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Most Cited Clinical Therapeutics Articles
The most cited articles published since 2011, extracted from Scopus.
A Review of Diabetes Treatment Adherence and the Association with Clinical and Economic OutcomesCarl Asche | Joanne LaFleur | Chris Conner
Volume 33, Issue 1, January 2011, Pages 74-109
Background: The benefits of drug therapy to diabetic patients in terms of glycemic control, microvascular complications, cardiovascular event risk, mortality, and quality of life have been well established by clinical trial data. However, it has been a challenge to quantify the relationship between adherence and outcomes such as glycemic control, disease-related events, hospitalizations, cost, and quality of life. Objective: This article provides a comprehensive summary of empirical studies that examine the associations between adherence and glycemic control, health care utilization, quality of life, and mortality in patients with diabetes. It is intended to provide a framework for researchers interested in conducting studies to improve their understanding of the value of medication adherence for patients with diabetes. Methods: Relevant published articles were identified through searches of the National Center for Biotechnology PubMed database. Medical subject heading (MESH) terms diabetes mellitus, hypoglycemic agents, and insulin, were each combined with the MESH term medication adherence and with the subheadings economics, prevention and control, psychology, statistics and numerical data, therapy, adverse effects, therapeutic use, and administration and dosage, where available. Studies were included if they met the following criteria: (1) analyzed empirical data on some measure of patient adherence to diabetes pharmacotherapy; (2) described methods for measuring patient adherence; (3) evaluated economic, clinical, or humanistic outcomes related to diabetes; and (4) had as a goal of the research to evaluate the link between patient adherence and outcomes (as a primary or secondary objective). The data from the articles meeting these criteria were then abstracted, including mention of the specific interventions being compared, specific methods for measuring adherence, outcomes compared between adherent and nonadherent patients and how these outcomes were measured, and information on variables that were adjusted for in predictive and causal multivariable models. Results: A total of 37 articles that met all 4 criteria in this review underwent data extraction. Of these studies, 22 (59%) used objective measures to assess adherence, with 1 study using pill counts to assess adherence and 21 using either pharmacy claims or similar refill records to assess refill behavior. The remaining 15 (41%) studies used a wide variety of subjective patient-reported adherence assessments. The majority (13/23 [57%]) of the glycemic control studies reported that improved adherence was associated with better glycemic control. The ability to draw a distinction between adherence and glycemic control tended to occur more frequently [7/9 (78%)] among studies that characterized adherence in terms of prescription refills compared with studies that used various constructs for patient-reported adherence measures. Conclusions: Based on the literature, better adherence was found to be associated with improved glycemic control and decreased health care resource utilization. There was no consistent association between improved adherence and decreased health care costs. Little data were available on the association between adherence and quality of life. © 2011 Elsevier HS Journals, Inc.
Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic ReviewVanita R. Aroda | Robert R. Henry | Jenny Han | Wenying Huang | Mary Beth DeYoung | Tamara Darsow | Byron J. Hoogwerf
Volume 34, Issue 6, June 2012, Page
Background: Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available. Objective: This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. Methods: The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks' duration and having change from baseline in hemoglobin (Hb) A 1c as the primary end point. The random effects meta-analyses models examined HbA 1c, fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. Results: The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA 1c values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA 1c of -1.1% to -1.6% and -0.6% to -1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >-2.0 and -0.2 to -0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). Conclusions: All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA 1c and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified. © 2012 Elsevier HS Journals, Inc.
Childhood Obesity: A Review of Increased Risk for Physical and Psychological ComorbiditiesElizabeth R. Pulgarón
Volume 35, Issue 1, January 2013, Page
Background: Worldwide estimates of childhood overweight and obesity are as high as 43 million, and rates continue to increase each year. Researchers have taken interest in the childhood obesity epidemic and the impact of this condition across health domains. The consequences of childhood and adolescent obesity are extensive, including both medical and psychosocial comorbidities. Objective: The purpose of this review was to consolidate and highlight the recent literature on the comorbidities associated with childhood obesity, both nationally and internationally. Methods: PubMed and PsychINFO searches were conducted on childhood obesity and comorbidities. Results: The initial search of the terms obesity and comorbidity yielded >5000 published articles. Limits were set to include studies on children and adolescents that were published in peer-reviewed journals from 2002 to 2012. These limits narrowed the search to 938. Review of those articles resulted in 79 that are included in this review. The major medical comorbidities associated with childhood obesity in the current literature are metabolic risk factors, asthma, and dental health issues. Major psychological comorbidities include internalizing and externalizing disorders, attention-deficit hyperactivity disorder, and sleep problems. Conclusions: The high prevalence rates of childhood obesity have resulted in extensive research in this area. Limitations to the current childhood obesity literature include differential definitions of weight status and cut-off levels for metabolic risk factors across studies. Additionally, some results are based on self-report of diagnoses rather than chart reviews or physician diagnosis. Even so, there is substantial support for metabolic risk factors, internalizing disorders, attention-deficit hyperactivity disorder, and decreased health-related quality of life as comorbidities to obesity in childhood. Additional investigations on other diseases and conditions that might be associated with childhood obesity are warranted and intervention research in this area is critical. © 2013 Elsevier HS Journals, Inc.
Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical TrialsAdedigbo A. Fasanmade | Omoniyi J. Adedokun | Marion Blank | Honghui Zhou | Hugh M. Davis
Volume 33, Issue 7, July 2011, Pages 946-964
Background: Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. Objectives: The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohn's disease (CD) from 2 Phase III studies. Methods: This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6-76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease] and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. Results: Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; V d in the central compartment (V 1), 54.2 (1.15) mL/kg; V d in the peripheral compartment (V 2), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V 1, 52.7 (0.49) mL/kg; V 2, 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V 2 decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t 1/2 (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults. Conclusions: Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator coadministration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6-76 years). © 2011 Elsevier HS Journals, Inc.
Changes in herb and dietary supplement use in the US adult population: A comparison of the 2002 and 2007 national health interview surveysChung Hsuen Wu | Chi Chuan Wang | Jae Kennedy
Volume 33, Issue 11, November 2011, Pages 1749-1758
Background: Past national surveys indicate that use of herbs and dietary supplements rose rapidly in the United States during the 1990s and early 2000s. Additional research is needed to determine whether this growth rate and associated patterns of use have persisted over time. Objectives: The objectives of this study were: (1) to assess population and subpopulation changes in rates of herb and supplement use; and (2) to assess changes in rates of disclosure of herb and supplement use to conventional medical providers. Methods: This study used data from the 2002 (n = 30,427) and 2007 (n = 22,657) Adult Complementary and Alternative Medicine File to the National Health Interview Survey (NHIS). Weighted group and subgroup comparisons used the Wald χ 2 tests to compare differences in herb and supplement use between 2002 and 2007. Results: The number of adults in the United States that ever used herbs or supplements grew slightly, from 50.6 million in 2002 to 55.1 million in 2007. However, the proportion of adults who reported use of herbs or supplements in the past 12 months dropped significantly: from 18.9% in 2002 to 17.9% in 2007 (P < 0.05). Subpopulation comparisons revealed that younger adults were less likely to use herbs and supplements in 2007 (17.6%) than in 2002 (20.0%), whereas older adults (ie, those aged ≥65 years) were more likely to do so (19.5% in 2007 vs. 13.2% in 2002). Racial and ethnic minorities also reported a significant decline in recent use. The proportion of respondents that disclosed herb or supplement use to their physician or another conventional medical professional rose, from 33.4% in 2002 to 45.4% in 2007. However, <1% of recent herb and supplement users disclosed this use to their pharmacist. Limitations of this research are that the 2 national data sets were not directly comparable and that questionnaires in the 2 surveys assessed were not identical. Conclusions: Herbal preparations and dietary supplements remain popular in the United States, but the user population and patterns of use are changing. Ongoing surveillance of this health behavior is a public health priority. © 2011 Elsevier HS Journals, Inc.
