials and presents a comprehensive review of preclinical studies reported in the orthopedic literature. Clinical studies will be reviewed in Part II. PMID:9349887
Simon, J A; Ricci, J L; Di Cesare, P E
Systematic reviews and meta-analysis of preclinical studies: why perform them and how to appraise them critically
The use of systematic review and meta-analysis of preclinical studies has become more common, including those of studies describing the modeling of cerebrovascular diseases. Empirical evidence suggests that too many preclinical experiments lack methodological rigor, and this leads to inflated treatment effects. The aim of this review is to describe the concepts of systematic review and meta-analysis and consider how these tools may be used to provide empirical evidence to spur the field to improve the rigor of the conduct and reporting of preclinical research akin to their use in improving the conduct and reporting of randomized controlled trials in clinical research. As with other research domains, systematic reviews are subject to bias. Therefore, we have also suggested guidance for their conduct, reporting, and critical appraisal.
Sena, Emily S; Currie, Gillian L; McCann, Sarah K; Macleod, Malcolm R; Howells, David W
Meta-Analysis of Pre-Clinical Studies of Early Decompression in Acute Spinal Cord Injury: A Battle of Time and Pressure
Background The use of early decompression in the management of acute spinal cord injury (SCI) remains contentious despite many pre-clinical studies demonstrating benefits and a small number of supportive clinical studies. Although the pre-clinical literature favours the concept of early decompression, translation is hindered by uncertainties regarding overall treatment efficacy and timing of decompression. Methods We performed meta-analysis to examine the pre-clinical literature on acute decompression of the injured spinal cord. Three databases were utilised; PubMed, ISI Web of Science and Embase. Our inclusion criteria consisted of (i) the reporting of efficacy of decompression at various time intervals (ii) number of animals and (iii) the mean outcome and variance in each group. Random effects meta-analysis was used and the impact of study design characteristics assessed with meta-regression. Results Overall, decompression improved behavioural outcome by 35.1% (95%CI 27.4-42.8; I2=94%, p<0.001). Measures to minimise bias were not routinely reported with blinding associated with a smaller but still significant benefit. Publication bias likely also contributed to an overestimation of efficacy. Meta-regression demonstrated a number of factors affecting outcome, notably compressive pressure and duration (adjusted r2=0.204, p<0.002), with increased pressure and longer durations of compression associated with smaller treatment effects. Plotting the compressive pressure against the duration of compression resulting in paraplegia in individual studies revealed a power law relationship; high compressive forces quickly resulted in paraplegia, while low compressive forces accompanying canal narrowing resulted in paresis over many hours. Conclusion These data suggest early decompression improves neurobehavioural deficits in animal models of SCI. Although much of the literature had limited internal validity, benefit was maintained across high quality studies. The close relationship of compressive pressure to the rate of development of severe neurological injury suggests that pressure local to the site of injury might be a useful parameter determining the urgency of decompression.
Skeers, Peta; Battistuzzo, Camila R.; Macleod, Malcolm R.; Howells, David W.; Sena, Emily S.
Fabry Disease: Preclinical Studies Demonstrate the Effectiveness of ?-Galactosidase A Replacement in Enzyme-Deficient Mice
Preclinical studies of enzyme-replacement therapy for Fabry disease (deficient ?-galactosidase A [?-Gal A] activity) were performed in ?-Gal A�deficient mice. The pharmacokinetics and biodistributions were determined for four recombinant human ?-Gal A glycoforms, which differed in sialic acid and mannose-6-phosphate content. The plasma half-lives of the glycoforms were ?2�5 min, with the more sialylated glycoforms circulating longer. After intravenous doses of 1 or 10 mg/kg body weight were administered, each glycoform was primarily recovered in the liver, with detectable activity in other tissues but not in the brain. Normal or greater activity levels were reconstituted in various tissues after repeated doses (10 mg/kg every other day for eight doses) of the highly sialylated AGA-1 glycoform; 4 d later, enzyme activity was retained in the liver and spleen at levels that were, respectively, 30% and 10% of that recovered 1 h postinjection. Importantly, the globotriaosylceramide (GL-3) substrate was depleted in various tissues and plasma in a dose-dependent manner. A single or repeated doses (every 48 h for eight doses) of AGA-1 at 0.3�10.0 mg/kg cleared hepatic GL-3, whereas higher doses were required for depletion of GL-3 in other tissues. After a single dose of 3 mg/kg, hepatic GL-3 was cleared for ?4 wk, whereas cardiac and splenic GL-3 reaccumulated at 3 wk to ?30% and ?10% of pretreatment levels, respectively. Ultrastructural studies demonstrated reduced GL-3 storage posttreatment. These preclinical animal studies demonstrate the dose-dependent clearance of tissue and plasma GL-3 by administered ?-Gal A, thereby providing the in vivo rationale�and the critical pharmacokinetic and pharmacodynamic data�for the design of enzyme-replacement trials in patients with Fabry disease.
Ioannou, Yiannis A.; Zeidner, Ken M.; Gordon, Ronald E.; Desnick, Robert J.
Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II.
Mucopolysaccharidosis II (MPS II; Hunter syndrome) is an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), which catalyzes the catabolism of glycosaminoglycans (GAG) by cleaving the O-linked sulfate from dermatan sulfate and heparan sulfate. Recently, enzyme replacement therapy (ERT) with recombinant human I2S (Elaprase (idursulfase), Shire Human Genetic Therapies, Inc.), has been approved in the US and European Union for the treatment and management of MPS II. The purpose of the studies presented here was to describe some of the preclinical development of idursulfase using the I2S knock-out mouse model of MPS II designed to study the effect of dose and various dosing regimens of idursulfase on urine and tissue GAG levels. Urine and tissue samples were collected prior to idursulfase treatment and periodically throughout each study and analyzed for GAGs. The presence of anti-idursulfase antibodies in the mice serum after idursulfase use was also determined. Results showed that idursulfase, at several doses and at several dosing frequencies, caused a reduction in tissue and urine GAG levels in a dose-dependent manner. These studies also demonstrated that after IV administration, idursulfase is biologically active in the IdS-KO mouse model and is transported to key target tissues, reaching the lysosomes in an active form, and degrading the accumulated GAG. In conclusion, these results indicated that ERT with idursulfase produced in a human cell line could be useful in the treatment and management of MPS II, and were used in the design of clinical studies to evaluate the efficacy of idursulfase in MPS II patients. PMID:17459751
Garcia, Antony R; DaCosta, Jeffrey M; Pan, Jing; Muenzer, Joseph; Lamsa, Justin C
Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model
Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular). The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions.
Giraud, S.; Favreau, F.; Chatauret, N.; Thuillier, R.; Maiga, S.; Hauet, T.
Wireless video capsule enteroscopy in preclinical studies: methodical design of its applicability in experimental pigs.
The aim of this project was to develop a methodology to introduce wireless video capsule endoscopy in preclinical research. Five mature female pigs (Sus scrofa domestica) were selected for the study. Capsule endoscopes (the EndoCapsule system; Olympus) were introduced into the duodenum endoscopically in each of the animals. The life span of batteries (i.e., total time of endoscopy recording) was 487-540 min (median 492 min). The capsule endoscope reached the cecum during enteroscopy once (after 7 h 57 min), in the remaining cases, endoscopy recordings terminated in the distal or terminal ileum. All capsule enteroscopies found a normal pattern of the small intestine. The intestinal lumen is narrower, transverse folds are sparse or even absent, villi are wider but less prominent in pigs compared to humans. Capsule endoscopy in experimental pigs will be helpful for future trials on injury of different drugs and xenobiotics to the small bowel. PMID:19294508
Kop�cov�, Marcela; Tachec�, Ilja; Kvetina, Jaroslav; Bures, Jan; Kunes, Martin; Spelda, Stanislav; Tycov�, Vera; Svoboda, Zbynek; Rejchrt, Stanislav
Preparation and preclinical pharmacological study on a novel bone imaging agent (99m)Tc-EMIDP.
A novel zoledronic acid (ZL) derivative, 1-hydroxy-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid (EMIDP), was prepared and labeled with (99)(m)Tc successfully in a high labeling yield and good stability in vitro. The preclinical pharmacological properties of (99)(m)Tc-EMIDP were investigated and compared with (99)(m)Tc-MDP and (99)(m)Tc-ZL. The studies of biodistribution in mice and SPECT bone imaging of the rabbit suggest that (99)(m)Tc-EMIDP has highly selective uptake in the skeletal system and rapid clearance in the soft tissues. The present findings indicate that (99)(m)Tc-EMIDP holds great potential for bone scintigraphy. PMID:20363146
Lin, Jianguo; Luo, Shineng; Chen, Chuanqing; Qiu, Ling; Wang, Yan; Cheng, Wen; Ye, Wanzhong; Xia, Yongmei
Resveratrol: A Review of Pre-clinical Studies for Human Cancer Prevention
The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3, 4?, 5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and anti-oxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol�s anti-cancer effects to support its potential as an anticancer agent in human populations.
Athar, Mohammad; Back, Jung Ho; Tang, Xiuwei; Kim, Kwang Ho; Kopelovich, Levy; Bickers, David R.; Kim, Arianna L.
Immune Competency of a Hairless Mouse Strain for Improved Preclinical Studies in Genetically-Engineered Mice
Genetically-engineered mouse models (GEMMs) of cancer are of increasing value to preclinical therapeutics. Optical imaging is a cost-effective method of assessing deep-seated tumor growth in GEMMs whose tumors can be encoded to express luminescent or fluorescent reporters, although reporter signal attenuation would be improved if animals were fur-free. In this study, we sought to determine whether hereditable furlessness resulting from a hypomorphic mutation in the Hairless gene would or would not also affect immune competence. By assessment of humoral and cellular immunity of the SKH1 mouse line bearing the hypomorphic Hairless mutation, we determined that blood counts, immunoglobulin levels, and CD4+ and CD8+ T cells were comparable between SKH1 and the C57Bl/6 strain. On examination of T cell subsets, statistically significant differences in na�ve T cells (1.7 vs. 3.4 � 105 cells/spleen in SKH1 vs. C57Bl/6, p=0.008) and memory T cells (1.4 vs. 0.13 � 106 cells/spleen in SKH1 vs. C57Bl/6, p=0.008) were detected. However, the numerical differences did not result in altered T cell functional response to antigen re-challenge (keyhole limpet hemocyanin) in a lymph node cell in vitro proliferative assay. Furthermore, interbreeding the SKH1 mouse line to a rhabdomyosarcoma GEMM demonstrated preserved anti-tumor responses of CD56+ Natural Killer cells and CD163+ macrophages, without any differences in tumor pathology. The fur-free GEMM was also especially amenable to multiplex optical imaging. Thus, SKH1 represents an immune competent, fur-free mouse strain which may be of use for interbreeding to other genetically-engineered mouse models of cancer for improved preclinical studies.
Schaffer, Beverly S.; Grayson, Marcia H.; Wortham, Joy M.; Kubicek, Courtney B.; McCleish, Amanda T.; Prajapati, Suresh I.; Nelon, Laura D.; Brady, Michelle M.; Jung, Inkyung; Hosoyama, Tohru; Sarro, Leslea M.; Hanes, Martha A.; Rubin, Brian P.; Michalek, Joel E.; Clifford, Charles B.; Infante, Anthony J.; Keller, Charles
Glucocorticoid-Treated Mice Are an Inappropriate Positive Control for Long-Term Preclinical Studies in the mdx Mouse
Background Dmdmdx (mdx) mice are used as a genetic and biochemical model of dystrophin deficiency. The long-term consequences of glucocorticoid (GC) treatment on dystrophin-deficient skeletal and heart muscle are not yet known. Here we used systematic phenotyping to assess the long-term consequences of GC treatment in mdx mice. Our investigation addressed not only the effects of GC on the disease phenotype but also the question of whether GCs can be used as a positive control for preclinical drug evaluations. Methods and Findings We performed nine pre-clinical efficacy trials (treated N?=?129, untreated N?=?106) of different durations in 9-to-50-week-old dystrophic mdx mice over a 3-year time period using standardized methods. In all these trials, we used either 1 mg/kg body weight of prednisone or 5 mg/kg body weight of prednisolone as positive controls to compare the efficacy of various test drugs. Data from untreated controls and GC-treated mice in the various trials have been pooled and analyzed to assess the effects of GCs on dystrophin-deficient skeletal and cardiac muscles of mdx mice. Our results indicate that continuous GC treatment results in early (e.g., at 50 days) improvements in normalized parameters such as grip strength, motor coordination and maximal in vitro force contractions on isolated EDL muscle, but these initial benefits are followed by a progressive loss of muscle strength after 100 days. We also found a significant increase in heart fibrosis that is reflected in a significant deterioration in cardiac systolic function after 100 days of treatment. Conclusion Continuous administration of prednisone to mdx mice initially improves skeletal muscle strength, but further therapy result in deterioration of muscle strength and cardiac function associated with enhanced cardiac fibrosis. These results suggest that GCs may not serve as an appropriate positive control for long-term mdx mouse preclinical trials.
Gordish-Dressman, Heather; Spurney, Christopher F.; Iantorno, Micaela; Hoffman, Eric P.; Nagaraju, Kanneboyina
Preclinical pharmacology, efficacy, and safety of varenicline in smoking cessation and clinical utility in high risk patients
Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain ?4?2 nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel ?4?2 nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing postmarketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and psychosis as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles and heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline.
Xi, Zheng-Xiong
Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies
Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations.
Smith, Mark A.; Lynch, Wendy J.
Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease.
Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting A? amyloid may have clinical benefit in Alzheimer's disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native A? amyloid-specific binding peptide, lowers brain A? amyloid plaque burden and brain A?1-40 and A?1-42 peptide levels, improves cognitive learning and memory in Morris water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-A? amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited A? amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target A? amyloid oligomers using an engineered peptide-mimotope strategy. PMID:24021662
Camboni, Marybeth; Wang, Chiou-Miin; Miranda, Carlos; Yoon, Jung Hae; Xu, Rui; Zygmunt, Deborah; Kaspar, Brian K; Martin, Paul T
CCD-camera-based diffuse optical tomography to study ischemic stroke in preclinical rat models
NASA Astrophysics Data System (ADS)
Stroke, due to ischemia or hemorrhage, is the neurological deficit of cerebrovasculature and is the third leading cause of death in the United States. More than 80 percent of stroke patients are ischemic stroke due to blockage of artery in the brain by thrombosis or arterial embolism. Hence, development of an imaging technique to image or monitor the cerebral ischemia and effect of anti-stoke therapy is more than necessary. Near infrared (NIR) optical tomographic technique has a great potential to be utilized as a non-invasive image tool (due to its low cost and portability) to image the embedded abnormal tissue, such as a dysfunctional area caused by ischemia. Moreover, NIR tomographic techniques have been successively demonstrated in the studies of cerebro-vascular hemodynamics and brain injury. As compared to a fiberbased diffuse optical tomographic system, a CCD-camera-based system is more suitable for pre-clinical animal studies due to its simpler setup and lower cost. In this study, we have utilized the CCD-camera-based technique to image the embedded inclusions based on tissue-phantom experimental data. Then, we are able to obtain good reconstructed images by two recently developed algorithms: (1) depth compensation algorithm (DCA) and (2) globally convergent method (GCM). In this study, we will demonstrate the volumetric tomographic reconstructed results taken from tissuephantom; the latter has a great potential to determine and monitor the effect of anti-stroke therapies.
Lin, Zi-Jing; Niu, Haijing; Liu, Yueming; Su, Jianzhong; Liu, Hanli
Agent Identification and Preclinical Testing
\\u000a This chapter provides an overview of the preclinical screening assays and animal efficacy testing models currently utilized\\u000a by the drug discovery and development program of the Division of Cancer Prevention (DCP), National Cancer Institute (NCI)\\u000a to identify chemical agents or natural biological products which may be efficacious in preventing human cancers. The first\\u000a step of the drug discovery process involves
James A. Crowell; Cathy J. Holmes
Dried blood spot sampling: practical considerations and recommendation for use with preclinical studies.
At present it is necessary to use animals to generate toxicokinetic data as part of preclinical safety studies. However, ethical standards require animal use to be carefully monitored and the principles of the 3Rs: replacement, reduction and refinement, to be considered and applied. Use of dried blood spot (DBS) samples, typically 10 to 20 �l, rather than the larger blood volumes required to obtain plasma samples, fully embraces the latter two principles of reduction and refinement. The use of DBS sampling enables the number of rodents per study to be reduced whilst also refining the way blood samples are taken from both rodents and non-rodents. The recent changes to the European Directive on the protection of animals used for scientific purposes favor DBS sampling becoming the standard for generation of toxicokinetic data, and imply that pharmaceutical companies will have to justify why plasma samples (and therefore larger blood volumes) are required for bioanalysis. Use of DBS samples has been, and is being, discussed widely within the pharmaceutical industry as the move away from taking large blood volumes becomes inevitable. PMID:21585305
Burnett, Josephine Ec
A novel bone conduction implant (BCI): engineering aspects and pre-clinical studies.
Percutaneous bone anchored hearing aids (BAHA) are today an important rehabilitation alternative for patients suffering from conductive or mixed hearing loss. Despite their success they are associated with drawbacks such as skin infections, accidental or spontaneous loss of the bone implant, and patient refusal for treatment due to stigma. A novel bone conduction implant (BCI) system has been proposed as an alternative to the BAHA system because it leaves the skin intact. Such a BCI system has now been developed and the encapsulated transducer uses a non-screw attachment to a hollow recess of the lateral portion of the temporal bone. The aim of this study is to describe the basic engineering principals and some preclinical results obtained with the new BCI system. Laser Doppler vibrometer measurements on three cadaver heads show that the new BCI system produces 0-10 dB higher maximum output acceleration level at the ipsilateral promontory relative to conventional ear-level BAHA at speech frequencies. At the contralateral promontory the maximum output acceleration level was considerably lower for the BCI than for the BAHA. PMID:20105095
H�kansson, Bo; Reinfeldt, Sabine; Eeg-Olofsson, M�ns; Ostli, Per; Taghavi, Hamidreza; Adler, Johannes; Gabrielsson, John; Stenfelt, Stefan; Granstr�m, G�sta
Preclinical studies of a specific PPAR? modulator in the control of skin inflammation.
Peroxisome proliferator-activated receptor ? (PPAR?) antagonizes inflammatory signals by interfering with NF-?B nuclear translocation. Consistently, PPAR? agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPAR? agonism have been designed to selectively target inflammatory pathways. Among these compounds, GED-0507-34L has been developed and recently used in phase II clinical trials for inflammatory bowel diseases. This study was aimed at assessing the role of GED-0507-34L in preclinical models of inflammatory skin diseases. The compound modulated PPAR? function and suppressed the inflammatory process inhibiting NF-?B nuclear translocation with the consequent reduction of inflammatory cytokines expression, such as IL-6, IL-8, IL-12, IL-21, IL-23, tumor necrosis factor-? (TNF-?), and cyclooxygenase-2 (COX-2) in normal human keratinocytes and lymphocytes treated with lipopolysaccharide (LPS) or TNF-?. Moreover, an altered proliferation and expression of differentiation markers induced by TNF-? were also counteracted. In psoriasis-like skin lesions elicited in mice by IL-21, topical application of GED-0507-34L reduced cellular infiltrate and epidermal hyperplasia, normalizing the differentiation process. The results indicate that GED-0507-34L possesses anti-inflammatory properties useful for the management of patients with inflammatory skin diseases including psoriasis. Phase I trial on patients is ongoing. PMID:24166135
Mastrofrancesco, Arianna; Kovacs, Daniela; Sarra, Massimiliano; Bastonini, Emanuela; Cardinali, Giorgia; Aspite, Nicaela; Camera, Emanuela; Chavatte, Philippe; Desreumaux, Pierre; Monteleone, Giovanni; Picardo, Mauro
Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) in Preclinical Studies of Antivascular Treatments
Antivascular treatments can either be antiangiogenic or targeting established tumour vasculature. These treatments affect the tumour microvasculature and microenvironment but may not change clinical measures like tumour volume and growth. In research on antivascular treatments, information on the tumour vasculature is therefore essential. Preclinical research is often used for optimization of antivascular drugs alone or in combined treatments. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is an in vivo imaging method providing vascular information, which has become an important tool in both preclinical and clinical research. This review discusses common DCE-MRI imaging protocols and analysis methods and provides an overview of preclinical research on antivascular treatments utilizing DCE-MRI.
Nielsen, Thomas; Wittenborn, Thomas; Horsman, Michael R.
Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies
Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72?h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible and that it can improve clinical and neurological outcomes and reduce health care costs. Based on the current clinical evidence using a Delphi process, an expert panel recommended that early surgical intervention should be considered in all patients from 8 to 24?h following acute traumatic SCI.
Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.
Sex differences in the vulnerability to drug abuse: a review of preclinical studies
Clinical and preclinical findings indicate that males and females differ on several aspects of drug reinforcement. Females are more vulnerable than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. It has been suggested that ovarian hormones contribute to the mechanisms
Megan E. Roth; Kelly P. Cosgrove; Marilyn E. Carroll
Application of tetra-isopalmitoyl ascorbic acid in cosmetic formulations: stability studies and in vivo efficacy.
Liposoluble vitamin C derivatives, such as tetra-isopalmitoyl ascorbic acid (IPAA), are often used in dermocosmetic products due to their higher stability than vitamin C free form as well as its proposed effects in skin; however, there are no studies analyzing IPAA stability or its in vivo effects when present in dermocosmetic formulations. Thus, this study aimed to evaluate chemical stability and pre-clinical and clinical efficacy of dermocosmetic formulations containing IPAA in skin hydration and microrelief. Chemical stability of the formulations added with 1% IPAA was evaluated by heat stress during 35 days by HPLC. For pre-clinical evaluation, experimental formulations were topically applied on hairless skin mice during 5 days and animal skins were analyzed by non-invasive biophysic techniques (water content of stratum corneum, TEWL, viscoelasticity, and microrelief) and by histopathological studies. For clinical efficacy tests, the formulations were topically applied to the forearm and face of human volunteers, and 3h and 15 days after applications, the skins were evaluated by the same non-invasive techniques mentioned before. Results showed that formulations containing IPAA had medium stability and had pronounced moisturizing effects on stratum corneum and on viable epidermis. These formulations also improved skin microrelief especially in relation to skin smoothness and roughness. PMID:22974986
Maia Campos, Patr�cia M B G; Gianeti, Mirela D; Camargo, Fl�vio B; Gaspar, Lorena R
Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study
NASA Astrophysics Data System (ADS)
Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.
Escoffre, Jean-Michel; Novell, Anthony; Serri�re, Sophie; Bouakaz, Ayache
Long-term Safety and Efficacy of Human-Induced Pluripotent Stem Cell (iPS) Grafts in a Preclinical Model of Retinitis Pigmentosa
The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell�based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65rd12/Rpe65rd12 mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65rd12/Rpe65rd12 mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss.
Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H
Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa.
The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell-based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65(rd12)/Rpe65(rd12) mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65(rd12)/Rpe65(rd12) mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss. PMID:22895806
Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H
Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid ?-glucosidase.
A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid ?-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5�10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0�10(5) vg/?g genomic DNA (gDNA), while uninjected sites had up to 1.0�10(4) vg/?g gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0�10(6) vg/?g gDNA, followed by a decrease to 1.0�10(3) vg/?g gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections. PMID:24021025
Conlon, Thomas J; Erger, Kirsten; Porvasnik, Stacy; Cossette, Travis; Roberts, Cheryl; Combee, Lynn; Islam, Saleem; Kelley, Jeffry; Cloutier, Denise; Cl�ment, Nathalie; Abernathy, Corinne R; Byrne, Barry J
Temple study's pre-clinical data shows Angiocidin effective against leukemia
Angiocidin, a novel tumor-inhibiting protein, has been shown to reduce acute myeloid leukemia (AML) cells in mice by almost two-thirds in pre-clinical experiments. A researcher from Temple University�s School of Medicine who discovered Angiocidin, presented the findings during the American Society of Hematology�s national meeting in Atlanta on Dec. 9. Temple University is home to the Fox Chase Cancer Center.
A study on spiral cone beam scanning mode for preclinical micro-CT
In preclinical micro-CT, a circular scanning trajectory is widely used, and the Feldkamp algorithm is usually the standard reconstruction method to recover the images. This imaging mode has the advantages of fast reconstruction speed and good intra-slice resolution for images near the central plane. However, it shows cone-beam artifacts for images at relatively large cone angles. To address this problem,
Junjun Deng; Shikui Yan; Hengyong Yu; Ge Wang; Mu Chen
Preclinical drug metabolism and pharmacokinetics, and prediction of human pharmacokinetics and efficacious dose of the investigational Aurora A kinase inhibitor alisertib (MLN8237).
Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 �M for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose. PMID:24484538
Yang, Johnny J; Li, Yu; Chakravarty, Arijit; Lu, Chuang; Xia, Cindy Q; Chen, Susan; Pusalkar, Sandeep; Zhang, Mengkun; Ecsedy, Jeffrey; Manfredi, Mark G; Wu, Jing-Tao; Shyu, Wen Chyi; Balani, Suresh K
Cell-Seeded Tubularized Scaffolds for Reconstruction of Long Urethral Defects: A Preclinical Study
Background The treatment options for patients requiring repair of a long segment of the urethra are limited by the availability of autologous tissues. We previously reported that acellular collagen-based tubularized constructs seeded with cells are able to repair small urethral defects in a rabbit model. Objective We explored the feasibility of engineering clinically relevant long urethras for surgical reconstruction in a canine preclinical model. Design, setting, and participants Autologous bladder epithelial and smooth muscle cells from 15 male dogs were grown and seeded onto preconfigured collagen-based tubular matrices (6 cm in length). The perineal urethral segment was removed in 21 male dogs. Urethroplasties were performed with tubularized collagen scaffolds seeded with cells in 15 animals. Tubularized constructs without cells were implanted in six animals. Serial urethrography and three-dimensional computed tomography (CT) scans were performed pre- and postoperatively at 1, 3, 6, and 12 mo. The animals were euthanized at their predetermined time points (three animals at 1 mo, and four at 3, 6, and 12 mo) for analyses. Outcome measurements and statistical analysis Statistical analysis of CT imaging and histology was not needed. Results and limitations CT urethrograms showed wide-caliber urethras without strictures in animals implanted with cell-seeded matrices. The urethral segments replaced with acellular scaffolds collapsed. Gross examination of the urethral implants seeded with cells showed normal-appearing tissue without evidence of fibrosis. Histologically, an epithelial cell layer surrounded by muscle fiber bundles was observed on the cell-seeded constructs, and cellular organization increased over time. The epithelial and smooth muscle phenotypes were confirmed using antibodies to pancytokeratins AE1/AE3 and smooth muscle�specific desmin. Formation of an epithelial cell layer occurred in the unseeded constructs, but few muscle fibers formed. Conclusions Cell-seeded tubularized collagen scaffolds can be used to repair long urethral defects, whereas scaffolds without cells lead to poor tissue development and strictures. This study demonstrates that long tissue-engineered tubularized urethral segments may be used for urethroplasty in patients.
Orabi, Hazem; AbouShwareb, Tamer; Zhang, Yuanyuan; Yoo, James J.; Atala, Anthony
Rational design of murine secreted alkaline phosphatase for enhanced performance as a reporter gene in mouse gene therapy preclinical studies.
Many preclinical gene therapy studies use a reporter gene to evaluate vector design and performance in mouse models of human disease. Unfortunately, most commonly used reporter genes are immunogenic in mice, which confounds accurate evaluation of vector function. In previous studies, we showed that the murine secreted alkaline phosphatase (mSEAP) gene functions well as a simple and sensitive reporter gene in mice. In this study, we have used rational design to enhance mSEAP performance. The majority of native mSEAP remains attached to the outer surface of the cell through glycan phosphatidylinositol linkage; removal of the carboxy-terminal tail of mSEAP resulted in a dramatic enhancement of release of the protein into cell culture medium and into mouse plasma in whole animal experiments. We increased the heat stability of mSEAP through mutation of a key residue in the crown domain of the protein (H451E), thus allowing us to reduce endogenous, background AP activity through heat inactivation for enhanced sensitivity. We show that these alterations in mSEAP result in enhanced performance in tissue culture and mouse studies. Taken together, these data illustrate that mSEAP is a sensitive, nonimmunogenic reporter for preclinical mouse studies. PMID:21083426
Christou, Carin; Parks, Robin J
Evaluation of wound healing activity of Lantana camara L. - a preclinical study.
