text:
2. The method of claim 1, wherein the inflammatory condition or disease is selected from the group consisting of septic shock, rheumatoid arthritis, osteroarthritis, asthma, bronchitis, chronic obstructive airway disease, psoriasis, alergic rhinitis, dermatitis, and inflammatory bowel disease.
This applications claims benefit of U.S. Provisional application Ser. No. 60/020,406, filed Jun. 25, 1996.
The invention relates to a ring-substituted derivative of K-252a for use in methods directed to ameliorating the deleterious effects of a variety of diseases, disorders and conditions.
I. The Indolocarbazole K-252a
K-252a is a compound having an indolocarbazole skeleton [Japanese Published Unexamined Patent Application No. 41489/85 (U.S. Pat. No. 4,555,402)] with the stereochemistry shown in Formula I.
It has been reported that K-252a strongly inhibits protein kinase C (PKC) which plays a central role in regulating cell functions, and has various activities such as the action of inhibiting smooth muscle contraction (Jpn. J. Pharmacol. 43 (suppl.): 284, 1987), the action of inhibiting elongation of neurazone (J. Neuroscience, 8: 715, 1988), the action of inhibiting histamine release (Allergy, 43: 100, 1988), the action of inhibiting smooth muscle MLCK (J. Biol. Chem., 263: 6215, 1988), anti-inflammatory action (Acta Physiol. Hung., 80: 423, 1992), and the activity of cell survival (J. Neurochemistry, 64: 1502, 1995). It has also been disclosed in Experimental Cell Research, 193: 175-182, 1991, that K-252a has the activity of inhibiting IL-2 production.
In addition, it has been reported that derivatives of K-252a have PCK inhibitory activity, the activity of inhibiting histamine release (Japanese Published Unexamined Patent Application No. 295588/88), antitumor activity [Japanese Published Unexamined Patent Application No. 168689/89 (U.S. Pat. No. 4,877,776), WO 88/07045 (U.S. Pat. No. 4,923,986), WO 94/04541], the action of increasing blood platelets [WO 94/06799 (EP 630898A)], vasodepressor activity (Japanese Published Unexamined Patent Application No. 120388/87), the action of accelerating cholinergic neuron functions [WO 94/02488 (U.S. Pat. No. 5,461,146 and U.S. Pat. No. 5,621,100)] and, curative effect on prostate cancer [WO 94/27982 (U.S. Pat. No. 5,516,771)]. Selected amino-containing trindene compounds have been prepared by Beckmann rearrangement of the corresponding staurosporine oximes (WO 97/05140).
The indolocarbazoles are generally lypophilic. Because of this feature, the indolocarbazoles are able to cress biological membranes with relative ease, compared to proteins. Also indolocarbazoles generally have longer in vivo half lives than proteins.
In addition to K-252a itself, various derivatives of K-252a have been synthesized and tested for biological activity. Among the K-252a derivatives shown to have biological activity is a compound disclosed in Lewis et al., U.S. Pat. Nos. 5,461,146, and 5,621,100, and PCT Publication WO 94/02488, and designated therein as "Compound II-51." Compound II-51 has been shown to enhance the function of cholinergic neurons, striatal neurons, and sensory neurons.
II. Neurodegenerative Diseases and Disorders
Parkinson's disease is a neurodegenerative disorder that involves progressive and selective loss of dopaminergic neurons of the nigro-striatal pathway (Agid, Lancet: 337:1991). Administration of 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) to mice leads to dopaminergic neuron degeneration and serves as an animal model for the dopaminergic neuronal loss and behavioral deficits observed in Parkinson's disease. Peripheral administration of MPTP leads to a highly selective degeneration of the nigrostriatal dopaminergic neuronal system in humans, monkeys and mice (Heikkila et al., Science 224; 1451-1453, 1984; Burns et al., Proc Natl. Acad. Sci. USA 80:4546-4550, 1983).
Neurodegeneration in the MPTP mouse model has been well-characterized. Systemic administration of MPTP produces selective loss of dopamine content (and metabolites), tyrosine hydroxylase activity, and dopamine uptake sites in dopaminergic neurons of the murine striatum (Heikkila et al., Nature 311:467-469, 1984a,b; Tipton et al., J. Neurochem. 61:1191-1206, 1993). This effect is dose-dependent. Maximal loss occurs between 3 and 7 days post-lesion (Jackson-Lewis et al., Neurodegeneration 4:257-269, 1995). The dopaminergic cell bodies in the nigra are less sensitive to MPTP toxicity than their corresponding nerve terminals. At high MPTP doses, or multiple MPTP injections, substantial loss of TH immunopositive cells in the substantia nigra occurs within a week (Heikkila et al., Science 224; 1451-1453, 1984; Jackson-Lewis et al., Neurodegeneration 4:257-269, 1995). At lower MPTP doses, or with a single injection, loss of nigral tyrosine hydroxylase positive cells occurs later (Tatton et al., J. Neuroscience. Res. 30:666-672, 1991). Thus, at lower doses of MPTP and a short-time period after lesion, striatal damage can be observed in the absence of nigral tyrosine hydroxylase-positive cell loss. This neurodegenerative sequence is similar to that observed in the disease. The MPTP mouse model is a recognized and widely used model for the study of Parkinson's disease.
Non-cholinergic neurons that use γ-aminobutyric acid (GABA) as a neurotransmitter (i.e., GABA-ergic neurons) are widespread throughout the brain. For example, they are found in the nucleus basalis magnocellularis in the rodent (the equivalent region in the human brain is called nucleus basalis of Meynert), a region of the basal forebrain important in attention and memory functions. Damage to GABA-ergic neurons in the basal forebrain may also contribute to behavioral deficits in neurodegenerative diseases such as Alzheimer's disease (Dekker et al., Neurosci. and Biobehav. Rev., 15:299-317, 1991; Gallagher et al., Seminars in Neuroscience, 6;351-358, 1994; Torres et al., Neuroscience, 63:95-122, 1994).
Neurons in the basal forebrain die in several diseases of the central nervous system, notably Alzheimer's disease (Arendt et al., Acta Neuropathol. (Berl.) 61:101-108, 1983; Iraizoz et al., Neuroscience, 41:33-40, 1991; Vogels et al., Neurobiol. Aging, 11:3-13, 1990). A contributing factor in such neuronal cell death is glutamate excitotoxity, i.e. over-stimulation of neurons by excess glutamate (Choi, Neuron, 1:623-634, 1988). Accordingly, several animal models of Alzheimer's disease use glutamate or a glutamate analog to produce excitotoxic death in the region of the basal forebrain where neuron death occurs, i.e., the nucleus basalis magnocellularis (Wenk, Beh. Brain Res., 72:17-24, 1996).