Coronary hypersensitivity disorder: The kounis syndromeNicholas G. Kounis
Volume 35, Issue 5, May 2013, Pages 563-571
Background: When allergy or hypersensitivity and anaphylactic or anaphylactoid insults lead to cardiovascular symptoms and signs, including acute coronary events, the result might be the recently defined nosologic entity Kounis syndrome. Vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus infiltrated by eosinophils and/or mast cells are the 3 reported variants of this syndrome. Objective: The purpose of this review was to highlight and consolidate the recent literature on allergic angina and allergic myocardial infarction and to propose new therapeutic modalities for stabilizing mast cells. Methods: A search for current literature on the pathophysiology, causality, clinical appearance, variance, prevention, and treatment of Kounis syndrome was conducted. Results: Kounis syndrome is caused by inflammatory mediators such as histamine; neutral proteases, including tryptase, chymase, and cathepsin-D; arachidonic acid products; platelet-activating factor; and a variety of cytokines and chemokines released during the mast-cell activation. Platelets with Fc γ receptor (FcγR) Ι, FcγRII, FcεRI, and FcεRII also have a role in the activation cascade. The same mediators released from the similar inflammatory cells are involved in acute coronary events of nonallergic etiology. These cells are not only present in the involved region before plaque erosion or rupture but also release their contents just before an acute coronary event. Pro-inflammatory mediators similar to those found in Kounis syndrome are found in some cases with nonallergic etiology, suggesting that this is a more general problem. The acute coronary and cerebrovascular events in Kounis syndrome may be prevented by the inhibition of mast-cell degranulation. Substances and natural molecules that protect the mast-cell surface and stabilize the mast-cell membrane are emerging as novel agents in the prevention of acute coronary and other arterial events. Conclusions: The 3 reported variants of Kounis syndrome-vasospastic allergic angina, allergic myocardial infarction, and stent thrombosis with occluding thrombus-are caused by inflammatory mediators. Agents that inhibit mast-cell degranulation may be efficacious in preventing the acute coronary and cerebrovascular events of Kounis syndrome. © 2013 Elsevier HS Journals, Inc.
Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic Agent Targeting the Interleukin-6 ReceptorIris Navarro-Millán | Jasvinder A. Singh | Jeffrey R. Curtis
Volume 34, Issue 4, April 2012, Page
Background: Tocilizumab (TCZ), a humanized anti-interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti-tumor necrosis factor therapy. Objective: The goal of this study was to summarize the efficacy and safety profile of TCZ. Methods: A systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ≥6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire-Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics. Results: Ten published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (. P < 0.001), ACR50 (. P = 0.002), and ACR70 (. P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti-tumor necrosis factor therapy (. P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (. P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo. Conclusion: The short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk-benefit profile of this agent. © 2012 Elsevier HS Journals, Inc.
New LDL-cholesterol lowering therapies: Pharmacology, clinical trials, and relevance to acute coronary syndromesAmirhossein Sahebkar | Gerald F. Watts
Volume 35, Issue 8, August 2013, Pages 1082-1098
Background: Reduction in plasma low-density lipoprotein cholesterol (LDL-C) is a fundamental treatment for the prevention of acute coronary syndromes (ACS). Although statin therapy confers significant protection against ACS in both primary and secondary prevention, a considerable residual risk remains after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the optimal LDL-C goal recommended in the current guidelines (<1.8 mmol/L). Hence, novel LDL-C-lowering agents that act via mechanisms distinct from HMG-CoA reductase inhibition are under investigation. Objective: We reviewed the recent literature on the development of novel LDL-C-lowering agents that could potentially be used as an alternative or adjunct to statin therapy in high-risk coronary patients. Methods: PubMed and Scopus databases were searched to retrieve studies on the efficacy and/or tolerability of novel LDL-C-lowering agents in animals and humans. Results: Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein (apo) B, and microsomal triglyceride transfer protein (MTTP) are the most promising therapies. Inhibition of PCSK9, apoB, and MTTP has been achieved mostly via fully humanized monoclonal antibodies (mAbs), antisense oligonucleotides, and synthetic compounds, respectively. PCSK9 inhibitors increase the hepatic uptake of LDL-C, while apoB and MTTP inhibitors decrease the synthesis and secretion of apoB-containing lipoproteins. These 3 mechanisms lead to marked reductions in plasma LDL-C in patients with hypercholesterolemia at risk for ACS, particularly those with familial hypercholesterolemia. Moreover, these agents can exert additional benefits by decreasing plasma levels of apoB, triglycerides, and lipoprotein(a). Mipomersen and lomitapide have been approved by the United States Food and Drug Administration (US FDA) for use in patients with homozygous familial hypercholesterolemia. PCSK9 inhibitors are currently under final evaluation in clinical outcomes studies and are anticipated to find wide application either as monotherapy or as an adjunct to statins. A main safety concern is the risk for hepatic steatosis with apoB and MTTP inhibitors, which needs to be explored in prospective, long-term trials. Conclusions: PCSK9, apoB, and MTTP inhibitors can exert potent reductions in plasma LDL-C and apoB concentrations, either as monotherapy or in combination with statins. These effects are particularly relevant to high-risk individuals with marked hypercholesterolemia, such as those with familial hypercholesterolemia. Although the use of mipomersen and lomitapide is limited to severe familial hypercholesterolemia as a replacement for LDL-apheresis, PCSK9 inhibitors are likely to be more widely prescribed in patients at high risk for CVD, especially those who are resistant to or intolerant of high-intensity statin therapy. PCSK9 mAbs are efficacious and have an excellent safety profile, but their long-term impact on cardiovascular events is currently under investigation. Whether PCSK9 mAbs decrease the rates of recurrent cardiovascular events within 3 months following ACS is questionable; however, these agents, unlike statins, may not have pleiotropic benefits on the unstable plaque. © 2013 Elsevier HS Journals, Inc..
Analysis of Different Recommendations From International Guidelines for the Management of Acute Pharyngitis in Adults and ChildrenElena Chiappini | Marta Regoli | Francesca Bonsignori | Sara Sollai | Alessandra Parretti | Luisa Galli | Maurizio de Martino
Volume 33, Issue 1, January 2011, Pages 48-58
Background: Streptococcal pharyngitis is a frequently observed condition, but its optimal management continues to be debated. Objective: The goal of this study was to evaluate the available guidelines, developed at the national level, for the management of streptococcal pharyngitis in Western countries, with a focus on their differences. Methods: A literature search was conducted of the Cochrane Library, EMBASE, TRIP, and MEDLINE databases from their inception (1993 for the Cochrane Library, 1980 for EMBASE, 1997 for TRIP, and 1966 for MEDLINE) through April 25, 2010. The following search terms were used: pharyngitis, sore throat, tonsillitis, pharyngotonsillitis, Streptococcus pyogenes, Group A β- haemolytic Streptococcus pyogenes, and streptococcal pharyngitis. Searches were limited to type of article or document (practice guideline or guideline) with no language restrictions or language limits. Results: Twelve national guidelines were identified: 6 from European countries (France, United Kingdom, Finland, Holland, Scotland, and Belgium), 5 from the United States, and 1 from Canada. Recommendations differ substantially with regard to the use of a rapid antigen diagnostic test or throat culture and the indications for antibiotic treatment. The North American, Finnish, and French guidelines recommend performing one timely microbiologic investigation in suspected cases, and prescribing antibiotics in confirmed cases to prevent suppurative complications and acute rheumatic fever. According to the remaining European guidelines, however, acute sore throat is considered a benign, self-limiting disease. Microbiologic tests are not routinely recommended by these latter guidelines, and antibiotic treatment is reserved for well-selected cases. The use of the Centor score, for evaluation of the risk of streptococcal infection, is recommended by several guidelines, but subsequent decisions on the basis of the results differ in terms of which subjects should undergo microbiologic investigation. All guidelines agree that narrow-spectrum penicillin is the first choice of antibiotic for the treatment of streptococcal pharyngitis and that treatment should last for 10 days to eradicate the microorganism. Once-daily amoxicillin was recommended by 2 US guidelines as equally effective. Conclusion: The present review found substantial discrepancies in the recommendations for the management of pharyngitis among national guidelines in Europe and North America. © 2011 Elsevier HS Journals, Inc.
Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP DatabaseEnnie L. Cano | Nadia Z. Haque | Verna L. Welch | Cynthia M. Cely | Paula Peyrani | Ernesto G. Scerpella | Kimbal D. Ford | Marcus J. Zervos | Julio A. Ramirez | Daniel H. Kett
Volume 34, Issue 1, January 2012, Pages 149-157
Background: The 2005 guidelines from the American Thoracic Society and the Infectious Diseases Society of America recommend vancomycin trough levels of 15 to 20 mg/L for the therapy of hospital-acquired (HAP), ventilator-associated (VAP), and health care-associated (HCAP) pneumonia. Objective: The goal of this article was to report the incidence of nephrotoxicity and associated risk factors in intensive care unit patients who received vancomycin for the treatment of HAP, VAP, and HCAP. Methods: This was a retrospective analysis of data from a multicenter, observational study of pneumonia patients. Antibiotic-associated nephrotoxicity was defined as either an increase in serum creatinine ≥0.5 mg/dL or 50% above baseline, from initiation of vancomycin to 72 hours after completion of therapy. Univariate and multivariate logistic regression analyses were performed to identify risk factors for development of renal dysfunction. Results: Of the 449 patients in the database, 240 received at least one dose of vancomycin and 188 had sufficient data for analysis. In these 188 patients, 63% were male. Mean (SD) age was 58.5 (17.2) years, and the mean Acute Physiology and Chronic Health Evaluation II score was 19.4 (6.4). Nephrotoxicity occurred in 29 of 188 (15.4%) vancomycin-treated patients. In multivariate analysis, initial vancomycin trough levels ≥15 mg/L (odds ratio [OR], 5.2 [95% CI, 1.9-13.9]; . P = 0.001), concomitant aminoglycoside use (OR, 2.67 [95% CI, 1.09-6.54]; . P = 0.03), and duration of vancomycin therapy (OR for each additional treatment day, 1.12 [95% CI, 1.02-1.23]; . P = 0.02) were independently associated with nephrotoxicity. The incidence of nephrotoxicity increased as a function of the initial vancomycin trough level, rising from 7% at a trough <10 mg/L to 34% at >20 mg/L (. P = 0.001). The mean time to nephrotoxicity decreased from 8.8 days at vancomycin trough levels <15 mg/L to 7.4 days at >20 mg/L (Kaplan-Meier analysis, . P = 0.0003). Conclusions: Nephrotoxicity may be common among intensive care unit patients with pneumonia treated with broad-spectrum antibiotic therapy that includes vancomycin. The finding that an initial vancomycin trough level ≥15 mg/L may be an independent risk factor for nephrotoxicity highlights the need for additional studies to assess current recommendations for vancomycin dosing for ICU patients with pneumonia. © 2012 Elsevier HS Journals, Inc.
Tetrabenazine for the Treatment of Hyperkinetic Movement Disorders: A Review of the LiteratureJack J. Chen | William G. Ondo | Khashayar Dashtipour | David M. Swope
Volume 34, Issue 7, July 2012, Pages 1487-1504
Background: Tetrabenazine (TBZ) is a monoamine storage inhibitor that was first introduced in the 1970s for the management of hyperkinetic movement disorders. Despite acceptance and usage worldwide, TBZ was only recently approved in the United States for the treatment of Huntington chorea. This review focuses on the use of TBZ in various hyperkinetic movement disorders, which are considered "rare" or "orphan" diseases, to help practitioners better understand its clinical role and use. Objective: This review describes the clinical efficacy and tolerability of TBZ in the management of dystonia, Huntington chorea, tardive dyskinesia (TDk), and tic disorders. Methods: A Cochrane Library, EMBASE, MedlinePlus, PubMed, and clinical trials database search (up to May 2012) was conducted to identify articles and studies using the subject terms tetrabenazine, Huntington disease, dystonia, tardive dyskinesia, Tourette, tics, and hyperkinetic movement. Only English-language articles were reviewed. Results: TBZ variably undergoes extensive first-pass metabolism to active metabolites, some of which are metabolized by the cytochrome P450 2D6 isozyme. Pharmacology studies demonstrate that TBZ reversibly inhibits the activity of vesicular monoamine transporter 2, resulting in depletion of central dopamine. For management of dystonias, 1 of 3 small prospective blinded studies and 4 of 5 retrospective studies reported clinical benefit with TBZ use in pediatrics and adults. For Huntington chorea, 2 randomized, double-blind, placebo-controlled studies along with open-label studies demonstrate the effectiveness of TBZ in adults. For TDk, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit. For Gilles de la Tourette syndrome, 9 of 11 studies (prospective controlled and retrospective) reported positive benefit on motor and phonic tics in pediatric and adult patients. Overall, adverse effects are dose and age related and include depression, fatigue, parkinsonism, and somnolence. Conclusions: TBZ is an effective oral therapy for chorea of Huntington disease and may be considered as an alternative agent for the management of dystonia, TDk, and tic disorders (these latter 3 conditions are off-label uses in the United States). The drug possesses an acceptable tolerability profile and has been used in pediatric and adult populations. © 2012 Elsevier HS Journals, Inc.
Steady-State Plasma Concentration Profile of Transdermal Rotigotine: An Integrated Analysis of Three, Open-Label, Randomized, Phase I Multiple Dose Studies**Results of study SP630 were partially presented at the 58th Annual Meeting of the American Academy of Neurology, San Diego, California, April 1-8, 2006, and at the 9th CongJan Peer Elshoff | Marina Braun | Jens Otto Andreas | Michelle Middle | Willi Cawello
Volume 34, Issue 4, April 2012, Pages 966-978
Background: The dopamine agonist rotigotine is formulated in a transdermal delivery system (patch) for once-daily application. It has been reported as efficacious in the treatment of idiopathic Parkinson's disease (PD) and restless legs syndrome. Objective: This article summarizes the results of 3 clinical studies conducted to characterize the 24-hour pharmacokinetic profile of rotigotine in steady state and the effect of different patch application sites on this profile. In addition, the relative bioavailability of a single, large patch versus 2 smaller patches was assessed. Methods: One Phase I study (SP871) assessed the steady-state pharmacokinetic properties at different application sites at a rotigotine maintenance dose of 3 mg/24 hours in healthy participants. Due to tolerability issues, the steady-state pharmacokinetic properties of rotigotine at higher doses (8 mg/24 hours) was assessed in 2 Phase I studies (SP630, SP651) in early-stage PD patients. Relative rotigotine bioavailability from a 40 cm 2 patch versus 2 × 20 cm 2 patches (SP651) and from a 15 cm 2 patch versus 1 × 5 cm 2 + 1 × 10 cm 2 patches (SP871) was also evaluated. Rotigotine concentrations in plasma were analyzed using a validated LC-MS/MS method. The pharmacokinetic variables were calculated using standard noncompartmental analysis. Results: Release of rotigotine to the skin was 31% to 62% of total drug content in the patch. Variability of rotigotine exposure was low within participants (15%) compared with the variability observed between participants (54%). Rotigotine exposure increased proportionally in the therapeutic dose range of 2 mg/24 hours to 8 mg/24 hours. Plasma concentrations at steady state were stable over the 24-hour patch-on period. Delivery via a single, large patch compared with a combination of smaller patches did not appear to influence exposure to rotigotine. Bioavailability showed some variability depending on patch application site (hip, shoulder, abdomen, flank, thigh, upper arm); the respective mean ratios for AUC ranged between 0.87 (abdomen vs flank) and 1.46 (shoulder vs thigh). Conclusions: Continuous rotigotine delivery via a once-daily transdermal patch generated stable mean steady-state 24-hour plasma concentrations in healthy participants as well as patients with early-stage PD. Doses were achieved either by application of 1 large patch or a combination of smaller patches, resulting in the same total surface area. © 2012 Elsevier HS Journals, Inc.
Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitusR. Keith Campbell
Volume 33, Issue 5, May 2011, Pages 511-527
Background: Glucose homeostasis is the result of a complex interaction of a spectrum of hormones, including insulin, glucagon, amylin, and the incretins. Incretins are released by enteroendocrine cells in the intestine in response to a meal. Incretin dysfunction, along with a number of other defects, has been implicated in contributing to the pathogenesis of type 2 diabetes mellitus (T2DM). Therapies that restore incretin activity may reduce the pathophysiologic consequences of diabetes. Objectives: The aim of this article was to review incretin physiology and studies of incretin therapy with glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors that were developed to specifically address the blunted incretin response in patients with T2DM. Methods: Relevant English-language publications between 1995 and 2010 were identified through a search of the MEDLINE and EMBASE databases using the search terms incretin, type 2 diabetes mellitus, GLP-1, glucose-dependent insulinotropic polypeptide, and DPP-4. Review articles and preclinical and clinical trials that described relevant details of the epidemiology of diabetes and incretin physiology in health and in T2DM were selected for review and inclusion. Clinical trials were used to describe the clinical efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors in patients with T2DM. An occasional systematic review article and/or meta-analysis summarizing numerous clinical trials of a particular agent was selected for summarizing key data. Results: Pharmacologic modulation of incretin pathophysiology by GLP-1 receptor agonists and DPP-4 inhibitors significantly improved glycemic control, benefited β-cell function, improved dyslipidemia, and lowered the risk of hypoglycemia compared with insulin and sulfonylureas. Unlike the DPP-4 inhibitors, GLP-1 receptor agonist therapy also produced weight loss, an important consideration given the close association among T2DM, overweight/obesity, and cardiovascular disease. The most common adverse events with GLP-1 receptor agonist therapy included nausea (28%-44%), vomiting (13%-17%), and diarrhea (11%-17%), which generally reduced in incidence and severity with continued therapy. The tolerability profile of the DPP-4 inhibitors was very good, with the incidence of adverse events similar to that of placebo. There was a suggestion of an increased incidence of nasopharyngitis versus placebo (5%-6% vs 3%-4%) with sitagliptin and urinary tract infection (6.8% vs 6.1% with placebo) and headache with saxagliptin (6.5% vs 5.9% with placebo). Conclusion: The 2 incretin drug classes provided effective and consistent glycemic control with a good tolerability profile. These agents might also improve long-term β-cell function and either reduce body weight or be weight neutral. Their role in the therapeutic armamentarium of T2DM is evolving as their potential strengths and weaknesses become better defined. © 2011 Elsevier HS Journals, Inc.
Vemurafenib in Patients With BRAF V600E Mutation-Positive Advanced MelanomaMarcus C. Ravnan | Mazen S. Matalka
Volume 34, Issue 7, July 2012, Pages 1474-1486
Background: Vemurafenib is an oral, small-molecule kinase inhibitor that selectively targets activated BRAF V600E and has been approved for the treatment of advanced BRAF mutation-positive melanoma. Objective: This article reviews the clinical pharmacology, efficacy, tolerability, and pharmacokinetics of vemurafenib and in addition outlines proposed mechanisms of vemurafenib resistance. Methods: A literature search of MEDLINE and ScienceVerse Scopus was performed using the key words malignant melanoma, BRAF, vemurafenib, and PLX4032. Scientific abstracts, US Food and Drug Administration Web site data (www.accessdata.fda.gov), the manufacturer-submitted approval data from ClinicalTrials.gov (www.clinicaltrials.gov), and the references from applicable publications were also consulted. Results: Clinical studies have reported that vemurafenib is efficacious and acceptably well-tolerated. In a Phase I study (BRIM-1), a 960-mg BID dose achieved an objective response rate of 81% among 32 patients with melanoma who carried a BRAF V600E mutation. Of the 26 responders, 2 achieved a complete response and 24 a partial response. In BRIM-2, 132 BRAF V600E-positive patients achieved an overall response rate of 53% (95% CI, 44%-62%); 6% achieved a complete response and 47%, a partial response. Response was noted at 6 weeks and lasted a median of 6.7 months (95% CI, 5.6-8.6). Median survival was 15.9 months (95% CI, 11.6-18.3); 77% of patients survived to 6 months (95% CI, 70-85) and 58% to 12 months (95% CI, 11.6-18.3), and an estimated 43% were expected to survive to 18 months (95% CI, 33-53). The Phase III study (BRIM-3) compared vemurafenib to dacarbazine. The hazard ratio (HR) for death with vemurafenib was 0.37 (95% CI, 0.26-0.55; P < 0.001). At 6 months, overall survival was 84% (95% CI, 78-89) versus 64% (95% CI, 56-73) in the vemurafenib and dacarbazine treatment arms, respectively. The HR for tumor progression in the vemurafenib cohort was 0.26 (95% CI, 0.20-0.33; P < 0.001), and the estimated median progression-free survival was 5.3 months with vemurafenib versus 1.6 months with dacarbazine. Finally, the difference in response rates was significant (48% vs 5%, respectively; P < 0.001). The most common adverse events reported have been arthralgia, rash, photosensitivity, fatigue, pruritus, alopecia, cutaneous squamous cell carcinoma, diarrhea, and mild to moderate nausea. Conclusions: Vemurafenib is effective for advanced melanomas expressing the BRAF V600E mutations. Resistance to BRAF inhibition can be problematic, but new evidence suggests that combination therapy may attenuate the issue. Targeting the cellular activity of melanoma cells is reported to be efficacious and is expected to delay progression and prolong survival. © 2012 Elsevier HS Journals, Inc.
Antimicrobial Susceptibility Among Gram-Negative Isolates Collected From Intensive Care Units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa Between 2004 and 2009 as Part of the Tigecycline Evaluation and Surveillance TrialXavier Bertrand | Michael J. Dowzicky
Volume 34, Issue 1, January 2012, Pages 124-137
Background: The Tigecycline Evaluation and Surveillance Trial is an antimicrobial susceptibility surveillance program that collects gram-positive and gram-negative organisms globally. Objective: This analysis reports on antimicrobial susceptibility among 23,918 gram-negative isolates collected from intensive care units globally between 2004 and 2009. Methods: MICs and susceptibility were determined according to the guidelines of the Clinical and Laboratory Standards Institute (US Food and Drug Administration breakpoints were applied against tigecycline). Results: Gram-negative isolates were collected from 6 geographical regions: North America, 8099 isolates; Europe, 9244; Asia-Pacific Rim, 1573; Latin America, 3996; the Middle East, 635; and Africa, 371. North America reported the lowest rates of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and Escherichia coli both overall (12.8% and 4.7%, respectively) and in each year of collection. High rates of ESBL production were reported among K pneumoniae from Latin America (45.5%) and Africa (54.9%) and for E coli from the Middle East (32.4%). Imipenem and tigecycline maintained >90% susceptibility against K pneumoniae, E coli, Klebsiella oxytoca, Enterobacter cloacae, and Serratia marcescens for all regions. Susceptibility to meropenem was >90% against all K oxytoca and S marcescens. Large regional variations in susceptibility among Acinetobacter baumannii were reported, with the largest variations reported for amikacin (75.2% in North America, 21.8% in the Middle East) and meropenem (60.4% in North America, 15.9% in Africa). MIC 90 values for tigecycline against A baumannii were low (1-2 mg/L) for all regions. Against P aeruginosa, susceptibility to amikacin (97.5% in North America, 67.5% in Latin America) and meropenem (79.1% in North America, 51.4% in Africa) had the largest variations. Conclusions: Antimicrobial resistance among gram-negative intensive care unit isolates was highly variable between geographic regions. The carbapenems were active in vitro against Enterobacteriaceae, . A baumannii and . P aeruginosa, and tigecycline continued to be active in vitro against members of the Enterobacteriaceae and . A baumannii collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa. © 2012 Elsevier HS Journals, Inc.