Lantana camara is used in herbal medicine for the treatment of skin itches, as an antiseptic for wounds, and externally for leprosy and scabies. The objective of our study was to investigate excision wound healing activity of the leaf extract of L. camara in rats. The animals were divided into two groups of 12 each in both the models. The test group animals were treated with the aqueous extract of L. camara (100 mg/kg/day) topically and the control group animals were left untreated. Wound healing efficacy was measured by determining the morphological and biochemical parameters. Wound healing time, wound contraction and synthesis of collagen were monitored periodically. Antimicrobial activities of the extract against the microorganisms were also assessed. Treatment of the wounds with extract enhanced significantly the rate of wound contraction (98%), synthesis of collagen and decreased mean wound healing time. These studies demonstrate that L. camara is effective in healing excision wounds in the experimental animal and could be evaluated as a therapeutic agent in tissue repair processes associated with skin injuries. PMID:18844241
Nayak, B Shivananda; Raju, S Sivachandra; Eversley, Mathew; Ramsubhag, Adash
Cardiac arterial spin labeling using segmented ECG-gated Look-Locker FAIR: variability and repeatability in preclinical studies.
MRI is important for the assessment of cardiac structure and function in preclinical studies of cardiac disease. Arterial spin labeling techniques can be used to measure perfusion noninvasively. In this study, an electrocardiogram-gated Look-Locker sequence with segmented k-space acquisition has been implemented to acquire single slice arterial spin labeling data sets in 15 min in the mouse heart. A data logger was introduced to improve data quality by: (1) allowing automated rejection of respiration-corrupted images, (2) providing additional prospective gating to improve consistency of acquisition timing, and (3) allowing the recombination of uncorrupted k-space lines from consecutive data sets to reduce respiration corruption. Finally, variability and repeatability of perfusion estimation within-session, between-session, between-animal, and between image rejection criteria were assessed in mice. The criterion used to reject images from the T(1) fit was shown to affect the perfusion estimation. These data showed that the between-animal coefficient of variability (24%) was greater than the between-session variability (17%) and within-session variability (11%). Furthermore, the magnitude of change in perfusion required to detect differences was 30% (within-session) and 55% (between-session) according to Bland-Altman repeatability analysis. These technique developments and repeatability statistics will provide a platform for future preclinical studies applying cardiac arterial spin labeling. PMID:22411842
Campbell-Washburn, Adrienne E; Price, Anthony N; Wells, Jack A; Thomas, David L; Ordidge, Roger J; Lythgoe, Mark F
Ovarian hyperstimulation syndrome inhibition by targeting VEGF, COX-2 and Calcium pathways: a preclinical randomized study.
Abstract Objective: The efficacy of vascular endothelial growth factor (VEGF), COX-2, calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome (OHSS) rat model was tested. Methods: One hundred and eight female Wistar rats were randomly divided in nine groups. The control group received saline, while the OHSS group received rec-FSH for 4 consecutive days. The other seven groups received rec-FSH (4d) and Bevacizumab twice, Parecoxib daily, Verapamil daily, Parecoxib daily and Bevacizumab twice, Verapamil daily and Bevacizumab twice, Parecoxib and Verapamil daily, Letrozole and Meloxicam daily, respectively. All groups received also hCG at the 5th day. Results: All intervention groups were characterized by reduced vascular permeability compared to the OHSS group, which in the groups of Verapamil (Calcium inhibition) and Parecoxib?+?Verapamil (COX-2?+?Calcium inhibition) presented significant statistical difference. The Verapamil group showed the lowest corpus luteum formation, while the Parecoxib (COX-2 inhibition), the Parecoxib?+?Verapamil (COX-2?+?Calcium inhibition), the Bevacizumab?+?Parecoxib (VEGF?+?COX-2 inhibition) and the Bevacizumab?+?Verapamil (VEGF?+?Calcium inhibition) groups were also characterized by lower corpus luteum numbers compared to the OHSS group. Furthermore, lower graafian follicle formation was observed in the above groups, while the ovarian weight and the hormonal profile were not significantly affected. Conclusions: Studying the different check points of the VEGF pathway, we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model. PMID:24819316
Kitsou, Chrysoula; Kosmas, Ioannis; Lazaros, Leandros; Hatzi, Elissavet; Euaggelou, Aggelos; Mynbaev, Ospan; Tournaye, Herman; Prapas, Nikolaos; Prapas, Ioannis; Zikopoulos, Konstantinos; Galani, Vasiliki; Georgiou, Ioannis
The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML
Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2V617F mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2V617F mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.
Novotny-Diermayr, V; Hart, S; Goh, K C; Cheong, A; Ong, L-C; Hentze, H; Pasha, M K; Jayaraman, R; Ethirajulu, K; Wood, J M
Latent Structure and Factorial Invariance of a Neuropsychological Test Battery for the Study of Preclinical Alzheimer's Disease
Objective To examine the latent structure of a test battery currently being used in a longitudinal study of asymptomatic middle-aged adults with a parental history of Alzheimer�s disease (AD) and test the invariance of the factor solution across subgroups defined by selected demographic variables and known genetic risk factors for AD. Method An exploratory factor analysis (EFA) and a sequence of confirmatory factor analyses (CFA) were conducted on 24 neuropsychological measures selected to provide a comprehensive estimate of cognitive abilities most likely to be affected in preclinical AD. Once the underlying latent model was defined and the structural validity established through model comparisons, a multi-group confirmatory factor analysis model was used to test for factorial invariance across groups. Results The EFA solution revealed a factor structure consisting of 5 constructs: verbal ability, visuo-spatial ability, speed & executive function, working memory, and verbal learning & memory. The CFA models provided support for the hypothesized 5-factor structure. Results indicated factorial invariance of the model across all groups examined. Conclusions Collectively, the results suggested a relatively strong psychometric basis for using the factor structure in clinical samples that match the characteristics of this cohort. This confirmed an invariant factor structure should prove useful in research aimed to detect the earliest cognitive signature of preclinical AD in similar middle aged cohorts.
Dowling, N. Maritza; Hermann, Bruce; La Rue, Asenath; Sager, Mark A.
Phase II study evaluating the efficacy and safety of sagopilone (ZK-EPO) in patients with metastatic breast cancer that has progressed following chemotherapy
Sagopilone is a novel, fully synthetic epothilone that has shown promising preclinical activity in a range of tumor models,\\u000a including platinum-resistant ovarian cancer and metastatic breast cancer (MBC). This open-label, multicenter, Phase II study\\u000a investigated the efficacy, safety, and tolerability of sagopilone administered to patients with MBC. Women with MBC whose\\u000a previous chemotherapy regimen included a taxane and an anthracycline
Phuong K. Morrow; Stephen Divers; Louise Provencher; Shiuh-Wen Luoh; Teresa M. Petrella; Marius Giurescu; Thomas Schmelter; Yao Wang; Gabriel N. Hortobagyi; Linda T. Vahdat
[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].
The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented. PMID:9848161
Ternovo?, K S; Kryzhanovski?, G N; Musi?chuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F
Activity of PXD101, a histone deacetylase inhibitor, in preclinical ovarian cancer studies.
Histone deacetylase inhibitors represent a promising new class of anticancer agents. In the current investigation, we examined the activity of PXD101, a potent histone deacetylase inhibitor, used alone or in combination with clinically relevant chemotherapeutics (docetaxel, paclitaxel, and carboplatin), in preclinical in vitro and in vivo models of ovarian cancer. In vitro activity was examined in ovarian cancer and multidrug-resistant cell lines grown in monolayer culture, and in primary clinical ovarian cancer specimens grown in three-dimensional organoid culture. PXD101 was found to inhibit in vitro cancer cell growth at sub- to low micromolar IC(50) potency, exhibited synergistic activity when used in combination with relevant chemotherapeutics, and effectively inhibited the growth of multidrug-resistant cells. In vivo, PXD101 displayed single-agent antitumor activity on human A2780 ovarian cancer s.c. xenografts which was enhanced via combination therapy with carboplatin. In support of these findings, PXD101 was shown to increase the acetylation of alpha-tubulin induced by docetaxel and the phosphorylation of H2AX induced by carboplatin. Taken together, these results support the clinical evaluation of PXD101 used alone or in combination therapy for the treatment of ovarian cancer. PMID:16928830
Qian, Xiaozhong; LaRochelle, William J; Ara, Gulshan; Wu, Frank; Petersen, Kamille Dumong; Thougaard, Annemette; Sehested, Maxwell; Lichenstein, Henri S; Jeffers, Michael
Characterization of the potent 5-HT(1A/B) receptor antagonist and serotonin reuptake inhibitor SB-649915: preclinical evidence for hastened onset of antidepressant/anxiolytic efficacy.
An increase in brain serotonin (5-HT) levels is thought to be a key mechanism of action responsible for generating antidepressant efficacy. It has been proven that selective serotonin reuptake inhibitors are effective antidepressants, but the delay to therapeutic onset of these agents is thought to be due to the time required for 5-HT1A, and possibly 5-HT1B, autoreceptors to desensitize. Therefore, an agent incorporating 5-HT reuptake inhibition coupled with 5-HT1A and/or 5-HT1B autoreceptor antagonism may provide a fast-acting clinical agent. The current studies review the profile of SB-649915 (6-[(1-{2-[(2-methylquinolin-5-yl)oxy]ethyl}piperidin-4-yl)methyl]-2H-1,4-benzoxazin-3(4H)-one), a novel compound with high affinity for human (h) 5-HT1A and 5-HT1B receptors (pKi values of 8.6 and 8.0, respectively) as well as the (h) 5-HT transporter (SERT) (pKi value of 9.3). SB-649915 behaved as an antagonist at both 5-HT1A and 5-HT1B receptors in vitro and in vivo, reversing 5-HT, (+)8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and SKF99101-induced functional/behavioral responses. Furthermore, it inhibited [3H]5-HT reuptake in rat cortical synaptosomes, in vitro and ex vivo. In electrophysiological studies SB-649915 had no effect on rat dorsal raphe neuronal cell firing per se, but reversed 8-OH-DPAT-induced inhibition of firing both in vitro and in vivo. In addition, in a microdialysis study, it produced an acute increase in extracellular 5-HT in forebrain structures of the rat. Finally, SB-649915 demonstrated acute anxiolytic activity in both rodent and non-human primate and reduced the latency to onset of anxiolytic behavior, compared to paroxetine, in the rat social interaction paradigm. In summary, SB-649915 is a novel, potent 5-HT1A/1B autoreceptor antagonist, and 5-HT reuptake inhibitor. This particular pharmacological profile provides a novel mechanism that could offer fast-acting antidepressant activity. PMID:17627673
Watson, Jeannette M; Dawson, Lee A
Cannabinoids and Dementia: A Review of Clinical and Preclinical Data
The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer�s disease (AD), Huntington�s disease (HD), Parkinson�s disease (PD) and vascular dementia (VD). Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies.
Walther, Sebastian; Halpern, Michael
Efficient vitreolysis by combining plasmin and sulfur hexafluoride injection in a preclinical study in rabbit eyes
Purpose To investigate the efficacy of plasmin and sulfur hexafluoride (SF6) on the vitreoretinal junction, as well as the long-term safety in the eye and effect on the recipient�s general health after application in the eye. Methods The study design included four groups of rabbits with three animals in each group. Group 1 received an intravitreal injection (IVI) of plasmin and SF6 in the right eye; group 2 received an IVI of plasmin in the right eye; group 3 received an IVI of SF6 in the right eye; and group 4 received an IVI of balanced salt solution in the right eye, which served as a normal control. Long-term safety (up to approximately three months) after plasmin and/or SF6 injection was evaluated morphologically by clinical examination, histology, and immunohistochemistry, and functionally by electroretinograms (ERGs). General health evaluations after intravitreal injection included the assessment of weight gain, food intake, body temperature, and complete blood count analysis. Results Plasmin plus SF6 injection resulted in complete posterior vitreous detachment (PVD), whereas plasmin or SF6 injection alone resulted in only partial PVD. Balanced salt solution did not induce PVD. Eighty days after intravitreal injection, there were no major differences among the eyes of the three groups of animals compared with the normal control animals upon clinical evaluation, or regarding retinal morphology and ERGs. The lenses examined remained clear for up to 80 days following the intravitreal injection of plasmin plus SF6, except one eye in the plasmin-treated group. ERGs decreased transiently one week after intravitreal injection in groups 1 through 3, but animals recovered fully to normal status afterward. General health was not affected after the injection of plasmin plus SF6. Conclusions Efficient vitreoretinal separation could be achieved, and an acceptable long-term safety profile was noted after plasmin plus SF6 injection in the eye. No major ocular toxicity or systemic toxicity was found after the injection of plasmin plus SF6. These results provide good support for the future clinical use of plasmin plus SF6 for treatment of a variety of vitreoretinopathies.
Wu, Wei-Chi; Liu, Chi-Hsien; Chen, Chih-Chun; Wang, Nan-Kai; Chen, Kwan-Jen; Chen, Tun-Lu; Hwang, Yih-Shiou; Li, Lien-Min
Kidney Injury Molecule-1 Outperforms Traditional Biomarkers of Kidney Injury in Multi-site Preclinical Biomarker Qualification Studies
Kidney toxicity accounts for a significant percentage of morbidity and drug candidate failure. Serum creatinine (SCr) and blood urea nitrogen (BUN) have been used to monitor kidney dysfunction for over a century but these markers are insensitive and non-specific. In multi-site preclinical rat toxicology studies the diagnostic performance of urinary kidney injury molecule-1 (Kim-1) was compared to traditional biomarkers as predictors of kidney tubular histopathologic changes, currently considered the �gold standard� of nephrotoxicity. In multiple models of kidney injury, urinary Kim-1 significantly outperformed SCr and BUN. The area under the receiver operating characteristic curve for Kim-1 was between 0.91 and 0.99 as compared to 0.79 to 0.9 for BUN and 0.73 to 0.85 for SCr. Thus urinary Kim-1 is the first injury biomarker of kidney toxicity qualified by the FDA and EMEA and is expected to significantly improve kidney safety monitoring.
Vaidya, Vishal S.; Ozer, Josef S.; Frank, Dieterle; Collings, Fitz B.; Ramirez, Victoria; Troth, Sean; Muniappa, Nagaraja; Thudium, Douglas; Gerhold, David; Holder, Daniel J.; Bobadilla, Norma A.; Marrer, Estelle; Perentes, Elias; Cordier, Andre; Vonderscher, Jacky; Maurer, Gerard; Goering, Peter L.; Sistare, Frank D.; Bonventre, Joseph V.
Analysis of machine perfusion benefits in kidney grafts: a preclinical study
Background Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. Methods We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. Results ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and ?-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. Conclusions With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits.
The Relationship between Lesson Study and Self-Efficacy
ERIC Educational Resources Information Center
This article addresses a gap in the literature by developing a theory that bridges lesson study and self-efficacy. Since self-efficacy has been linked to student achievement, the theory is important as an explanatory mechanism linking lesson study to student achievement. The theory was developed using grounded theory based on primary source data�
Sibbald, Tim
Retrospect and Prospect of Studies of Teacher Efficacy in China
ERIC Educational Resources Information Center
Teacher efficacy is a powerful variable in educational and psychological studies. And it aroused much attention and interest from Chinese scholars in the past decade, which led to an accumulation of documents in this field. Following an introduction of efficacy studies in the west, the article reviews the brief history of those in China,�
He, Ning; Miao, Danmin
Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy
JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.
Heo, Jeong; Breitbach, Caroline J; Moon, Anne; Kim, Chang Won; Patt, Rick; Kim, Mi Kyung; Lee, Yu Kyung; Oh, Sung Yong; Woo, Hyun Young; Parato, Kelley; Rintoul, Julia; Falls, Theresa; Hickman, Theresa; Rhee, Byung-Geon; Bell, John C; Kirn, David H; Hwang, Tae-Ho
Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.
JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors. PMID:21427706
Heo, Jeong; Breitbach, Caroline J; Moon, Anne; Kim, Chang Won; Patt, Rick; Kim, Mi Kyung; Lee, Yu Kyung; Oh, Sung Yong; Woo, Hyun Young; Parato, Kelley; Rintoul, Julia; Falls, Theresa; Hickman, Theresa; Rhee, Byung-Geon; Bell, John C; Kirn, David H; Hwang, Tae-Ho
Self-Efficacy and Interest: Experimental Studies of Optimal Incompetence.
ERIC Educational Resources Information Center
To test the optimal incompetence hypothesis (high self-efficacy lowers task interest), 30 subjects rated interest, perceived difficulty, and confidence of success in different tasks. In study 2, 33 subjects completed a dart-game task in easy, moderate, and difficult conditions. In both, interest was a quadratic function of self-efficacy,�
Silvia, Paul J.
A Case Study of Elementary Beginning Mathematics Teachers' Efficacy Development
ERIC Educational Resources Information Center
The main purpose of this research was to explore the developmental process of and possible changes in beginning elementary mathematics teachers' efficacy. Beginning teachers with and without mathematics and science backgrounds were also compared to explore differences in their efficacy development. A multiple-case study method with a process and�
Chang, Yu-Liang
The discovery of rivaroxaban: translating preclinical assessments into clinical practice
Direct oral anticoagulants that target a single coagulation factor (such as factor Xa or thrombin) have been developed in recent years in an attempt to address some of the limitations of traditional anticoagulants. Rivaroxaban is an oral, direct factor Xa inhibitor that inhibits free and clot-bound factor Xa and factor Xa in the prothrombinase complex. Preclinical studies demonstrated a potent anticoagulant effect of rivaroxaban in plasma as well as the ability of this agent to prevent and treat venous and arterial thrombosis in animal models. These studies led to an extensive phase I clinical development program that investigated the pharmacological properties of rivaroxaban in humans. In these studies, rivaroxaban was shown to exhibit predictable pharmacokinetics and pharmacodynamics and to have no clinically relevant interactions with many commonly prescribed co-medications. The pharmacodynamic effects of rivaroxaban (for example, inhibition of factor Xa and prolongation of prothrombin time) were closely correlated with rivaroxaban concentrations in plasma. The encouraging findings from preclinical and early clinical studies were expanded upon in large, randomized phase III studies, which demonstrated the clinical efficacy and safety of rivaroxaban in a broad spectrum of patients. This article provides an overview of the discovery and development of rivaroxaban, describing the pharmacodynamic profile established in preclinical studies and the optimal translation to clinical studies in healthy subjects and patient populations.
Kubitza, Dagmar; Perzborn, Elisabeth; Berkowitz, Scott D.
Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety
Background Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Methods Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. Results We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Conclusions Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.
Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions
NASA Astrophysics Data System (ADS)
Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.
Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian
Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies
Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.
Miller, Janine D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Baron, Elma D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Louis-Stokes VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106 (United States); Scull, Heather [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Hsia, Andrew [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Berlin, Jeffrey C. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Department of Chemistry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States)] (and others)
Preclinical Studies of the Chinese Herbal Medicine formulation PHY906 as a Potential Adjunct to Radiation Therapy
Purpose/Objectives Abdominal and pelvic radiotherapy is limited by the radiosensitivity of the small and large intestine. PHY906, a state-of-the-art adaptation of a traditional Chinese medicine, decreased intestinal injury from chemotherapy in preclinical studies and is in clinical trials with chemotherapy. This project assessed whether PHY906 would also reduce intestinal injury from whole-abdomen irradiation in mice. Materials/Methods BALB/c mice received whole-abdomen irradiation (2 Gy/day) � PHY906 by oral gavage twice daily for 4 days. Intestinal injury was assayed by physiological observations and histological studies. Effects of PHY906 on tumor radiation response were assayed in tumor growth studies. Results PHY906 decreased the toxicity of fractionated abdominal irradiation. Radiation alone produced marked blunting and loss of villi, crypt loss, crypt hyperplasia and irregular crypt morphology, which were reduced by PHY906. The radiation-induced reduction in viable crypt counts was also mitigated by PHY906. PHY906 did not alter radiation-induced weight loss, but resulted in more rapid recovery. PHY906 did not alter growth, local invasion or metastatic spread of EMT6 mouse mammary tumors or protect tumors from growth delays produced by single-dose and fractionated irradiation. Conclusion In this mouse model system, PHY906 decreased the toxicity of abdominal irradiation, without protecting tumors, thereby increasing the therapeutic ratio.
Rockwell, Sara; Grove, Tina A.; Liu, Yanfeng; Cheng, Yung-Chi; Higgins, Susan A; Booth, Carmen J
Preclinical Toxicology of New Drugs.
National Technical Information Service (NTIS)
Preclinical toxicology studies of WR238605, Succinate and Pyridostigmine Bromide are being performed to assist the U.S. Army Medical R&D Command (USAMRDC) in its decision of whether or not to allow widespread clinical use of these agents. Subacute (28 day...
J. G. Page
Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells.
Basal breast cancer, common among patients presenting with inflammatory breast cancer (IBC), has been shown to be resistant to radiation and enriched in cancer stem cells. The Notch pathway plays an important role in self-renewal of breast cancer stem cells and contributes to inflammatory signaling which promotes the breast cancer stem cell phenotype. Herein, we inhibited Notch signaling using a gamma secretase inhibitor, RO4929097, in an in vitro model that enriches for cancer initiating cells (3D clonogenic assay) and conventional 2D clonogenic assay to compare the effect on radiosensitization of the SUM149 and SUM190 IBC cell lines. RO4929097 downregulated the Notch target genes Hes1, Hey1, and HeyL, and showed a significant reduction in anchorage independent growth in SUM190 and SUM149. However, the putative self-renewal assay mammosphere formation efficiency was increased with the drug. To assess radiosensitization of putative cancer stem cells, cells were exposed to increasing doses of radiation with or without 1 ?M RO4929097 in their standard (2D) and self-renewal enriching (3D) culture conditions. In the conventional 2D clonogenic assay, RO4929097 significantly sensitized SUM190 cells to ionizing radiation and has a modest radiosensitization effect in SUM149 cells. In the 3D clonogenic assays, however, a radioprotective effect was seen in both SUM149 and SUM190 cells at higher doses. Both cell lines express IL-6 and IL-8 cytokines known to mediate the efficacy of Notch inhibition and to promote self-renewal of stem cells. We further showed that RO429097 inhibits normal T-cell synthesis of some inflammatory cytokines, including TNF-?, a potential mediator of IL-6 and IL-8 production in the microenvironment. These data suggest that additional targeting agents may be required to selectively target IBC stem cells through Notch inhibition, and that evaluation of microenvironmental influences may shed further light on the potential effects of this inhibitor. PMID:22547109
Debeb, Bisrat G; Cohen, Evan N; Boley, Kimberly; Freiter, Erik M; Li, Li; Robertson, Fredika M; Reuben, James M; Cristofanilli, Massimo; Buchholz, Thomas A; Woodward, Wendy A
Pre-clinical toxicokinetics and safety study of M2ES, a PEGylated recombinant human endostatin, in rhesus monkeys.
PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30mg/kg body weight per day) for 3months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study. PMID:24878240
Guo, Lifang; Geng, Xingchao; Chen, Yang; Qi, Feifei; Liu, Li; Miao, Yufa; Lin, Zhi; Yu, Min; Li, Zuogang; Fu, Yan; Li, Bo; Luo, Yongzhang
Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model.
Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2'-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (approximately 46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols. PMID:20407428
Heemskerk, Hans; de Winter, Christa; van Kuik, Petra; Heuvelmans, Niki; Sabatelli, Patrizia; Rimessi, Paola; Braghetta, Paola; van Ommen, Gert-Jan B; de Kimpe, Sjef; Ferlini, Alessandra; Aartsma-Rus, Annemieke; van Deutekom, Judith C T
Preclinical PK and PD Studies on 2?-O-Methyl-phosphorothioate RNA Antisense Oligonucleotides in the mdx Mouse Model
Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2?-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (~46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.
Heemskerk, Hans; de Winter, Christa; van Kuik, Petra; Heuvelmans, Niki; Sabatelli, Patrizia; Rimessi, Paola; Braghetta, Paola; van Ommen, Gert-Jan B; de Kimpe, Sjef; Ferlini, Alessandra; Aartsma-Rus, Annemieke; van Deutekom, Judith CT
Common handling procedures conducted in preclinical safety studies result in minimal hepatic gene expression changes in sprague-dawley rats.
Gene expression profiling is a tool to gain mechanistic understanding of adverse effects in response to compound exposure. However, little is known about how the common handling procedures of experimental animals during a preclinical study alter baseline gene expression. We report gene expression changes in the livers of female Sprague-Dawley rats following common handling procedures. Baseline gene expression changes identified in this study provide insight on how these changes may affect interpretation of gene expression profiles following compound exposure. Rats were divided into three groups. One group was not subjected to handling procedures and served as controls for both handled groups. Animals in the other two groups were weighed, subjected to restraint in Broome restrainers, and administered water via oral gavage daily for 1 or 4 days with tail vein blood collections at 1, 2, 4, and 8 hours postdose on days 1 and 4. Significantly altered genes were identified in livers of animals following 1 or 4 days of handling when compared to the unhandled animals. Gene changes in animals handled for 4 days were similar to those handled for 1 day, suggesting a lack of habituation. The altered genes were primarily immune function related genes. These findings, along with a correlating increase in corticosterone levels suggest that common handling procedures may cause a minor immune system perturbance. PMID:24551150
He, Yudong D; Karbowski, Christine M; Werner, Jon; Everds, Nancy; Di Palma, Chris; Chen, Yuan; Higgins-Garn, Marnie; Tran, Sandra; Afshari, Cynthia A; Hamadeh, Hisham K
Dillenia species: A review of the traditional uses, active constituents and pharmacological properties from pre-clinical studies.
Abstract Context: Dillenia (Dilleniaceae) is a genus of about 100 species of flowering plants in tropical and subtropical trees of Southern Asia, Australasia, and the Indian Ocean Islands. Until now, only eight Dillenia species have been reported to be used traditionally in different countries for various medical purposes. Out of eight species, D. pentagyna (Roxb), D. indica (Linn.) and D. suffruticosa (Griffith Ex. Hook. F. & Thomsom Martelli) have been reported to be used to treat cancerous growth. Objective: The present review explored and provided information on the therapeutic potential of Dillenia species. Methods: Comprehensive and relevant literature on the therapeutic potential of Dillenia species was gathered through electronic databases including Google Scholar, Scopus, PubMed, and books, without limiting the dates of publication. Results and conclusion: The review demonstrated that only a few Dillenia species have been proven scientifically for their therapeutic potential in pre-clinical studies, including D. pentagyna, D. indica, D. papuana (Martelli), D. meliosmifolia (Hook. F. Ex. Thomsom) and D. suffruticosa (Griffith Ex Hook. F. & Thomson). A few species of Dillenia have undergone isolation and characterization of compounds with lupeol and betulinic acids having tremendous pharmacological potential. Dillenia species warrant further studies on their therapeutic potential, which may eventually lead to the development of new drug candidates for treatment of various diseases. PMID:24766363
Saiful Yazan, Latifah; Armania, Nurdin
Investigation of the robustness of two models for assessing synergy in pre-clinical drug combination studies.