Neuronal pathology in Alzheimer's disease is first seen in the entorhinal cortex, and loss of neurons in this region becomes severe as the disease progresses (Braak et al., Acta Neuropathol. 82:239-259, 1991; Hyman et al., Ann. Neurol. 20:472-481, 1986). Neurons in layer 2 of the entorhinal cortex project to the dentate syrus of the hippocampus, and this neuronal pathway plays an important role in memory formation (Levisohn et al., Brain Res. 564:230-244, 1991; Olton et al., Brain Res. 139:295-308, 1978; Steward et al., Brain Res. Bull. 2:41-48, 1977). Neurons in layer 2 of the entorhinal cortex, like many other neurons in the cerebral cortex, use glutamate as a neurotransmitter (Mattson et al., Neuron 1:865-876, 1988; White et al., Nature 270:356-357, 1977). Thus, loss of flutamatergic neurons in the entorhinal cortex contributes to the behavioural deficits seen in Alzheimer's disease and other neurological disorders.
III. Peripheral Neuropathy
Peripheral neuropathy generally refers to a disorder that affects the peripheral nerves, most often manifested as one or a combination of motor, sensory, sensorimotor, or autonomic neural dysfunction. The wide variety of morphologies exhibited by peripheral neuropathies can each be uniquely attributed to an equally wide variety of causes. For instance, peripheral neuropathies can be genetically acquired, can result from a systemic disease, or can be induced by a toxic agent. Some toxic agents that cause neurotoxicities are therapeutic drugs, antineoplastic agents, contaminants in foods or medicinals, and environmental and industrial pollutants.
In particular, chemotherapeutic agents known to cause sensory and/or motor neuropathies include vineristine, an antineoplastic drug used to treat haematological malignancies and sarcomas. The neurotoxicity is dose-related, and exhibits as reduced intestinal motility and peripheral neuropathy, expecially in the distal muscles of the hands and feet, postural hypotension, and atony of the urinary bladder. Similar problems have been documented with taxol and cisplatin (Mollman, 1990, New Eng. Jour. Med. 322:126-127), although cisplatin-related neurotoxicity can be alleviated with nerve growth factor (NGF) (Apfel, et al., 1992, Annals of Neurology 31:76-80). Although the neurotoxicity is sometimes reversible after removal of the neurotoxic agent, recovery can be a very slow process (Legha, 1986, Medical Toxicology 1:421-427; Olesen, et al., 1991, Drug Safety 6:302-314).
There are a number of inherited peripheral neuropathies, including: Rofsum's disease, A-betalipoproteinemia, Tangier disease, Krabbe's disease, Metachromatic leukodystrophy, Fabry's disease, Dejerine-Sottas syndrome, and others. Of all the inherited neuropathies, the most common by far is Charcot-Marie-Tooth disease (see also, U.S. Pat. No. 5,420,112 for additional information on peripheral neuropathies).
IV. Cytokines
Tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) are polypeptides known to be involved in a number of inflammatory and metabolic processes in vivo. For a review which relates the role of TNF-α in inflammatory diseases, including septic shock, see Ann. Rev. Immunol. 7:625 (1980), and Clinical Trials for the Treatment of Sepsis, Sibbald, W. J. and Vincent, J.-L. (Eds.), Springer-Verlag Berlin Heidelberg 1995. It is generally accepted that the overproduction or inappropriate production of TNF-α is involved in several pathological conditions, including septic shock (Spooner et al., Clinical Immunology and Immunopathology, 62:p. S11 (1992)) and various other allergic and inflammatory conditions or diseases, including but not limited to rheumatoid arthritis, osteoarthritis, asthma, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and inflammatory bowel disease, and other autoimmune diseases. Immunol. Res. 10:122 (1991), Science 229:896 (1985) and Proc. Natl. Acad. Sci. 89:7375 (1992).
Generally, the invention features methodologies for ameliorating the deleterious effects of a variety of diseases, disorders and conditions by treating a subject in need thereof with a therapeutically effective amount of compound A.
More specifically, the invention features a method for treating the deleterious effects of diseases, disorders and conditions which lead to or cause the death of, or lead to or cause inhibition of the function of, certain neurons by enhancing the function or survival of a dopaminergic, GABA-ergic, or glutamatergic neuron in a mammal, comprising the step of contacting the neuron with Compound A. Typically, the mammal in which the neuron is found in a human. Typically, the dopaminergic, GABA-ergic, or glutamatergic neuron contacted with Compound A has impaired function, or is at risk of dying, because of a neurodegenerative disease. Typically, the neurodegenerative disease is Parkinson's disease or Alzheimer's disease.
More specifically, the invention also features a method of reducing a peripheral neuropathy comprising administering to a mammal a neuropathy-reducing amount of Compound A.
While it has been reported that the indolocarbazole compound K-252a reduces the lethality resulting from endotoxin administration, this ability has been ascribed to the ability of K-252a to inhibit protein kinases, especially protein kinase C (Inaba et al., Jpn. J. Surg 23:234 (1993). It has unexpectedly been found that Compound A, which has little or no inhibitory activity against PKC, provides surprisingly good activity as an inhibitor of TNF-α production and production of the cytokine IL-1β. Therefore, and with further specificity, the invention also features a method of inhibiting production of TNF-α and IL-1β in a mammal and a method of treating or alleviating inflammatory conditions or diseases, including but not limited to septic shock, rheumatoid arthritis, osteoarthritis, asthma, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and inflammatory bowel disease and other autoimmune diseases, which method comprises administering to said mammal an effective amount of Compound A and pharmaceutically acceptable salts thereof in combination with a pharmaceutically acceptable carrier.
As used herein, "Compound A" means the compound whose chemical structure is shown below.
Compound A is also referred to as Compound II-51 (Lewis et al., U.S. Pat. Nos. 5,461,146 and 5,621,100; WO 94/02488).
As used herein, "ameliorate" and "ameliorating" mean to therapeutically improve and/or therapeutically reduce and/or to make more therapeutically tolerable.
As used herein, "deleterious" means damaging and/or harmful and/or negative.
As used herein, the word "overproduction" when used to modify TNF-α and IL-1β means production of TNF-α and/or IL-1β leading to deleterious conditions such as, for example, septic shock, allergic conditions, inflammatory conditions, etc.
As used herein, the terms "inhibit" or "inhibiting" means that the presence of Compound A has a comparatively greater effect on reducing and/or prohibiting and/or preventing the production of a material contacted with Compound A than a comparative material not contacted with Compound A.
As used herein, the terms "enhance" or "enhancing" when used to modify the terms "function" or "survival" means that the presence of Compound A has a comparatively greater effect on the function and/or survival of the specified neuron that a comparative neuron not presented with Compound A. For example, and not by way of limitation, with respect to the survival of, e.g., a dopaminergic neuron, Compound A would evidence enhancement of the function of a dopaminergic neuronal population at risk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a dopaminergic neuronal population not presented with Compound A, if the treated population has a comparatively greater period of functionality than the non-treated population.
As used herein, "dopaminergic neuron" means a neuron that uses dopamine as a neurotransmitter.
As used herein, "GABA-ergic neuron" means a neuron that uses β-aminobutyric acid as a neurotransmitter.
As used herein, "glutamatergic neuron" means a neuron that uses glutamate as a neurotransmitter.
As used herein, "nbm" means nucleus basalis magnocellularis.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present document, including definitions, will control. Unless otherwise indicated, materials, methods, and examples described herein are illustrative only and not intended to be limiting. Various features and advantages of the invention will be apparent from the following detailed description and from the claims.