Pharmacologic Treatment of Attention-Deficit/Hyperactivity Disorder in Children: Incidence, Prevalence, and Treatment Patterns in The NetherlandsPaul Hodgkins | Rahul Sasané | Willemijn M. Meijer
Volume 33, Issue 2, February 2011, Pages 188-203
Background: The prevalence of attention-deficit/hyperactivity disorder (ADHD) and the associated use of stimulant medications may have increased in the Netherlands in recent years, but there is a lack of data to confirm this trend. This retrospective analysis examined the incidence, prevalence, and treatment pattern of ADHD among children from a large sample representation of the general population of the Netherlands and represents the first such analysis in a large cohort of European children. Objective: The aim of this study was to estimate the incidence and prevalence of children receiving initial pharmacotherapy for ADHD between 2000 and 2007 in the Netherlands and to describe treatment patterns (including persistence and adherence to ADHD medications) in this pediatric population. Methods: Prescription and hospitalization data from the PHARMO medical record linkage system database in the Netherlands (2003 to 2006) were analyzed for patients with newly prescribed ADHD medication who were aged 6 to 17 years and received follow-up for at least 12 months after treatment initiation with methylphenidate, dexamphetamine, atomoxetine, or combination therapy. The yearly incidence and prevalence of children receiving ADHD pharmacotherapy were estimated for the period 2000 to 2007. Demographic characteristics and baseline medication data at treatment initiation were collected along with data on hospitalizations and psychotropic treatments in the year before initiation of ADHD treatment. Results: Of the 4909 patients in the study cohort, 82% were male and 46% were between 6 and 9 years of age. The yearly incidence of children receiving ADHD medication-extrapolated from the PHARMO database to the Netherlands population-increased from 30 per 10,000 in the year 2000 to 75 per 10,000 in the year 2007. Prevalence rates showed a similar trend, increasing from 110 per 10,000 in 2000 to 210 per 10,000 in 2007. Prevalence and incidence rates both were consistently higher among boys than girls, although the greatest increases over time were observed in female patients. Analysis of treatment patterns revealed that most children (98%) initiated treatment with methylphenidate. Of those, 89% received an immediate-release formulation, although increased use of long-acting amphetamine and atomoxetine was apparent over the study period. Persistence and adherence rates varied according to the medications used and the prescribing physician. Antipsychotic agents and melatonin were the most commonly used therapeutics in the year before ADHD treatment initiation (6% and 4% of patients, respectively). Conclusions: The incidence and prevalence of children treated for ADHD increased from 2000 to 2007. Most children (98%) initiated treatment with immediate-release methylphenidate. © 2011 Elsevier HS Journals, Inc.
Does Packaging with a Calendar Feature Improve Adherence to Self-Administered Medication for Long-Term Use? A Systematic ReviewBarbara K. Zedler | Priyanka Kakad | Susan Colilla | Lenn Murrelle | Nirav R. Shah
Volume 33, Issue 1, January 2011, Pages 62-73
Background: The therapeutic benefit of self-administered medications for long-term use is limited by an average 50% nonadherence rate. Patient forgetfulness is a common factor in unintentional nonadherence. Unit-of-use packaging that incorporates a simple day-and-date feature (calendar packaging) is designed to improve adherence by prompting patients to maintain the prescribed dosing schedule. Objective: To review systematically, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, randomized controlled trial evidence of the adherence benefits and harms of calendar blister packaging (CBP) and calendar pill organizers (CPO) for self-administered, long-term medication use. Methods: Data sources included the MEDLINE and Web of Science and Cochrane Library databases from their inception to September 2010 and communication with researchers in the field. Key search terms included blister-calendar pack, blister pack, drug packaging, medication adherence, medication compliance, medication compliance devices, medication containers, medication organizers, multicompartment compliance aid, persistence, pill-box organizers, prescription refill, randomized controlled trials, and refill compliance. Selected studies had an English-language title; a randomized controlled design; medication packaged in CBP or CPO; a requirement of solid, oral medication self-administered daily for longer than 1 month in community-dwelling adults; and at least 1 quantitative outcome measure of adherence. Two reviewers extracted data independently on study design, sample size, type of intervention and control, and outcomes. Results: Ten trials with a total of 1045 subjects met the inclusion criteria, and 9 also examined clinical outcomes (seizures, blood pressure, psychiatric symptoms) or health care resource utilization. Substantial heterogeneity among trials precluded meta-analysis. In 3 studies, calendar packaging was part of a multicomponent adherence intervention. Six of 10 trials reported higher adherence, but it was associated with clinically significant improvement in only 1 study: 50% decreased seizure frequency with a CPO-based, multicomponent intervention. No study reported sufficient information to examine conclusively potential harms related to calendar packaging. Limitations: All trials had significant methodological limitations, such as inadequate randomization or blinding, or reported insufficient information regarding enrolled subjects and attrition, which resulted in a moderate-to-high risk of bias and, in 2 studies, unevaluable outcome data. Trials were generally short and sample sizes small, with heterogeneous adherence outcome measures. Conclusions: Calendar packaging, especially in combination with education and reminder strategies, may improve medication adherence. Methodological limitations preclude definitive conclusions about the effect size of adherence and clinical benefits or harms associated with CBP and CPO. High-quality trials of adequate size and duration are needed to assess the clinical effectiveness of such interventions. © 2011 Elsevier HS Journals, Inc.
Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: A review of preclinical and clinical dataDavid W. Dempster | Cheryl L. Lambing | Paul J. Kostenuik | Andreas Grauer
Volume 34, Issue 3, March 2012, Pages 521-536
Background: Postmenopausal osteoporosis results from bone loss and decreased bone strength mediated by an increased rate of bone remodeling secondary to reduced estrogen levels. Remodeling cycles are initiated by osteoclasts, the formation, function, and survival of which depend on RANK ligand (RANKL). RANKL inhibition therefore represents a novel strategy for reducing remodeling and its effects on fracture risk. Objectives: The goal of this study was to review the preclinical and clinical evidence supporting the value of RANKL inhibition in conditions of bone loss and to provide the rationale for the use of the fully human antibody denosumab, a RANKL inhibitor, in such conditions. Methods: We searched PubMed from January 2005 to May 2011 using the following terms: RANK Ligand, RANKL, denosumab, and NOT cancer, metastatic bone, or rheumatoid in the title. Results: The search method retrieved 111 articles. Preclinical evidence from several bone disease models suggests that RANKL inhibition leads to increased bone volume, density, and strength. Denosumab prevents RANKL from binding to its receptor, decreasing osteoclast activity and thereby reducing bone resorption and increasing cortical and trabecular bone mass and strength. It has consistently been reported to reduce bone turnover, increase bone density, and reduce the risk of fracture in clinical studies of postmenopausal women. Phase III head-to-head trials comparing denosumab with the bisphosphonate alendronate reported that denosumab was associated with significantly greater increases in bone density. Eczema as an adverse event and cellulitis as a serious adverse event were more common with denosumab than with placebo. Conclusions: Preclinical studies defined the role of RANKL in bone remodeling and provided evidence for the therapeutic potential of RANKL inhibition in conditions of bone loss. Clinical studies evaluating RANKL inhibition with denosumab in postmenopausal women have reported significant reductions in vertebral, nonvertebral, and hip fractures, providing evidence compatible with the use of denosumab in postmenopausal women with osteoporosis. © 2012.