Pre-clinical studies may be used to screen for synergistic combinations of drugs. The types of in vitro assays used for this purpose will depend upon the disease area of interest. In oncology, one frequently used study measures cell line viability: cells placed into wells on a plate are treated with doses of two compounds, and cell viability is assessed from an optical density measurement corrected for blank well values. These measurements are often transformed and analysed as cell survival relative to untreated wells. The monotherapies are assumed to follow the Hill equation with lower and upper asymptotes at 0 and 1, respectively. Additionally, a common variance about the dose-response curve may be assumed. In this paper, we consider two models for incorporating synergy parameters. We investigate the effect of different models of biological variation on the assessment of synergy from both of these models. We show that estimates of the synergy parameters appear to be robust, even when estimates of the other model parameters are biased. Using untransformed measurements provides better coverage of the 95% confidence intervals for the synergy parameters than using transformed measurements, and the requirement to fit the upper asymptote does not cause difficulties. Assuming homoscedastic variances appears to be robust. The added complexity of determining and fitting an appropriate heteroscedastic model does not seem to be justified. PMID:23907796
Whitehead, Anne; Su, Ting-Li; Thygesen, Helene; Sperrin, Matthew; Harbron, Chris
In vitro studies of the efficacy of antimicrobials against fungi
Objective. The purpose of this study was to compare the efficacy of Listerine Antiseptic, Tartar Control Listerine Antiseptic, and Peridex mouthrinses and a 0.2% chlorhexidine digluconate solution against known pathogenic fungi. Study design. Standardized methods were used to compare the antimicrobial efficacy of the above agents versus representative fungal species. Minimum inhibitory concentration-minimum fungicidal concentrations in macrobroth dilutions, suspension kill-time,
Timothy F. Meiller; Jacqueline I. Kelley; Mary Ann Jabra-Rizk; Louis G. DePaola; A. A. M. Abdullahel Baqui; William A. Falkler
Minnelide reduces tumor burden in preclinical models of osteosarcoma.
Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-?B pathway. PMID:23499892
Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya
Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy
Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.
Kim, Chae-Young; Park, Soon-Hye; Jeong, Moonsup; Kwon, O-Seo; Doh, Hyounmie; Kang, Su-Hyung; Robbins, Paul D.; Kim, Byong-Moon
Re-Evaluate the Effect of Hyperbaric Oxygen Therapy in Cancer - A Preclinical Therapeutic Small Animal Model Study
Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model.
Pande, Sneha; Sengupta, Amit; Srivastava, Anurag; Gude, Rajiv P.; Ingle, Arvind
The role of preclinical models in radiopharmaceutical therapy.
Radiopharmaceutical therapy (RPT) is a treatment modality that involves the use of radioactively labeled targeting agents to deliver a cytotoxic dose of radiation to tumor while sparing normal tissue. The biologic function of the target and the biologic action of the targeting agent is largely irrelevant as long as the targeting agent delivers cytotoxic radiation to the tumor. Preclinical RPT studies use imaging and ex vivo evaluation of radioactivity concentration in target and normal tissues to obtain biodistribution and pharmacokinetic data that can be used to evaluate radiation absorbed doses. Since the efficacy and toxicity of RPT depend on radiation absorbed dose, this quantity can be used to translate results from preclinical studies to human studies. The absorbed dose can also be used to customize therapy to account for pharmacokinetic and other differences among patients so as to deliver a prespecified absorbed dose to the tumor or to dose-limiting tissue. The combination of RPT with other agents can be investigated and optimized by identifying the effect of other agents on tumor or normal tissue radiosensitivity and also on how other agents change the absorbed dose to these tissues. RPT is a distinct therapeutic modality whose mechanism of action is well understood. Measurements can be made in preclinical models to help guide clinical implementation of RPT and optimize combination therapy using RPT. PMID:24857091
Sgouros, George; Hobbs, Robert F; Abou, Diane S
Use of mixed-effect models and tolerance limits to evaluate control cynomolgus monkey body weight change and variability during preclinical toxicology studies
Cynomolgus monkeys are an important and widely used species in preclinical toxicology studies. During the in-life phase of study, body weight effects may be indicative of toxicity; however, trends in body weight and body weight variability are often difficult to interpret due to small sample size and\\/or inter- and intra-animal variability. The present analysis utilizes mixed-effect modelling, which incorporates random
Ronnie L. Yeager; Dong Zhao; Yan Lan; Duane Poage; C. Thomas Lin; Michael D. DuVall
Scanning Electron Microscope Studies of the Chemotherapeutic Control of Preclinical Cariogenic Infection.
National Technical Information Service (NTIS)
In summary, the joint AFIP and NMRI studies in early enamel infection are producing the following results: (1) Information regarding variations in enamel topography, their precise locations, and varied susceptibility to demineralizing agents. This may hel...
S. Hoffman H. D. Tow J. S. Cole
Pre-Clinical Atherosclerosis due to HIV Infection: Carotid Intima-Medial Thickness Measurements from the FRAM Study
Background Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Methods Cross-sectional study of HIV-infected and control subjects without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Pre-clinical atherosclerosis was assessed by carotid intima-medial thickness (IMT) measurements in the internal/bulb and common regions in HIV-infected and control subjects after adjusting for traditional CVD risk factors. Results For internal carotid, mean IMT was 1.17�0.50mm for HIV-infected participants and 1.06�0.58mm for controls (p<0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected vs. controls was +0.188mm (95%CI 0.113-0.263, p<0.0001). Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (+0.148mm, 95%CI 0.072-0.224, p=0.0001). For the common carotid, HIV infection was independently associated with greater IMT (+0.033mm, 95%CI 0.010, 0.056, p=0.005). The association of HIV infection with IMT was similar to that of smoking which was also associated with greater IMT (internal +0.173mm, common +0.020mm). Conclusions Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared to the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking.
Grunfeld, C.; Delaney, J.A.C.; Wanke, C.; Currier, J.S.; Scherzer, R.; Biggs, M. L.; Tien, P.; Shlipak, M.; Sidney, S.; Polak, J.F.; O'Leary, D.; Bacchetti, P.; Kronmal, R.
Mesenchymal stem cell therapy for salivary gland dysfunction and xerostomia: a systematic review of preclinical studies.
The most severe forms of xerostomia and salivary gland dysfunction, as well as a severely reduced quality of life, are seen in Sj�gren syndrome (SS) and after radiotherapy for head and neck cancer. For both conditions, no effective regenerative therapies yet exist. Thus, the aim of this article was to assess, through systematic review, the potential benefit of mesenchymal stem cell (MSC) therapy in radiation-induced and SS-related salivary gland dysfunction and xerostomia. We searched PubMed/MEDLINE, Embase, Web of Science, the Cochrane Database of Systematic Reviews, the World Health Organization Clinical Trials Registry Platform, and Google Scholar. We identified 6 separate study comparisons eligible for inclusion. Owing to the limited number of studies, we conclude that more randomized, adequately powered clinical trials are needed to validate the potential beneficial effect of MSCs on salivary gland dysfunction and xerostomia. Nonetheless, the preliminary studies identified in the present review were encouraging for further research. PMID:24528792
Jensen, David Hebbelstrup; Oliveri, Roberto Stefan; Trojahn K�lle, Stig-Frederik; Fischer-Nielsen, Anne; Specht, Lena; Bardow, Allan; Buchwald, Christian
Preclinical Toxicology Study of Guanazole (Nsc 1895) Administered by 48-Hour Infusion in Dogs. Part III.
National Technical Information Service (NTIS)
NSC 1895, Guanazole, Triazole 3,5-diamino-s, which shows strong antitumor activity against L1210 in mic3 when administered by the intraperitoneal route, and moderate activity by the intravenous, oral, intramuscular, and subcutaneous routes, has been studi...
P. E. Palm G. J. Kensler
Task III Preclinical Five Daily Dose Local Vasotoxicity Study of Acodazole (NSC-305884) in Rabbits.
National Technical Information Service (NTIS)
A five daily dose vasotoxicity study was conducted to evaluate the local vasotoxicity resulting from five daily intravenous injections of NSC-305884 in the lateral marginal ear vein of the left rabbit ear. Doses administered, 0.97, 9.72 and 29.16 mg/kg/da...
J. M. Morgan T. B. Barnes G. D. Taylor J. E. Whalan M. D. Kastello
Preclinical development of keliximab, a Primatized� anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies
The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal anti-bodies are a promising class ofbiopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized&) monoclonal antibody with
P J Bugelskil; D J Herzykl; S. Rehm; A. G. Harmsen; E. V. Gore; D. M. Williams; B. E. Maleeff; A. M. Badger; A. Truneh; S R OBrien; R A Macial; P. J. Wier; D. G. Morgan; T. K. Hart
Preclinical toxicology studies with the new dopamine agonist pergolide. Acute, subchronic, and chronic evaluations.
Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treatment of Parkinson's disease, was evaluated for toxicity in acute, subchronic, and chronic studies. Acute toxicity tests using oral, intravenous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in rabbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for ICR mice. The predominant signs of toxicity in the acute studies included hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs were administered pergolide either by gavage or in the diet for up to 1 year. Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-related effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clinical signs in rats and dogs, weight loss or decreased weight gain, emesis in dogs, and inhibition of lysis of corpora lutea with a corresponding increase in the weight of the uterus and ovaries. Pergolide treatment was not associated with any specific target organ toxicity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8192691
Francis, P C; Carlson, K H; Owen, N V; Adams, E R
Preclinical studies of the proteasome inhibitor bortezomib in malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm that is resistant to chemotherapy. Bortezomib is an FDA-approved\\u000a proteasome inhibitor that is currently under clinical investigation in multiple neoplasms but has not been studied extensively\\u000a in MPM. In this report, we determine the biological and molecular response of cultured MPM cells to bortezomib alone and in\\u000a combination with cisplatin or
Gavin J. Gordon; Madhubalan Mani; Gautam Maulik; Lipi Mukhopadhyay; Beow Y. Yeap; Hedy L. Kindler; Ravi Salgia; David J. Sugarbaker; Raphael Bueno
In Situ and Ex Vivo Nasal Models for Preclinical Drug Development Studies
Advances in drug delivery research are to a reasonable extent dependent on the use of innovative experimental models. As a\\u000a result of many experimental, methodological, and ethical limitations associated with the use of the human species, animal\\u000a models are routinely used for drug delivery studies, especially during early stages of drug development. The use of excised\\u000a and cultured human or
Remigius U. Agu; Michael I. Ugwoke
Mentalizing in preclinical Huntington's disease: an fMRI study using cartoon picture stories.
Huntington's disease (HD) is an autosomal dominant degenerative brain disorder that is characterized by motor, cognitive and affective symptoms. Previous research has shown that patients with HD, similar to patients with schizophrenia, are impaired in their ability to appreciate the mental states of others. Functional brain imaging studies have shown that patients with schizophrenia underactivate the neural network involved in mentalizing, and that deviant patterns of brain activation are also present in individuals at high risk of developing a psychotic disorder. Accordingly, the present study sought to examine the brain activation in premanifest mutation carriers for HD. Thirty premanifest mutation carriers (13 males) defined by a positive gene test and absence of unequivocal HD symptoms ("pre-HD") performed a cartoon mentalizing task during functional brain imaging. For comparison, a group of 26 healthy controls took part in the study. BOLD responses revealed that pre-HD subjects activated the mentalizing network comprising prefrontal, temporoparietal and parietal brain regions during task performance. A comparison between pre-HD patients and healthy controls revealed no significant activation differences. Premanifest mutation carriers of HD activated the neural network involved in mentalizing similar to healthy control subjects. This suggests that impaired mentalizing emerges with the clinical manifestation of the disease, but is not necessarily part of the pre-manifest stage. PMID:23179063
Saft, Carsten; Lissek, Silke; Hoffmann, Rainer; Nicolas, Volkmar; Tegenthoff, Martin; Juckel, Georg; Br�ne, Martin
The role of orbitofrontal cortex in drug addiction: a review of preclinical studies
Studies using brain imaging methods have shown that neuronal activity in the orbitofrontal cortex, a brain area thought to promote the ability to control behavior according to likely outcomes or consequences, is altered in drug addicts. These human imaging findings have led to the hypothesis that core features of addiction like compulsive drug use and drug relapse are mediated in part by drug-induced changes in orbitofrontal function. Here, we discuss results from laboratory studies using rats and monkeys on the effect of drug exposure on orbitofrontal-mediated learning tasks and on neuronal structure and activity in orbitofrontal cortex. We also discuss results from studies on the role of the orbitofrontal cortex in drug self-administration and relapse. Our main conclusion is that while there is clear evidence that drug exposure impairs orbitofrontal-dependent learning tasks and alters neuronal activity in orbitofrontal cortex, the precise role these changes play in compulsive drug use and relapse has not yet been established.
Schoenbaum, Geoffrey; Shaham, Yavin
A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats.
Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on the dorsal surface of rats under aseptic conditions. The aqueous lyophilized extract of seabuckthorn leaves, at doses of 0.5%, 1.0%, and 1.5% w/v prepared in propylene glycol, were applied topically twice daily for 7 days. Control animals received the vehicle alone in an identical manner. Wound granulation tissues were excised on eighth day postwounding, and the hydroxyproline, hexosamine, total protein content, and antioxidant levels were determined. Wound surface area was also measured on the eighth day before wound excision to determine wound contraction. Topical application of 1.0% seabuckthorn leaf extract statistically significantly augmented the healing process, as evidenced by increases in the content of hydroxyproline and protein as well as the reduction in wound area when compared with similar effects in response to treatment using povidone-iodine ointment (standard care). The reduced glutathione, vitamin C, superoxide dismutase, catalase, and glutathione peroxidase activities showed significant increases in seabuckthorn leaf extract-treated wounds as compared to controls. The lipid peroxide levels were significantly decreased in leaf extract-treated wounds. The results suggest that aqueous leaf extract of seabuckthorn promotes wound healing, which may be due to increased antioxidant levels in the granulation tissue. PMID:15911921
Gupta, Asheesh; Kumar, Ratan; Pal, Karan; Banerjee, Pratul K; Sawhney, Ramesh C
Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.
High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244
Aboody, Karen S; Najbauer, Joseph; Metz, Marianne Z; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J; Synold, Timothy W; Couture, Larry A; Blanchard, Suzette; Moats, Rex A; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V; Frank, Richard T; Barish, Michael E; Brown, Christine E; Kim, Seung U; Badie, Behnam; Portnow, Jana
Neural Stem Cell-Mediated Enzyme-Prodrug Therapy for Glioma: Preclinical Studies
High-grade gliomas are extremely difficult to treat because they are invasive and therefore are not curable by surgical resection; the toxicity of currently chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles that can target enzyme/prodrug therapy selectively to tumors. We have used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the tumor-localized prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, indicating that these cells are genetically and functionally stable. In vivo biodistribution studies demonstrated that these NSCs retained tumor tropism, even in mice pre-treated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor bearing, and in orthotopic glioma-bearing, immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was approximately one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, non-toxic and effective in mice. These data have led to approval of a first-inhuman study of an allogeneic NSC-mediated enzyme/prodrug targeted cancer therapy in patients with recurrent high-grade glioma.
Aboody, Karen S.; Najbauer, Joseph; Metz, Marianne Z.; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J.; Synold, Timothy W.; Couture, Larry A.; Blanchard, Suzette; Moats, Rex A.; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V.; Frank, Richard T.; Barish, Michael E.; Brown, Christine E.; Kim, Seung U.; Badie, Behnam; Portnow, Jana
Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study.
Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 ?mol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. PMID:24431074
Kathawala, Rishil J; Sodani, Kamlesh; Chen, Kang; Patel, Atish; Abuznait, Alaa H; Anreddy, Nagaraju; Sun, Yue-Li; Kaddoumi, Amal; Ashby, Charles R; Chen, Zhe-Sheng
Hydration with Saline Decreases Toxicity of Mice Injected With Calcitriol in Preclinical Studies
The effectiveness of saline injection in reducing the toxicity profile of calcitriol when coadministered in mice was evaluated. Mortality was used as an end point to study the toxic effects of calcitriol; the relative risk of mortality in mice injected with saline was evaluated from our previously published animal experiments. We discovered that coadministration with 0.25 mL normal saline solution injected intraperitoneally is associated with a lower mortality rate than calcitriol given alone. The estimated relative risk of mortality was 0.0789 (95% confidence interval, 0.0051�1.22; z = 1.82; P = 0.070) when saline is administered with calcitriol compared to calcitriol alone. There was a reduction in serum calcium levels in mice that received saline (11.4 � 0.15 mg/dL) compared to mice that did not receive saline (12.42 � 1.61 mg/dL). Hydration with saline seems to reduce mortality and toxicity in mice receiving calcitriol. Given the decrease in mortality rates, intraperitoneal injections of saline should be considered in studies involving mice receiving injections of calcitriol.
Azari, Amir A; Kanavi, Mozhgan R.; Darjatmoko, Soesiawati R.; Lee, Vivian; Kim, KyungMann; Potter, Heather D.; Albert, Daniel M.
Efficacy of levocabastine in conjunctival provocation studies
Levocabastine is a new topical histamine H1 antagonist. The antihistaminic and antiallergic effects of levocabastine eye drops have been evaluated in eight conjuctival provocation studies (n = 238). Two studies used a histamine challenge; five studies used allergen challenge; one study used both and in one study allergic provocation was with compound 48\\/80. In all but one study, only one
Monique Janssens
Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study
Background We have previously shown that nuclear factor (NF)-?B activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-?B activation and not proliferation specifically inhibits MPE formation by LLC cells. Results Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-?B activation and NF-?B-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-?B activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. Conclusions These studies indicate that proteasome inhibition tailored to block NF-?B activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE.
Preclinical toxicology studies with acyclovir: carcinogenicity bioassays and chronic toxicity tests.
Acyclovir (ACV), a nucleoside analog that is a new herpes-specific antiviral drug, was given by gavage at 50, 150 and 450 mg/kg/day to Sprague Dawley rats and Swiss mice for most of their lifetime to assess chronic toxicity and carcinogenicity. Treatment with ACV did not shorten the lifespan of either rats or mice. In fact, female mice given 150 and 450 mg/kg/day had significantly longer mean durations of survival than control female mice when analyzed by the life table technique. There were no signs of toxicosis produced by chronic exposure to ACV in either the rats or mice, and there was no drug-related increase in neoplasms in either species. Four groups of Beagle dogs were initially given daily oral doses of 15, 45 or 150 mg/kg ACV in a 1 year chronic toxicity study. Dogs treated at 150 mg/kg/day vomited, had diarrhea, consumed less feed and lost weight within 2 weeks. Dogs treated at 45 mg/kg/day also had minimal signs of gastrointestinal toxicosis. These dose levels were then decreased to 60 and 30 mg/kg/day for the rest of the one year test period. With the exception of occasional and inconsistent emesis and diarrhea, the 60 mg/kg/day dose level was well tolerated. Some mid and high dose dogs had sore paws due to erosion of footpads and cracking, splitting and loosening of the nails first becoming evident during the 13th week of the study.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6662300
Tucker, W E; Krasny, H C; de Miranda, P; Goldenthal, E I; Elion, G B; Hajian, G; Szczech, G M
[Developing and standardizing experimental protocols using human iPS-derived cells to predict adverse drug reactions in pre-clinical safety studies].
In this study, we have standardized experimental protocols to evaluate the possibility of using cells differentiated from human induced pluripotent stem cells (hiPSCs) in the pre-clinical studies for the drug approval processes. Cells differentiated from hiPSC, especially cardiomyocytes, neurons and hepatocytes, are expected to be used as new pharmacological and toxicological assay tools. Current preclinical test methods have limitations for predicting clinical adverse drug reactions. This is because of the so-called 'problem of species difference'. Drug-induced arrhythmia, cognitive impairment and hepatotoxicity which can't be predicted in pre-clinical studies are major causes of the high rate attrition of new-drug candidates in clinical studies and of withdrawal of products from the market. The development of new pre-clinical test methods using cells differentiated from hiPSCs would resolve these problems, in addition to solving the issue of "the replacement, refinement and reduction (3Rs)" of animal experiments. From 2010 to 2011, we surveyed companies belonging to the Japan Pharmaceutical Manufacturers Association (JPMA) and academic researchers about the usage of differentiated cells in their laboratories. We found that studies were performed using differentiated cells from different cell lines of hiPSC with laboratory-specific differentiation methods. The cells were cultured in various conditions and their activities were measured using different methods. This resulted in a variety of pharmacological responses of the cells. It is therefore impossible to compare reproducibility and ensure reliability of experiments using these cells. To utilize the cells in the drug approval processes, we need robust, standardized test methods to accurately reproduce these methods in all laboratories. We will then be able to compare and analyze the obtained results. Based on the survey, the Ministry of Health, Labor and Welfare funded our study. In our study, we standardize pharmacological methods among several laboratories, including our laboratory, to develop robust tests, using the same lot of cells, the same culture conditions, reference compounds, experimental protocols, and analysis methodology. In conclusion, to standardize robust test methods, we need a consistent supply of high-quality differentiated cells. Further, indexes to quantify the quality of the differentiated cells will be needed for their effective usage in the pre-clinical safety studies. PMID:24340667
Sekino, Yuko; Sato, Kaoru; Kanda, Yasunari; Ishida, Seiichi
Novel transdermal delivery of Timolol maleate using sugar esters: preclinical and clinical studies.
The feasibility of matrix controlled transdermal patch based on sugar fatty acid ester (SE) as penetration and absorption enhancer containing Timolol maleate (TM) was investigated. The influence of fatty acid type, chain length and hydrophile-lipophile balance (HLB) on the in vitro drug release as well as its permeation across hairless rat skin were studied and compared aiming to select a patch formula for clinical performance. Skin irritation induced by SE patch was evaluated by visual scoring, color reflectance measurements and non-invasive transepidermal water loss (TEWL) technique. The results indicated that among different SEs tried, laurate SE with shorter fatty acid chain length and higher HLB value significantly increased the amount of TM liberated from the patch (99+/-2.1%) and its permeation across rat skin (86+/-4.3%). The total drug permeation and flux values were approximately 5-fold greater compared to SE free patch. The extent of absorption of TM-SE patch expressed by AUC was 64% larger as compared to the oral solution with steady plasma concentration over 18 h and relative bioavailability (F(rel)) of 163%. The developed patch was well tolerated by all the subjects with only moderate skin irritation, which was recovered in 24h after patch removal. The results are very encouraging and offer an alternative approach to maintain higher, prolonged and controlled blood level profile of the drug over 18-24h. PMID:19126429
El-Laithy, Hanan M
GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies.
There is a considerable body of literature demonstrating that adolescence is a unique age period, which includes rapid and dramatic maturation of behavioral, cognitive, hormonal and neurobiological systems. Most notably, adolescence is also a period of unique responsiveness to alcohol effects, with both hyposensitivity and hypersensitivity observed to the various effects of alcohol. Multiple neurotransmitter systems are undergoing fine-tuning during this critical period of brain development, including those that contribute to the rewarding effects of drugs of abuse. The role of developmental maturation of the ?-amino-butyric acid (GABA) system, however, has received less attention in contributing to age-specific alcohol sensitivities. This review integrates GABA findings from human magnetic resonance spectroscopy studies as they may translate to understanding adolescent-specific responsiveness to alcohol effects. Better understanding of the vulnerability of the GABA system both during adolescent development, and in psychiatric conditions that include alcohol dependence, could point to a putative mechanism, boosting brain GABA, that may have increased effectiveness for treating alcohol use disorders. PMID:24631274
Silveri, Marisa M
Receptor-selective mutants of tumour necrosis factor in the therapy of cancer: preclinical studies.
The use of TNF-mutants that are selective agonists of the TNF-R55 is one strategy that is being explored to broaden the therapeutic margin of TNF. Several problems still have to be overcome before they can be used in clinical trials. Regarding the sensitizing effect of some infections and some tumours, we identified IFN-gamma as a mediator in BCG- but not in tumour-induced sensitization. In both models, the vessel wall is most probably the key tissue as alpha-LFA-1 antibodies could protect against lethality. Studies in primates showed that an unexpected feature, namely, the longer half-life of such mutants, might interfere with this strategy. Recent observations also indicate that the mechanism of tolerance-induction, another way to separate antitumour and toxic effects of TNF, might reside in the functional ablation of the TNF-R75. Using IL-60/0 knockout mice, we could not find any causal role for IL-6 in TNF-mediated lethality, this in contrast to results obtained previously with neutralizing antibodies. Finally, we identified the acute phase protein alpha 1-acid glycoprotein as a protein with protective properties towards TNF-induced lethality and liver damage. PMID:7895324
Brouckaert, P; Ameloot, P; Cauwels, A; Everaerdt, B; Libert, C; Takahashi, N; Van Molle, W; Fiers, W
Silver nanoparticle/chitosan oligosaccharide/poly(vinyl alcohol) nanofibers as wound dressings: a preclinical study
In this study, a mixture of poly(vinyl alcohol) (PVA) and chitosan oligosaccharides (COS) was electrospun with silver nanoparticles (AgNPs) to produce fibrous mats for use in wound healing. The AgNPs were reduced by COS prior to electrospinning or Ag+ was reduced via ultraviolet irradiation in nanofibers. The morphologies of the PVA/COS/AgNO3 and PVA/COS-AgNP nanofibers were analyzed by scanning electron microscopy. Formation of the AgNPs was investigated by field emission transmission electron microscopy, ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction. We also evaluated the biocompatibility of the nanofibers, particularly their cytotoxicity to human skin fibroblasts and potential to cause primary skin irritation. The in vitro antibacterial activity and in vivo wound healing capacity of the nanofibers were also investigated. The nanofibers had a smooth surface with an average diameter of 130�192 nm. The diameters of the AgNPs were in the range of 15�22 nm. The nanofibers significantly inhibited growth of Escherichia coli and Staphylococcus aureus bacteria. PVA/COS-AgNP nanofibers accelerated the rate of wound healing over that of the control (gauze). The results of our in vitro and in vivo animal experiments suggest that PVA/COS-AgNP nanofibers should be of greater interest than PVA/COS/AgNO3 nanofibers for clinical use as a bioactive wound dressing.
Li, Chenwen; Fu, Ruoqiu; Yu, Caiping; Li, Zhuoheng; Guan, Haiyan; Hu, Daqiang; Zhao, Dehua; Lu, Laichun
Preclinical studies of vascular acting photosensitizer bacteriopheophorbide for the treatment of prostate cancer
NASA Astrophysics Data System (ADS)
Photodynamic therapy (PDT) mediated with vascular acting photosensitizer pd-bacteriopheophorbide (Tookad), is investigated as an alternative modality for the total ablation of prostate cancer. In vivo normal canine prostate is used as the animal model. Interstitial PDT was performed by irradiating the surgically exposed prostates with a diode laser (763 nm, 150 mW/cm) to activate the IV infused photosensitizer drug. The prostate and its adjacent tissues were harvested and subjected to histopathological examination. At one-week post PDT, the animals recovered well with little or no urethral complications. Prostatic urethra and prostate adjacent tissues (bladder and underlying colon) were well preserved. PDT induced prostate lesions were characterized by marked hemorrhagic necrosis. Prostate lesions could be detected by MRI scan as early as 48 h post PDT. Maximum lesion size of 1.5 cm3 and 2.9 cm3 could be achieved at 50 J/cm and 100 J/cm, respectively, with interstitial treatment using a single 1-cm diffuser fiber, suggesting the Tookad-PDT is very effective in ablating prostatic tissue. Pharmacokinetic studies show that the photosensitizer is cleared rapidly from the circulation. In conclusion, the novel photosensitizer Tookad mediated PDT may provide an effective alternative to treat localized prostate cancer.
Hetzel, Fred W.; Chen, Qun; Luck, David; Beckers, Jill; Huang, Zheng
Preclinical episodes of orofacial pain symptoms and their association with healthcare behaviors in the OPPERA prospective cohort study.
The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial- and recurrent-symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 people aged 18-44 years with lifetime absence of TMD when enrolled completed 25,103 quarterly (three-monthly) questionnaires during amedian 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance and analgesic usage and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with healthcare and analgesic use. One third of people developed TMD symptoms and for one quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at anannual rate of 18.8 episodes per 100 people. The annual rate more than doubled for first-recurrence and doubled again for second-or-subsequent recurrence such that, one year after first recurrence, 71% of people experienced second recurrence. The overall rate increased with age and was greater in African-Americans and lower in Asians relative to Whites. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache and body pain were associated with increases of ~10% in probability of analgesic usage and healthcare attendance. Yet, even when TMD, headache and body pain occurred concurrently, 27% of people neither attended healthcare nor used analgesics.