FIG. 1 is a graph of data demonstrating that Compound A is not a monoamine oxidase-A inhibitor. The IC50 of Clorgyline was 21 nm. Upright triangles, Clorgyline; inverted triangles, Compound A; squares, L-deprenyl.
FIG. 2 is a graph of data demonstrating that Compound A is not a monoamine oxidase-B inhibitor. The IC50 of Clorgyline was 21 nm. Upright triangles, Clorgyline; inverted triangles, Compound A; squares, L-deprenyl.
FIG. 3 is a bar graph showing that animals receiving Compound A (light bars) had significantly more Fluoro-Gold-labeled neurons in the rostral portion of the lesioned nbm (over 400 μm from the midpoint of the lesion), compared to lesioned animals receiving vehicle only (dark bars). *=P<0.05 by Newman-Keuls test.
FIG. 4 is a bar graph showing the total number of errors committed in the T-maze rewarded alternation task by normal control animals, sham surgery animals, surgically-lesioned animals receiving vehicle only ("Les") and surgically-lesioned animals receiving Compound A at a dose of 0.1 mg/kg q.o.d. ("0.1"). Numbers of animals in each group are shown in parentheses. *=P<0.05 compared to Sham, ¶¶=P<0.01 compared to Les, by Newman-Keuls tests.
FIG. 5 shows the effect of Compound A on acrylamide-induced peripheral neuropathy.
Generally, the invention features methodologies for ameliorating the deleterious effects of a variety of diseases, disorders and conditions by treating a subject in need thereof with a therapeutically effective amount of Compound A.
This invention provides a method for treating the deleterious effects of diseases, disorders and conditions which negatively affect the function and/or survival of neurons at risk of dying due to such diseases and disorders by enhancing the function or survival of specific types of neurons of the mammalian central nervous system. More particularly, the invention provides a method for enhancing the function or survival of dopaminergic neurons, GABA-ergic neurons, and glutamatergic neurons in a mammal by administering to the mammal Compound A, a ring-substituted K-252a derivative with the following chemical structure:
Dopaminergic neurons, GABA-ergic neurons, and glutamatergic neurons are widespread in the mammalian central nervous system. Each of these three neuronal cell types suffers impaired function, or even death, in one or more neurodegenerative diseases of the central nervous system. Parkinson's disease involves progressive loss of dopaminergic neurons of the nigrostriatal pathway. Alzheimer's disease involves the death of various types of neurons, including GABA-ergic neurons in the nucleus basalis of Meynert of the basal forebrain. Alzheimer's disease also involves death of glutamatergic neurons in the entorhinal cortex.
One method of treating Parkinson's disease or Alzheimer's disease is to administer a compound that enhances the function or survival of dopaminergic neurons, GABA-ergic neurons, or glutamatergic neurons. Compound A is pharmacologically active in biological assays and in vivo models for enhanced function or survival of dopaminergic neurons, GABA-ergic neurons, and glutamatergic neurons. Therefore, the present invention has utility for treating Parkinson's disease or Alzheimer's disease. The invention, however, is not limited to the treatment of those diseases. The use of Compound A to enhance the function or survival of dopaminergic neurons, GABA-ergic neurons, or glutamatergic neurons whose impaired function or risk of dying results from causes other than Parkinson's disease or Alzheimer's disease is also within the scope of the present invention.
This invention also features a method of reducing a peripheral neuropath. The method involves administering a neuropathy-reducing amount of Compound A to a mammal. In various preferred embodiments, the mammal is a human, or an agricultureal or domestic mammal that develops a neuropathy, e.g., as a result of treatment of a neoplasm with a chemotherapeutic agent. Compound A can be administered in a manner deemed effective by one skilled in the art; a preferred mode of administration is subcutaneous injection.
As used herein, "peripheral neuropathy" refers to a disorder affecting a segment of the peripheral nervous system. The invention involves using Compound A to reduce a neurotoxicity, including, but not limited to, distal sensorimotor neuropathy, or autonomic neuropathies such as reduced motility of the gastrointestinal tract or atony of the urinary bladder.
Preferred neuropathies that can be effectively treated with Compound A include neuropathies associated with systemic disease, e.g., post-polio syndrome; genetically acquired neuropathies, e.g., Charcot-Marie-Tooth disease; and neuropathies caused by a toxic agent, e.g., acrylamide, or a chemotherapeutic agent, e.g., vincristine.
Where Compound A is used to treat a neuropathy induced by a toxic agent, it can be administered before, simultaneously with, or after exposure to the toxic agent, or before, during or after administration of a chemotherapeutic. Preferably, Compound A and the chemotherapeutic agent are each administered at effective time intervals, during an overlapping period of treatment. Compound A can be administered to the mammal following exposure to the neurotoxic agent, or following chemotherapy, to restore at least a portion of the neurofunction destroyed by the neurotoxic agent or chemotherapeutic. The chemotherapeutic can be any chemotherapeutic agent that causes neurotoxicity, such as vincristine, taxol, dideoxyinosine, or cisplatin.
By "toxic agent" or "neurotoxic agent," is meant a substance that through its chemical action injures, impairs, or inhibits the activity of a component of the nervous system. The list of neurotoxic agents that cause neuropathies is lengthy, and includes, but is not limited to, neoplastic agents such as vincristine, vinblastine, cisplatin, taxol, or dideoxy-compounds, e.g., dideoxyinosine; alcohol; metals; industrial toxins involved in occupational or environmental exposure; contaminants of food or medicinals; or over-doses of vitamins or therapeutic drugs, e.g., antibiotics such as penicillan or chloramphenicol, or megadoses of vitamins A, D, or B6. An extensive, although not complete, list of chemical compounds with neurotoxic side-effects is found in Table 1. Although this list provides examples of neurotoxic compounds, it is intended to exemplify, not limit, the scope of the invention. Other toxic agents can cause neuropathies, and can be characterized by methods known to one skilled in the art. By "exposure to a toxic agent" is meant that the toxic agent is made available to, or comes into contact with, a mammal of the invention. Exposure to a toxic agent can occur by direct administration, e.g., by ingestion or administration of a food, medicinal, or therapeutic agent, e.g., a chemotherapeutic agent, by accidental contamination, or by environmental exposure, e.g., aerial or aqueous exposure.
Despite the widely disparate morphologies and causes attributed to peripheral neuropathies in vivo, applicants have hypothesized that Compound A can be an effective means of preventing or treating such neuropathies in a mammal.
Compound A has also been demonstrated to inhibit production of the cytokine TNF-α, despite having little or no inhibitory activity against PKC. Compound A also inhibits the production of the cytokine IL-1β. The production of TNF-α is associated with a variety of diseases and disorders such that the inhibition thereof via use of Compound A can beneficially provide value to a subject in need of such inhibition of TNF-α production.