Tolerability of dipeptidyl peptidase-4 inhibitors: A reviewKathleen R. Richard | Jamie S. Shelburne | Julienne K. Kirk
Volume 33, Issue 11, November 2011, Pages 1609-1629
Background: Oral glucose-lowering agents are used to treat patients with type 2 diabetes mellitus (T2DM). Most patients require multiple agents to maintain glycemic targets. Dipeptidyl peptidase-4 (DPP-4) inhibitors are administered as monotherapy and in combination therapy for the treatment of T2DM. Objective: The aim of this article was to provide a thorough review of published tolerability data on 5 DPP-4 inhibitors. Methods: PubMed and Web of Science were searched for English-language clinical trials published from January 2000 to June 2001, using the following key words: dipeptidyl peptidase-4 inhibitor, vildagliptin, alogliptin, sitagliptin, saxagliptin, linagliptin, safety, tolerability, efficacy, effect, AE, and adverse effect. Studies were considered for inclusion if they were randomized, double-blind trials performed in patients ≥18 years of age with T2DM and with a hemoglobin A 1c of ≥6.5%; included ≥1 arm that received monotherapy with DPP-4; and reported adverse events (AEs). Studies in patients with a history of type 1 or secondary forms of diabetes, significant diabetic complications or cardiovascular disease within the 6 months before the start of the study, hepatic disease or abnormalities, and/or renal abnormalities were excluded. Results: A total of 45 clinical trials, 5 pharmacokinetic studies, and 28 meta-analyses or reviews were included. The duration of studies ranged from 7 days to 104 weeks. The most commonly reported AEs were nasopharyngitis, upper respiratory infections, all-cause infections, headache, gastrointestinal symptoms, and musculoskeletal pain. Based on the findings from the studies, the DPP-4 inhibitors had minimal impact on weight and were not associated with an increased risk for hypoglycemia relative to placebo. Rates of nasopharyngitis were higher with the DDP-4 inhibitors than with placebo. Pancreatitis was reported at lower rates with the DPP-4 inhibitors compared with other oral antihyperglycemic agents. Cardiovascular events were limited, and postmarketing studies are ongoing. Conclusions: The tolerability of DPP-4 inhibitors is supported by published clinical trials. The rates of weight gain, gastrointestinal AEs, and hypoglycemia were minimal with the DPP-4 inhibitors studied. © 2011 Elsevier HS Journals, Inc.
Use of Biologics in Rheumatoid Arthritis: Current and Emerging Paradigms of CareJeffrey R. Curtis | Jasvinder A. Singh
Volume 33, Issue 6, June 2011, Pages 679-707
Background: Improved understanding of rheumatoid arthritis (RA) pathogenesis has led to the development of new biologic treatments that target specific elements of RA inflammatory response. Objective: Our aim was to provide a comprehensive review of biologic therapies currently used for the treatment of RA. Methods: A search of MEDLINE (up to October 2010) was conducted. Preference for article inclusion was given to English language meta-analyses and large, Phase III, randomized controlled trials (RCTs) of biologic treatments in patients with RA. Results: In large RCTs, significantly more patients treated with tumor necrosis factor-α (TNF-α) antagonists (as monotherapy, or as an adjunct to methotrexate) versus controls (35%-67% vs 9%-33% of patients; P ≤ 0.01) achieved an American College of Rheumatology 20 response as a primary study end point. However, safety concerns-especially the potential for serious infections and malignancy-remain for TNF-α blockade. For example, 1 meta-analysis (>5000 patients) reported a 2-fold increase (95% CI, 1.3-3.1) in the risk of serious infections and a 3.3-fold increase (95% CI, 1.2-9.1) in the risk of malignancy. Abatacept and rituximab (given in combination with methotrexate) may be useful clinical alternatives for RA patients with an inadequate response to TNF-α antagonists. These agents do not appear to increase the risk of serious infections (OR, 1.35-1.45; 95% CI, 0.56-3.73), although rituximab may rarely cause progressive multifocal leukoencephalopathy (0.4 cases per 100,000 hospitalizations). Conclusions: Over the last decade, targeted biologic agents have transformed RA treatment. Although relatively expensive in the short term, the direct costs of these biologics may be offset by slowed disease progression and significant improvements in RA symptoms, physical function, and quality of life. © 2011 Elsevier HS Journals, Inc.
Adherence to Statin Treatment and Health Outcomes in an Italian Cohort of Newly Treated Patients: Results From an Administrative Database AnalysisLuca Degli Esposti | Stefania Saragoni | Paolo Batacchi | Silvia Benemei | Pierangelo Geppetti | Alessandra Sturani | Stefano Buda | Ezio Degli Esposti
Volume 34, Issue 1, January 2012, Pages 190-199
Background: Adherence to statin treatment is expected to be associated with health outcomes. Much of the available evidence is derived from studies conducted on selected populations (eg, Medicaid population), on specific cohorts of patients (eg, patients with diabetes mellitus or those who have experienced acute myocardial infarction [AMI]), or with respect to a single outcome (eg, only death or only AMI). Objective: The aim of this study was to evaluate the association between adherence to statin therapy and all-cause mortality and cardiovascular morbidity (AMI and stroke) in an unselected cohort of newly treated patients. Methods: We performed a population-based retrospective cohort study that included adult patients with a first prescription of a statin from January 1, 2004, through December 31, 2006, using data from the administrative databases of the Local Health Unit of Florence in Italy. Adherence to statin treatment was estimated as the proportion of days covered (PDC) by filled prescriptions and classified as . low (PDC, 21%-40%), . intermediate-low (PDC, 41%-60%), . intermediate-high (PDC, 61%-80%), and . high (PDC, >80%). Cases with PDC ≤20% were excluded. A Cox regression model was used to investigate the association between adherence to treatment and all-cause mortality and hospitalization for AMI or stroke. Results: The cohort consisted of 19,232 patients (9823 men and 9409 women) aged 18 to 102 years (mean [SD], 66.5 [11.4] years): 20.1% had been previously hospitalized for cardiovascular events and 17.6% had been treated with hypoglycemic drugs. Adherence to statins was low in 4427 patients (23.0%), intermediate-low in 3117 (16.2%), intermediate-high in 3784 (19.7%), and high in 7904 (41.1%). Lower-adherent patients were younger and had fewer comorbidities compared with higher-adherent patients. In our multivariable analyses, high adherence was significantly associated with decreased risk of all-cause death, AMI, or stroke. Compared with low adherence (hazard ratio [HR] = 1), the risk was lower in intermediate-low adherence (HR = 0.83; 95% confidence interval [CI], 0.71-0.98; . P < 0.05) and much lower in intermediate-high (HR = 0.60; 95% CI, 0.51-0.70; . P < 0.001) and high adherence (HR = 0.61; 95% CI, 0.54-0.71; . P < 0.001). Conclusions: In this Italian cohort of newly treated patients, suboptimal adherence to statins occurred in a substantial proportion of patients and was associated with increased risk of adverse health outcomes. © 2012 Elsevier HS Journals, Inc.