Slade, Gary D.; Sanders, Anne E.; Bair, Eric; Brownstein, Naomi; Dampier, Dawn; Knott, Charles; Fillingim, Roger; Maixner, William O.; Smith, Shad; Greenspan, Joel; Dubner, Ron; Ohrbach, Richard
A transplantable TH-MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma.
Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH-MYCN-derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild-type and Rag1(-/-) mice, showing an important role for NK cells in the natural anti-NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti-GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH-MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients. PMID:24038106
Kroesen, Michiel; Nierkens, Stefan; Ansems, Marleen; Wassink, Melissa; Orentas, Rimas J; Boon, Louis; den Brok, Martijn H; Hoogerbrugge, Peter M; Adema, Gosse J
Systematic reviews and meta-analyses of preclinical studies: publication bias in laboratory animal experiments.
In 2006, Peters et al. identified 86 systematic reviews (SRs) of laboratory animal experiments (LAEs). They found 46 LAE meta-analyses (MAs), often of poor quality. Six of these 46 MAs tried to assess publication bias. Publication bias is the phenomenon of an experiment's results determining its likelihood of publication, often over-representing positive findings. As such, publication bias is the Achilles heel of any SR. Since researchers increasingly become aware of the fact that SRs directly support the 'three Rs', we expect the number of SRs of LAEs will sharply increase. Therefore, it is useful to see how publication bias is dealt with. Our objective was to identify all SRs and MAs of LAEs where the purpose was to inform human health published between July 2005 and 2010 with special attention to MAs' quality features and publication bias. We systematically searched Medline, Embase, Toxline and ScienceDirect from July 2005 to 2010, updating Peters' review. LAEs not directly informing human health or concerning fundamental biology were excluded. We found 2780 references of which 163 met the inclusion criteria: 158 SRs, of which 30 performed an MA, and five MAs without an SR. The number of SRs roughly doubled every three years since 1997. The number of MAs roughly doubled every five years since 1999. Compared with before July 2005, more MAs were preceded by SR and reported on (quality) features of included studies and heterogeneity. A statistically significant proportion of MAs considered publication bias (26/35) and tried to formally assess it (21/35). PMID:21737463
Korevaar, D A; Hooft, L; ter Riet, G
Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study
Objectives To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). Design Randomised study with an experimental model of CPB (3?h CPB with 2?h of cardioplegic arrest). Twelve 15?kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6?h. Intervention rIPC was induced by four 5?min cycles of lower limb ischaemia before CPB. Main outcome measures Troponin I, glial protein S?100B, lactate concentrations, load?independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6?h after CPB. Results Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve ?57.3 (SEM 7.3) v 89.0 (11.6)?ng�h/ml, p??=??0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p??=??0.04). S?100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p??=??0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p??=??0.02). Subsequently, peak inspiratory pressure was lower (p??=??0.001). Conclusion rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.
Kharbanda, R K; Li, J; Konstantinov, I E; Cheung, M M H; White, P A; Frndova, H; Stokoe, J; Cox, P; Vogel, M; Van Arsdell, G; MacAllister, R; Redington, A N
Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders
Lithium has been used clinically to treat bipolar disorder for over half a century, and remains a fundamental pharmacological therapy for patients with this illness. Although lithium�s therapeutic mechanisms are not fully understood, substantial in vitro and in vivo evidence suggests that it has neuroprotective/neurotrophic properties against various insults, and considerable clinical potential for the treatment of several neurodegenerative conditions. Evidence from pharmacological and gene manipulation studies support the notion that glycogen synthase kinase-3 inhibition and induction of brain-derived neurotrophic factor-mediated signaling are lithium�s main mechanisms of action, leading to enhanced cell survival pathways and alteration of a wide variety of downstream effectors. By inhibiting N-methyl-D-aspartate receptor-mediated calcium influx, lithium also contributes to calcium homeostasis and suppresses calcium-dependent activation of pro-apoptotic signaling pathways. In addition, lithium decreases inositol 1,4,5-trisphosphate by inhibiting phosphoinositol phosphatases, a process recently identified as a novel mechanism for inducing autophagy. Through these mechanisms, therapeutic doses of lithium have been demonstrated to defend neuronal cells against diverse forms of death insults and to improve behavioral as well as cognitive deficits in various animal models of neurodegenerative diseases, including stroke, amyotrophic lateral sclerosis, fragile X syndrome, as well as Huntington�s, Alzheimer�s, and Parkinson�s diseases, among others. Several clinical trials are also underway to assess the therapeutic effects of lithium for treating these disorders. This article reviews the most recent findings regarding the potential targets involved in lithium�s neuroprotective effects, and the implication of these findings for the treatment of a variety of diseases.
Chiu, Chi-Tso; Chuang, De-Maw
Photoacoustic spectroscopy in the monitoring of breast tumor development: a pre-clinical study
NASA Astrophysics Data System (ADS)
Breast cancer is the most frequently diagnosed cancer type and its detection at an early stage can reduce the mortality rate substantially. With the aim to detect breast cancer early, by studying tumor progression in nude mice, a pulsed laser induced photoacoustic spectroscopy set up has been designed and developed. MCF-7 cells xenografts were developed using six to eight weeks old female nude mice and tumor tissues were extracted on different days (10th, 15th and 20th Day) post injection and the corresponding photoacoustic spectra were recorded at 281nm excitation. A total of 144 time domain spectra were recorded from 36 animals belonging to the three time points (10th, 15th and 20th day post injection) and converted into frequency domains by Fast Fourier Transform (FFT) tools of the MATLAB algorithms and analyzed. The frequency patterns of the tumor masses on 10th, 15th and 20th day of tumor development showed a gradual increase in intensity at certain frequencies, 5.93 x103 Hz, 15.9 x103 Hz, 29.69 x103 Hz and 32.5 x103 Hz in the FFT patterns indicating that these frequencies were more sensitive towards tumor development. Further analysis of the data yielded a clear variation in the spectral parameters with progression of the disease suggesting that the technique may be suitable for early detection of the disease. Thus, we expect that the developed setup may be useful in assessing the different phases of tumor development which may have clinical implications.
Priya, Mallika; Rao, Bola Sadashiva Satish; Ray, Satadru; Mahato, Krishna Kishore
Paromomycin-loaded albumin microspheres: efficacy and stability studies.
In the present work, paromomycin-loaded albumin microspheres (PM-MS) have been formulated for passive targeting of paromomycin (PM) to macrophages, for the treatment of visceral leishmaniasis (VL). PM-MS were prepared by spray-drying method with a mean particle size of???3?�m. Thermal and chemical cross-linking methods were used for controlling drug release from the prepared microspheres (MS). PM-MS were then tested for efficacy and stability studies. In efficacy study, in vitro promastigote assay was carried out to assess the susceptibility of promastigote to PM in the concentration range of 5.0-150?�g/ml; cytotoxicity assay was performed to determine possible toxicity of PM for the host cells (peritoneal macrophages) and intracellular amastigote assay was carried out to determine the efficacy of free PM (PM solution) and encapsulated PM (PM-MS). Results obtained indicated a significant increase in efficacy of PM-MS in comparison to PM solution at equivalent concentration. Subsequently, stability studies of prepared formulation was carried out at various temperature and humidity conditions, these studies provided stability of formulation at all tested conditions including accelerated conditions. Thus, it can be concluded that present work provides an optimized formulation with stability and enhanced efficacy. PMID:22514145
Khan, Wahid; Kumar, Rajendra; Singh, Sukhvinder; Arora, Sunil Kumar; Kumar, Neeraj
A Study of Cardiac Monitor Safety and Efficacy.
National Technical Information Service (NTIS)
The objective of this study was to investigate the safety and efficacy of cardiac monitors and to identify those parameters which should be included in a standard. The primary focus of the study was on ECG monitors with their associated QRS detectors, hea...
A. A. Schoenberg
No Association of nineteen COX-2 gene variants to preclinical markers of atherosclerosis The Cardiovascular Risk in Young Finns Study
Backgroud The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults. Methods SNPs for association analysis were collected from the COX-2 gene and 5?kb up- and downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias. Results Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p?=?0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p?=?0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p?=?0.046) and maximal carotid intima-media thickness (p?=?0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found. Conclusions Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood.
Red diode laser for photodynamic therapy: a small animal efficacy study
NASA Astrophysics Data System (ADS)
Lasers have traditionally been the preferred light source for activation of the photosensitizing agents used in photodynamic therapy (PDT). Their monochromaticity, high power, and the ability to efficiently couple that power into optical fibers have dictated their use. Dye lasers, metal vapor lasers, or ion gas lasers have been used in the past as the excitation source for PDT, largely because they provided the only available alternatives. These laser systems are very large and complex, and are very expensive to operate. The introduction of high power visible red laser diodes have provided a cost effective alternative to existing lasers for use in PDT. This paper will describe the features of a prototype preclinical red laser diode source for photodynamic therapy, and will present the results of an animal study conducted with this device. The study, using the photosensitizer SnET2, compared the efficacy of PDT performed with the diode laser system with the results obtained from a traditional dye laser system. Future plans for a clinical version of the system will also be discussed.
Lytle, A. Charles; Doiron, Daniel R.; Selman, Steven H.
Studies on the Efficacy of Child Psychoanalysis.
ERIC Educational Resources Information Center
Summarizes three studies on psychoanalytic psychotherapeutic treatment of diabetic children and adolescents with grossly abnormal blood glucose profiles necessitating repeated admissions to hospital. Used time series analysis, comparative analysis, and single-case experimental design to illustrate effectiveness of psychotherapeutic intervention�
Fonagy, Peter; Moran, George S.
The Efficacy of Math Coaching: An Evaluative Case Study
ERIC Educational Resources Information Center
There is a lack of implementation of instructional strategies to assist middle school teachers in improving mathematics education for their students. Coaching is one solution to this problem, but its impact on student achievement is unclear. This case study evaluated the relationship between coaching and teacher efficacy and the impact of these�
Dobbins, C. Neelie
Year 3 ASK/FOSS Efficacy Study. CRESST Report 782
ERIC Educational Resources Information Center
This efficacy study was designed to examine the traditional FOSS curriculum (Delta Publishing, Full Option Science System/FOSS, magnetism and electricity, structures of life, and water modules, 2005), and the new ASK/FOSS curriculum (magnetism and electricity, structures of life, and water modules, 2005), a revised version of the original FOSS�
Osmundson, Ellen; Dai, Yunyun; Herman, Joan
Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies.
The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity. PMID:10918514
Bugelski, P J; Herzyk, D J; Rehm, S; Harmsen, A G; Gore, E V; Williams, D M; Maleeff, B E; Badger, A M; Truneh, A; O'Brien, S R; Macia, R A; Wier, P J; Morgan, D G; Hart, T K
Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies
While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics.
Barone, Linda R.; Boyer, Scott; Damewood, James R.; Fikes, James; Ciaccio, Paul J.
Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies.
While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636
Barone, Linda R; Boyer, Scott; Damewood, James R; Fikes, James; Ciaccio, Paul J
Preclinical stem cell therapy in Chagas Disease: Perspectives for future research
Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease.
de Carvalho, Katherine Athayde Teixeira; Abdelwahid, Eltyeb; Ferreira, Reginaldo Justino; Irioda, Ana Carolina; Guarita-Souza, Luiz Cesar
Pre-clinical investigations of physical activity and cancer: a brief review and analysis.
There is substantial evidence that physical inactivity is an important risk factor for a number of chronic diseases, including cancer. As consequences of physical inactivity on cancer risk and treatment efficacy surface, there is increasing interest in determining the benefits of a physically active lifestyle and of exercise as a component of that lifestyle. In the cancer research field, the spectrum of research activities includes pre-clinical studies and clinical and population-based interventions; of these approaches, pre-clinical experiments combining animal cancer models with physical activity (PA) have been underutilized. Clarifying the amounts and types of PA that inhibit carcinogenesis is best done in animals, where mechanistic inquiry and biomarker evaluation of the protected state can be carried out in a more favorable environment than in clinical populations. The expertise required to integrate models for investigating PA with those used to study carcinogenesis is not trivial, but mastery of these models is likely to result in highly translatable pre-clinical findings that advance this important field of investigation. This brief review and analysis is intended to focus attention on the issues and opportunities associated with the pre-clinical investigations of PA and cancer. PMID:16885198
Thompson, Henry J
Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates.
A nonhuman-primate model of human immunodeficiency virus type 1 (HIV-1) infection that more closely emulates human heterosexual transmission by use of multiple exposures to low doses of virus is critical to better evaluate intervention strategies that include microbicides or vaccines. In this report, we describe such a system that uses female pig-tailed macaques exposed vaginally to a CCR5-using simian-human immunodeficiency virus (SHIV(SF162P3)) at weekly intervals. Results of dose-titration experiments indicated that 3 once-weekly exposures to 10 tissue culture infectious doses of SHIV(SF162P3) resulted in consistent transmission of virus and establishment of systemic infection. The efficacy of cellulose acetate phthalate (CAP) as a vaginal microbicide was evaluated by applying it to the vaginal vault of macaques (n = 4) 15 min before each weekly exposure to SHIV(SF162P3). One conclusion that can be drawn from the data derived from multiple exposures to virus is that CAP prevented infection in 12 of 13 possible chances for infection, over the course of 39 total exposures. Our findings provide a basis to refine monkey models for transmission of HIV-1, which may be relevant to preclinical evaluation for therapeutic interventions. PMID:15609225
Otten, Ron A; Adams, Debra R; Kim, Caryn N; Jackson, Eddie; Pullium, Jennifer K; Lee, Kemba; Grohskopf, Lisa A; Monsour, Michael; Butera, Sal; Folks, Thomas M
Genetic strategies to study TDP-43 in rodents and to develop preclinical therapeutics for amyotrophic lateral sclerosis
The neuropathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) and a class of frontotemporal lobar degeneration is ubiquitinated cytoplasmic aggregates composed of transactive response DNA binding protein 43 kDa (TDP-43). Genetic manipulation of TDP-43 in animal models has been used to study the protein's role in pathogenesis. Transgenic rodents for TDP-43 have recapitulated key aspects of ALS such as paralysis, loss of spinal motor neurons and muscle atrophy. Viral vectors are an alternate approach to express pathological proteins in animals. Use of the recombinant adeno-associated virus vector serotype 9 has permitted widespread transgene expression throughout the central nervous system after intravenous administration. Expressing TDP-43 in rats with this method produced a phenotype that was consistent with and similar to TDP-43 transgenic lines. Increased levels of TDP-43 in the nucleus are toxic to neurons and sufficient to produce ALS-like symptoms. Animal models based on TDP-43 will address the relationships between TDP-43 expression levels, pathology, neuronal loss, muscle atrophy, motor function and causative mechanisms of disease. New targets that modify TDP-43 function, or targets from previous ALS models and other models of spinal cord diseases, could be tested for efficacy in the recent rodent models of ALS based on TDP-43. The vector approach could be an important therapeutic channel because the entire spinal cord can be affected from a one-time peripheral administration.
Wang, David B.; Gitcho, Michael A.; Kraemer, Brian C.; Klein, Ronald L.
In vitro Immunogenicity Risk-assessment of Therapeutic Proteins in Preclinical Setting
Immunogenicity against therapeutic proteins is a clinical problem in the successful treatment of many diseases and as such, immunogenicity risk assessment in preclinical setting would be useful to improve safety and efficacy of protein based therapeutics in the product development stages. Here, we attempted a mechanism based in vitro studies as screening tool to capture clinically observed antibody based immune response against two representative therapeutic proteins; recombinant human Erythropoietin-alpha (rHuEPO) and recombinant Factor VIII (rFVIII). Flow cytometry was used to determine the maturation level of dendritic cells (DCs), a primary initiator of T-cell responses. Studies to capture T-lymphocyte proliferation upon challenge with free rFVIII were performed and secretion of immunomodulatory cytokines was analyzed by ELISA assay. These in vitro techniques could be used as risk assessment tool to determine the immunogenic potential of formulations of recombinant proteins in preclinical setting.
Gaitonde, Puneet; Balu-Iyer, Sathy V
Premarket Safety and Efficacy Studies for ADHD Medications in Children
Background Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing. Methods We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug�s clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials. Results A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after <100 participants were studied and 14 (70%) after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied <4 weeks and 10 (77%) after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed. Conclusions Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved.
Bourgeois, Florence T.; Kim, Jeong Min; Mandl, Kenneth D.
Preclinical Applications of Quantitative Imaging Cytometry to Support Drug Discovery
Preclinical drug development is actively involved in testing compounds to find cures or to manage the effects of disease, such as diabetes. Animal models, such as the Zucker diabetic fatty (ZDF) rat, are used to measure efficacy of candidate drugs. This animal model was selected because of its clinical and pathological similarities to diabetic human patients. A method using immunofluorescence
David L. Krull; Richard A. Peterson
Naturally occurring disk herniation in dogs: an opportunity for pre-clinical spinal cord injury research.
Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation. PMID:21438715
Levine, Jonathan M; Levine, Gwendolyn J; Porter, Brian F; Topp, Kimberly; Noble-Haeusslein, Linda J
Naturally Occurring Disk Herniation in Dogs: An Opportunity for Pre-Clinical Spinal Cord Injury Research
Abstract Traumatic spinal cord injuries represent a significant source of morbidity in humans. Despite decades of research using experimental models of spinal cord injury to identify candidate therapeutics, there has been only limited progress toward translating beneficial findings to human spinal cord injury. Thoracolumbar intervertebral disk herniation is a naturally occurring disease that affects dogs and results in compressive/contusive spinal cord injury. Here we discuss aspects of this disease that are analogous to human spinal cord injury, including injury mechanisms, pathology, and metrics for determining outcomes. We address both the strengths and weaknesses of conducting pre-clinical research in these dogs, and include a review of studies that have utilized these animals to assess efficacy of candidate therapeutics. Finally, we consider a two-species approach to pre-clinical data acquisition, beginning with a reproducible model of spinal cord injury in the rodent as a tool for discovery with validation in pet dogs with intervertebral disk herniation.
Levine, Gwendolyn J.; Porter, Brian F.; Topp, Kimberly; Noble-Haeusslein, Linda J.
System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test
Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, ?2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing.
Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari
Porcine adipose-derived stem cells from buccal fat pad and subcutaneous adipose tissue for future preclinical studies in oral surgery
Introduction Adipose-derived stem cells (ASCs) are progenitor cells used in bone tissue engineering and regenerative medicine. Despite subcutaneous adipose tissue being more abundant, the buccal fat pad (BFP) is easily accessible for dentists and maxillofacial surgeons. For this reason, considering the need for preclinical study and the swine as an optimal animal model in tissue engineering applications, we compared the features of porcine ASCs (pASCs) from both tissue-harvesting sites. Methods ASCs were isolated from interscapular subcutaneous adipose tissue (ScI) and buccal fat pads of six swine. Cells were characterized for their stemness and multipotent features. Moreover, their osteogenic ability when cultured on titanium disks and silicon carbide-plasma-enhanced chemical vapor-deposition fragments, and their growth in the presence of autologous and heterologous serum were also assessed. Results Independent of the harvesting site, no differences in proliferation, viability, and clonogenicity were observed among all the pASC populations. Furthermore, when induced toward osteogenic differentiation, both ScI- and BFP-pASCs showed an increase of collagen and calcified extracellular matrix (ECM) production, alkaline phosphatase activity, and osteonectin expression, indicating their ability to differentiate toward osteoblast-like cells. In addition, they differentiated toward adipocyte-like cells, and chondrogenic induced pASCs were able to increase glycosaminoglycans (GAGs) production over time. When cells were osteoinduced on synthetic biomaterials, they significantly increased the amount of calcified ECM compared with control cells; moreover, titanium showed the osteoinductive effect on pASCs, also without chemical stimuli. Finally, these cells grew nicely in 10% FBS, and no benefits were produced by substitution with swine serum. Conclusions Swine buccal fat pad contains progenitor cells with mesenchymal features, and they also osteo-differentiate nicely in association with synthetic supports. We suggest that porcine BFP-ASCs may be applied in preclinical studies of periodontal and bone-defect regeneration.
Learning and confirming with preclinical studies: modeling and simulation in the discovery of GDC-0917, an inhibitor of apoptosis proteins antagonist.
The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process. GDC-0917 [(S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propanamido)acetyl)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)pyrrolidine-2-carboxamide] is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitro-in vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED50 and ED90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process. PMID:24041744
Wong, Harvey; Gould, Stephen E; Budha, Nageshwar; Darbonne, Walter C; Kadel, Edward E; La, Hank; Alicke, Bruno; Halladay, Jason S; Erickson, Rebecca; Portera, Chia; Tolcher, Anthony W; Infante, Jeffery R; Mamounas, Michael; Flygare, John A; Hop, Cornelis E C A; Fairbrother, Wayne J
Teacher Self-Efficacy and Teacher Burnout: A Study of Relations
ERIC Educational Resources Information Center
The purpose of this study was partly to test the factor structure of a recently developed Norwegian scale for measuring teacher self-efficacy and partly to explore relations between teachers' perception of the school context, teacher self-efficacy, collective teacher efficacy, teacher burnout, teacher job satisfaction, and teachers' beliefs that�
Skaalvik, Einar M.; Skaalvik, Sidsel
Comparative Effectiveness of 3-Dimensional vs 2-Dimensional and High-Definition vs Standard-Definition Neuroendoscopy: A Preclinical Randomized Crossover Study
BACKGROUND: Although the potential benefits of 3-dimensional (3-D) vs 2-dimensional (2-D) and high-definition (HD) vs standard-definition (SD) endoscopic visualization have long been recognized in other surgical fields, such endoscopes are generally considered too large and bulky for use within the brain. The recent development of 3-D and HD neuroendoscopes may therefore herald improved depth perception, better appreciation of anatomic details, and improved overall surgical performance. OBJECTIVE: To compare simultaneously the effectiveness of 3-D vs 2-D and HD vs SD neuroendoscopy. METHODS: Ten novice neuroendoscopic surgeons were recruited from a university hospital. A preclinical randomized crossover study design was adopted to compare 3-D vs 2-D and HD vs SD neuroendoscopy. The primary outcomes were time to task completion and accuracy. The secondary outcomes were perceived task workload using the NASA (National Aeronautics and Space Administration) Task Load Index and subjective impressions of the endoscopes using a 5-point Likert scale. RESULTS: Time to task completion was significantly shorter when using the 3-D vs the 2-D neuroendoscopy (P = .001), and accuracy of probe placement was significantly greater when using the HD vs the SD neuroendoscopy (P = .009). We found that 3-D endoscopy significantly improved perceived depth perception (P < .001), HD endoscopy significantly improved perceived image quality (P < .001), and both improved participants� overall impression (P < .001). CONCLUSION: Three-dimensional neuroendoscopy and HD neuroendoscopy have differing but complementary effects on surgical performance, suggesting that neither alone can completely compensate for the lack of the other. There is therefore strong preclinical evidence to justify 3-D HD neuroendoscopy. ABBREVIATIONS: HD, high definition SD, standard definition
Hughes-Hallett, Archie; Cundy, Thomas P.; Di Marco, Aimee; Pratt, Philip; Nandi, Dipankar; Darzi, Ara; Yang, Guang-Zhong
Characterization of Novel PI3K? Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies
SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T�B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase ? (PI3K?) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3K? inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP�) without detecting signs of undesired toxicity. In an IFN?-accelerated mouse SLE model, our PI3K? inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3K? inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3K? inhibitors in SLE and lupus nephritis.
Haselmayer, Philipp; Camps, Montserrat; Muzerelle, Mathilde; El Bawab, Samer; Waltzinger, Caroline; Bruns, Lisa; Abla, Nada; Polokoff, Mark A.; Jond-Necand, Carole; Gaudet, Marilene; Benoit, Audrey; Bertschy Meier, Dominique; Martin, Catherine; Gretener, Denise; Lombardi, Maria Stella; Grenningloh, Roland; Ladel, Christoph; Petersen, J?rgen S?berg; Gaillard, Pascale; Ji, Hong
Preclinical cardiorenal interrelationships in essential hypertension.
A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart-kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin-angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation. PMID:23946723
Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos
Preclinical Cardiorenal Interrelationships in Essential Hypertension
A diseased heart causes numerous adverse effects on kidney function, and vice versa renal disease can significantly impair cardiac function. Beyond these heart-kidney interrelationships at the clinical level, a reciprocal association has been suggested to exist even in the early stages of those organs' dysfunction. The aim of the present review is to provide evidence of the presence of a preclinical cardiorenal syndrome in the particular setting of essential hypertension, focusing on the subsequent hypertensive sequelae on heart and kidneys. In particular, a plethora of studies have demonstrated not only the predictive role of kidney damage, as expressed by either decreased glomerular filtration or increased urine albumin excretion, for adverse left ventricular functional and structural adaptations but also preclinical heart disease, i.e. left ventricular hypertrophy that is associated with deterioration of renal function. Notably, these reciprocal interactions seem to exist even at the level of microcirculation, since both coronary flow reserve and renal hemodynamics are strongly related with clinical and preclinical renal and cardiac damage, respectively. In this preclinical setting, common pathophysiological denominators, including the increased hemodynamic load, sympathetic and renin-angiotensin system overactivity, increased subclinical inflammatory reaction, and endothelial dysfunction, account not only for the reported associations between overt cardiac and renal damage but also for the parallel changes that occur in coronary and renal microcirculation.
Tsioufis, Costas; Tsiachris, Dimitrios; Kasiakogias, Alexandros; Dimitriadis, Kyriakos; Petras, Dimitris; Goumenos, Dimitris; Siamopoulos, Konstantinos; Stefanadis, Christodoulos
Paclitaxel-hyaluronic nanoconjugates prolong overall survival in a preclinical brain metastases of breast cancer model.
Brain (central nervous system; CNS) metastases pose a life-threatening problem for women with advanced metastatic breast cancer. It has recently been shown that the vasculature within preclinical brain metastasis model markedly restricts paclitaxel delivery in approximately 90% of CNS lesions. Therefore to improve efficacy, we have developed an ultra-small hyaluronic acid (HA) paclitaxel nanoconjugate (?5 kDa) that can passively diffuse across the leaky blood-tumor barrier and then be taken up into cancer cells (MDA-MB-231Br) via CD44 receptor-mediated endocytocis. Using CD44 receptor-mediated endocytosis as an uptake mechanism, HA-paclitaxel was able to bypass p-glycoprotein-mediated efflux on the surface of the cancer cells. In vitro cytoxicity of the conjugate and free paclitaxel were similar in that they (i) both caused cell-cycle arrest in the G2-M phase, (ii) showed similar degrees of apoptosis induction (cleaved caspase), and (iii) had similar IC50 values when compared with paclitaxel in MTT assay. A preclinical model of brain metastases of breast cancer using intracardiac injections of Luc-2 transfected MDA-MB-231Br cells was used to evaluate in vivo efficacy of the nanoconjugate. The animals administered with HA-paclitaxel nanoconjugate had significantly longer overall survival compared with the control and the paclitaxel-treated group (P < 0.05). This study suggests that the small molecular weight HA-paclitaxel nanoconjugates can improve standard chemotherapeutic drug efficacy in a preclinical model of brain metastases of breast cancer. PMID:24002934
Mittapalli, Rajendar K; Liu, Xinli; Adkins, Chris E; Nounou, Mohamed I; Bohn, Kaci A; Terrell, Tori B; Qhattal, Hussaini S; Geldenhuys, Werner J; Palmieri, Diane; Steeg, Patricia S; Smith, Quentin R; Lockman, Paul R
Non-invasive molecular imaging for preclinical cancer therapeutic development
Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development.
