Department of Pharmacy
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Item Antioxidant properties of Indian medicinal plants(Wiley, 2002-11) Jadhav, Hemant R.The antioxidant properties of methanol extracts of 12 Indian medicinal plants, traditionally used in disease areas that probably involve free radical mechanisms, were evaluated by two methods, namely the DPPH (1,1-diphenyl-2-picryl hydrazyl) test and the lipid peroxidation assay. In the latter assay, seven of these extracts showed 90% or more activity compared with the standard, vitamin E and hence were studied in detail after the removal of interfering pigments. The selective pigment removal from the extracts led to an increase in free radical scavenging activity and a decrease in inhibition of lipidItem 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 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 Rationale for immunomodulatory and anti-inflammatory effects of Ocimum sanctum: radical scavenging potential and effect on nitric oxide production(International Society for Horticultural Science, 2005) Jadhav, Hemant R.Antioxidant activity of polar methanolic extract of aerial parts of Ocimum sanctum using multiple screens was studied. Various concentrations of the standardized extract were examined for the free radical scavenging activity, superoxide radical scavenging potential and effect on nitric oxide production in RAW 264.7 mouse monocytes cell line. The results indicated that the O. sanctum extract has strong antioxidant activity. In the assay for free radical scavenging activity measured in terms of scavenging of DPPH (1,1-diphenyl-2-picryl hydrazyl) radical, the extract exhibited the IC50 of 94.51 ± 6.47 µg/ml. NBT reduction assay was used to measure the superoxide reducing capacity of the extract and the extract inhibited the NBT reduction with IC50 of 71.17 µ 8.13 µg/ml. Effect on nitrite production was tested in Lipopolysaccharide (LPS) activated RAW 264.7 mouse monocytes cell line. In this assay, biphasic response was observed for the extract. At lower concentration it stimulated nitrite production while at higher doses the nitrite production was suppressed (EC50 4.89 ± 0.47 µg/ml and IC50 66.67 ± 0.91 µg/ml). These results suggest that the antioxidant activity of O. sanctum may be partly responsible for its reported immunomodulatory and anti-inflammatory effects.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 Cosmetic potential of herbal extracts(NISCAIR, 2005-08) Jadhav, Hemant R.Cosmetology, the science of alteration of appearance, has been practiced since primordial times. In India, the concept of using herbs for beautification finds its origin in traditional medicine literature like Ayurveda. The cosmetic preparations were used for the purpose of worship and sensual enjoyment. Moreover, since centuries, the herbal extracts, as a whole or part thereof, have been used for various ailments of the skin, hair and for overall appearance. The market research shows upward trend in the herbal trade with the herbal cosmetic industry playing a major role in fuelling this worldwide demand for herbals. The recent interest of consumers in herbal cosmetics has been stimulated by the decline of faith in modern cosmetics, the belief that plant remedies were natural and thereby superior to man-made synthetic cosmetics, and the reference to successful historical use by different cultures. These reasons have contributed to the increased acceptance as well as manufacture of herbal cosmetics. Many herbs have been scientifically evaluated for their cosmetic potential. Some traditional plants like Trigonella foenum-graecum Linn., Azadirachta indica A. Juss., Mimosa tenuiflora Benth., Aloe vera Linn., etc. need special mention. The great void remains though for a systematic, thorough review of scientific data that provides a basis for the use of specific herbs and their efficacy as cosmetics. Similarly, there is a lack of scientific review of phytochemicals that are used in cosmetic preparations. This review attempts to fill-up this gap and emphasizes the need for safety evaluation of herbal cosmetics.Item Current Advances in Antifungal Targets and Drug Development(Bentham Science, 2006) Sundriyal, SandeepFungi are one of the most neglected pathogens apparent from the fact that the Amphotericin B, a polyene antibiotic, discovered way back in 1956 is still used as a gold standard for antifungal therapy. Past two decades have witnessed a dramatic rise in the incidences of life threatening systemic fungal infections. This can be ascribed to the increase in the number of immuno-compromised patients due to rise in HIV infected population, cancer chemotherapy and indiscriminate use of antibiotics. Majority of clinically used antifungals suffer from various drawbacks in terms of toxicity, efficacy and cost, and their frequent use has led to the emergence of resistant strains. Hence, there is a great demand for novel antifungals belonging to wide range of structural classes, selectively acting on novel targets with fewer side effects. This article aims at reviewing recent efforts made towards discovering novel antifungal drug targets and investigational