Efficacy and Safety Profile of Exenatide Once Weekly Compared With Insulin Once Daily in Japanese Patients With Type 2 Diabetes Treated With Oral Antidiabetes Drug(s): Results From a 26-Week, Randomized, Open-Label, Parallel-Group, Multicenter, Noninferiority StudyNobuya Inagaki | Yoshihito Atsumi | Tomonori Oura | Hitoshi Saito | Takeshi Imaoka
Volume 34, Issue 9, September 2012, Page
Background: Exenatide once weekly (QW) is an extended-release formulation of exenatide, a glucagon-like peptide-1 receptor agonist that reportedly improves glycemic control in patients with type 2 diabetes. Objective: The goal of this study was to test the hypothesis that exenatide QW is noninferior to insulin glargine, as measured by change in glycosylated hemoglobin (HbA1c) from baseline to end point (week 26 [primary end point]) in Japanese patients with type 2 diabetes who have inadequate glycemic control with oral antidiabetes drugs. Methods: In this open-label, parallel-group, multicenter, noninferiority registration study, patients were randomized (1:1) to add exenatide QW (2 mg) or once-daily insulin glargine (starting dose, 4 U) to their current oral antidiabetes drug treatment. The primary analysis was change in HbA1c from baseline to end point, evaluated by using a last-observation-carried-forward ANCOVA model, with a predefined noninferiority margin of 0.4%. Secondary analyses (a priori) included analysis of superiority for between-group comparisons of change in weight and the proportion of patients reaching HbA1c target levels of ≤7.0% or ≤6.5%. Results: The baseline characteristics of the exenatide QW (215 patients) and insulin glargine (212 patients) treatment groups were similar: mean (SD) age, 57 (10) years and 56 (11) years, respectively; 66.0% and 69.8% male; mean HbA1c, 8.5% (0.82%) and 8.5% (0.79%); and mean weight, 69.9 (13.2) kg and 71.0 (13.9) kg. Exenatide QW was statistically noninferior to insulin glargine for the change in HbA1c from baseline to end point (least squares mean difference, -0.43% [95% CI, -0.59 to -0.26]; P < 0.001), with the 95% CI upper limit less than the predefined noninferiority margin (0.4%). A significantly greater proportion of patients receiving exenatide QW compared with insulin glargine achieved HbA1c target levels of ≤7.0% (89 of 211 [42.2%] vs 44 of 210 [21.0%]) or ≤6.5% (44 of 214 [20.6%] vs 9 of 212 [4.2%]) at end point (P < 0.001 for both). Patient weight was reduced with exenatide QW compared with insulin glargine at end point (least squares mean difference, -2.01 kg [95% CI, -2.46 to -1.56]; P < 0.001). Exenatide QW was well tolerated, with a lower risk of hypoglycemia compared with insulin glargine but a higher incidence of injection-site induration. Conclusions: Exenatide QW was statistically noninferior to insulin glargine for the change in HbA1c from baseline to end point; these results suggest that exenatide QW may provide an effective alternative treatment for Japanese patients who require additional therapy to control their diabetes. ClinicalTrials.gov identifier: NCT00935532. © 2012 Elsevier HS Journals, Inc..
Measurement and Rates of Persistence With and Adherence to Biologics for Rheumatoid Arthritis: A Systematic ReviewMarissa A. Blum | Danielle Koo | Jalpa A. Doshi
Volume 33, Issue 7, July 2011, Pages 901-913
Background: Biologics are an important addition to the conventional care of patients with rheumatoid arthritis (RA). Poor persistence with and adherence to biologics can undermine the effectiveness of these medications. There are no standardized methods to track persistence with and adherence to biologics. Objective: The goal of this systematic review was to assess the methods of measurement and reported rates of persistence with and adherence to biologic regimens in patients with RA in clinical practice. Methods: Observational studies that evaluated persistence with and adherence to biologic treatments in patients with RA were identified by searching Medline and SCI-Expanded for observational studies published in English between January 1995 and May 2009, using the following search terms: adalimumab, adherence, arthritis, biologics, compliance, discontinuation, etanercept, infliximab, persistence, RA, treatment retention, and TNF. The articles were independently reviewed to identify relevant studies and abstracted data. Results: Of the 52 studies identified, 73% were based in Europe and 21% were set in the United States. All but 1 study reported measures of persistence, such as median drug survival and rates of discontinuation and retention. Four studies reported on adherence, all of which were conducted in the United States and used administrative claims data. Methods of persistence and adherence measurement were unclear or, if recorded, varied considerably across studies. Although various continuation rates (persistence) were reported across studies, the overall range of continuation at 12 months was 32.0% to 90.9%. Continuation rates were generally higher with the addition of methotrexate or other disease-modifying antirheumatic drugs. Conclusion: The data from the available studies on RA treatments suggest a need for better methods for tracking persistence and adherence, for examining prescribing patterns, and for identifying interventions to improve adherence. © 2011 Elsevier HS Journals, Inc.
A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of Empagliflozin and Linagliptin After Coadministration in Healthy Male VolunteersChristian Friedrich | Katrin Metzmann | Peter Rose | Michaela Mattheus | Sabine Pinnetti | Hans J. Woerle
Volume 35, Issue 1, January 2013, Page
Background: Empagliflozin is an oral, potent, and selective inhibitor of sodium glucose cotransporter 2, inhibition of which reduces renal glucose reabsorption and results in increased urinary glucose excretion. Linagliptin is an oral inhibitor of dipeptidyl pepti- dase-4 approved for the treatment of type 2 diabetes in the United States, Europe, Japan, and Canada. Due to their complementary modes of action, there is a good rationale to combine empagliflozin with linagliptin to improve glycemic control in patients with type 2 diabetes. Objective: This study was conducted to investigate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy volunteers. Methods: Thiswas an open-label, randomized,mul-tiple-dose, crossover study with 3 treatments in 2 treat-ment sequences. Sixteen healthy male subjects received treatment A (empagliflozin 50 mg once daily [QD] for 5 days), treatment B (empagliflozin 50 mg QD and linagliptin 5mgQD for 7 days), and treatment C (linagliptin 5 mg QD for 7 days) in sequence AB then C, or sequence C then AB. Results: Sixteen healthy male subjects aged between 18 and 50 years with a bodymass index of 18.5 to 29.9 kg/m2 were included in the study. Linagliptin total ex-posure (AUC over a uniform dosing interval Τ at steady state geometric mean ratio [GMR], 1.03 [90%CI, 0.96-1.11]) and peak exposure (Cmax at steady state GMR, 1.01 [90% CI, 0.87-1.19) exposure was unaffected by coadministration of empagliflozin. empagliflozin total exposure (AUC over a uniformdosing interval Τ at steady state GMR, 1.02 [90% CI, 0.97-1.07]) was unaffected by coadministration of linagliptin. There was a reduction in empagliflozin peak exposure (Cmax at steady state GMR, 0.88 [90% CI, 0.79-0.99]) when linagliptin was coadministered that was not considered clinically mean-ngful. No adverse events were reported during the coad-ministration period. No hypoglycemiawas reported. Em-paglifozin and linagliptin were well tolerated. Conclusion: These data support the coadministration of empagliflozin and linagliptin without dose adjust-ments. European Union Drug Regulating Authorities Clinical Trials Registration: EudraCT 2008-006089-27. © 2013 Published by Elsevier HS Journals, Inc. © 2013 Elsevier HS Journals, Inc.
Design and Recruitment for the GAP Trial, Investigating the Preventive Effect on Asthma Development of an SQ-Standardized Grass Allergy Immunotherapy Tablet in Children with Grass Pollen-Induced Allergic RhinoconjunctivitisErkka Valovirta | Aud Katrine Herland Berstad | Jacques de Blic | Albrecht Bufe | Peter Eng | Susanne Halken | Pedro Ojeda | Graham Roberts | Lene Tommerup | Eva Maria Varga | Inger Winnergard
Volume 33, Issue 10, October 2011, Pages 1537-1546
Background: Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published. Objective: The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial. Methods: The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities. Results: The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen-induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries. Conclusions: To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12. © 2011 Elsevier HS Journals, Inc.


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Charles Pitman & Martha Paul of Somerset, England
CHARLES PITMAN was son of William Pitman and Mary nee Raison of South Petherton.
Charles Pitman born abt 1799 and christened in 1800 at South Petherton. He married Martha Paul, daughter of William Paul and his wife, Elizabeth. Martha born abt 1799 at possibly Martock. She was christened at Martock on 7th January 1799. William Paul was later the South Petherton Constable. Both William and Eizabeth Paul were deceased before 1853, according to Marthas immigration records when she and Charles sailed to Australia in 1853.
Charles was a carpenter by trade.