O'Farrell, AC; Shnyder, SD; Marston, G; Coletta, PL; Gill, JH
Neighborhoods and violent crime: a multilevel study of collective efficacy.
It is hypothesized that collective efficacy, defined as social cohesion among neighbors combined with their willingness to intervene on behalf of the common good, is linked to reduced violence. This hypothesis was tested on a 1995 survey of 8782 residents of 343 neighborhoods in Chicago, Illinois. Multilevel analyses showed that a measure of collective efficacy yields a high between-neighborhood reliability and is negatively associated with variations in violence, when individual-level characteristics, measurement error, and prior violence are controlled. Associations of concentrated disadvantage and residential instability with violence are largely mediated by collective efficacy. PMID:9252316
Sampson, R J; Raudenbush, S W; Earls, F
Clinical study evaluating efficacy of praziquantel in clonorchiasis.
In 74 patients with clonorchiasis, the efficacy and safety of praziquantel was evaluated in a two-phase study: a double-blind, randomized controlled trial of praziquantel versus placebo (42 patients) and an open study (32 patients). All but one of the patients were Laotians. The intensity of clonorchiasis was light in 85% (63 of 74) and moderate in 15% (11 of 74) of the patients. Cure based on our established criteria was noted in 67 of 67 patients (100%) treated with praziquantel at a dose of 75 mg/kg per day. In contrast, four patients (20%) in the placebo group, each with light infection, ceased passing eggs and were, according to our established protocol, considered spontaneous cures (P less than 0.0001). Adverse effects of praziquantel were transient and included nausea and vomiting (15%), vertigo (12%), hepatomegaly (4.5%), headache (1.5%), rash (1.5%), and hypotension (1.5%). Of 20 patients who received placebo, 1 (5%) developed transient skin rash, fever, and chills. Clinically minor and transient, but statistically significant, changes in hemoglobin, total protein in serum, and levels of uric acid, cholesterol, and bilirubin in serum were noted. Results of this study showed that praziquantel is safe, well tolerated, and effective and should be considered as the drug of choice for treatment of clonorchiasis. In moderate infections, a second course of praziquantel therapy may be necessary to eliminate infection.
Yangco, B G; De Lerma, C; Lyman, G H; Price, D L
Pre-clinical validation of orthotopically-implanted pulmonary tumor by imaging with 18F-fluorothymidine-positron emission tomography/computed tomography.
The development of positron-emission tomography (PET) and X-ray computed tomography (CT) imaging has improved the detection of tumor burden and, in turn, pre-clinical drug development and clinical treatment. In pre-clinical drug development, clinically-relevant murine cancer models, such as orthotopic models of lung cancer, have provided an accurate representation of tumor burden in humans. However, evidence demonstrating the capability of imaging-guided evaluation of these clinically-relevant models is limited. Here, we combined (18)F-fluorothymidine (FLT)-PET/CT imaging and a murine model of human non-small cell lung cancer (NSCLC) to improve the accuracy of anticancer drug evaluation in pre-clinical studies. We found that FLT-PET/CT imaging enabled the progression of pulmonary tumors to be longitudinally monitored rather than FDG-PET/CT. Furthermore, in an efficacy study of a standard treatment of docetaxel in a murine lung cancer model, FLT-PET imaging detected the anticancer response earlier than volumetric analysis by CT imaging. We, thus, observed a relationship between the alteration of FLT signals and Ki-67 index in the pulmonary tumor during the period of chemotherapy. These results indicate that the combination of FLT-PET/CT imaging and an orthotopic NSCLC model is an effective strategy for evaluating clinical efficacy and potential of an anticancer agent during pre-clinical development. PMID:24222108
Fushiki, Hiroshi; Miyoshi, Sosuke; Noda, Akihiro; Murakami, Yoshihiro; Sasaki, Hiroshi; Jitsuoka, Makoto; Mitsuoka, Keisuke; Matsunari, Ichiro; Nishimura, Shintaro
Ultrasound guided fluorescence molecular tomography with improved quantification by an attenuation compensated born-normalization and in vivo preclinical study of cancer
NASA Astrophysics Data System (ADS)
Ultrasound imaging, having the advantages of low-cost and non-invasiveness over MRI and X-ray CT, was reported by several studies as an adequate complement to fluorescence molecular tomography with the perspective of improving localization and quantification of fluorescent molecular targets in vivo. Based on the previous work, an improved dual-modality Fluorescence-Ultrasound imaging system was developed and then validated in imaging study with preclinical tumor model. Ultrasound imaging and a profilometer were used to obtain the anatomical prior information and 3D surface, separately, to precisely extract the tissue boundary on both sides of sample in order to achieve improved fluorescence reconstruction. Furthermore, a pattern-based fluorescence reconstruction on the detection side was incorporated to enable dimensional reduction of the dataset while keeping the useful information for reconstruction. Due to its putative role in the current imaging geometry and the chosen reconstruction technique, we developed an attenuation compensated Born-normalization method to reduce the attenuation effects and cancel off experimental factors when collecting quantitative fluorescence datasets over large area. Results of both simulation and phantom study demonstrated that fluorescent targets could be recovered accurately and quantitatively using this reconstruction mechanism. Finally, in vivo experiment confirms that the imaging system associated with the proposed image reconstruction approach was able to extract both functional and anatomical information, thereby improving quantification and localization of molecular targets.
Li, Baoqiang; Berti, Romain; Abran, Maxime; Lesage, Fr�d�ric
Early prediction of response to radiotherapy and androgen-deprivation therapy in prostate cancer by repeated functional MRI: a preclinical study
Background In modern cancer medicine, morphological magnetic resonance imaging (MRI) is routinely used in diagnostics, treatment planning and assessment of therapeutic efficacy. During the past decade, functional imaging techniques like diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI have increasingly been included into imaging protocols, allowing extraction of intratumoral information of underlying vascular, molecular and physiological mechanisms, not available in morphological images. Separately, pre-treatment and early changes in functional parameters obtained from DWMRI and DCEMRI have shown potential in predicting therapy response. We hypothesized that the combination of several functional parameters increased the predictive power. Methods We challenged this hypothesis by using an artificial neural network (ANN) approach, exploiting nonlinear relationships between individual variables, which is particularly suitable in treatment response prediction involving complex cancer data. A clinical scenario was elicited by using 32 mice with human prostate carcinoma xenografts receiving combinations of androgen-deprivation therapy and/or radiotherapy. Pre-radiation and on days 1 and 9 following radiation three repeated DWMRI and DCEMRI acquisitions enabled derivation of the apparent diffusion coefficient (ADC) and the vascular biomarker Ktrans, which together with tumor volumes and the established biomarker prostate-specific antigen (PSA), were used as inputs to a back propagation neural network, independently and combined, in order to explore their feasibility of predicting individual treatment response measured as 30 days post-RT tumor volumes. Results ADC, volumes and PSA as inputs to the model revealed a correlation coefficient of 0.54 (p < 0.001) between predicted and measured treatment response, while Ktrans, volumes and PSA gave a correlation coefficient of 0.66 (p < 0.001). The combination of all parameters (ADC, Ktrans, volumes, PSA) successfully predicted treatment response with a correlation coefficient of 0.85 (p < 0.001). Conclusions We have in a preclinical investigation showed that the combination of early changes in several functional MRI parameters provides additional information about therapy response. If such an approach could be clinically validated, it may become a tool to help identifying non-responding patients early in treatment, allowing these patients to be considered for alternative treatment strategies, and, thus, providing a contribution to the development of individualized cancer therapy.
Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013.
Abstract Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure-function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose-response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar. PMID:24024472
da Silva, Antonio; Kronthaler, Ulrich; Koppenburg, Vera; Fink, Martin; Meyer, Ines; Papandrikopoulou, Anastassia; Hofmann, Matthias; Stangler, Thomas; Visser, Jan
Studies on antimicrobial efficacy of medicinal tuberous shrub Talinum cuneifolium.
Talinum cuneifolium (Vahl.) Willd. an erect shrub with subterranian tuber (Portulacaceae) is endowed with wide range of pharmacological activities. The antimicrobial efficacy of the plant is evaluated against three bacteria and two fungal species by disc diffusion method. Preliminary phytochemical screening was carried out among hexane, ethylacetate, methanolic extracts of leaf and roottuber for different potent chemicals. The leaf methanolic extract of T cuneifolium showed maximum effect on the growth of Proteus (25.8 mm) followed by Bacillus (24.62 mm) and E. coli (19.42 mm). The tuberous methanolic extract of T cuneifolium showed maximum effect on growth of Proteus (28.15 mm) followed by Bacillus (26.88 mm) and E. coli (24.51 mm). The Gram-positive bacterial strains (Bacillus) were more susceptible to the extractions of T cuneifolium as compared to Gram-negative bacteria (E. coli, Pseudomonas aeruginosa, Proteus vulgaris and Klebsiella pneumoneia). The antifungal activity of selected plant leaf and root tubers exhibit pronounced activity against Candida albicans rather than Aspergillus niger. These studies showed that the methanolic extracts of T cuneifolium plant parts were certainly much better and powerful. This may be due to the better solubility of the action components in organic solvent. PMID:23360007
Savithramma, N; Ankanna, S; Rao, M Linga; Saradvathi, J
Preclinical Evaluation of HIV Eradication Strategies in the Simian Immunodeficiency Virus-Infected Rhesus Macaque: A Pilot Study Testing Inhibition of Indoleamine 2,3-Dioxygenase
Abstract Even in the setting of maximally suppressive antiretroviral therapy (ART), HIV persists indefinitely. Several mechanisms might contribute to this persistence, including chronic inflammation and immune dysfunction. In this study, we have explored a preclinical model for the evaluation of potential interventions that might serve to eradicate or to minimize the level of persistent virus. Given data that metabolic products of the inducible enzyme indoleamine 2,3-dioxygeanse (IDO) might foster inflammation and viral persistence, chronically simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques were treated with the IDO inhibitor 1-methyl tryptophan (1mT). Orally administered 1mT achieved targeted plasma levels, but did not impact tryptophan metabolism or decrease viral RNA or DNA in plasma or in intestinal tissues beyond levels achieved by ART alone. Animals treated with 1mT showed no difference in the levels of T cell activation or differentiation, or in the kinetics or magnitude of viral rebound following cessation of ART. Notwithstanding these negative results, our observations suggest that the chronically SIV-infected rhesus macaque on suppressive ART can serve as a tractable model in which to test and to prioritize the selection of other potential interventions designed to eradicate HIV in vivo. In addition, this model might be used to optimize the route and dose by which such interventions are administered and the methods by which their effects are monitored.
Dunham, Richard M.; Gordon, Shari N.; Vaccari, Monica; Piatak, Michael; Huang, Yong; Deeks, Steven G.; Lifson, Jeffrey; Franchini, Genoveffa
Preclinical studies with the anti-CD19-saporin immunotoxin BU12-SAPORIN for the treatment of human-B-cell tumours.
The immunotoxin BU12-SAPORIN was constructed by covalently coupling the single-chain ribosome-inactivating protein saporin to the anti-CD19 monoclonal antibody BU12 via a disulphide linker using the heterobifunctional reagent SPDP. The immunoreactivity and specificity of BU12-SAPORIN was identical to that of unmodified native BU12 antibody. BU12-SAPORIN was selectively cytotoxic in vitro in a dose-dependent manner for the CD19+ human common acute lymphoblastic leukaemia (cALL) cell line NALM-6 but exhibited no toxicity for the CD19- T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2. The survival of severe combined immunodeficient (SCID) mice with disseminated NALM-6 leukaemia was significantly prolonged compared with sham-treated control animals by a course of therapy with BU12-SAPORIN but not with the irrelevant anti-CD7 immunotoxin HB2-SAPORIN. BU12-SAPORIN had no therapeutic effect in SCID mice with disseminated CD19- HSB-2 leukaemia. These preclinical studies have clearly demonstrated the selective cytotoxicity of BU12-SAPORIN for CD19+ target cells both in vitro and in vivo. This, taken together with the lack of expression of the CD19 molecule by any normal life-sustaining tissue and its ubiquitous and homogeneous expression by the majority of cALL and B-NHL cells, provides the rationale for undertaking a phase I trial of systemic therapy with BU12-SAPORIN. Images Figure 1
Flavell, D. J.; Flavell, S. U.; Boehm, D. A.; Emery, L.; Noss, A.; Ling, N. R.; Richardson, P. R.; Hardie, D.; Wright, D. H.
Preclinical Neonatal Rat Studies of Heparin-Binding EGF-Like Growth Factor in Protection of the Intestines From Necrotizing Enterocolitis
We have previously demonstrated that enterally administered heparin-binding EGF-like growth factor (HB-EGF) produced in Escherichia coli decreases the incidence and severity of intestinal injury in a neonatal rat model of necrotizing enterocolitis (NEC). In preparation for upcoming human clinical trials, large-scale production of HB-EGF according to Good Manufacturing Practice (GMP) has been successfully accomplished using a Pichia pastoris yeast system. The current studies used a neonatal rat model of NEC to elucidate several important preclinical characteristics of HB-EGF therapy. We found that enteral administration of HB-EGF (800 ?g/kg/dose) four times a day effectively reduced the incidence and severity of NEC, that Pichia-derived HB-EGF was not significantly different from E. coli-derived HB-EGF in preventing NEC, that EGF was not superior to HB-EGF in preventing NEC, and that prophylactic administration of HB-EGF added to formula starting with the first feed or 12 h later significantly reduced the incidence of NEC, with no change in the incidence of NEC noted if HB-EGF was added to the formula starting 24, 48, or 72 h after birth. Thus, large-scale production of GMP-grade HB-EGF in Pichia pastoris yeast produces a biologically active molecule suitable for human clinical trials.
Relationship between Critical Thinking Skills and Success in Preclinical Courses.
ERIC Educational Resources Information Center
A study of 92 medical students found that critical thinking skills, as measured by the Watson-Glaser Critical Thinking Appraisal, were moderately predictive of academic success during the preclinical years of medical education. (Author/MSE)
Scott, Jane N.; Markert, Ronald J.
Emotional intelligence and teacher efficacy: a study of Turkish EFL pre-service teachers
This study investigated the relationship between emotional intelligence and teacher efficacy among 90 English language pre-service teachers from a university in Turkey. Data sources included Tschannen-Moran and Woolfolk-Hoy�s Teachers� Sense of Efficacy Scale and Reuven Bar-On�s Emotional Quotient Inventory. The findings indicated that Turkish EFL pre-service teachers felt more efficacious in managing the class rather than in making the class
Zeynep Ko�o?lu
Efficacy of Counseling and Psychotherapy in Schools: A Meta-Analytic Review of Treatment Outcome Studies
ERIC Educational Resources Information Center
This study investigated the efficacy of counseling and psychotherapy interventions for youth in schools. Data were examined for 107 studies that included 132 treatment interventions. Overall efficacy was d = 0.45 and was significantly different from zero. Interventions for adolescents outperformed those of children, treatment groups that were�
Baskin, Thomas W.; Slaten, Christopher D.; Crosby, Nicole R.; Pufahl, Tiffany; Schneller, Cali L.; Ladell, Monica
Female Mecp2+/? mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies
Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the gene encoding the transcriptional modulator methyl-CpG-binding protein 2 (MeCP2). Typical RTT primarily affects girls and is characterized by a brief period of apparently normal development followed by the loss of purposeful hand skills and language, the onset of anxiety, hand stereotypies, autistic features, seizures and autonomic dysfunction. Mecp2 mouse models have extensively been studied to demonstrate the functional link between MeCP2 dysfunction and RTT pathogenesis. However, the majority of studies have focused primarily on the molecular and behavioral consequences of the complete absence of MeCP2 in male mice. Studies of female Mecp2+/? mice have been limited because of potential phenotypic variability due to X chromosome inactivation effects. To determine whether reproducible and reliable phenotypes can be detected Mecp2+/? mice, we analyzed Mecp2+/? mice of two different F1 hybrid isogenic backgrounds and at young and old ages using several neurobehavioral and physiological assays. Here, we report a multitude of phenotypes in female Mecp2+/? mice, some presenting as early as 5 weeks of life. We demonstrate that Mecp2+/? mice recapitulate several aspects of typical RTT and show that mosaic expression of MeCP2 does not preclude the use of female mice in behavioral and molecular studies. Importantly, we uncover several behavioral abnormalities that are present in two genetic backgrounds and report on phenotypes that are unique to one background. These findings provide a framework for pre-clinical studies aimed at improving the constellation of phenotypes in a mouse model of RTT.
Samaco, Rodney C.; McGraw, Christopher M.; Ward, Christopher S.; Sun, Yaling; Neul, Jeffrey L.; Zoghbi, Huda Y.
Comparative in vitro efficacy of antimicrobial shampoos: a pilot study.
This study compared the antimicrobial efficacy of shampoos against meticillin-sensitive Staphylococcus pseudintermedius (MSSP), meticillin-resistant S. pseudintermedius (MRSP), antibiotic-sensitive Pseudomonas aeruginosa (PA), multidrug-resistant P. aeruginosa (MDR-PA) and Malassezia pachydermatis. Three isolates were incubated for 10, 30 and 60 min with each shampoo diluted in phosphate-buffered saline. Aliquots were then incubated for 16-18 h on sheep blood agar (bacteria) or for 3 days on Sabouraud's dextrose agar (Malassezia). The minimal bactericidal concentrations (MBCs) for chlorhexidine products (Malaseb(�), Pyoderm(�)/Microbex(�) and Hibiscrub(�)) were 1:1,024-1:2,048 for MSSP and MRSP, 1:512-1:1,024 for PA and MDR-PA, and 1:2,048-1:5,096 for Malassezia at all time points. The MBCs for benzoyl peroxide (Paxcutol(�)) for MSSP and MRSP were 1:2-1:8 at 10 min, and 1:256 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and 1:512-1:1,024 dilutions were effective against Malassezia at all time points. The MBCs for ethyl lactate (Etiderm(�)) for MSSP and MRSP were 1:2 at 10 min, and 1:2-1:16 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and a 1:512 dilution was effective against Malassezia at all time points. Chloroxylenol (Coatex(�)) and acetic acid-boric acid (Malacetic(�)) were not effective against MSSP, MRSP or Pseudomonas. Both were effective against Malassezia at 1:8-1:16 dilution at 10 min, and at 1:8-1:32 dilution after 30 and 60 min. In conclusion, chlorhexidine appeared to be the most effective topical biocide, and MRSP and MDR-PA were no less susceptible than antibiotic-sensitive organisms. These results should, however, be confirmed with larger numbers of isolates. PMID:21777309
Young, Rebecca; Buckley, Laura; McEwan, Neil; Nuttall, Tim
Changes in self-efficacy and dietary adherence: the impact on weight loss in the PREFER study
Findings from studies examining self-efficacy and its relationship to weight loss have been inconsistent. We examined self-efficacy\\u000a specific to changing eating behaviors in the PREFER trial, an 18-month behavioral weight-loss study, to determine if self-efficacy\\u000a and dietary adherence were associated with weight change, and what impact self-efficacy had on weight change after controlling\\u000a for adherence. Measurements included the weight efficacy
Melanie T. Warziski; Susan M. Sereika; Mindi A. Styn; Lora E. Burke
Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication
1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ?50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94.
Koszalka, George W.; Johnson, Nelson W.; Good, Steven S.; Boyd, Leslie; Chamberlain, Stanley C.; Townsend, Leroy B.; Drach, John C.; Biron, Karen K.
Evaluation of wound-healing potential of Pisonia grandis R.Br: a preclinical study in Wistar rats.
Pisonia grandis R.Br (family: Nyctaginaceae) is a herb claimed to be used for treatment of inflammation, wound healing, algesia, and ulcer. The present study was done to evaluate the wound-healing potential of methanolic extract of its leaves. Following preliminary photochemical evaluation, the extract was incorporated in simple ointment base and evaluated using 2 types of wound models in Wistar rats-excision wound and incision wound. The results were significantly different ( p <0.05) when compared with control group for wound contraction, tensile strength, and histopathological and biological parameters. Antibacterial studies against different bacterial strains of the test samples were performed by the disk-diffusion method and were compared with standard ofloxacin and erythromycin. Test sample showed comparable zone of inhibition to the standards. It is hypothesized that the presence of phytoconstituents with the antibacterial effect helps in wound healing. PMID:18372265
Prabu, D; Nappinnai, M; Ponnudurai, K; Prabhu, K
A simulation framework for pre-clinical studies on dose and image quality: concept and first validation
NASA Astrophysics Data System (ADS)
Purpose: The purposes of the study were to set-up and validate a simulation framework for dose and image quality optimization studies. In a first phase we have evaluated whether CDRAD images as obtained with computed radiography plates could be simulated. Material and Methods: The Monte Carlo method is a numerical method that can be used to simulate radiation transport. It is in diagnostic radiology often used in dosimetry, but in present study it is used to simulate X-ray images. With the Monte Carlo software, MCNPX, the successive steps in the imaging chain were simulated: the X-ray beam, the attenuation and scatter process in a test object and image generation by an ideal detector. Those simulated images were further modified for specific properties of CR imaging systems. The signal-transfer-properties were used to convert the simulated images into the proper grey scale. To account for resolution properties the simulated images were convolved with the point spread function of the CR systems. In a last phase, noise, based on noise power spectrum (NPS) measurements, was added to the image. In this study, we simulated X-ray images of the CDRAD contrast-detail phantom. Those simulated images, modified for the CR-system, were compared with real X-ray images of the CDRAD phantom. All images were scored by computer readings. Results: First results confirm that realistic CDRAD images can be simulated and that reading results of series of simulated and real images have the same tendency. The simulations also show that white noise has a large influence on image quality and CDRAD analyses.
Smans, Kristien; Pauwels, Herman; Rogge, Frank; Struelens, Lara; Dragusin, Octavian; Vanhavere, Filip; Bosmans, Hilde
Preclinical potency and safety studies of an AAV2-mediated gene therapy vector for the treatment of MERTK associated retinitis pigmentosa.
Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium-specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague-Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control-injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial. PMID:23692380
Conlon, Thomas J; Deng, Wen-Tao; Erger, Kirsten; Cossette, Travis; Pang, Ji-jing; Ryals, Renee; Cl�ment, Nathalie; Cleaver, Brian; McDoom, Issam; Boye, Shannon E; Peden, Marc C; Sherwood, Mark B; Abernathy, Corinne R; Alkuraya, Fowzan S; Boye, Sanford L; Hauswirth, William W
Preclinical Potency and Safety Studies of an AAV2-Mediated Gene Therapy Vector for the Treatment of MERTK Associated Retinitis Pigmentosa
Abstract Proof of concept for MERTK gene replacement therapy has been demonstrated using different viral vectors in the Royal College of Surgeon (RCS) rat, a well characterized model of recessive retinitis pigmentosa that contains a mutation in the Mertk gene. MERTK plays a key role in renewal of photoreceptor outer segments (OS) by phagocytosis of shed OS tips. Mutations in MERTK cause impaired phagocytic activity and accumulation of OS debris in the interphotoreceptor space that ultimately leads to photoreceptor cell death. In the present study, we conducted a series of preclinical potency and GLP-compliant safety evaluations of an adeno-associated virus type 2 (AAV2) vector expressing human MERTK cDNA driven by the retinal pigment epithelium�specific, VMD2 promoter. We demonstrate the potency of the vector in RCS rats by improved electroretinogram (ERG) responses in treated eyes compared with contralateral untreated controls. Toxicology and biodistribution studies were performed in Sprague�Dawley (SD) rats injected with two different doses of AAV vectors and buffer control. Delivery of vector in SD rats did not result in a change in ERG amplitudes of rod and cone responses relative to balanced salt solution control�injected eyes, indicating that administration of AAV vector did not adversely affect normal retinal function. In vivo fundoscopic analysis and postmortem retinal morphology of the vector-injected eyes were normal compared with controls. Evaluation of blood smears showed the lack of transformed cells in the treated eyes. All injected eyes and day 1 blood samples were positive for vector genomes, and all peripheral tissues were negative. Our results demonstrate the potency and safety of the AAV2-VMD2-hMERTK vector in animal models tested. A GMP vector has been manufactured and is presently in clinical trial.
Deng, Wen-Tao; Erger, Kirsten; Cossette, Travis; Pang, Ji-jing; Ryals, Renee; Clement, Nathalie; Cleaver, Brian; McDoom, Issam; Boye, Shannon E.; Peden, Marc C.; Sherwood, Mark B.; Abernathy, Corinne R.; Alkuraya, Fowzan S.; Boye, Sanford L.; Hauswirth, William W.
Validation of a Preclinical Spinal Safety Model: Effects of Intrathecal Morphine in the Neonatal Rat
Background Preclinical studies demonstrate increased neuroapoptosis after general anesthesia in early life. Neuraxial techniques may minimize potential risks, but there has been no systematic evaluation of spinal analgesic safety in developmental models. We aimed to validate a preclinical model for evaluating dose-dependent efficacy, spinal cord toxicity, and long term function following intrathecal morphine in the neonatal rat. Methods Lumbar intrathecal injections were performed in anesthetized rats aged postnatal day (P)3, 10 and 21. The relationship between injectate volume and segmental spread was assessed post mortem and by in-vivo imaging. To determine the antinociceptive dose, mechanical withdrawal thresholds were measured at baseline and 30 minutes following intrathecal morphine. To evaluate toxicity, doses up to the maximum tolerated were administered, and spinal cord histopathology, apoptosis and glial response were evaluated 1 and 7 days following P3 or P21 injection. Sensory thresholds and gait analysis were evaluated at P35. Results Intrathecal injection can be reliably performed at all postnatal ages and injectate volume influences segmental spread. Intrathecal morphine produced spinally-mediated analgesia at all ages with lower dose requirements in younger pups. High dose intrathecal morphine did not produce signs of spinal cord toxicity or alter long-term function. Conclusions The therapeutic ratio for intrathecal morphine (toxic dose / antinociceptive dose) was at least 300 at P3, and at least 20 at P21 (latter doses limited by side effects). This data provides relative efficacy and safety data for comparison with other analgesic preparations and contributes supporting evidence for the validity of this preclinical neonatal safety model.
Westin, B. David; Walker, Suellen M.; Deumens, Ronald; Grafe, Marjorie; Yaksh, Tony L.
Gender, Group Composition, Cooperation, and Self-Efficacy in Computer Studies.
ERIC Educational Resources Information Center
Describes a study of Norwegian college students that investigated whether gender, group composition, or self-efficacy in computing has any impact on cooperation, giving or getting task-related help, and level of activity in student groups. Results confirms gender differences in self-efficacy in computing. (Author/LRW)
Busch, Tor
A Study of Teachers' Sense of Efficacy. Final Report, Volume II. [Appendices].
ERIC Educational Resources Information Center
This volume contains the appendices for the report on the Teacher Efficacy Study, an investigation of teachers' sense of efficacy and the extent to which teachers believe they can have a positive effect on student learning and achievement. Included in this volume are: (1) middle school site descriptions; (2) the middle school questionnaire; (3)�
Ashton, Patricia T.; And Others
Organizational Structure, Collegial Trust, and College Faculty Teaching Efficacy: A Case Study
ERIC Educational Resources Information Center
The purpose of this mixed-method study was to explore the relationship between faculty self-efficacy, organizational structure, and collegial trust. The concepts of teacher self-efficacy, organizational structure, and collegial trust were used to investigate any possible empirical relationships existing between these variables in a private,�
Okpogba, Desmond
Collective Efficacy: A Neglected Construct in the Study of Schools and Student Achievement
A theoretical analysis is advanced that discusses social cognitive theory at the group level to explain the formation and impact of collective efficacy. The study used student- and school-level data from a sample of urban elementary schools. Consistent with social cognitive theory, mastery experience was found to be a significant predictor of differences between schools in teachers� collective efficacy perceptions.
