Department of Pharmacy
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Item Depression: Current Therapy and ovel Anti-depressant Drug Targets(Pharmacologyonline, 2009) Mahesh, R.Affective disorders such as depression and anxiety are a major cause of disability and place a burden on society from both economic and social perspectives. In spite of over 50 years of effort in drug discovery and development, a substantial increase in the efficacy of antidepressant therapies has not been achieved, although improvements in safety and tolerability have been observed in newer drug therapies. Despite the advances in the anti-depressant therapy with various serotonergic and noradrenergic agents, a substantial unmet medical need in the treatment of depressive illness remains. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. At one end of the spectrum is combination therapies that maintain the benefits associated with standard anti-depressant drugs and at the other end more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis could fit to the need of antidepressant therapy. This review summarizes the pathological detail of depression, current anti-depressant therapy and development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategiesItem TAFI: A Potential Target for Fibrinolytic Drugs(Pharmacologyonline, 2009) Mahesh, R.Thrombosis is one the major cause of death worldwide. Clinicians and haematologists are confronted more and more with diagnosis and management of patients with venous and arterial thrombo-embolic phenomenon. In the recent past there have been major advancements in the field of the aetio-pathogenisis of haemostasis. Thrombosis occurs when there is an imbalance between pro-thrombotic and anti-thrombotic mechanisms. Thrombin activatable fibrinolysis inhibitor (TAFI) is a potential target to treat various thrombotic as well as metabolic disorders. TAFI is a Carboxypeptidase B like enzyme with a mol. wt. 60 kDa and it is activated by thrombin-thrombomodulin complex to activated form TAFIa which cleaves carboxyl-terminal lysine residues from partially degraded fibrin, rendering it resistant to fibrinolysis by endogenous tissue plasminogen activator (tPA). Thus inhibition of TAFI with an appropriate TAFI inhibitor will be an attractive strategy for various thrombotic as well as metabolic disorders in which levels of TAFI is highly elevated like deep vein thrombosis, angina pectoris, obesity and non insulin dependent diabetes mellitus.Item Pharmacophore Based Synthesis of 3-Chloroquinoxaline-2-carboxamides as Serotonin3 (5-HT3) Receptor Antagonist(The Pharmaceutical Society of Japan, 2004) Mahesh, R.A series of 3-chloroquinoxaline-2-carboxamides were designed and prepared by the condensation of 3-chloro-2-quinoxaloylchloride with appropriate Mannich bases of the p-aminophenol in the microwave environment. The synthesized compounds were evaluated for serotonin3 (5-HT3) receptor antagonistic activities in longitudinal muscle-myenteric plexus (LMMP) preparation from guinea pig ileum against the 5-HT3 agonist, 2-methyl-5-HT. Compound 3g exhibited comparable 5-HT3 antagonistic activity (pA2 6.4) to that of standard antagonist Ondansetron (pA2 6.9), while the other compounds exhibited mild to moderate 5-HT3 antagonistic activities.Item Synthesis and biological evaluation of a novel structural type of serotonin 5-HT3 receptor antagonists(Elsevier, 2006-05) Mahesh, R.A series of novel 3-substituted quinoxalin-2-carboxamides were designed as per the pharmacophoric requirement for 5-HT3 receptor antagonists and prepared by microwave irradiation and also by conventional method. The compounds were characterized by spectral data (IR, 1H NMR, and MS) and the purity was ascertained by microanalysis. The synthesized compounds were evaluated for 5-HT3 antagonisms in longitudinal muscle-myenteric plexus preparation from guinea pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Among the test compounds, N-{3-[(4-methylpiperazin-1-yl)methyl]-4-hydroxyphenyl}-3-methoxyquinoxalin-2-carboxamide 4e showed most favorable 5-HT3 receptor antagonism.Item Microwave assisted synthesis of 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile as a new class of serotonin 5-HT3 receptor antagonists(Elsevier, 2004-10) Mahesh, R.A series of novel 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6 were prepared by microwave irradiation and conventional heating. The intermediate, 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile 3, was prepared from 2-aminonicotinaldehyde 1 and ethyl cyanoacetate 2 in the presence of piperidine under solvent free condition. The synthesized compounds were evaluated for 5-HT3 antagonisms in longitudinal muscle-myenteric plexus (LMMP) preparation from Guinea pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Among the compounds tested, 2-(4-allylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6d showed most favorable 5-HT3 receptor antagonism in the Guinea pig ileum.Item 1-(m-Chlorophenyl)piperazine induces depressogenic-like behaviour in rodents by stimulating the neuronal 5-HT2A receptors: Proposal of a modified rodent antidepressant assay(Elsevier, 2009-04) Mahesh, R.1-(m-Chlorophenyl)piperazine (mCPP) has a fairly complex neuropsychopharmacological profile owing to its affinity to multiple serotonergic receptors. This investigation was designed to establish the effect of mCPP on rodent depression-like behaviour. mCPP was screened in a rodent behavioural test battery comprising of validated antidepressant assays and interaction studies with conventional antidepressants and ligands were carried out in forced swim and tail suspension test (in mice). mCPP (1 mg/kg, i.p.) exhibited depressant-like effects in forced swim and tail suspension test (in mice), without influencing the locomotor status. Potentiation of 5-hydroxytryptophan/pargyline induced head twitches (in mice) and hyperthermic effects (in rats) were