Accordingly, Compound A can also be utilized to inhibit production of TNF-α in a mammal and/or a method of treating or alleviating inflammatory conditions or disease, including but not limited to septic shock, rheumatoid arthritis, osteoarthritis, asthma, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and inflammatory bowel disease, and other autoimmune diseases which method comprises administering to said mammal a therapeutically effective amount of Compound A.
For use in the present invention, Compound A can be formulated into a pharmaceutical composition by admixture with pharmaceutically acceptable nontoxic excipients and carriers. Such a composition can be prepared for administration by any of various routes. Routes of administration and preferred dosage forms include the following: parenteral, preferably in the form of liquid solutions of suspensions; oral, preferably in the form of tablets of capsules; intranasal, preferably particularly in the form of powders, nasal drops, or aerosols; and dermal, via, for example, trans-dermal patches.
Composition A can be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, Pa., 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Other potentially useful parenteral delivery systems for Compound A include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes, Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for trans-dermal patches are preferably lipophilic emulsions.
Compound A can be employed as the sole active ingredient in a pharmaceutical composition. Alternatively, it can be used in combination with other active ingredients, e.g., growth factors that facilitate neuronal survival or axonal regeneration in diseases or disorders.
The concentration of Compound A used in the practice of this invention in a therapeutic composition can vary. The concentration will depend upon factors such as the total dosage of the drug to be administered and the route of administration. Compound A typically would be provided in an aqueots physiological buffer solution containing about 0.1 to 10% w/v for parenteral administration. Typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day. A preferred dosage of Compound A to be administered is likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative efficacy of Compound A for the particular disease or disorder treated, the particular formulation used, and its route of administration.
Compound A for use in the present invention is preferably obtained according to the methods described in Lewis et al., U.S. Pat. No. 5,461,146.
The present invention will be further illustrated by the following examples. These examples are not to be construed as limiting the scope of the invention, nor the scope of the claims appended hereto.
Pharmacological Activity on Dopaminergic Neurons
Experiments were conducted using Compound A in MPTP-lesioned dopaminergic neurons in mice (MPTP mouse model). A single s.c. dose of MPTP (20 mg/kg) provided to C57 black mice produced approximately 60% loss of striatal tyrosine hydroxylase activity. Administration of Compound A, at daily doses ranging from 0.01 to 10 mg/kg (s.c.), to such MPTP-treated mice reduced the loss of striatal tyrosine hydroxylase activity. These data are shown in Table 2.
Mice were treated with MPTP (20 mg/kg; s.c.) 4-6 hours after the first Compound A injection. Compound A was then injected every day until the end of the experiment, which was 7 days in duration. Striata were assessed for tyrosine hydroxylase enzyme activity. Asterisk indicates statistically significant difference (p<0.05) from MPTP-Vehicle treated animals.
In a separate experiment, the activities of Compound A were assessed in a high dose MPTP-mouse model. A single 40 mg/kg injection of MPTP produced a 95% depletion in striatal tyrosine hydroxylase enzyme activity 7 days post-injection. Administration of Compound A at daily doses of between 0.03 and 3.0 mg/kg reduced the magnitude of the lesion, in a dose dependent manner. These data are shown in Table 3.
Mice were treated with MPTP (40 mg/kg; s.c.) 4-6 hrs after the first Compound A injection. Compound A was then injected every day until the end of the experiment which was 7 days in duration. Striata were assessed for tyrosine hydroxylase enzyme activity. Asterisk indicates statistically significant difference (p<0.05) from MPTP-Vehicle treated animals.
MPTP-mediated dopaminergic toxicity is dependent on MAO mediated conversion of MPTP to MPP+ (1-methyl-4-phenylpyridinium ion) and uptake of MPP+ into dopaminergic neurons. Compounds found to be active in the MPTP-mouse model should be determined not to be inhibitors of MAO or dopamine uptake. Compound A has been found not to inhibit monoamine oxidase A or B in vitro (FIGS. 1 and 2) or block uptake of catecholamines into nerve endings, indicating that this compound does not prevent the metabolic conversion of MPTP to MPP+ or inhibit the active uptake of MPP+ into dopaminergic neurons.
These data demonstrating efficacy of Compound A in the MPTP-mouse dopaminergic lesion model indicate utility of Compound A in the treatment of neurodegenerative disorders such as Parkinson's disease.
Pharmacological Activity on GABA-ergic Neurons
Compound A was tested for its ability to prevent depletion (e.g., enhance the survival) of GABA-ergic neurons in the nucleus basalis magnocellularis, using the well-established ibotenic acid lesion mode. Ibotenic acid, an excitotoxin, is known to reduce numbers of GABA-expressing neurons in the nbm region (Lindefors et al., Neurosci. Lett., 135:262-264, 1992; Shaugnessy et al., Brain Res., 637:15-26, 1994).
Adult male Sprague-Dawley rats received injections of ibotenic acid (5.0 g) into the nbm unilaterally. The rats were then dosed with Compound A (0.03 mg/kg) via subcutaneous injection beginning 18 hours after the lesion, and continuing q.o.d. until 18 days post-lesion. Tissue sections were then collected throughout the rostral-caudal extent of the nbm, and processed to detect glutamic acid decarboxylase, an enzyme required for biosynthesis of GABA. The numbers of neurons expressing glutamic acid decarboxylase were then counted throughout the rostral-caudal extent of the nucleus basalis magnocellularis, in a region where glutamic acid decarboxylase-expressing neurons of the nbm are easily distinguished from glutamic acid decarboxylase-expressing neurons in adjacent structures (white matter medial and ventral to the globus pallidus). The results were expressed as percent glutamic acid decarboxylase-expressing neurons on the lesioned side relative to the number on the opposite, unlesioned side. The results were also calculated separately for the rostral nbm, mid-nmb, and caudal nbm.
A mean of 78 (±16 s.c.m.) percent glutamic acid decarboxylase neurons were counted in the rostral nbm of animals receiving Compound A, compared to 34 (±19 s.e.m.) percent in animals receiving vehicle only, a statistically significant difference by t test (p<0.05). No statistically significant differences between Compound A-treated animals and vehicle-only (control) animals were seen in mid-nbm or caudal nbm.
These results demonstrate that Compound A can protect against a GABA-ergic neuron loss that results from an excitotoxic lesion, and thus has a neurotrophic effect on that neuronal population.
Pharmacological Activity on nbm Neurons
To test directly the ability of Compound A to prevent excitotoxic neuron death, nbm neurons in adult male Sprague-Dawley rats were first labeled with a long-lasting marker. This was done by injecting Fluoro-Gold (FG), a neuronal tracer that is taken up by nerve terminals and transported back to the cell body (Book et al., J. Neuropath. Exp. Neurology, 53:95-102, 1994), into target regions of nbm neurons in the frontal and parietal cortex. 7-10 days later the animals received lesion of the nbm unilaterally, using 5 μg of ibotenic acid. Beginning 18 hours after this lesion, the animals received Compound A (0.03 mg/kg) via subcutaneous injection, every other day until 18 days post-lesion. Tissue sections were collected throughout the entire rostral-caudal extent of the nbm on both sides of the brain, and numbers of nbm neurons with the FG label were counted. The counts were corrected for size differences using standard procedures, and the results expressed as the percent of labeled neurons in the nbm on the lesioned side of each animal relative to the number of labeled neurons in the nbm on the opposite unlesioned side of the brain.