Roger D. Goddard
Using Mathematics in Teaching Science Self-Efficacy Scale--UMSSS: A Validity and Reliability Study
ERIC Educational Resources Information Center
In this study, an instrument, Using Mathematics in Science Self-efficacy Scale (UMSSS), was developed in order to determine preservice science teachers' self-efficacy toward the use of mathematics in their lessons. Data gathered from 250 preservice science teachers were used for Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis�
Can, Bilge Taskin; Gunhan, Berna Canturk; Erdal, Sevinc Ongel
Education for Sustainability: A Case Study of Preservice Primary Teachers' Knowledge and Efficacy
ERIC Educational Resources Information Center
This study investigated the relationships between knowledge and efficacy for teaching sustainability in a sample of 266 pre-service primary teachers at a large, metropolitan university in Australia. A survey gathered information about the participant's attitudes and self-efficacy for education for sustainability, along with their perceived�
Effeney, Gerard; Davis, Julie
Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors
ERIC Educational Resources Information Center
The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that�
Morris, David B.; Usher, Ellen L.
Ultrastructural analysis in preclinical safety evaluation.
The first electron microscopic images of biological specimens were made in the 1940s, and the next 30 years comprised an era of descriptive ultrastructure during which transmission electron microscopy (TEM) was integral to an explosion in cellular and molecular biology. However, when questions could no longer be answered by ultrastructural information alone, the use of TEM in biological research declined. Innovative molecular techniques and newer imaging technologies such as confocal fluorescence microscopy filled the gap, providing faster answers with less rigorous training as a prerequisite to data collection. The use of TEM in toxicologic pathology has paralleled the rise and fall of its popularity in other disciplines. However, TEM remains an essential resource that provides direct and unequivocal data to explain and address safety concerns in preclinical toxicity studies. There is still an important place for TEM in preclinical safety evaluation and mechanistic studies, particularly when visualization of subcellular structures provides a link to other endpoints. This review reinforces the value of TEM in preclinical safety testing and model development and encourages best practices for ultrastructural evaluation. PMID:22215513
Fagerland, Jane A; Wall, Henry G; Pandher, Karamjeet; LeRoy, Bruce E; Gagne, Gerard D
Bioplasty for vertebral fractures: preliminary results of a pre-clinical study on goats using autologous modified skin fibroblasts
Summary The debate is still ongoing about the long term effects of the mininvasive vertebral augmentation techniques and their usefulness in treating more complex cases where a bone inducing effect more than a merely bone substitution would be suitable, such as the vertebral fractures in young patients. We previously developed a clinically relevant gene therapy approach using modified dermal fibroblasts for inducing bone healing and bone formation in different animal models. The aim of this study is to show the feasibility of a minimally invasive percutaneous intrasomatic ex vivo gene therapy approach to treat thoracolumbar vertebral fractures and anterior column bone defects in a goat model.
Pola, Enrico; Nasto, Luigi A.; Tampieri, Anna; Lattanzi, W.; Di Giacomo, G.; Colangelo, D.; Ciriello, V.; Pagano, E.; Spinelli, S.; Robbins, P.D.; Logroscino, G.
Preclinical pharmacodynamic and pharmacokinetic studies of investigational new drugs. Annual report, 1 November 1993-31 October 1994
During the past year of this contract pharmacokinetic, pharmacodynamic, bioavailability and metabolism studies have been conducted on two anti-cyanotic agents (WR242511 and p-aminohetanophenone (PAHP)) and one nerve agent antidote (HI-6) which are under consideration for clinical development by the U.S. Army. Radiolabeled formulations of WR242511, PAHP and HI-6 were used in these investigations. Information has been obtained on the half-lives of absorption and elimination of both radioactivity and the parent compound following oral and i.v. administration of these three compounds to dogs and, for PAHP, also to rats. In addition, the rates and extent of urinary and fecal elimination of the agents has been characterized; the pharmacodynamics, as assessed by the production of methemoglobin, of two compounds (WR242511 and PAHP) has been studied; and the metabolism of each compound has been investigated. Data obtained to date indicate that: WR242511 does not directly produce methemoglobinemia but a metabolite sequestered in red cells is the responsible agent; dogs appear to metabolize PAHP differently than do rats; the major urinary metabolite of HI-6 is 2-pyridine aldoxime. Further efforts to isolate and identify the metabolites of all three compounds are in progress.
Noker, P.E.
[111In-DOTA]Somatostatin-14 analogs as potential pansomatostatin-like radiotracers - first results of a preclinical study
Background In this study, we report on the synthesis, radiolabeling, and biological evaluation of two new somatostatin-14 (SS14) analogs, modified with the universal chelator DOTA. We were interested to investigate if and to what extent such radiotracer prototypes may be useful for targeting sst1-5-expressing tumors in man but, most importantly, to outline potential drawbacks and benefits associated with their use. Methods AT1S and AT2S (DOTA-Ala1-Gly2-c[Cys3-Lys4-Asn5-Phe6-Phe7-Trp8/DTrp8-Lys9-Thr10-Phe11-Thr12-Ser13-Cys14-OH], respectively) were synthesized on the solid support and labeled with 111In. The sst1-5 affinity profile of AT1S/AT2S was determined by receptor autoradiography using [Leu8,dTrp22,125I-Tyr25]SS28 as radioligand. The ability of AT2S to stimulate sst2 or sst3 internalization was qualitatively analyzed by an immunofluorescence-based internalization assay using hsst2- or hsst3-expressing HEK293 cells. Furthermore, the internalization of the radioligands [111In]AT1S and [111In]AT2S was studied at 37?�C in AR4-2J cells endogenously expressing sst2. The in vivo stability of [111In]AT1S and [111In]AT2S was tested by high-performance liquid chromatography analysis of mouse blood collected 5?min after radioligand injection, and biodistribution was studied in normal mice. Selectively for [111In]AT2S, biodistribution was further studied in SCID mice bearing AR4-2J, HEK293-hsst2A+, -hsst3+ or -hsst5+ tumors. Results The new SS14-derived analogs were obtained by solid phase peptide synthesis and were easily labeled with 111In. Both SS14 conjugates, AT1S, and its DTrp8 counterpart, AT2S, showed a pansomatostatin affinity profile with the respective hsst1-5 IC50 values in the lower nanomolar range. In addition, AT2S behaved as an agonist for sst2 and sst3 since it stimulated receptor internalization. The 111In radioligands effectively and specifically internalized into rsst2A-expressing AR4-2J cells with [111In]AT2S internalizing faster than [111In]AT1S. Ex vivo mouse blood analysis revealed a rapid degradation of both radiopeptides in the bloodstream with the DTrp8 analog showing higher stability. Biodistribution results in healthy mice were consistent with these findings with only [111In]AT2S showing specific uptake in the sst2-rich pancreas. Biodistribution of [111In]AT2S in tumor-bearing mice revealed receptor-mediated uptake in the AR4-2J (1.82?�?0.36 %ID/g - block 0.21?�?0.17 %ID/g at 4?h post injection (pi)), the HEK293-hsst2A+ (1.49?�?0.2 %ID/g - block 0.27?�?0.20 %ID/g at 4?h pi), the HEK293-hsst3+ (1.24?�?0.27 %ID/g - block 0.32?�?0.06 %ID/g at 4?h pi), and the HEK293-hsst5+ tumors (0.41?�?0.12 %ID/g - block 0.22?�?0.006 %ID/g at 4?h pi). Radioactivity washed out from blood and background tissues via the kidneys. Conclusions This study has revealed that the native SS14 structure can indeed serve as a motif for the development of promising pansomatostatin-like radiotracers. Further peptide stabilization is required to increase in vivo stability and, consequently, to enhance in vivo delivery and tumor targeting.
Preclinical models in radiation oncology
As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic.
Child and Adolescent Behavior Inventory (CABI): A New Instrument for Epidemiological Studies and Pre-Clinical Evaluation
Background: Some questionnaires have already been elaborated to collect information from parents of children and adolescents, both as preparation for clinical evaluation and for screening and epidemiological studies. Here a new questionnaire, the CABI, is proposed, and it is validated in a population of 8-10 year-old children. Compared to existing questionnaires, the CABI has been organized so as to be of medium length, with items concerning the most significant symptoms indicated by the DSM-IV-TR for the pertinent disorders, and covering a wider range than existing instruments. There is no charge for its use. Methods: The answers of the parents of 302 children in the last 3 years of primary school provided the normative data. A discriminant validation was done for internalizing and externalizing disorders and as a comparison with self-administered anxiety and depression scales. Exploratory factor analysis and internal consistency were also performed. Results: Distribution of scores on the main scales in the normal population shows positive skewness, with the most frequent score being zero. A highly discriminant capability was found in regard to the sample of children with internalizing and externalizing disorders, with high correlation with the self-administered anxiety and depression scales. Conclusion: The CABI appears to be capable, at least for 8-10 year-old children, of effectively discriminating those with pathological symptoms from those without. Compared with the widely- used CBCL, it has the advantages of a lower number of items, which should facilitate parental collaboration especially in epidemiological studies, and of being free of charge.
Cianchetti, Carlo; Pittau, Andrea; Carta, Valeria; Campus, Grazia; Littarru, Roberta; Ledda, Maria Giuseppina; Zuddas, Alessandro; Fancello, Giuseppina Sannio
A comparative study of students' performance in preclinical physiology assessed by multiple choice and short essay questions.
This study was designed to compare the performance of medical students in physiology when assessed by multiple choice questions (MCQs) and short essay questions (SEQs). The study also examined the influence of factors such as age, sex, O/level grades and JAMB scores on performance in the MCQs and SEQs. A structured questionnaire was administered to 264 medical students' four months before the Part I MBBS examination. Apart from personal data of each student, the questionnaire sought information on the JAMB scores and GCE O' Level grades of each student in English Language, Biology, Chemistry, Physics and Mathematics. The physiology syllabus was divided into five parts and the students were administered separate examinations (tests) on each part. Each test consisted of MCQs and SEQs. The performance in MCQs and SEQs were compared. Also, the effects of JAMB scores and GCE O/level grades on the performance in both the MCQs and SEQs were assessed. The results showed that the students performed better in all MCQ tests than in the SEQs. JAMB scores and O' level English Language grade had no significant effect on students' performance in MCQs and SEQs. However O' level grades in Biology, Chemistry, Physics and Mathematics had significant effects on performance in MCQs and SEQs. Inadequate knowledge of physiology and inability to present information in a logical sequence are believed to be major factors contributing to the poorer performance in the SEQs compared with MCQs. In view of the finding of significant association between performance in MCQs and SEQs and GCE O/level grades in science subjects and mathematics, it was recommended that both JAMB results and the GCE results in the four O/level subjects above may be considered when selecting candidates for admission into the medical schools. PMID:11713989
Oyebola, D D; Adewoye, O E; Iyaniwura, J O; Alada, A R; Fasanmade, A A; Raji, Y
Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies
In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe`s sensitivity was determined to be 58 and 11 cps/{mu}Ci for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results; the probe was generally able to discriminate between tumor and normal tissue. This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer. 23 refs., 5 figs.
Raylman, R.R.; Fisher, S.J.; Brown, R.S.; Ethier, S.P.; Wahl, R.L. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)
Detection of circulating tumor cells is improved by drug-induced antigen up-regulation: preclinical and clinical studies.
(51)Cr-prelabelled colon cancer cells (simulating 'circulating tumor cells', CTCs) were added to human peripheral blood and exposed to staurosporine (ST) to increase carcinoembryonic antigen (CEA) expression. CTCs were captured with immunomagnetic beads coated with Ber-EP4 monoclonal antibody, recognizing the common epithelial antigen present in the majority of cancer cells of epithelial origin, with capture efficiency of more than 80%. Moreover, ST treatment increased CEA expression without compromising Ber-EP4 capture efficiency. In a pilot clinical study on 37 patients, CTCs were captured using Ber-EP4 beads, and recognized by RT-PCR set for CEA or cytokeratin-19 (CK) mRNA detection. The results showed that: (a) the percentage of CEA-positive CTCs (CTC(CEA), 54.1%) was lower than that of CK-positive CTCs (CTC(CK), 70.3%); (b) in vitro ST treatment converted a significant number of CTC(CEA)-negative into CTC(CEA)-positive cases. Therefore, immunomagnetic capture combined with exposure to ST provides a feasible and sensitive technique for the detection of functionally-active CTCs responsive to ST-mediated CEA up-regulation. PMID:21115931
Bonmassar, Laura; Fossile, Emanuela; Scoppola, Alessandro; Graziani, Grazia; Prete, Salvatore P; Formica, Vincenzo; Cappelletti, Daniela; De Vecchis, Liana; Cardillo, Anna; Concolino, Francesco; D'Atri, Stefania; Balduzzi, Alessandra; Torino, Francesco; Caporaso, Patrizia; Greiner, Jack W; Bonmassar, Enzo; Roselli, Mario; Aquino, Angelo
The feasibility of using coronally advanced flap with an extracellular matrix membrane for treating gingival recession defects: a preclinical study.
The guided tissue regeneration (GTR) procedure has been demonstrated to successfully correct gingival recession (GR) defects. The aim of this study was to assess the feasibility of using the combination of a coronally advanced flap (CAF) with an extracellular membrane (ECM) to correct GR. GR defects were induced in the maxillary posterior region in five baboons. A 3-month healing period followed before the ECM was placed over the defect and covered with a CAF. Probing depth (PD), recession depth (RD), recession width (RW), and keratinized tissue width (KTW) were measured at baseline and 3 months postoperatively. Block biopsies of the treated areas were submitted for histologic review after a healing period of 3 months. There were no significant differences between the test (ECM + CAF) and control (CAF) groups in terms of changes in PD, RD, RW, and KTW after 3 months of treatment. However, significant differences have been noted for preoperation and postsurgery RD and RW values for both the control and test groups. Histomorphometric results showed minimal alveolar bone and connective tissue replacing the ECM membrane. CAF (either with or without the use of an ECM) is effective for the treatment of GR defects. PMID:24804288
Al Hezaimi, Khalid; Al Askar, Mansour; Kim, David M; Chung, Jamie Hyewon; Gil, Mindy S; Nevins, Myron
Pre-clinical study of in vivo magnetic resonance-guided bubble-enhanced heating in pig liver.
Bubble-enhanced heating (BEH) can be exploited to increase heating efficiency in treatment of liver tumors with non-invasive high-intensity focused ultrasound (HIFU). The objectives of this study were: (i) to demonstrate the feasibility of increasing the heating efficiency of sonication exploiting BEH in pig liver in vivo using a clinical platform; (ii) to determine the acoustic threshold for such effects with real-time, motion-compensated magnetic resonance-guided thermometry; and (iii) to compare the heating patterns and thermal lesion characteristics resulting from continuous sonication and sonication including a burst pulse. The threshold acoustic power for generation of BEH in pig liver in vivo was determined using sonication of 0.5-s duration ("burst pulse") under real-time magnetic resonance thermometry. In a second step, experimental sonication composed of a burst pulse followed by continuous sonication (14.5 s) was compared with conventional sonication (15 s) of identical energy (1.8 kJ). Modification of the heating pattern at the targeted region located at a liver depth between 20 and 25 mm required 600-800 acoustic watts. The experimental group exhibited near-spherical heating with 40% mean enhancement of the maximal temperature rise as compared with the conventional sonication group, a mean shift of 7 � 3.3 mm toward the transducer and reduction of the post-focal temperature increase. Magnetic resonance thermometry can be exploited to control acoustic BEH in vivo in the liver. By use of experimental sonication, more efficient heating can be achieved while protecting tissues located beyond the focal point. PMID:23562012
Elbes, Delphine; Denost, Quentin; Laurent, Christophe; Trillaud, Herv�; Rullier, Anne; Quesson, Bruno
Psychiatric disorders in preclinical Huntington's disease
Background Psychiatric symptoms are a common feature of Huntington's disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period. Objectives To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non?carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset. Methods Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non?carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow?up of gene carriers (n?=?51) enabled analysis of the role of temporal proximity to clinical onset. Results Gene carriers and non?carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset. Conclusions Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.
Julien, Camille L; Thompson, Jennifer C; Wild, Sue; Yardumian, Pamela; Snowden, Julie S; Turner, Gwen; Craufurd, David
Preclinical Pharmacology and Toxicology Studies
OF RECEIPT for determining TIMELY DELIVERY is the address provided for the OFFICE OF ACQUISITIONS. IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR HIS DESIGNEE AT THE PLACE AND TIME SPECIFIED FOR THE OFFICE OF ACQUISITIONS, THEN IT WILL BE CONSIDERED LATE AND HANDLED IN ACCORDANCE WITH subparagraph (c)(3) of FAR Clause 52.215-1, Instructions to Offerors--Competitive Acquisition," LOCATED IN SECTION L.1. OF THIS SOLICITATION. 10.
The Efficacy of Influenza Vaccine for Healthy Children A Meta-Analysis Evaluating Potential Sources of Variation in Efficacy Estimates Including Study Quality
Background: Two systematic reviews evaluating influenza vaccine efficacy in healthy children have recently been published. Although quantitative summary estimates were similar, authors' conclusions were quite contrasting. We carried out another meta-analysis reeval- uating study inclusion criteria and using metaregression techniques in addition to sensitivity and subgroups analyses to evaluate poten- tial sources of heterogeneity of efficacy estimates, including meth- odologic
Lamberto Manzoli; Francesco Schioppa; Antonio Boccia; Paolo Villari
Advances in Preclinical SPECT Instrumentation
Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well.
Peterson, Todd E.; Shokouhi, Sepideh
Self-efficacy is mainly genetic, not learned: a multiple-rater twin study on the causal structure of general self-efficacy in young people.
Social learning theory postulates that self-efficacy is learned through the person's interaction with his/her physical and social environment. In this genetically informative, population-based, multi-informant study of 1,394 adolescent twin pairs, self-efficacy was modeled as one latent psychometric self-efficacy factor with genetic and environmental effects common to all informants, as well as for effects specific for each informant. The results showed that 75% of variation in self-efficacy was due to genetic factors. Non-shared environmental causes explained the remaining 25% of the variance in the latent factor, with no effect of common environment. Some informant-specific effects were also found. The present study challenges the theoretical assumption of learning as the dominant etiological factor behind self-efficacy in young people. PMID:23601253
Waaktaar, Trine; Torgersen, Svenn
Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans
3,4-Methylenedioxymethamphetamine (MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain 5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the drug in humans or animals. The recreational use of MDMA and current clinical investigations of the drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on MDMA in animals and humans are reviewed and indicate that the risks following MDMA ingestion should be re-evaluated. Acute behavioural and body temperature changes result from rapid MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute hyperthermia in humans probably limits the chance of recreational users ingesting sufficient MDMA to produce neurotoxicity, unlike in the rat. MDMA also inhibits the major enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, although when taken in combination with other recreational drugs it may induce neurotoxicity. LINKED ARTICLES This article is commented on by Parrott, pp. 1518�1520 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.x and to view the the rebuttal by the authors (Green et al., pp. 1521�1522 of this issue) visit http://dx.doi.org/10.1111/j.1476-5381.2012.01940.x
Green, AR; King, MV; Shortall, SE; Fone, KCF
Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis.
There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post-infection. In the infected monkeys, DB829 attained a median C(max) (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days), oral regimen for first stage HAT. PMID:23755309
Thuita, John K; Wolf, Kristina K; Murilla, Grace A; Liu, Qiang; Mutuku, James N; Chen, Yao; Bridges, Arlene S; Mdachi, Raymond E; Ismail, Mohamed A; Ching, Shelley; Boykin, David W; Hall, James Edwin; Tidwell, Richard R; Paine, Mary F; Brun, Reto; Wang, Michael Zhuo
Preclinical immunogenicity and functional activity studies of an A+W meningococcal outer membrane vesicle (OMV) vaccine and comparisons with existing meningococcal conjugate- and polysaccharide vaccines.
Meningococci of serogroups A and W (MenA and MenW) are the main causes of epidemic bacterial meningitis outbreaks in sub-Saharan Africa. In this study we prepared a detergent extracted outer membrane vesicle (dOMV) vaccine from representative African MenA and MenW strains, and compared the immunogenicity of this vaccine with existing meningococcal conjugate and polysaccharide (PS) vaccines in mice. NMRI mice were immunized with preclinical batches of the A+W dOMV vaccine, or with commercially available vaccines; a MenA conjugate vaccine (MenAfriVac(�), Serum Institute of India), ACYW conjugate vaccine (Menveo(�), Novartis) or ACYW PS vaccine (Mencevax(�), GlaxoSmithKline). The mice received 2 doses of 1/10 or 1/50 of a human dose with a three week interval. Immune responses were tested in ELISA, serum bactericidal activity (SBA) and opsonophagocytic activity (OPA) assays. High levels of IgG antibodies against both A and W dOMV were detected in mice receiving the A+W dOMV vaccine. High SBA titers against both MenA and MenW vaccine strains were detected after only one dose of the A+W dOMV vaccine, and the titers were further increased after the second dose. The SBA and OPA titers in mice immunized with dOMV vaccine were significantly higher than in mice immunized with the ACYW-conjugate vaccine or the PS vaccine. Furthermore, the A+W dOMV vaccine was shown to induce SBA and OPA titers against MenA of the same magnitude as the titers induced by the A-conjugate vaccine. In conclusion, the A+W dOMV vaccine induced high levels of functional antibodies to both MenA and MenW strains, levels that were shown to be higher or equal to the levels induced by licensed meningococcal vaccines. Thus, an A+W dOMV vaccine could potentially serve as an alternative or a supplement to existing conjugate and PS vaccines in the African meningitis belt. PMID:24120679
Tunheim, G; Arnemo, M; N�ss, L M; Fjeldheim, � K; Nome, L; Bolstad, K; Aase, A; Mandiarote, A; Gonz�lez, H; Gonz�lez, D; Garc�a, L; Cardoso, D; Norheim, G; Rosenqvist, E
Comparative study of the neurotrophic effects elicited by VEGF-B and GDNF in preclinical in vivo models of Parkinson's disease.
Vascular endothelial growth factor B (VEGF-B) has recently been shown to be a promising novel neuroprotective agent for several neurodegenerative conditions. In the current study we extended previous work on neuroprotective potential for Parkinson's disease (PD) by testing an expanded dose range of VEGF-B (1 and 10 ?g) and directly comparing both neuroprotective and neurorestorative effects of VEGF-B in progressive unilateral 6-hydroxydopamine (6-OHDA) PD models to a single dose of glial cell line-derived neurotrophic factor (GDNF, 10 ?g), that has been established by several groups as a standard in both preclinical PD models. In the amphetamine-induced rotational tests the treatment with 1 and 10 ?g VEGF-B resulted in significantly improved motor function of 6-OHDA-lesioned rats compared to vehicle-treated 6-OHDA-lesioned rats in the neuroprotection paradigm. Both doses of VEGF-B caused an increase in tyrosine hydroxylase (TH)-positive cell and fiber count in the substantia nigra (SN) and striatum in the neuroprotective experiment. The effect size was comparable to the effects seen with GDNF. In the neurorestoration paradigm, VEGF-B injection had no significant effect in either the behavioral or the immunohistochemical analyses, whereas GDNF injection significantly improved the amphetamine-induced rotational behavior and reduced TH-positive neuronal cell loss in the SN. We also present a strong positive correlation (p=1.9e-50) of the expression of VEGF-B with nuclear-encoded mitochondrial genes involved in fatty acid metabolism in rat midbrain, pointing to the mitochondria as a site of action of VEGF-B. GDNF showed a positive correlation with nuclear-encoded mitochondrial genes that was not nearly as strong (p=0.018). VEGF-B counteracted rotenone-induced reduction of (a) fatty acid transport protein 1 and 4 levels and (b) both Akt protein and phosphorylation levels in SH-SY5Y cells. We further verified VEGF-B expression in the human SN pars compacta of healthy controls and PD patients, in neuronal cells that show co-expression with neuromelanin. These results have demonstrated that VEGF-B has potential as a neuroprotective agent for PD therapy and should be further investigated. PMID:24291725
Yue, X; Hariri, D J; Caballero, B; Zhang, S; Bartlett, M J; Kaut, O; Mount, D W; W�llner, U; Sherman, S J; Falk, T
Preclinical multimodality phantom design for quality assurance of tumor size measurement
Background Evaluation of changes in tumor size from images acquired by ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) is a common measure of cancer chemotherapy efficacy. Tumor size measurement based on either the World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST) is the only imaging biomarker for anti-cancer drug testing presently approved by the United States Food and Drug Administration (FDA). The aim of this paper was to design and test a quality assurance phantom with the capability of monitoring tumor size changes with multiple preclinical imaging scanners (US, CT and MRI) in order to facilitate preclinical anti-cancer drug testing. Methods Three phantoms (Gammex/UTHSCSA Mark 1, Gammex/UTHSCSA Mark 2 and UTHSCSA multimodality tumor measurement phantom) containing tumor-simulating test objects were designed and constructed. All three phantoms were scanned in US, CT and MRI devices. The size of test objects in the phantoms was measured from the US, CT and MRI images. RECIST, WHO and volume analyses were performed. Results The smaller phantom size, simplified design and better test object CT contrast of the UTHSCSA multimodality tumor measurement phantom allowed scanning of the phantom in preclinical US, CT and MRI scanners compared with only limited preclinical scanning capability of Mark 1 and Mark 2 phantoms. For all imaging modalities, RECIST and WHO errors were reduced for UTHSCSA multimodality tumor measurement phantom (?1.69 � 0.33%) compared with both Mark 1 (? -7.56 � 6.52%) and Mark 2 (? 5.66 � 1.41%) phantoms. For the UTHSCSA multimodality tumor measurement phantom, measured tumor volumes were highly correlated with NIST traceable design volumes for US (R2 = 1.000, p < 0.0001), CT (R2 = 0.9999, p < 0.0001) and MRI (R2 = 0.9998, p < 0.0001). Conclusions The UTHSCSA multimodality tumor measurement phantom described in this study can potentially be a useful quality assurance tool for verifying radiologic assessment of tumor size change during preclinical anti-cancer therapy testing with multiple imaging modalities.
Preliminary study of the safety and efficacy of extended-release oxybutynin in children
Objectives. To test the safety and efficacy of extended-release oxybutynin in children with bladder dysfunction. The efficacy of oxybutynin in children has been limited by side effects. A new extended-release formulation of oxybutynin has some benefits versus traditional oxybutynin but has never been evaluated in children.Methods. A retrospective study was performed on 25 children who had been treated with extended-release
Katrin Youdim; Barry A. Kogan
Neuropsychological and neuroimaging changes in preclinical Alzheimer's disease
Alzheimer's disease (AD) is a common, devastating form of dementia. With the advent of promising symptomatic treatment, the importance of recognizing AD at its very earliest stages has increased. We review the extant neuropsychological and neuroimaging literature on preclinical AD, focusing on longitudinal studies of initially nondemented individuals and cross-sectional investigations comparing at-risk with normal individuals. We systematically reviewed 91 studies of neuropsychological functioning, structural neuroimaging, or functional neuroimaging in preclinical AD. The neuropsychological studies indicated that preclinical AD might be characterized by subtle deficits in a broad range of neuropsychological domains, particularly in attention, learning and memory, executive functioning, processing speed, and language. Recent findings from neuroimaging research suggest that volume loss and cerebral blood flow or metabolic changes, particularly in the temporal lobe, may be detected before the onset of dementia. There exist several markers of a preclinical period of AD, in which specific cognitive and biochemical changes precede the clinical manifestations. The preclinical indicators of AD reflect early compromise of generalized brain integrity and temporal lobe functioning in particular.