The following transcriptions of SS Peter and Paul parish records show:
Born to Charles Pitman and Martha:-
Leah Baptised 3rd November 1824 at South Petherton.
Migrated to Australia. Married Joseph Hull in Parramatta, NSW, Australia in 1856.
Eliza Baptised 29 August 1827 at South Petherton. Born about March 1826.
Married Henry Griffen at South Petherton on 21st August 1848, and migrated to Australia.
William Baptised 29 August 1827 at South Petherton. Born 5th August 1827.
Migrated to Australia. May have married Cathrine Calder in Sydney, Australia in 1854.
Ann Baptised 25 November 1830 at South Petherton. Born 29th August 1830.
& possibly Ebenezer born about 1825. (Ebenezer was in 1841 census records. Have not found him again).
& possibly Charles who born April 8th 1840,and christened April 16th
1840 and died South Petherton on 22nd April 1840 age 10 days. Transcripts say he was born to Charles and Leah Pitman. This possibly should have been Martha.
1841 census sees Charles and Martha Pitman living at Whitehall Street, Yeovil, Somerset. Very near the town of South Petherton. They are with their daughter, Ann, age 9 years. Charles is a carpenter.
1850 Directory of South Petherton and Martock shows Charles Pitman as a carpenter.
1851 census sees Charles and Martha Pitman living in South Petherton with Leah and Ann, their daughters. And Benjamin Pitman, age 5, Charles grandson. We later find he was born to Leah.
Charles Pitman and his wife, Martha left England for Australia in 1853. Their son, William, and daughter, Eliza were already in Australia. Charles and Martha took Leah with them, and Leahs son, Benjamin.
Charles and Martha, with daughter, Leah, and grandson, Benjamin, sailed on the ship "Talavera" from Southampton, England on 1st June 1853 to New South Wales, Australia. Arrived 25th August 1853.
Film number 2465
Ships records contain the following information:
Charles Pitman age 50 Born South Petherton, Somerset.
Parents: William & Mary, both deceased. Church of England.
Occupation: Carpenter. Can read & write. In good health.
Martha Pitman age 50 Born Martock, Somerset.
Parents: William & Elizabeth, both deceased. Church of England.
Wife of Charles. Can read & write. In good health.
Leah Pitman age 27 Born South Petherton, Somerset.
Parents: Charles & Martha, both on board ship. Church of England.
Occupation: Domestic Servant. Can read & write. In good health.
Benjamin Pitman age 7 Born South Petherton, Somerset.
Parents: on board ship. Church of England.
Notes on the family:
Have a son, William, & daughter, Eliza, both living at Woolomooloo, NSW. Son, William Pitman paid 34 pounds for travel cost under the ??? regulations.
As inspected by Immigration Board September 1853.
The ship was released from quarantine following inspection on 6th September 1853.
Charles died about 1876 in Dubbo, NSW, Australia.
on 2008-05-27 23:15:51
Julie07 has been a Family Tree Circles member since May 2008. is researching the following names: SEMMLER, MUHLNICKEL, KRAUSE and 7 other(s).


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There is some great pitching talent in the NL Central. It's arguable that over the past two seasons, the NL Central has improved more in pitching than any other division in baseball aside from perhaps the NL East.
I compiled this list using an extremely unscientific method. The two main factors I took into account to make these rankings were career resumes and future potential. I also took into account the importance of each pitcher to their respective teams.


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Seeking admission for various medical complaints.62 Parents who fake signs of illness and laboratory tests of their children are fda viagra hearing loss said to have factitious disorder "by proxy", such patients commonly "hospital-hop". An example of a patient with a likely factitious disorder follows. Malingering is associated with antisocial personality disorder.41 The person with factitious disorder is said to have no obvious reason to fake illness, but rather the "psychological need" to be a patient. These parents are still said to have a "psychological need" to be in a sick role, although treated as child abusers. When pronounced and chronic, it is referred to as Munchausen's syndrome.
Technology, particularly computers, fda viagra hearing loss can be viewed as an extension of human cognitive capability. Related to this view is the framework of cognitive engineering, in which humans and intelligent computer systems constitute "joint cognitive systems" (Hutchins, 1995. Cognitive neuroscience proposes that neural structure and function constrain and in some cases determine theories of human mental processes.
If neuroscience has freed cognitive science from rigid functionalism, then ergonomics may serve to liberate it from a disembodied existence devoid of context and provide it an anchor in the real world. The recent influence of cognitive neuroscience has led fda viagra hearing loss to a retreat from this position, however. Mainly due to the influence of researchers from artificial intelligence and computer science, cognitive psychology also went through a functionalist period in the 1967s and 1980s.
Even though researchers are aware of the importance of ecological validity, modern cognitive psychology (with a few exceptions) tends to study mental processes in isolation, apart from the artifacts and technologies of the world that require the use of those processes. Roth, Bennett, & Woods, 1985).
Have you ever had fda viagra hearing loss an unexpected or unusually high-energy period unconnected to a depression?. But has there ever been a time when a depression just changed into an excited or high-energy period?. Summarizing the results for the patient helps segue into the next topic, " Once the domain is covered. .
"As I understand it, this depression is like the others, but a bit worse. " Special examination techniques Some clinical circumstances require specific techniques.
This disease fda viagra hearing loss has been found almost exclusively in African Americans (Bauer et al., 2002. Spinocerebellar Ataxias SCAs are a heterogeneous group of neurological disorders with varied clinical presentation and genetic etiology. Margolis, Rudnicki, & Holmes, 2005).
Because HD is an autosomal dominant disorder, identification of a mutation has profound repercussions for the patient and biologically related relatives. Pathology is fda viagra hearing loss similar to HD, with striatal and cortical atrophy with intranuclear inclusions. The range of normal and abnormal repeats is similar to those for HD.
The disease is very similar to HD but is caused by a CTG/CAG mutation expansion in chromosome 13q23.4 in the gene coding for junctophilin-6. HD-Like 1 HD-Like 4 is an adult-onset autosomal dominant, neurodegenerative disorder characterized by a progressive hyperkinetic movement disorder, dementia, and psychiatric features.
Not uncommonly, a lesbian batterer will attempt to fda viagra hearing loss control her partner by threatening to "out" her if she reveals the abuse or tries to leave (homophobic control. Internalized responses to homophobia and violence in a woman's family of origin may contribute both to perpetration and to an increased vulnerability to victimization once it occurs. West 1996) fda viagra hearing loss. Hard 1986) or by defining the woman's efforts to defend herself as "mutual combat," undermining her efforts to get help (Hard 1986.
Although there are couples in which the abuse or violence is mutual or in which one partner initiates and the other fights back, for many women the pattern of one partner systematically controlling the other is no different from that in abusive heterosexual relationships (Marrujo and Kreger 1993).
Wang X, deLeve LD fda viagra hearing loss. 122. Decrease in nitric oxide production contributes to hepatic venoocclusive disease. Hepatology 1997.


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Squash centre
The National Squash Centre on Mt Albert campus has six courts and is ideal for all levels, from beginners to professionals.
A joint venture between Squash New Zealand, Squash Auckland and Unitec, the National Squash Centre provides the first ever home for squash in New Zealand.
Unitec students or staff members who use the squash centre during our off-peak times (before 5pm from Monday to Friday and on weekends) pay half price to hire a court.
If you don't have your own squash gear; you can hire squash shoes, racquets or balls.
Alternatively, you can buy them from the centre's shop.
|Building 201, Mt Albert campus
|Monday to Thursday 11am - 9 pm
Friday 11am - 8pm
Saturday 9am - 5pm
Sunday 9am - 5pm
National Squash Centre
|General Manager
|Robbie Yam
Mobile 021 132 5691


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WWE SmackDown vs. Raw 2008 DS
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Also on:Nintendo DS PS3 PSP Xbox 360 Wii
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Best Fishing Times: 3:38AM to 5:38AM, and 4:08PM to 6:08PM
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