Animals receiving compound A had significantly more FG-labeled neurons in the rostral portion of the lesioned nbm (over 400 μm from the mid-point of the lesion), compared to lesioned animals receiving vehicle only (FIG. 3). At mid-lesion and caudal to the lesion Compound A had a declining effect.
These results demonstrate directly that Compound A can prevent the loss of pre-labeled neurons in the nbm that results from excitotoxic damage.
Long-Lasting Functional Improvement Upon Short Term Dosing with Compound A
Adult male Sprague-Dawley rats were first trained to alternate responses in a standard rewarded-alternation T-maze task (Hepler et al., J. Neurosci., 5:866-873, 1985). The animals then received bilateral lesions of the nucleus basalis magnocellularis, to impair performance in T-maze tasks (e.g., Salamone et al., Behav. Brain Res., 13:63-70, 1984). Beginning 18 hours after the lesion, the animals received Compound A via subcutaneous injection (0.1 mg/kg) every other day until 12 days post-lesion. Twenty-four hours following the last injection all animals were placed in the T-maze once a day, until their alternation performance reached pre-operative levels, which took anywhere from 3 to 10 days. After reaching criterion, the animals were not further tested for 8-10 weeks. At that point the animals were again placed in the T-maze, once a day until they reached pre-operative performance. The total number of errors the animals committed during this test is shown in FIG. 4. The lesioned animals receiving vehicle only committed significantly more errors than either unoperated normals or sham-operates, while lesioned animals that received Compound A 10-12 weeks previously were not different from normals.
These results demonstrate that Compound A produces a chronic improvement in a behavior reflective of an improvement in attention or memory several months after dosing has ceased.
Efficiency of Compound A in Entorhinal Cortex Lesion Model
Glutamate-containing neurons in layer 2 of the entorhinal cortex project to the molecular layer of the dentate gyrus, where they form synapses on the dendrites of the dentate gyrus granule cells. A lesion can be created in layer 2 of entorhinal cortex by stereotaxic injection of the excitotoxin N-methyl-D-asparate (NMDA). Under sodium pentobarbitol anesthesia, rats received an injection of NMDA (15 nmols/site) at each of 2 sites in the entorhinal cortex. Two weeks later, the rats were sacrificed and perfused with a 50 mM sodium sulfide solution. The brains were removed, sectioned in the horizontal plane at a thickness of 40 μm, and stained with either Cresyl violet or Timm'stain. The survival of neurons in layer 2 of entorhinal cortex was assessed in Cresyl violet stained sections, while the integrity of their axon terminals in the molecular layer of the dentate gyrus was measured in alternate sections stained with Timm's stain.
Injection of NMDA destroyed 62±11% (s.e.m.) of entorhinal layer 2 and decreased the area of the dentate gyrus middle molecular layer by 19±6% (s.e.m.). Daily treatment with Compound A (1 mg/kg, s.c.), with the first injection given immediately after injection of NMDA, reduced the loss of entorhinal layer 2 neurons to 22±10% (s.e.m.)(p<0.05, 't' test) and prevented the decrease in area of the middle molecular layer (p<0.05, 't' test). Thus, Compound A protected neurons in the entorhinal cortex from an excitotoxic lesion and maintained the integrity of their axon terminals in the dentate gyrus.
These data demonstrate the efficacy of Compound A in protecting glutamatergic neurons of the entorhinal cortex. Lesions of entorhinal cortex in animal models have been shown to produce memory deficits, and severe degeneration of these neurons occurs in Alzheimer's disease. This supports the position that Compound A is useful in treating neurological disorders that involve loss of or damage to glutamatergic neurons and neurons of the cerebral cortex, including but not limited to Alzheimer's disease, stroke and head trauma.
Effect of Compound A on Acrylamide-Induced peripheral Neuropathy
Acrylamide produces a "dying back" central-peripheral distal neuropathy in humans and animals. The lesion is a mixed sensory/motor neuropathy characterized by weakness, tremor and ataxia in humans. In animals, acrylamide produces changes in behavior (sensory, motor and proprioceptive), histopathology, electrophysiology and weight loss. In the periphery, large diameter, long axon, Ab fibers are preferentially affected by acrylamide. In rats, acrylamide administration produces an axonopathy as measured by increased landing foot spread (LFS), a measure of proprioception.
Acrylamide-induced neuropathy is a model of chemically induced toxicity. It differs from other chemically-induced models (such as chemotherapeutic models) in that the duration is relatively short (3 weeks) and the animals are in relatively good health. Acrylamide does not produce gross systemic toxicity.
Male Sprague-Dawley rats weighing 250 grams at the start of the experiment were used. Acrylamide (50 mg/kg, IP) was administered three times/week for three weeks. The animals were dropped from a height of 30 cm and the distance between the hindfeet was recorded (Edwards, P. M. and Parker, V. H. (1977) "A simple, sensitive, and objective method for early assessment of acrylamide neuropathy in rats." Toxicol. Appl Pharmacol, 40:589-591). Compound A (0.1, 0.3 or 1.0 mg/kg, s.c. in 5% solutol) was administered once daily for the duration of the experiment.
Acrylamide-treated animals had larger distances in the LFS than the vehicle treated animals. Compound A (0.3 mg/kg/day) reduced the magnitude of the increase in LFS produced by acrylamide (FIG. 5).
These data indicate that Compound A is useful for the treatment of peripheral neuropathies.
Failure of Compound A to Inhibit Protein Kinase C, In Vitro
The protein kinase C assay and the inhibition of protein kinase C by K-252a is disclosed in U.S. Pat. No. 4,923,986 and Kase, H. et.al., (eds.) Japan Scientific Societies Press, Tokyo, pp 293-296, (1988). By means of an essentially similar assay, it was found that K-252a inhibits protein kinase C with an IC50 of 0.028 μM while the IC50 of Compound A is 16.0 μM, i.e., 570 fold less active. Compound A has an IC50 of 139 nM, as an inhibitor of the production of TNF-α, and an IC50 value of 261 nM as an inhibitor of the production of IL-1β, concentrations at which Compound A is inactive as an inhibitor of protein kinase C.