MRI-monitored transcatheter intraarterial delivery of SPIO-labeled natural killer cells to hepatocellular carcinoma: preclinical studies in a rodent model
Object To test the hypotheses that intraarterial (IA) infusion allows for targeted natural killer (NK) lymphocyte delivery to hepatocellular carcinoma (HCC) and that iron oxide labeling allows for quantitative visualization of IA NK delivery with magnetic resonance imaging (MRI). Materials and Methods Experiments received institutional animal care and use committee approval. NK-92MI cells were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Cell viability, labeling efficacy, and cell phantom imaging studies were performed. Six rats were each implanted with two HCC tumors. Catheter was placed in proper hepatic artery for NK infusion. MRI T2* measurements for tumor and normal liver were compared pre and post infusion and correlated with histological measurements; Prussian blue staining was used for labeled NK identification. Spearman correlation coefficients and t-tests were calculated for statistical analyses. Results Increasing SPIO incubation concentration decreased cell viability. Labeling efficacy was 88.0�3.1% (mean�SD) across samples. The spatial extent of T2*-weighted contrast and R2* relaxivity values increased for cell phantom samples incubated with increasing SPIO concentrations. T2* measurements decreased in the tumor and normal liver tissues after NK infusion (p<0.001); ?T2* was greater in tumors than in normal liver tissue (p<0.001). Histological measurements demonstrated increased NK delivery to the tumor compared to the normal liver (p<0.001). ?T2* was well-correlated with histological NK measurements (?=0.70). Conclusion IA infusion permitted selective delivery of NK cells to HCC. Transcatheter delivery of SPIO-labeled NK cells can be quantitatively visualized with MRI.
Sheu, Alexander Y.; Zhang, Zhuoli; Omary, Reed A.; Larson, Andrew C.
A Cross-Sectional Study of Engineering Students' Self-Efficacy by Gender, Ethnicity, Year, and Transfer Status
ERIC Educational Resources Information Center
This is a cross-sectional study of 519 undergraduate engineering majors' self-efficacy beliefs at a large, research extensive, Midwestern university. Engineering self-efficacy is an individual's belief in his or her ability to successfully negotiate the academic hurdles of the engineering program. Engineering self-efficacy was obtained from four�
Concannon, James P.; Barrow, Lloyd H.
Preclinical and Clinical Evaluation of Intraductally Administered Agents in Early Breast Cancer
Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N�-nitrosourea�treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for �breast-sparing mastectomy� in select women.
Stearns, Vered; Mori, Tsuyoshi; Jacobs, Lisa K.; Khouri, Nagi F.; Gabrielson, Edward; Yoshida, Takahiro; Kominsky, Scott L.; Huso, David L.; Jeter, Stacie; Powers, Penny; Tarpinian, Karineh; Brown, Regina J.; Lange, Julie R.; Rudek, Michelle A.; Zhang, Zhe; Tsangaris, Theodore N.; Sukumar, Saraswati
Navigating non-positivity in neighbourhood studies: an analysis of collective efficacy and violence
Background In multilevel studies, strong correlations of neighbourhood exposures with individual and neighbourhood confounders may generate problems with non-positivity (ie, inferences that are `off-support'). The authors used propensity restriction and matching to (1) assess the utility of propensity restriction to ensure analyses are `on-support' and (2) examine the relation between collective efficacy and violence in a previously unstudied city. Methods Associations between neighbourhood collective efficacy and violent victimisation were estimated in data from New York City in 2005 (n=4000) using marginal models and propensity matching. Results In marginal models adjusted for individual confounders and limited to observations `on-support', under conditions of high collective efficacy, the estimated prevalence of violent victimisation was 3.5/100, while under conditions of low collective efficacy, it was 7.5/100, resulting in a difference of 4.0/100 (95% CI 2.6 to 5.8). In propensity-matched analysis, the comparable difference was 4.0/100 (95% CI 2.1 to 5.9). In analyses adjusted for individual and neighbourhood confounders and limited to observations 'on-support', the difference in violent victimisation associated with collective efficacy was 3.1/100 (95% CI 1.2 to 5.2) in marginal models and 2.4/100 (95% CI 0.2 to 4.5) in propensity-matched analysis. Analyses without support restrictions produced surprisingly similar results. Conclusions Under conditions of high collective efficacy, there was about half the prevalence of violence compared with low collective efficacy. The results contribute to a growing body of evidence that suggests collective efficacy may shape violence, and illustrate how careful techniques can be used to disentangle exposures from highly correlated confounders without relying on model extrapolation.
Ahern, Jennifer; Cerda, Magdalena; Lippman, Sheri A; Tardiff, Kenneth J; Vlahov, David; Galea, Sandro
Lesson study: Professional development and its impact on science teacher self-efficacy
NASA Astrophysics Data System (ADS)
This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal relationships is a relevant consideration in the development of science teacher's self-efficacy. From this study, it is apparent that teachers who are collaboratively involved in a supportive setting such as lesson study can increase their level of self-efficacy and thus improve their teaching practice.
Roberts, Megan Rae
Sleep quality and preclinical Alzheimer Disease
Objective Sleep and circadian problems are very common in Alzheimer Disease (AD). Recent animal studies suggest a bidirectional relationship between sleep and amyloid-? (A?), a key molecule involved in AD pathogenesis. This study tested whether A? deposition in preclinical AD, prior to the appearance of cognitive impairment, is associated with changes in quality or quantity of sleep. Methods Cognitively normal, middle-aged individuals (n=142) had sleep objectively measured using actigraphy for 2 weeks. Concurrent sleep diaries provided nap information. Cerebrospinal fluid A?42 levels were used to determine whether amyloid deposition was present or absent. Sleep parameters were assessed with regard to amyloid deposition. Results Amyloid deposition was associated with worse sleep quality, specifically worse sleep efficiency (% time in bed that was spent asleep), compared to those without amyloid deposition. In contrast, quantity of sleep was not different between groups, as measured by total sleep time. Frequent napping was associated with amyloid deposition. Interpretation Amyloid deposition in the preclinical stage of AD appears to be associated with worse sleep quality, but not with changes in sleep quantity.
Ju, Yo-El S.; McLeland, Jennifer S.; Toedebusch, Cristina D.; Xiong, Chengjie; Fagan, Anne M; Duntley, Stephen P.; Morris, John C.; Holtzman, David M.
Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation
Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.
McMillin, Douglas W.; Delmore, Jake; Negri, Joseph; Ooi, Melissa; Klippel, Steffen; Miduturu, Chandrasekhar V.; Gray, Nathanael S.; Richardson, Paul G.; Anderson, Kenneth C.; Kung, Andrew L.; Mitsiades, Constantine S.
Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28.
Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2r? knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo. PMID:24598534
Poirier, Nicolas; Mary, Caroline; Le Bas-Bernardet, Stephanie; Daguin, Veronique; Belarif, Lyssia; Chevalier, Melanie; Hervouet, Jeremy; Minault, David; Ville, Simon; Charpy, Vianney; Blancho, Gilles; Vanhove, Bernard
Novel anticonvulsants for reducing alcohol consumption: A review of evidence from preclinical rodent drinking models
Alcohol use disorders (AUDs) are a major public health issue and have an enormous social and economic burden in developed, developing, and third-world countries. Current pharmacotherapies for treating AUDs suffer from deleterious side effects and are only effective in preventing relapse in a subset of individuals. This signifies an essential need for improved medications to reduce heavy episodic drinking and alcohol-related problems. Growing literature has provided support for the use of anticonvulsants in suppressing symptoms induced by alcohol withdrawal. Emerging clinical and preclinical evidence suggests that a number of well-tolerated anticonvulsants may also decrease alcohol drinking. This review will focus on recent evidence supporting the efficacy of novel anticonvulsants in reducing voluntary alcohol consumption in rodent models. The data demonstrate that anticonvulsants reduce drinking in standard home cage two-bottle choice paradigms, self-administration of alcohol in operant chambers, and cue- and stress-induced reinstatement of alcohol seeking behaviors in rats and mice. This review also highlights evidence that some anticonvulsants were only moderately effective in reducing drinking in select strains of rodents or models. This suggests that genetics, possible neuroadaptations, or the pharmacological target affect the ability of anticonvulsants to attenuate alcohol consumption. Nonetheless, anticonvulsants are relatively safe, have little abuse potential, and can work in combination with other drugs. The results from these preclinical and clinical studies provide compelling evidence that anticonvulsants are a promising class of medication for the treatment of AUDs.
Griffin, WC; Lopez, MF; Becker, HC; Mulholland, PJ
A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models.
Antibodies targeting the Clostridium difficile toxin A and toxin B confer protective immunity to C. difficile associated disease in animal models and provided protection against recurrent C. difficile disease in human subjects. These antibodies are directed against the receptor binding domains (RBD) located in the carboxy-terminal portion of both toxins and inhibit binding of the toxins to their receptors. We have constructed a recombinant fusion protein containing portions of the RBD from both toxin A and toxin B and expressed it in Escherichia coli. The fusion protein induced high levels of serum antibodies to both toxins A and B capable of neutralizing toxin activity both in vitro and in vivo. In a hamster C. difficile infection model, immunization with the fusion protein reduced disease severity and conferred significant protection against a lethal dose of C. difficile spores. Our studies demonstrate the potential of the fusion protein as a vaccine that could provide protection from C. difficile disease in humans. PMID:22537987
Tian, Jing-Hui; Fuhrmann, Steven R; Kluepfel-Stahl, Stefanie; Carman, Robert J; Ellingsworth, Larry; Flyer, David C
MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications
Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications.
Meng, Ellis; Hoang, Tuan
Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research
There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages.
Mata, Elena; Salvador, Aiala; Igartua, Manoli; Hernandez, Rosa Maria; Pedraz, Jose Luis
Intravenous Immunoglobulin (IVIG) Treatment Exerts Antioxidant and Neuropreservatory Effects in Preclinical Models of Alzheimer's Disease.
Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent. PMID:24760109
Counts, Scott E; Ray, Balmiki; Mufson, Elliott J; Perez, Sylvia E; He, Bin; Lahiri, Debomoy K
Pomegranate Extracts in the Management of Men's Urologic Health: Scientific Rationale and Preclinical and Clinical Data
Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical in vitro and in vivo studies. Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in the management of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.
N., Kroeger; A. S., Belldegrun; A. J., Pantuck
Outcomes of usual chiropractic, harm & efficacy, the ouch study: study protocol for a randomized controlled trial
Background Previous studies have demonstrated that adverse events occur during chiropractic treatment. However, because of these studies design we do not know the frequency and extent of these events when compared to sham treatment. The principal aims of this study are to establish the frequency and severity of adverse effects from short term usual chiropractic treatment of the spine when compared to a sham treatment group. The secondary aim of this study is to establish the efficacy of usual short term chiropractic care for spinal pain when compared to a sham intervention. Methods One hundred and eighty participants will be randomly allocated to either usual chiropractic care or a sham intervention group. To be considered for inclusion the participants must have experienced non-specific spinal pain for at least one week. The study will be conducted at the clinics of registered chiropractors in Western Australia. Participants in each group will receive two treatments at intervals no less than one week. For the usual chiropractic care group, the selection of therapeutic techniques will be left to the chiropractors' discretion. For the sham intervention group, de-tuned ultrasound and de-tuned activator treatment will be applied by the chiropractors to the regions where spinal pain is experienced. Adverse events will be assessed two days after each appointment using a questionnaire developed for this study. The efficacy of short term chiropractic care for spinal pain will be examined at two week follow-up by assessing pain, physical function, minimum acceptable outcome, and satisfaction with care, with the use of the following outcome measures: Numerical Rating Scale, Functional Rating Index, Neck Disability Index, Minimum Acceptable Outcome Questionnaire, Oswestry Disability Index, and a global measure of treatment satisfaction. The statistician, outcome assessor, and participants will be blinded to treatment allocation. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000542998
Micro-ultrasound for preclinical imaging
Over the past decade, non-invasive preclinical imaging has emerged as an important tool to facilitate biomedical discovery. Not only have the markets for these tools accelerated, but the numbers of peer-reviewed papers in which imaging end points and biomarkers have been used have grown dramatically. High frequency �micro-ultrasound� has steadily evolved in the post-genomic era as a rapid, comparatively inexpensive imaging tool for studying normal development and models of human disease in small animals. One of the fundamental barriers to this development was the technological hurdle associated with high-frequency array transducers. Recently, new approaches have enabled the upper limits of linear and phased arrays to be pushed from about 20 to over 50 MHz enabling a broad range of new applications. The innovations leading to the new transducer technology and scanner architecture are reviewed. Applications of preclinical micro-ultrasound are explored for developmental biology, cancer, and cardiovascular disease. With respect to the future, the latest developments in high-frequency ultrasound imaging are described.
Foster, F. Stuart; Hossack, John; Adamson, S. Lee
Enzalutamide: looking back at its preclinical discovery.
Introduction: In patients with metastatic prostate cancer (PCa), castration is the standard first-line therapy. However, all patients eventually develop castration-recurrent PCa (CRPC). In these patients who fail the first-line therapy, enzalutamide has emerged as a viable alternative. Enzalutamide is a second-generation small molecule androgen receptor (AR) antagonist that blocks the AR nuclear translocation and DNA binding without any known AR agonist activity. Areas covered: This review provides an overview of the history of the oral selective AR modulator, enzalutamide, and discusses its discovery and current preclinical experimental results including resistance mechanisms. The article illustrates the history of discovery based on enzalutamide's mechanism of action. Furthermore, the authors highlight the drug's clinical development and post-launch developments. Expert opinion: The landscape of CRPC has changed dramatically over the last few years, as new agents with proven benefit in overall survival have been approved. Compared to the average time of 10 - 15 years for a new drug to go from pre-clinical discovery to registration, enzalutamide obtained FDA approval in < 6 years after its initial characterization. Enzalutamide, a targeted agent of the androgen-AR axis, has shown promising results in CRPC and is generally well tolerated. However, drug resistance inevitably emerges is a severe limitation. The authors believe that further clinical studies that look at its use as either a combinational or sequential therapy could help to address these concerns. PMID:24820058
Ha, Yun-Sok; Kim, Isaac Yi
PREVENT Cancer Preclinical Drug Development Program
The PREVENT Cancer Drug Development Program is a National Cancer Institute-supported pipeline to bring new cancer preventing interventions and biomarkers through preclinical development towards clinical trials.
Flowing together: a longitudinal study of collective efficacy and collective flow among workgroups.
The aim of this study is to extend the Channel Model of Flow (Csikszentmihalyi, 1975, 1990) at the collective level (workgroups) by including collective efficacy beliefs as a predictor of collective flow based on the Social Cognitive Theory (Bandura, 1997, 2001). A two-wave longitudinal lab study was conducted with 250 participants working in 52 small groups. Longitudinal results from Structural Equation Modeling with data aggregated at the group level showed, as expected, that collective efficacy beliefs predict collective flow over time, both being related reciprocally. Findings and their theoretical and practical implications in the light of Social Cognitive Theory are discussed. PMID:24946388
Salanova, Marisa; Rodr�guez-S�nchez, Alma M; Schaufeli, Wilmar B; Cifre, Eva
Science knowledge and efficacy beliefs among preservice elementary teachers: A follow-up study
NASA Astrophysics Data System (ADS)
Slightly over two years ago aspects of knowledge and efficacy beliefs among preservice elementary teachers regarding science education were examined. Those results indicated a low level of science knowledge and a marked lack of confidence toward teaching science among prospective teachers. In the interim suggestions from that study have resulted in an increase in the number of required science courses that have been implemented in the teacher education program. The current, follow-up, study, found no increase in science content knowledge but did identify positive changes in efficacy beliefs. The results are discussed relative to Locus of Control theory.
Wenner, George
Efficacy of Eight Months of Nightly Zolpidem: A Prospective Placebo-Controlled Study
Study Objectives: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Sleep disorders and research center. Participants: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. Interventions: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and Results: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Randall S; Roehrs TA; Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. SLEEP 2012;35(11):1551-1557.
Randall, Surilla; Roehrs, Timothy A.; Roth, Thomas
The Study of Foreign Language Teachers-- Teacher Efficacy and Native Speakership
ERIC Educational Resources Information Center
This study aims at examining the differences between native and nonnative foreign language teachers at a major northeast university. The primary areas of investigation are "teacher efficacy" and "teacher perceptions of language teaching." The results of this study suggested that both nativeness and wide repertoire of teaching experience and�
Liaw, En-Chong
Case Study: Influence of Tracking on Achievement, Self-Efficacy and Instruction
ERIC Educational Resources Information Center
Focusing on a suburban Philadelphia high school's social studies classes, this research study investigated the influence of tracking on student achievement, on teachers' and students' perceptions of self-efficacy, and on teachers' instructional practices in the classroom. In order to address these research questions, the researcher used a�
Butz, Toni R.
A Reliability Generalization Study of the Teacher Efficacy Scale and Related Instruments.
ERIC Educational Resources Information Center
Studied sources of measurement error variance in the Teacher Efficacy Scale (TES) (Gibson and Dembo, 1984). Used reliability generalization to characterize the typical score reliability for the TES and potential sources of measurement error variance across 43 studies. Also examined related instruments for measurement integrity. (SLD)
Henson, Robin K.; Kogan, Lori R.; Vacha-Haase, Tammi
Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors
Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.
Radio-decontamination efficacy and safety studies on optimized decontamination lotion formulation.
Objective of the present study was to optimize decontamination lotion and to evaluate its relative decontamination efficacy using three radio-isotopes (Technetium-99m, Iodine-131 and Thallium-201) as contaminants with varying length of contaminant exposure (0-1h). Experiments were performed on Sprague Dawley rat's intact skin and human tissue equivalent models. Rat's hair was removed by using depilator after trimming with scissors. Relative decontamination efficacy of the optimized lotion was investigated and compared with water as control. Static counts were recorded before and after decontamination using single photon emission computed tomography (SPECT). Measured decontamination efficacy (DE) values were analyzed using one way ANOVA and Student's t-test (p value<0.05) and were found statistically significant. Decontamination efficacy of the lotion was observed to be 90 � 5%, 80 � 2% and 85 � 2%, for the (131)I, (201)Tl and (99m)Tc radio-contaminants respectively on skin. Reduced contaminant removal was recorded for the skin which was cleaned by depilator (50-60%). Skin decontamination was found more efficacious for rat skin decontamination than the human tissue equivalent model. Decontamination efficacy of the lotion against (99m)Tc was recorded 70 � 15% at 0-1h on the tissue equivalent model. In vitro chelation efficacy of the lotion was also established by using the instant thin layer chromatography-slica gel (ITLC-SG) and >95% of (99m)Tc was recorded. Neither erythema nor edema was scored in the primary skin irritancy test visually observed for two weeks. PMID:22609966
Rana, S; Bhatt, S; Dutta, M; Khan, A W; Ali, J; Sultana, S; Kotta, S; Ansari, S H; Sharma, R K
Modeling risk factors for nicotine and other drug abuse in the preclinical laboratory
Risk factors that predict vulnerability for nicotine and other drug abuse have been identified using preclinical models, and there is close agreement with clinical and epidemiological studies. The major risk factors to be discussed are age, sex\\/hormonal status, impulsivity, sweet-liking, novelty reactivity, proclivity for exercise, and environmental impoverishment (vs. enrichment). This discussion will focus on factors that preclinical research has
Marilyn E. Carroll; Justin J. Anker; Jennifer L. Perry
EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms
Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with
Michael Baumann; Mechthild Krause; Ekkehard Dikomey; Klaus Dittmann; Wolfgang D�rr; Ulla Kasten-Pisula; H. Peter Rodemann
Preclinical Efficacy of a Carboxylesterase 2-Activated Prodrug of Doxazolidine
Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homolog, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment.
Barthel, Benjamin L.; Zhang, Zhiyong; Rudnicki, Daniel L.; Coldren, Christopher D.; Polinkovsky, Margaret; Sun, Hengrui; Koch, Gary G.; Chan, Daniel C.F.; Koch, Tad H.
Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research.
Electroencephalography (EEG) and related methodologies offer the promise of predicting the likelihood that novel therapies and compounds will exhibit clinical efficacy early in preclinical development. These analyses, including quantitative EEG (e.g. brain mapping) and evoked/event-related potentials (EP/ERP), can provide a physiological endpoint that may be used to facilitate drug discovery, optimize lead or candidate compound selection, as well as afford patient stratification and Go/No-Go decisions in clinical trials. Currently, the degree to which these different methodologies hold promise for translatability between preclinical models and the clinic have not been well summarized. To address this need, we review well-established and emerging EEG analytic approaches that are currently being integrated into drug discovery programs throughout preclinical development and clinical research. Furthermore, we present the use of EEG in the drug development process in the context of a number of major central nervous system disorders including Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder, and pain. Lastly, we discuss the requirements necessary to consider EEG technologies as a biomarker. Many of these analyses show considerable translatability between species and are used to predict clinical efficacy from preclinical data. Nonetheless, the next challenge faced is the selection and validation of EEG endpoints that provide a set of robust and translatable biomarkers bridging preclinical and clinical programs. PMID:20937262
Leiser, Steven C; Dunlop, John; Bowlby, Mark R; Devilbiss, David M
Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.
Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey. PMID:15500257
Koll, R; Buhr, M; Dieter, R; Pabst, H; Predel, H G; Petrowicz, O; Giannetti, B; Klingenburg, S; Staiger, C
Longitudinal Study: Efficacy of Online Technology Tools for Instructional Use.
National Technical Information Service (NTIS)
Studies show that the student population (secondary and post secondary) is becoming increasingly more technologically savvy. Use of the internet, computers, MP3 players, and other technologies along with online gaming has increased tremendously amongst th...
M. D. Uenking
[An experimental study of the efficacy of enterosorbents in salmonellosis].
The effectiveness of enterosorbents (polymethylsiloxane used as enterosgel and activated charcoal) has been studied in experiments on white rats infected with low virulent Salmonella typhimurium strain N 79. As shown in this study, the use of sorbents normalizes the morphofunctional characteristics of the epithelium of the small intestine and decreases the degree of Salmonella colonization of the parietal layer in the lumen of the small intestine, causing the destruction of some adsorbed bacteria. PMID:8017132
Nikolaeva, L G; Grigor'ev, A V; Znamenski?, V A; Koval'chuk, V K; Alekseenko, E P
[Effectiveness of preclinical emergency management. Fiction or fact?].
The current increase in the cost of health care must be considered as a severe threat to the prehospital emergency services system. Two examples have been selected--the patient with polytrauma and the patient in cardiac arrest--to demonstrate the dilemma between a need for objective data and the requirements of emergency patients. Study results obtained in trauma patients indicating that total prehospital time, including scene time, is correlated to patient outcome have led to the conclusion that at the scene treatment by emergency physicians may be dispensable. It has, however also been demonstrated that the time required for medical treatment at the scene is equivalent to 20% of the total scene time, thus representing only a fraction of the total prehospital time. Correlating the total prehospital time or scene time to outcome therefore appears absurd. The treatment principle of aggressive shock treatment in polytrauma needs critical reevaluation on the basis of results obtained by recent preclinical studies in patients with penetrating torso injuries. Small volume resuscitation could not be demonstrated to improve outcome in polytrauma patients, although a slight improvement in patients with brain injury may be assumed. Endotracheal intubation and early artificial ventilation are proven therapeutic principles in polytraumatized patients. Unfortunately, for ethical reasons randomised carefully controlled comparative studies can not be performed in polytrauma patients unless the patient is fully conscious. The importance of endotracheal intubation and artificial ventilation in unconscious trauma patients becomes apparent under conditions of anaesthesia where the application of the endotracheal tube averts regurgitation, aspiration and concomitant morbidity and mortality. The common causes of cardiovascular collapse and their pathomechanisms, as well as the mechanisms of cardiopulmonary resuscitation, have been widely investigated. Nevertheless, various aspects of their application are still controversial. The most recent study results have recommended initial ventilation prior to thoracic compression. New methods of assisting mechanical cardiopulmonary resuscitation, such as ACD CPR or vest CPR, have shown promising results in animal experiments. However, the importance of results obtained by preclinical randomised controlled investigations in humans need to be confirmed by further studies as to outcome. The efficacy of defibrillation in cases of ventricular fibrillation has been clearly demonstrated, particularly with a view to the interval between ventricular fibrillation and defibrillation. It has further been demonstrated that basic cardiopulmonary resuscitation preserves ventricular fibrillation and thus improves the chance of survival. The present generation of defibrillators has been further improved, particularly by the introduction of biphasic defibrillator wave forms, which may reduce the required energy, as well as possible complications, while offering an increase in the efficacy of defibrillation and a reduction in defibrillator size. Scientific emergency medicine is responsible not only for the development and validation of new methods and concepts, but in particular for their application under quality control conditions. Politicians require an improvement in the quality of the validation of emergency measures, although the instruments available for the investigation of these measures are known to be obsolete (experimental models, experimental design). Additionally, the financial support of research in emergency medicine suffers from being accourded low priority by public research funds such as the German Research Fund. However, in view of the rapid application of experimental results to daily practice it should be emphasized that patients also support research in emergency medicine via their direct financial contributions to the health insurance companies. PMID:8678283
Dick, W F
Discourse-Based Language Intervention: An Efficacy Study.
ERIC Educational Resources Information Center
This study of a 5-year-old girl with sensorineural hearing loss examined the effect of supplementing a pragmatically based procedure of focused stimulation with structured opportunities for verbal practice using vertical constructions. Results indicated that focused stimulation was an effective treatment procedure, especially when enhanced by the�
Skarakis-Doyle, Elizabeth; Murphy, Lisa
Joint modeling of clinical efficacy and safety with an application to diabetes studies.
The purpose of drug development is to evaluate a drug's efficacy and safety profile. For a personalized medicine, it is important for patients and health care providers to understand the efficacy and safety trade-off when selecting a dose for a patient. In this article, we propose three different methods for jointly modeling the clinical safety and efficacy endpoints. These three methods model the correlation relationship in three different ways: modeling the joint distribution by a copula method, modeling conditional distributions, and modeling their correlations through individual means by a hierarchical model. We compare these three methods through simulations and apply these methods to a data set from a diabetes study. PMID:23957521
Zhao, Yang; Shen, Wei; Fu, Haoda
Tentative fingerprint-efficacy study of Houttuynia cordata injection in quality control of traditional Chinese medicine.
To establish potent fingerprint for quality control of traditional Chinese medicine, Houttuynia cordata (Saururaceae) injection (HCI), the attempt on fingerprint-efficacy was developed in this study. HCI from ten different factories were determined by gas chromatography-mass spectrum (GC-MS) and classified by hierarchical clustering. The anti-inflammatory effect of HCI was characterized with the rat pleurisy model induced by carrageenin and the mice ear edema model by xylene. The results showed that anti-inflammatory effect of the injections from most of factories on the two models was significant. There was corresponding relationship between the fingerprint of HCI and efficacy to certain extent. The main common constitutes in injection from the factories that possess anti-inflammatory activity were analysed with GC-MS and identified using the NIST Mass Spectral Database. This common pattern of HCI based on the efficacy was helpful for the purpose of quality control. PMID:16651779
Lu, Hong-Mei; Liang, Yi-Zeng; Wu, Xian-Jin; Qiu, Ping
Buprederm�, a New Transdermal Delivery System of Buprenorphine: Pharmacokinetic, Efficacy and Skin Irritancy Studies
Purpose��The pharmacokinetics, analgesic efficacy, and irritancy potential of Buprederm�, a new transdermal delivery system of buprenorphine,\\u000a was evaluated.\\u000a \\u000a \\u000a \\u000a Methods��Single and multiple dose pharmacokinetic studies were conducted in mice and rabbits. The analgesic efficacy and skin irritation\\u000a potential were determined by tail flick and writhing tests in mice and by the Draize dermal scoring system in rabbits.\\u000a \\u000a \\u000a \\u000a Results��Fast absorption of buprenorphine
Dongwon Kim; Jindeog Song; Chang Hoon In; Seung-Wei Jeong; Sang Hun Lee; Bumchan Min; Dongho Lee; Sun-Ok Kim
Study of the comparative efficacy of toltrazuril and diclazuril against ovine coccidiosis in housed lambs.