observed at the same dose level. Further, the behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic mCPP (1–2 mg/kg) treatment as observed from the modified open field, elevated plus maze and social interaction paradigms. Interaction studies revealed that the mCPP induced depressant-like effects were reversed by ketanserin, escitalopram, amitriptyline, ziprasidone, venlafaxine pretreatments but not by bupropion, harmane, ondansetron, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and MK-801. In conclusion, this study provided ample evidence that the stimulation of 5-HT2A receptors underlies the depressogenic-like effect of mCPP. Finally, the mCPP induced depression-like behaviour in rodents is envisaged as a modified antidepressant assay to identify novel serotonergic antidepressants.Item Cancer chemotherapy-induced nausea and vomiting: role of mediators, development of drugs and treatment methods(Avoxa, 2005-02) Mahesh, R.The development of serotonin 5-HT3 receptor antagonists dramatically improved the treatment of chemotherapy-induced nausea and vomiting. Ondansetron, a serotonin 5-HT3 receptor antagonist in combination with dexamethasone is widely used to treat chemotherapy-induced nausea and vomiting. This treatment regimen is effective against acute nausea and vomiting, but fails to control delayed nausea and vomiting. Metoclopramide along with other antiemetics are used to treat delayed nausea and vomiting. The high doses of metoclopramide needed may produce extra pyramidal side effects. The recent developments of 5-HT3 and dopamine D2 dual receptor antagonists have been found to exhibit a broad spectrum of activity against peripherally and centrally acting stimuli, but are not much effective against delayed emesis associated with chemotherapy. In various animal models, neurokinin NK1 receptor antagonists showed promising results against acute and delayed emesis, but the clinical trials revealed that triple therapy (NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone) is superior than standard therapy (5-HT3 receptor antagonist & dexamethasone) or NK1 receptor antagonist alone, in controlling acute as well as delayed nausea and vomiting. Ginger, which is used traditionally for controlling emesis induced by various stimuli, also showed good activity against chemotherapy-induced nausea and vomiting in animal models. Non-pharmacological methods such as acupressure and acustimulation are good adjunct methods in treating nausea and vomiting. Since many mediators are involved in emesis induced by chemotherapy, cocktail treatment is proven to be more efficacious than a single drug, but increases treatment costs. So there is a need of further research in this field to get economically useful methods for the treatment of acute and delayed chemotherapy-induced nausea and vomiting.Item Depression-like and anxiety-like behavioural aftermaths of impact accelerated traumatic brain injury in rats: A model of comorbid depression and anxiety?(Elsevier, 2009-12) Mahesh, R.Depression and anxiety tend to be the most prevalent conditions among the multitude of neurobehavioural disorders which cause distress in the survivors of traumatic brain injury (TBI). The objective of the present investigation was to examine depression-like and anxiety-like behaviour of rats following diffuse TBI. Impact accelerated TBI was induced in anaesthetised rats by a modified weight drop method. TBI and sham-operated rats received either a chronic (14 days) regimen of escitalopram (5–20 mg/kg) or vehicle, following which they were subjected to a behavioural test battery. The results evince the depression-like behaviour of TBI rats in modified open field exploration, hyperemotionality, socio-sexual interaction and elevated plus-maze exploration paradigms. In addition, an anxiety-like behaviour was evident in social interaction and marble-burying tests. Chronic escitalopram (10 and 20 mg/kg) treatment significantly attenuated the TBI associated behavioural deficits. In conclusion, the aforesaid behavioural anomalies observed in TBI rats are analogous to comorbid anxiety and depression in humans. These findings substantiate the TBI rats as a candidate model of comorbid anxiety and depression.Item Antidepressant-like effects of serotonin type-3 antagonist, ondansetron: an investigation in behaviour-based rodent models(Wolters Kluwer, 2008-02) Mahesh, R.The present behavioural investigation evaluates the antidepressant potential of ondansetron (OND), a widely used (in management of cancer chemotherapy-induced nausea and emesis) 5-HT3 receptor antagonist. Separate groups of mice received acute or chronic treatment of OND (0.005–1000 μg/kg), and were subjected to spontaneous locomotor activity test or antidepressant assays, namely, the forced swim and tail suspension tests. Interaction studies with fluoxetine, venlafaxine, desipramine and 8-hydroxy-2-(di-n-propylamino) tetralin were conducted in the forced swim test. The effect of OND (0.01–1000 μg/kg) in combination with paroxetine (10 mg/kg, for 14 days) on the behaviour of male bulbectomized or sham-operated rats was also assessed. The postbulbectomy behavioural analysis included exploration in the open field and elevated plus maze. OND exhibited a biphasic dose–response profile, with antidepressant-like effects peaking at 0.1 μg/kg, in the forced swim and tail suspension tests. None of the tested doses influenced spontaneous locomotor activity. Chronic OND pretreatment augmented the antidepressant effects of fluoxetine and venlafaxine but did not influence the effects of desipramine or 8-hydroxy-2-(di-n-propylamino) tetralin. Chronic OND (10 μg/kg) reversed hyperactivity in the open field, and decreased the percentage entry and time spent in open arms in the elevated plus maze. Summing up, it is observed that OND exhibits antidepressant-like effects, possibly mediated through postsynaptic 5-HT3 receptors.