In Vitro Inhibition of TNF-α and IL-1β Production by Compound A
The ability of Compound A to inhibit the induction of TNF-α was demonstrated by use of a standard in vitro pharmacological testing procedure as described below. Stock solutions consisting of 4 mM Compound A, in 100% DMSO, were stored at 4° C. Cell culture medium RPMI 1640 (Media Tech, Herndon, Va.) and fetal bovine serum (Hyclone, Logan, Utah) comprised the test medium. Lipopolysaccharide (LPS) (Sigma, St. Louis, Mo.) from E. coli serotype 0.111:B4, extracted with trichloroacetic acid, was used. Stock solutions of LPS were prepared and stored at 4° C. in phosphate-buffered saline (PBS). ELISA kits for assaying tumor necrosis factor alpha (TNF-α) and IL-1β were purchased from Boehringer-Mannheim, (Indianapolis, Ind.) and were used according to the manufacturer's instructions. THP-1 cells, a human monocyte-derived cell line, was obtained from the American Type Culture Collection (ATCC TIB 202). Cells were grown in RPMI 1640 containing 10% fetal bovine serum (medium) in a humidified atmosphere of 5% CO2:95% air at 37° C. Experiments were performed in 24 well culture plates (Nunc) with 5×105 THP-1 cells in 1 ml of medium. Cells were incubated with LPS at 2 ug/ml to induce TNF-α. After a 3-hr incubation period, the cells and medium were centrifuged at 1,000×g for 5 min, and the resulting supernatant fluid was either assayed immediately for TNF-α or stored at −70° C. and assayed later. Media samples were measured for content of TNF-α and IL-1β by Elisa assays.
To test Compound A for the ability to inhibit the induction of TNF-α, cells were incubated with varying concentrations of Compound A for 1 hr prior to the addition of LPS. Compounds were diluted so that DMSO was never present in the cell culture medium at a concentration higher than 0.1%. Compound A was tested and assayed as described above for its ability to inhibit TNF-α and IL-1β production.
Inhibition of LPS-Induced TNF-α and IL-1β in the Serum of Mice.
Sixty female C57BL mice (4-6 weeks old) were divided into six groups, each with 10 animals. Three groups (1,3,5) received vehicle only (PBS containing 0.1% TEA (tetraethyl ammonium hydrochloride)), 200 μl/mouse via intraperitoneal (ip) administration. The other three groups (2,4,6) received Compound A (30 mg/kg in 200 μl, ip) of vehicle (PBS containing 10% of the ethyl ester of 12-hydroxystearic acid; solutol). Two hours later, the animals received by ip administration, 0.1 mg/kg of LPS (groups 1 & 2), 0.5 mg/kg of LPS (groups 3 & 4), and 1.0 mg/kg of LPS (groups 5 % 6). Two hours after LPS administration, all of the animals were sacrificed, and plasma samples were obtained and assayed for their TNF-60 and IL-1β content. Assays were carried out as described in Example 8.
Data are summarized in Table 4. The numbers in () are the group numbers as described above. N indicates the number of animals from which plasma measurements where made. ND=not done.
As shown in Table 4, LPS administration to the mice caused the production by those mice of TNF-α, and the amount of TNF-α produced was markedly inhibited by a two hour pretreatment with Compound A. Pretreatment with Compound A also markedly inhibited the production of IL-1β, produced in response to the administration of 1.0 mg/kg of LPS.
Prevention of LPS-Induced Death in Mice
Forty mice were divided into three groups, two groups consisting of ten mice and one group of twenty mice. Administrations of vehicles, LPS, and Compound A were intraperitoneal. Group 1 (n=10) mice received vehicle (phosphate buffered saline for LPS, 200 μl/mouse) at time zero and vehicle for Compound A (200 μl/mouse) 2 hours later. Group 2 (n=10) mice received the vehicle for Compound A at zero time (200 μl/mouse) and LPS (2 mg in 200 μl/mouse) for two hours later. Group 3 (n=20) received Compound A (30 mg/kg in 200 μl of vehicle) at time zero and LPS (2 mg in 200 μl/mouse) two hours later.
The administration of LPS caused 90% mortality within 20 hours and 100% mortality by 42 hours after administration. In the group of animals which received Compound A two hours prior to receiving LPS, there was 25% mortality at 20 hours after LPS administration, 75% mortality at 42 hours after LPS, and 80% mortality one week after LPS administration. Vehicle treatments were well tolerated and caused no deaths.
Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the true spirit and scope of the invention. Documents cited throughout this patent disclosure are hereby incorporated herein by reference.
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Johnson & Johnson companies are equal opportunity employers. Oncology Sales Specialist (New Brunswick, NJ) - Janssen Biotech, Inc.-1246140806 Description Janssen Biotech, Inc., a member of Johnson & Johnson's Family of Companies, is recruiting for an Oncology Sales Specialist to support the New Brunswick, New Jersey territory. Janssen Biotech, Inc. is a leading biopharmaceutical company that p...
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Posting Date: 10-14-2014 Job Location: 959 Us Route 1 South, North Brunswick, NJ 08902 Location: 000338 County: Middlesex Job Status: Full-Time JobID: 1136980 Brand: Office Depot Category: Stores Responsibilities: The Assistant Store Manager I will be in Stores between $2.4M and $7.0M The Assistant Store Manager I will partner with the Store Manager to drive the overall customer, and sal...
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Inside Technical Sales Representative
$29,120.00 - $96,000.00
Typical Salary for Inside Technical Sales Representative in New Brunswick
(410 Respondents)
Source: Monster.com Careerbenchmarking Tool
Education / Training
Some College Coursework Completed
High School
(263 Respondents)
Source: Monster.com Careerbenchmarking Tool
Inside Technical Sales Representative
Generates revenue by soliciting and obtaining orders; understanding and interpreting technical requirements; providing technical information; developing accounts.
Rate of Growth
9.70 %
Size of Industry in 2006:
Source: Bureau of Labor Statistics, May 2006
Related Skills
Building Relationships
Closing Skills
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Prepares quotations for projects using provided organizational pricing tools.
Assists outside reps and sales team with quotation follow-up and competitor activity following.
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Your pics: #BlackFriday deals and selfies!
Tree lighting events to kick off the holidays
The kids of Black Friday: Just buy me a pillow
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Atty on Ferguson: Treat problems, not symptoms
Ferguson inspires 3rd graders to make 'Peace'
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Hear from Darren Wilson for the first time
Atty: 'Burn this b*tch down' was 'raw emotion'
Wear will.i.am's new 'experience' on your wrist
Your cheat sheet for Black Friday 2014 tech
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Would you pay for an internet without ads?
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Here are all the titles leaving Netflix December 1
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| Reviews
album reviews
T.I. - Paperwork
T.I.'s "Paperwork" plays out as an uneven effort that isn't so much inherently flawed as it is unentertaining through long stretches.
album reviews
Cozz - Cozz & Effect
There's bourgeoning imagination in every stanza. "Cozz & Effect" brims with promise.
album reviews
Childish Gambino - Kauai (EP)
Childish Gambino's "Kauai" does an admirable job putting raw feelings before agendas or aesthetics, and it is easy to enjoy as a result.
album reviews
Game - Blood Moon: The Year Of The Wolf
"Blood Moon: Year Of The Wolf" starts strong and is at times well crafted, but loses it's focus through features enough to detract from the project's cohesion.
album reviews
Keyshia Cole - Point Of No Return
Keyshia Cole successfully expresses fervent, unfettered emotion on "Point Of No Return", but finds it challenging to deliver a stand out single.
album reviews
Diamond District - March On Washington
With "March On Washington," Diamond District provide a concise, diverse package that showcases their skills while providing entertainment and social commentary.
album reviews
Rapsody - Beauty And The Beast (EP)
Rapsody's "Beauty and The Beast" is a stellar take on her strengths, but doesn't experiment enough with her delivery to truly carry Jamla's searing production.
album reviews
Flying Lotus - You're Dead!