A blinded, controlled and randomised field study was conducted on a sheep farm with a known history of coccidiosis and a high prevalence mainly of the pathogenic coccidium Eimeria ovinoidalis. The efficacy of treatment with toltrazuril (Baycox 5% suspension) against natural infections with Eimeria crandallis and/or Eimeria ovinoidalis in housed lambs was investigated in comparison with diclazuril and untreated controls. Both drugs were administered either metaphylactically (i.e., in the prepatency of Eimeria spp.) or therapeutically (after onset of oocyst excretion). A total of 145 animals aged 1 to 5 days at the start of the study were included. Examination of faecal samples was performed every second day between days 13 and 49 of the study. The assessment of treatment efficacy was based mainly on total oocyst excretion and the number of E. crandallis and E. ovinoidalis oocysts (OPG) shed throughout the study. Oocyst excretion was reduced significantly in both groups treated with toltrazuril compared with the untreated control group and with both diclazuril-treated groups. The most prevalent and most severe diarrhoea was observed in the untreated control group. In this study, toltrazuril proved to be highly effective in controlling ovine coccidiosis both metaphylactically and therapeutically. The efficacy of toltrazuril was significantly higher than the efficacy of the control substance with regard to the duration and amount of oocyst excretion, both for the comparison of metaphylactic as well as therapeutic treatment. PMID:19575235
Mundt, Hans-Christian; Dittmar, Katja; Daugschies, Arwid; Grzonka, Elmar; Bangoura, Berit
Examining motivations, efficacy and interest in graduate study among teacher participants of a summer institute
NASA Astrophysics Data System (ADS)
This study examined changes in self and general science teaching efficacy of teachers attending an environmental sciences summer institute in which they earned three hours of graduate credit. The Science Teaching Efficacy Belief Instrument Form A (STEBI A) (Riggs, 1988) was administered as a pretest and posttest at nine Texas universities during June and July of 1997. The population of 145 teachers voluntarily participated in the graduate course, Teaching Environmental Sciences (TES), co-sponsored by the state's regulatory agency, the Texas Natural Resource Conservation Commission and nine Texas universities. Demographic data and data related to teacher motivation were collected as an addendum to the STEBI A. Teacher participants' apparent motivation(s) to attend TES in the absence of state and district staff development mandates were examined. Correlations between demographic data and efficacy responses were analyzed. Qualitative data collected through telephone interviews with TES teachers examined participants' interest in entering graduate studies following this summer institute, particularly with respect to science-related advanced degrees. Generally, the data revealed an increase in science teaching efficacy on posttests, particularly with respect to positively stated STEBI items. Motivations of teachers to attend this summer institute were largely influenced by interest in the subject and an apparent interest in enhancing their skills and pedagogy. The data related to teacher participants' intent to enter graduate study was inconclusive. The information provided through interviews with professors was, however, encouraging but not conclusive with respect to this study and teachers' entering graduate studies following participation in the summer institute.
Hefty, Eunice Ann
Preclinical dosimetry of magnetic fluid hyperthermia for bladder cancer
NASA Astrophysics Data System (ADS)
Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42�C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder >1�C/min to a steady-state of 42�C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.
Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.
Preclinical Dosimetry of Magnetic Fluid Hyperthermia for Bladder Cancer
Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42�C in <10min and maintaining for 60min. Temperatures were measured throughout the rat with seven fiberoptic temperature probes (OpSens Technologies, Quebec Canada) to characterize our ability to localize heat within the bladder target. Results The MRI study confirms the effectiveness of the catheterization procedure to homogenously distribute nanoparticles throughout the bladder. Thermal dosimetry data demonstrate our ability to controllably raise temperature of rat bladder ?1�C/min to a steady-state of 42�C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.
Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.
Exercise Self-Efficacy and Perceived Wellness among College Students in a Basic Studies Course
ERIC Educational Resources Information Center
University basic studies courses provide a valuable opportunity for facilitating the knowledge, skills, and beliefs that develop healthy behaviors to last a lifetime. Belief in one's ability to participate in physical activity, exercise self-efficacy, is a psychological construct that has had a documented impact on physical activity. Although�
Sidman, Cara L.; D'Abundo, Michelle Lee; Hritz, Nancy
A Study of Teachers' Sense of Efficacy. Final Report, Executive Summary.
ERIC Educational Resources Information Center
A conceptual framework for the study of teachers' sense of efficacy was used to determine the extent to which teachers believed they could influence student learning. The framework was based on an extensive review of research literature on teaching, an ethnographic comparison of 2 organizationally different middle schools, and a process-product�
Ashton, Patricia T.; And Others
Pain self-efficacy beliefs and pain behaviour. A prospective study
This study examined the relationship between pain self-efficacy beliefs and a range of pain behaviours, as measured by the pain behaviour questionnaire (PBQ), using a prospective design. A heterogeneous sample of 145 chronic pain patients completed sets of questionnaires on four occasions over a nine-month period. Multiple hierarchical regression analyses revealed that the subjects' confidence in their ability to perform
Ali Asghari; Michael K Nicholas
Evaluating the efficacy of test-driven development: industrial case studies
This paper discusses software development using the Test Driven Development (TDD) methodology in two different environments (Windows and MSN divisions) at Microsoft. In both these case studies we measure the various context, product and outcome measures to compare and evaluate the efficacy of TDD. We observed a significant increase in quality of the c ode (greater than two times) for
Thirumalesh Bhat; Nachiappan Nagappan
The COACH prompting system to assist older adults with dementia through handwashing: An efficacy study
BACKGROUND: Many older adults with dementia require constant assistance from a caregiver when completing activities of daily living (ADL). This study examines the efficacy of a computerized device intended to assist people with dementia through ADL, while reducing caregiver burden. The device, called COACH, uses artificial intelligence to autonomously guide an older adult with dementia through the ADL using audio
Alex Mihailidis; Jennifer N Boger; Tammy Craig; Jesse Hoey
Math and Science Pursuits: A Self-Efficacy Intervention Comparison Study
ERIC Educational Resources Information Center
This study compared two interventions to increase math self-efficacy among undergraduate students. Ninety-nine first-year undergraduate students participated in an intervention involving performance accomplishment or an intervention combining performance accomplishment and belief-perseverance techniques in which participants constructed a�
Cordero, Elizabeth D.; Porter, Sarah H.; Israel, Tania; Brown, Michael T.
Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: A multicenter study
Peckham PH, Keith MW, Kilgore KL, Grill JH, Wuolle KS, Thrope GB, Gorman P, Hobby J, Mulcahey MJ, Carroll S, Hentz VR, Wiegner A, for the Implantable Neuroprosthesis Research Group. Efficacy of an implanted neuroprosthesis for restoring hand grasp in tetraplegia: a multicenter study. Arch Phys Med Rehabil 2001;82:1380-8. Objective: To evaluate an implanted neuroprosthesis that allows tetraplegic users to
P. Hunter Peckham; Michael W. Keith; Kevin L. Kilgore; Julie H. Grill; Kathy S. Wuolle; Geoffrey B. Thrope; Peter Gorman; John Hobby; M. J. Mulcahey; Sara Carroll; Vincent R. Hentz; Allen Wiegner
Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: A double-blind controlled study
A multiinstitutional cooperative study comparing carbamazepine (Tegretol) with chlorpromazine was performed using a controlled, double-blind trial design. In a series of 63 cases of endogenous manic psychosis, carbamazepine's clinical utility and efficacy, characteristics of therapeutic effect, and side effects were evaluated. Carbamazepine and chlorpromazine were given by a fixed, but flexible, method at an equipotent ratio of 2:1, starting from
Teruo Okuma; Kazutoyo Inanaga; Saburo Otsuki; Keisuke Sarai; Ryo Takahashi; Hidefumi Hazama; Atsuyoshi Mori; Masasuke Watanabe
Efficacy of Five Standards in Raising Student Achievement: Findings From Three Studies
The authors reported findings from 3 studies examining the efficacy of Five Standards pedagogy in raising student achievement. Studies 1 and 2 were randomized designs; Study 3 was a quasi-experimental design. Samples included 53 teachers and 622 predominantly low-income Latino students in Grades 1-4. Studies assessed model fidelity with the standards performance continuum and student achievement with norm-referenced, criterion-referenced, standards-based,
R. William Doherty; R. Soleste Hilberg
Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma
Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.
Matthews, G M; Lefebure, M; Doyle, M A; Shortt, J; Ellul, J; Chesi, M; Banks, K-M; Vidacs, E; Faulkner, D; Atadja, P; Bergsagel, P L; Johnstone, R W
Passive and Oxymetazoline-Enhanced Delivery with a Lens Device: Pharmacokinetics and Efficacy Studies with Rabbits
Abstract Purpose The aims of this study were to assess the trans-scleral delivery of dexamethasone phosphate (DexP) with a prototype lens device and a formulation comprising a vasoconstrictor and to determine the efficacy of this delivery system in treating experimentally induced uveitis in a rabbit model. Methods Passive trans-scleral delivery was performed on New Zealand white rabbits in vivo, using the lens device and a formulation of 0.034 M oxymetazoline (OMZ, the vasoconstrictor) and 0.5 M of dexamethasone sodium phosphate (DexNaP). Trans-scleral delivery of DexP without OMZ was the control. The amounts of DexP delivered into the eye and its distributions in the eye were determined by dissection of the eye and high-performance liquid chromatography assay in the pharmacokinetics study. The efficacy of the DexP delivery system in treating lipopolysaccharide-induced uveitis was also evaluated in the rabbit model in vivo. The effect of OMZ upon DexP delivery and its treatment efficacy was studied by comparing the DexP results with and without OMZ. Results In the pharmacokinetics study, the amounts of DexP delivered into the eye using the lens system with OMZ were significantly higher than those without OMZ. The results in the efficacy study showed a better treatment outcome with OMZ to relieve the symptoms of endotoxin-induced uveitis in rabbits. Conclusions The potential of vasoconstrictors to enhance eye disease treatments in passive trans-scleral drug delivery was demonstrated. The higher DexP level in the eye and the improvement of the outcome in the efficacy study in the presence of the vasoconstrictor are consistent with the hypothesis that the vasoconstrictor enhances drug delivery by decreasing clearance.
Miller, David J.; Tuitupou, Anthony L.; Kochambilli, Rajan P.; Papangkorn, Kongnara; Mix, Donald C.; Higuchi, William I.; Higuchi, John W.
Open, prospective study of the clinical efficacy of ciprofloxacin.
One hundred patients with infections mostly outside of the urinary tract were studied in a prospective, open manner to ascertain the effectiveness and safety of ciprofloxacin in a variety of clinical situations. There were 41 instances of bacteremia, including 38 with Salmonella typhi, and 21 respiratory, 17 skin and skin structure, 11 bone or joint, 6 gastrointestinal, and 4 urinary tract infections. The patients were given 500 mg of ciprofloxacin orally every 12 h for 2 to 107 days (mean, 15.1 days). Microorganisms isolated disclosed susceptibilities comparable to those reported previously, with a MIC for 90% of the strains of 0.25 microgram/ml. For Streptococcus pneumoniae the MIC for 90% of the strains was 0.03 microgram/ml, and it was higher for Pseudomonas aeruginosa (0.5 microgram/ml), although still in the therapeutic range. Levels in blood were lower than those reported in other series, and no accumulation of the drug during treatment was detected. In 88 instances there was resolution of the infectious process, in 7 there was improvement, in 3 there was a failure to respond, and in 2 the clinical response was indeterminate. Bacteriological eradication was documented in 87 infections. Despite extensive clinical and laboratory examinations before, during, and after therapy, no major abnormalities related to therapy were seen; only one patient required discontinuation of ciprofloxacin due to gastrointestinal intolerance. Ciprofloxacin is an effective and safe therapeutic alternative in many tissue infections caused by susceptible microorganisms.
Ramirez, C A; Bran, J L; Mejia, C R; Garcia, J F
The efficacy of prolotherapy for lateral epicondylosis: A pilot study
Objectives To assess whether prolotherapy, an injection-based therapy, improves elbow pain, grip strength and extension strength in patients with lateral epicondylosis. Setting Outpatient Sport Medicine clinic. Study Design Double-blind randomized controlled trial. Participants Twenty-four adults with at least 6 months of refractory lateral epicondylosis. Intervention Prolotherapy participants received injections of a solution made from 1 part 5% sodium morrhuate, 1.5 parts 50% dextrose, 0.5 parts 4% lidocaine, 0.5 parts 0.5% sensorcaine and 3.5 parts normal saline. Controls received injections of 0.9% saline. Three 0.5mL injections were made at the supracondylar ridge, lateral epicondyle and annular ligament at baseline, 4 and 8 weeks. Outcome Measures The primary outcome was resting elbow pain (0�10 Likert scale). Secondary outcomes were extension and grip strength. Each was performed at baseline, 8 and 16 weeks. One-year follow-up included pain assessment and effect of pain on activities of daily living. Results The groups were similar at baseline. Compared to Controls, Prolotherapy subjects reported improved pain scores (4.5�1.7, 3.6�1.2 and 3.5�1.5 versus 5.1�0.8, 3.3� 0.9 and 0.5�0.4 at baseline, 8 and 16 weeks, respectively); at 16 weeks, these differences were significant compared to baseline scores within and between groups (p<.001). Prolotherapy subjects also reported improvement extension strength compared to Controls (p<0.01) and grip strength compared to baseline (p<0.05). Clinical improvement in Prolotherapy subjects was maintained at 52 weeks. There were no adverse events. Conclusions Prolotherapy with dextrose and sodium morrhuate was well tolerated, effectively decreased elbow pain and improved strength testing in subjects with refractory lateral epicondylosis compared to Control injections.
Scarpone, M; Rabago, D; Zgierska, A; Arbogest, J; Snell, E
Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study.
Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness. PMID:24817188
Li, Cheng-Ta; Chen, Mu-Hong; Juan, Chi-Hung; Huang, Hsiang-Hsuan; Chen, Li-Fen; Hsieh, Jen-Chuen; Tu, Pei-Chi; Bai, Ya-Mei; Tsai, Shin-Jen; Lee, Ying-Chiao; Su, Tung-Ping
Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement
Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb �C� mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.
Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala
Registration of challenging pre-clinical brain images
The size and complexity of brain imaging studies in pre-clinical populations are increasing, and automated image analysis pipelines are urgently required. Pre-clinical populations can be subjected to controlled interventions (e.g., targeted lesions), which significantly change the appearance of the brain obtained by imaging. Existing systems for registration (the systematic alignment of scans into a consistent anatomical coordinate system), which assume image similarity to a reference scan, may fail when applied to these images. However, affine registration is a particularly vital pre-processing step for subsequent image analysis which is assumed to be an effective procedure in recent literature describing sophisticated techniques such as manifold learning. Therefore, in this paper, we present an affine registration solution that uses a graphical model of a population to decompose difficult pairwise registrations into a composition of steps using other members of the population. We developed this methodology in the context of a pre-clinical model of stroke in which large, variable hyper-intense lesions significantly impact registration performance. We tested this technique systematically in a simulated human population of brain tumour images before applying it to pre-clinical models of Parkinson's disease and stroke.
Crum, William R.; Modo, Michel; Vernon, Anthony C.; Barker, Gareth J.; Williams, Steven C.R.
Role Models, Approaches to Studying, and Self-Efficacy in Forensic and Mainstream High School Students: A Pilot Study
ERIC Educational Resources Information Center
This study investigated the relationships between role models, approaches to studying, and self-efficacy in students attending a high school specialising in educating those with emotional and behavioural difficulties (EBD, n = 30) and students attending a mainstream high school (n = 41) in the UK. Types and quantity of role models held by students�
Skidmore, Michael; Dede, Yemi U.; Moneta, Giovanni B.
A Priori Prediction of Tumor Payload Concentrations: Preclinical Case Study with an Auristatin-Based Anti-5T4 Antibody-Drug Conjugate.
The objectives of this investigation were as follows: (a) to validate a mechanism-based pharmacokinetic (PK) model of ADC for its ability to a priori predict tumor concentrations of ADC and released payload, using anti-5T4 ADC A1mcMMAF, and (b) to analyze the PK model to find out main pathways and parameters model outputs are most sensitive to. Experiential data containing biomeasures, and plasma and tumor concentrations of ADC and payload, following A1mcMMAF administration in two different xenografts, were used to build and validate the model. The model performed reasonably well in terms of a priori predicting tumor exposure of total antibody, ADC, and released payload, and the exposure of released payload in plasma. Model predictions were within two fold of the observed exposures. Pathway analysis and local sensitivity analysis were conducted to investigate main pathways and set of parameters the model outputs are most sensitive to. It was discovered that payload dissociation from ADC and tumor size were important determinants of plasma and tumor payload exposure. It was also found that the sensitivity of the model output to certain parameters is dose-dependent, suggesting caution before generalizing the results from the sensitivity analysis. Model analysis also revealed the importance of understanding and quantifying the processes responsible for ADC and payload disposition within tumor cell, as tumor concentrations were sensitive to these parameters. Proposed ADC PK model provides a useful tool for a priori predicting tumor payload concentrations of novel ADCs preclinically, and possibly translating them to the clinic. PMID:24578215
Shah, Dhaval K; King, Lindsay E; Han, Xiaogang; Wentland, Jo-Ann; Zhang, Yanhua; Lucas, Judy; Haddish-Berhane, Nahor; Betts, Alison; Leal, Mauricio
Recommendations for Preclinical Research in Hemorrhagic Transformation
Hemorrhagic transformation (HT) is an important complication of ischemic stroke and is responsible for most of the mortality associated with acute reperfusion therapy. Although many important publications address the preclinical models of ischemic stroke, there are no current recommendations on the conduct of research aimed at understanding the mechanisms and consequences of HT. The purpose of this review is to present the various models used in HT research, the clinical correlates, and the experimental variables known to influence the quantitation of HT in preclinical investigation. Lastly, recommendations for the conduct of preclinical research in HT are provided.
Fagan, Susan C.; Lapchak, Paul A.; Liebeskind, David S; Ishrat, Tauheed; Ergul, Adviye
Adult Attachment, Social Self-Efficacy, Self-Disclosure, Loneliness, and Subsequent Depression for Freshman College Students: A Longitudinal Study
ERIC Educational Resources Information Center
This longitudinal study examined whether social self-efficacy and self-disclosure serve as mediators between attachment and feelings of loneliness and subsequent depression. Participants were 308 freshmen at a large Midwestern university. Results indicated that social self-efficacy mediated the association between attachment anxiety and feelings�
Wei, Meifen; Russel, Daniel W.; Zakalik, Robyn A.
Exploring Inclusion Preservice Training Needs: A Study of Variables Associated with Attitudes and Self-Efficacy Beliefs
ERIC Educational Resources Information Center
The study examined attitudes towards inclusion and sense of efficacy of 1155 Israeli preservice teachers and variables related to these beliefs. Participants responded to an "Options related to inclusion scale", and a "Teacher efficacy scale". Findings revealed strong support for the principle of inclusion, yet also support for segregated special�
Romi, Shlomo; Leyser, Yona
Exploring inclusion preservice training needs: a study of variables associated with attitudes and self?efficacy beliefs
The study examined attitudes towards inclusion and sense of efficacy of 1155 Israeli preservice teachers and variables related to these beliefs. Participants responded to an Options related to inclusion scale, and a Teacher efficacy scale. Findings revealed strong support for the principle of inclusion, yet also support for segregated special education placements. Several concerns regarding inclusion were expressed, which were
Shlomo Romi; Yona Leyser
Teachers' Sense of Self-Efficacy, English Proficiency, and Instructional Strategies: A Study of Nonnative EFL Teachers in Iran
ERIC Educational Resources Information Center
This study examined the efficacy beliefs of nonnative English speaking (NNES) Iranian EFL teachers. EFL teachers' perceptions of their teaching efficacy in terms of personal capabilities to teach English as a Foreign Language (EFL) and their perceived English language proficiency level were examined. A modified version of the Teacher Sense of�
Eslami, Zohreh R.; Fatahi, Azizullah
The efficacy of Bridelia ferruginea Benth bark extract in wastewater treatment was investigated. Chemical analysis found the bark to contain potassium, sodium, calcium, magnesium, zinc, manganese, iron and copper. Phytochemical tests revealed the bark to contain tannins, phlobatannins, saponins, alkaloids, and steroids. Comparative studies using varying concentrations (0.5, 1.0, 2.5 and 5.0% w\\/v) with alum and ferric chloride showed that
O. M. Kolawole; S. O. Oguntoye; O. Agbede; A. B. Olayemi
Efficacy, safety, and clinical outcomes of endoscopic mucosal resection: A study of 101 cases
Background: Endoscopic mucosal resection (EMR) is an alternative to surgery for removal of superficial neoplastic lesions of the GI tract. The aim of this study was to assess the safety, efficacy, and clinical outcomes of EMR. Methods: Data from consecutive EMR procedures performed by using suction cap-assisted and\\/or saline solution-assisted snare resection techniques over a 45-month period were reviewed retrospectively.
Nuzhat A. Ahmad; Michael L. Kochman; William B. Long; Emma E. Furth; Gregory G. Ginsberg
Antihypertensive Efficacy of Candesartan in Comparison to Losartan: The CLAIM Study
and Introduction Abstract An 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study was conducted to evaluate the antihypertensive efficacy of candesartan vs. losartan in 654 hypertensive patients with a diastolic blood pressure between 95 and 114 mm Hg from 72 sites throughout the U.S. Eligible patients were randomized to candesartan cilexetil 16 mg once daily, or losartan 50 mg once daily.
George Bakris; Alan Gradman; Max Reif; Marian Wofford; Mark Munger; Susan Harris; Jennifer Vendetti; Eric L. Michelson; Rebecca Wang
Efficacy of statins in familial hypercholesterolaemia: a long term cohort study
Objective To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia.Design Cohort study with a mean follow-up of 8.5 years.Setting 27 outpatient lipid clinics.Subjects 2146 patients with familial hypercholesterolaemia without prevalent coronary heart disease before 1 January 1990.Main outcome measures Risk of coronary heart disease in treated and �untreated� (delay in starting
Jorie Versmissen; Dani�lla M Oosterveer; Mojgan Yazdanpanah; Joep C Defesche; Dick C G Basart; Anho H Liem; Jan Heeringa; Jacqueline C Witteman; Peter J Lansberg; John J P Kastelein; Eric J G Sijbrands
Safety and efficacy of therapy with botulinum toxin in obesity: a pilot study
Background. Botulin toxin (BTX) has been proposed as a potential obesity treatment. Methods. In a pilot study, the short-term efficacy and safety of BTX was assessed in eight subjects (four men, four women; median age, 46 years; range, 35?57 years) with severe obesity (median body mass index [BMI], 47.1 kg\\/m 2 ; range 38.2?56.7 kg\\/m 2 ) and multiple dietary
Giovanni Albani; Maria Letizia Petroni; Alessandro Mauro; Antonio Liuzzi; Giovanni Lezzi; Barbara Verti; Paolo Marzullo; Laila Cattani
A Nicotine Mouth Spray for Smoking Cessation: A Pilot Study of Preference, Safety and Efficacy
Background: Various formulations of nicotine replacement therapy are commercially available. Objectives: It was the aim of this study to test preference, safety and efficacy of a new nicotine mouth spray (1 mg\\/actuation; NicoNovum). Methods: One hundred healthy smokers wanting to quit (mean age 43.1 � 11.2 years) were included. They were given the mouth spray, as well as 2-mg nicotine
C. T. Bolliger; X. van Biljon; A. Axelsson
A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses
Abstract�Background: Teriflunomide, a dihydro-orotate dehydrogenase inhibitor, has immunomodulatory effects, in- cluding the ability to suppress experimental allergic encephalomyelitis. In this randomized, double-blind, placebo- controlled Phase II study, the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis (MS) with,relapses. Methods: Patients (n,179) with,relapsing�remitting MS (n,157) or secondary,progressive,MS with relapses (n 22) were randomized to receive placebo, teriflunomide
P. W. O'Connor; D. Li; M. S. Freedman; G. P. A. Rice; C. Confavreux
A study on the therapeutic efficacy of Cassia alata, Linn. leaf extract against Pityriasis versicolor.
The therapeutic efficacy of Cassia alata leaf extract against Pityriasis versicolor has been reported for the first time involving humans. For the collection of clinically effective antifungal compounds from the leaves of Cassia alata, a simple procedure has been devised. A 10-year human study indicates that the leaf extract can be reliably used as a herbal medicine to treat Pityriasis versicolor. The leaf extract has no side-effects. PMID:8046939
Damodaran, S; Venkataraman, S
Efficacy of transforaminal versus interspinous corticosteroid injectionin discal radiculalgia � a prospective, randomised, double-blind study
A prospective, randomised, double-blind study was carried out to compare the respective efficacies of transforaminal and interspinous epidural corticosteroid injections in discal radiculalgia. Thirty-one patients (18 females, 13 males) with discal radicular pain of less than 3 months� duration were consecutively randomised to receive either radio-guided transforaminal or blindly performed interspinous epidural corticosteroid injections. Post-treatment outcome was evaluated clinically at
E. Thomas; C. Cyteval; L. Abiad; M. C. Picot; P. Taourel; F. Blotman
Safety and efficacy of talonavicular arthroscopy in arthroscopic triple arthrodesis. A cadaveric study
This is a cadaveric study on the safety and efficacy of talonavicular arthroscopy in arthroscopic triple arthrodesis. Talonavicular\\u000a arthroscopy was performed in 18 feet of 9 fresh frozen cadavers. The specimens were divided into 3 groups (6 feet in each\\u000a group). The articular cartilage of the talar and navicular facet was abraded with a hemostat through the dorsolateral portal\\u000a in
Tun Hing Lui; L. K. Chan
Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: Postmarketing surveillance study
The efficacy and safety of the butterbur leaf extract Ze 339 (carbon dioxide extract from the leaves ofPetasites hybridus L., 8 mg petasines per tablet) were tested in patients with seasonal allergic rhinitis. In an open postmarketing surveillance\\u000a study, 580 patients were treated with an average of 2 tablets of Ze 339 daily for 2 weeks. Symptoms of rhinorrhea, sneezing,
Robert K�ufeler; Wolfgang Polasek; Axel Brattstr�m; Uwe Koetter
A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs.
The failure rate of randomized phase III oncology clinical trials is extremely high, even when preceded by encouraging preclinical studies and phase II trial results of the same therapy. Thus, there is considerable effort being made to improve the predictive clinical potential of preclinical models, in addition to improving phase II trial design. With respect to the former, preclinical models have historically relied heavily on treatment of primary spontaneous or transplanted tumors rather than the more common and therapeutically challenging clinical trial circumstance of advanced metastatic disease. Here, we show that the oral antiangiogenic tyrosine kinase inhibitor (TKI), sunitinib, which failed to meet primary or secondary survival endpoints in 4 separate phase III metastatic breast cancer (MBC) trials, either alone or with chemotherapy, similarly failed to show monotherapy or combination chemotherapy efficacy in a model of postsurgical advanced MBC using a metastatic variant of the MDA-MB-231 triple-negative human breast cancer. In contrast, the drug was effective when used to treat established orthotopic primary tumors. Similar results were obtained with pazopanib monotherapy, another antiangiogenic oral TKI. However, when an antibody targeting the VEGF pathway (DC101) was tested, it showed a trend in modestly improving the efficacy of paclitaxel therapy, thus resembling to a degree prior phase III clinical results of bevacizumab plus paclitaxel in MBC. Our results suggest the potential value of treating postsurgical advanced metastatic disease as a possible strategy to improve preclinical models for predicting outcomes in patients with metastatic disease. PMID:23610448
Guerin, Eric; Man, Shan; Xu, Ping; Kerbel, Robert S
A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II
An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of candesartan cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to candesartan cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of
DG Vidt; WB White; E Ridley; M Rahman; S Harris; J Vendetti; EL Michelson; R Wang
Preclinical Data of Eluting Stents
The concept of using stents coated with agents that could potentially inhibit neointimal hyperplasia has emerged and drug-eluting\\u000a stents (DES) represent one of the fastest growing fields in interventional cardiology today. Different animal models have\\u000a been used in order to test the safety and efficacy of DES. The drug-eluting coatings contain antimitotic (e.g., sirolimus\\u000a [SRL], SRL analogs, paclitaxel, and actinomycin),
Antonio Colombo; Alaide Chieffo