FlyLo's fifth LP is intimate and ethereal, and though its title embraces the macabre, the project favors liberation over lamentation.
album reviews
Vince Staples - Hell Can Wait
Concise, jarring, and ominous, "Hell Can Wait" succeeds at conveying the apocalypse of some realities, turning a local lament in to a universal one.
album reviews
The Black Opera - The Great Year
On "The Great Year," The Black Opera use their distinct sound to take a stance, but there are moments when that stance could use some nuance.
album reviews
Saigon - GSNT 3: The Troubled Times Of Brian Carenard
Saigon's latest iteration of "Greatest Story Never Told" isn't a retread, but it's a reminder that he's capable of better.
album reviews
OnCue - Angry Young Man
"Angry Young Man" finds OnCue immolating himself on wax with hell-bent bars over gnarled guitar synths, but he flattens out as songs become repeat affiars.
album reviews
Bishop Nehru & MF DOOM - NehruvianDOOM
Experimental in almost all the right ways and filled with well-crafted, ominous beats, "NehruvianDOOM" is a step up for the emcee in his young career.
album reviews
Childish Gambino - STN MTN
STN MTN has Childish Gambino rapping over the most accessible production of his career, but we also see his rhyme schemes fall short where they usually shine.
album reviews
Rich Gang - Tha Tour Pt. 1 (Mixtape)
The bizarre trinity of Birdman, Young Thug, and Rich Homie Quan makes for a surprisingly trap-love-fest that hypnotizes you for its entirety.
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Charge Anywhere LLC, a mobile payment and payment gateway provider, announced that it's teaming with RBM/Redeban Multicolor S.A., MasterCard Worldwide' s franchise manager for the country of Colombia. With RBM, Charge Anywhere will deploy a mobile point-of-sale technology to Colombian merchants that will allow them to accept credit and debit cards using smartphones.
Like other mobile POS solutions, Charge Anywhere's product uses a card-reading dongle attached to an Android, iOS or BlackBerry device, along with an app, to process electronic transactions. Aimed at small merchants, the solution charges a nominal fee on every transaction but gives merchants the ability to accept credit and debit cards, including EMV smartchip cards and NFC.
"At RBM we are committed to the people of Colombia, to our stakeholders and we continue to invest, implement and maintain the most modern, secure and efficient payment systems within the region," said Valetin Echeverry, RBM's vice president of technology. "We see mobile payments as a mission-critical tool to bridge the gap for electronic payment acceptance between the larger business owners capable of accepting electronic payments, and the many growing small and medium businesses established within the region."
Echeverry said RBM's goal is to bring electronic payment acceptance to areas of Columbia where consumers and businesses previously have not had the benefit of electronic payments. This effort will support the Columbian government's initiative to extend financial inclusion to unbanked citizens, he said.
For more stories like this, visit the POS research center.
Topics: POS , Region: Americas , Retail
Restaurants just getting started with mobile, Tillster CEO says
US smartphone owners want to use Apple Pay and Google Wallet
WorldRemit brings mobile money transfer services to US
Consumers shifting to mobile payments
Interactive Kiosks: Reprogram Customer Engagement
Digital Signage and Merchandising
Mobile Payment 2015 [infographic]
WEBINAR - Get Ready for the Holidays: Five Critical Mistakes in the Mobile Shopping Experience
Webinar: How operators can seize the carrier billing opportunity
Top Tips and Techniques for Holiday App Marketing
Webinar: There's more to mobile payments than payments: engaging your customers in the age of the new mobile wallet
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$16.97 $25.00*
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Product Information:
Show everyone patriotism is your thing in the Adrenaline® Men's Stars Lacrosse Hat. The structured, six-panel design comes complete with contrast-colored eyelets for ventilation. Repping your favorite lacrosse brand has never been easier with the Adrenaline® logo and two embroidered stars on the front. Wear the visor flat or curved and stay stylish on and off the field with this Adrenaline® hat.
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Country of Origin: MexicoWeb ID: 30767536


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The presence of numerous associations has fragmented the Malayalam film industry as no collective effort has been made so far to solve the present crisis, filmmaker Jayaraj has said.
Speaking at a meet-the-press organised by the Thiruvananthapuram Press Club here on Thursday in connection with the release of his latest film, Nayika , he said each association was fighting separately to solve their own issues in an industry that required combined efforts from all concerned to make progress.
He said though his film had received censor certificate in August, it was unnecessarily delayed because of "ego clash among the associations."
The Kerala Film Exhibitors' Federation had permitted the release of the film in 72 theatres.
However, only 52 theatres had agreed to screen the film. "The film was previously delayed due to the release of other-language films in the theatres .When a Sunday was proposed by them, we had to disagree because it would bring huge loss to the producer," he said.
Veteran actor Sharada, who plays a major role in the film, said films were related to art and not to strikes.
"In the 52 years of my acting career, I have never seen such a situation where a film is affected by some strikes," she said.
"What many a protestor forgets is that the lives of those associated with this industry are affected by the strike directly or indirectly," she added.
The film depicts the life of a yesteryear heroine of Malayalam cinema and her sudden and mysterious disappearance from the movie scene. According to Jayaraj, the film is a tribute to the actresses of yore.


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Queen Anne's Sheriff's Office said it is looking for three robbers who struck at a Burger King restaurant.
Authorities said three people, all dressed in black clothing and hooded sweatshirts, came into the restaurant at Kent Towne Market in Chester around 11 p.m. Wednesday and demanded money.
Two of the robbers were armed with handguns. The two employees were taken to the restaurant's office and an undisclosed amount of cash was taken. The two employees were not harmed.
Anyone with information is asked to contact the Sheriff's Office at 410-758-0770.
The views expressed are not those of this site, this station or its affiliated companies. By posting your comments you agree to accept our terms of use.blog comments powered by Disqus


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Dienst Appointed Martha Stewart Living CEO
Monday October 28th, 2013 - 9:54AM
These are shortcuts to your favorite social networking and bookmark sites. Add this story to your Facebook page, del.icio.us, DiggIt, and many others!
Martha Stewart Living Omnimedia, Inc. today announced that Daniel Dienst has been named CEO. Dienst was recently appointed to the MSLO Board of Directors and will continue to serve in that role.
Founder and non-executive Chairman Martha Stewart stated, "We are excited to welcome Dan as the new CEO of MSLO. He is a highly respected and experienced public company CEO with strong operating and financial discipline and a clear track record of creating significant value for shareholders. Dan will take on the important responsibility of leading the company and ensuring that we are able to deliver on our strategy for renewed growth."
Dienst said, "I have long been a fan of Martha Stewart, the person and the brand, and believe there is enormous untapped opportunity for this organization and a terrific base of talented people to help us realize that opportunity. The company has embarked on a turnaround plan that is expected to produce good early results, but there is a lot more to do to achieve our long-term objectives."
In a joint statement, the MSLO board of directors said, "In his short time on the board Dan has brought a fresh perspective to the business, which in combination with his operating skills, will help to strengthen our position and drive long-term growth. We are delighted that Dan is taking on the role of chief executive and we have the highest confidence that he will effectively lead the Company's turnaround plan and create added value for shareholders."
Dienst's previous experience includes several leadership positions at publicly-held companies. Most recently, from March 2008 through June 2013, Dienst served as CEO of Sims Metal Management, Ltd., He had served as Chairman and CEO of Metal Management from 2003-2008.
Tags: MSLO • Dan Dienst • Martha Stewart Living Omnimedia • Housewares • Home Decor • martha stewart • cookware • Housewares • Cookware & Bakeware • Home Décor • Tabletop • Gadgets & Kitchen Tools •
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November 23, 2014
A year after Republicans swept into office across the country, many have their sights on what has long been a fiscal conservative's dream: the steep reduction or even outright elimination of state income taxes.
The idea is gaining broader support, despite the fact that it would mean a total rewiring of tax systems at a time when most states are still struggling. And it's not clear how states would make up for the lost revenue.
Efforts are already under way in Idaho, Kansas, Maine, Missouri, Ohio, Oklahoma and South Carolina.
Nine states get by without an income tax, mostly by tapping other sources of revenue. But in the rest of the country, income taxes pay for everything from roads and bridges to schools and prison systems.
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Causes of Schizophrenia
Guests: Robert Conley, M.D. Associate Professor, Department of Psychiatry University of Maryland School of Medicine Baltimore, Maryland Ann Pulver Chief, Epimediology-Genetics Program in Psychiatry Associate Professor, Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore, Maryland Robert Yolken, M.D. Director, Stanley Neurovirology Laboratory Ted and Vada Stanley Professor of Developmental Neurovirology, Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland Some scientists are studying whether giving anti-psychotic drugs to teenagers deemed at risk for developing schizophrenia could actually prevent the disease—a controversial approach because it's so tough to determine who's at risk. In this hour, we'll discuss the causes of schizophrenia, including the role of genetics and a theory that viruses trigger the illness.
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News Archive
21.05.2014High Brightness and wide viewing angle: SGD's new 12,1″ TFT Display
With the GKVGC1MNDK2A0 Solomon Goldentek introduces a 12,1″ TFT display with a resolution of 1280x800, a brightness of 1300cd/m² and a symmetrical viewing angle of v/h 176°/176°. These features combined with a wide temperature...[more]
15.05.2014Plug & Play: TFT Display Kit Solutions
You want to integrate a TFT display quickly and easily into your application? Our kits offer the ideal solution! They consist of the TFT display, a controller board and all necessary accessories such as converter and cables. All...[more]
28.04.2014New Features of the Prisma -IIIA TFT Controller
Data Display Group's R&D department continues to improve the Prisma family TFT controllers by adding advanced new features. The Prisma-IIIA and its new firmware version, for example provide the following new features, some of...[more]
24.04.2014Compact Panel - ultra-slim open frame monitor
For demanding industrial applications with limited space the ultra-slim open frame monitor series Compact Panel provides the perfect solution. These monitors are available in sizes from 12.1" to 19" and can be integrated easily...[more]
17.04.2014Mitsubishi 7" TFT Display with 1500 cd/m²
Mitsubishi's AA070ME11 is a compact WVGA (800x480) high brightness 7" TFT display with 1500cd/m² and antiglare coating. Together with its wide operating temperature range of Top -30…+80°C it provides best characteristics for...[more]
07.04.2014POS-Line Monitor series leaves nothing to be desired
Data Display Group's POS-Line monitors series, leaves you the choice: sizes from 10.4" to 55", many different housings and a variety of controller solutions offer a flexibility that leaves nothing to be desired.[more]
01.04.20145000cd/m² - extremely bright 46″ Samsung TFT Display
Samsung presents the new LTI460HZ01-V, the follow-up version of the 1500 cd/m² CCFL TFT display LTI460HN03. It features an extreme brightness of 5000 cd/m², which guarantees perfect readability even in direct sunlight while...[more]


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Tiny Teacup Pom will be 3 1/2 - 4 lbs. full grown and cream in color.All of her features are so petite! She is very loveable gives puppy kisses and loves to be held. She loves to be carried around in your arms. She is quiet not barky. All of our puppies are up to date on ...
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$30 Furniture for saleFurniture · Erlanger, KYHi everyone, I've got the following items up for sale. • Wooden Console Table - $30 • Black painted wood coffee table - $15 • Boxing tr...Rodolfo P. · 1 day ago
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Building Lots - Council, ID
Primarily rolling, broken terrain, tucked away benches, draws, secluded homesites. Plenty of privacy, room for gardens, yards, orchards. - Creed Noah, Voice: (208) 257-3355, Creed Noah Real Estate Company, Main: (208) 257-3355, firstname.lastname@example.com, email@example.com
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Aztec Chicken Salad
Source: dLife
Southwest style chicken salad mixed with corn, tomatoes, peas, beans, peppers, and a chili cumin dressing.
1 cup Corn, yellow, sweet, kernels, cooked, drained
1 each fresh tomatoes
1 cup frozen green peas
0 1/2 cup chopped green bell peppers
0 1/2 cup red bell peppers, sliced
0.3333 cup canned black beans
2 cup cooked chicken breast, diced
1 tbsp extra virgin olive oil
0 1/4 cup fresh lime juice
2 tsp ground cumin
1 tbsp fresh cilantro
2 tsp chili powder
1 tsp ground oregano
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Can anyone help me figure out what this is? Thx.
Yellow oblong pill, V on one side, 36 01 on other side
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Service Archive/Podcast
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What You Do When No One Else is Around (Psalm 19:12)
Eric Ramos, June 12, 2014
Part of the Summer Camp 2014 series, preached at a Special Event service
Psalm 19:12
12Who can understand his errors? cleanse thou me from secret faults. (KJV)


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White's Boots
Firefighters have the single most demanding job out there and White's Boots have been expertly crafted to take on each and every one of those demands. Made from the best materials on the market, like full-grain leather uppers and non-slip Vibram rubber outsoles, these high-quality boots are tough enough to handle the most extreme work environment of all: a raging fire. The White's Boots 400V Waterproof Smoke Jumper Firefighter Boots have been specially designed to provide excellent flexibility along with first-rate waterproofing. For the rest of us, there are the White's Boots 3610 Waterproof Outdoorsman Work Boots, which provide the same amazing quality and craftsmanship with a more accessible design. Firefighters deserve the toughest boots they can get and that's just what they get with a pair of rugged White's Boots. These boots are custom made so please allow 6 to 8 weeks for delivery.
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White's Boots Preservative: 8-Ounce Natural Leather Preservative WP08
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$463.00 Free Shipping 15 Reviews 1621
White's Boots: Men's New Smoke Jumper Work Boots 400VLTT
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Just a quick note to let you know how great your customer service was on the phone. It was really awesome. I am ordering more clothing and products from your company because of the wonderful experience. It was such a pleasure speaking with someone so professional and caring and helpful. You have quite a team there. Keep up the great work!"
Juliet S. from New York, New York


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