molecules acting on them.Item Molecular Electrostatic Potentials in the Design of Dendrimers for the Delivery of Glitazones(American Scientific Publishers, 2006) Sundriyal, SandeepGlitazones are PPARγ agonistic insulin sensitizers used clinically for the treatment of type-2 diabetes. The delivery of these compounds with the help of dendrimers is possible. Ab initio MO calculations and MESP analysis indicate that the dendrimers with complementary electrostatic potential to glitazones can be designed. The estimated binding strength between one arm of dendrimer and thiazolidinedione is about 15–20 kcal/mol. This binding strength originates from three hydrogen bonds between the dendrimer and each molecule of glitazone. This binding strength is quite suitable for drug encapsulation on the dendrimer based nanoparticles and can be employed for drug delivery.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 Modulating TNF-α signaling with natural products(Elsevier, 2006-08) Paul, Atish TulshiramNatural products have been, and continue to be, a major source of pharmacologically active substances from which drugs can be developed. Currently, tumor necrosis factor-α (TNF-α) inhibitors from natural origins are being advanced for the treatment of inflammatory disorders. Elevated TNF-α synthesis has been associated with the development of diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Currently, only protein-based drugs are available for the clinical inhibition of TNF-α activity. Small-molecule drugs that can regulate TNF-α levels or activity might provide a cost-effective alternative to protein-based therapeutics. This review briefly highlights the physiological and pathological roles of TNF-α, and covers those natural compounds capable of interfering with TNF-α activity.Item Biodegradable Injectable In Situ Depot-Forming Drug Delivery Systems(Wiley, 2006-11) Chitkara, DeepakThe scope of drug-delivery systems has expanded significantly in recent years providing new ways to deliver life saving therapeutics to patients. The development of new injectable drug-delivery systems has provided new vistas and opened up unexplored horizons in the field of science, particularly in controlled drug delivery since these systems possess unique advantages over traditional ones, which include ease of application, and localized and prolonged drug delivery. In the past few years, an increasing number of such systems has been reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling within the desired site. For this purpose both natural (chitosan, alginates) as well as synthetic polymers (PEGylated polyesters, ricinoleic acid-based polymers) have been utilized. These systems have been explored widely for the delivery of various therapeutic agents ranging for anti-neoplastic agents like paclitaxel to proteins and peptides such as insulin, almost covering every segment of the pharmaceutical field. This manuscript focuses on the recent advancements in the area of in situ forming biodegradable polymeric drug-delivery systems.Item Modeling and Informatics in Designing Anti-Diabetic Agents(Bentham Science, 2007) Sundriyal, SandeepDiabetes mellitus is a chronic metabolic disorder, characterized by glucose overproduction and glucose underutilization. Current therapy for T2DM includes drugs, like metformin, glitazones, sulphonyl ureas, etc. Extensive research has been carried out world wide on molecular targets for T2DM like PPARγ, PTP1B, DPP-IV, GSK-3, cannabinoid receptor, fructose-bisphosphatases, β3 adrenoceptor, etc. in the development of newer anti-diabetic agents. These therapeutic targets are quite important and most of them are suitable for in silico analysis. Hence, many molecular modeling and informatics studies like, molecular docking, pharmacophore mapping, 3DQSAR, virtual screening, quantum chemical studies, and pharmacoinformatics like bioinformatics and chemoinformatics studies have been performed on the drugs / leads / targets associated with T2DM. Several of these in silico efforts are exemplary studies; the methodologies adopted in these studies can be emulated in many other therapeutic areas. A review of the rational approaches reported in designing anti-diabetic agents is presented in this article.Item Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53(Elsevier, 2007-03) Gaikwad, Anil BhanudasDiabetic nephropathy (DN) is one of the main causes of end stage renal disease (ESRD) and a leading cause of diabetes mellitus related morbidity and mortality. Recently, sirtuin are reported to have emerging pathogenetic roles in cancer, muscle differentiation, heart failure, neurodegeneration, diabetes and aging. The aim of the present study was to study the role of intermittent fasting (IF) on DN and studying the expression of Sir2 and p53. At biochemical level, we found that IF causes significant improvement in blood urea nitrogen (BUN), creatinine, albumin and HDL cholesterol, parameters that are associated with the development of DN. Diabetic rats on IF also show significant improvement in onset of hypertension. Interestingly, the expression of Sir2, a NAD dependent histone deacetylase, decreases in diabetic rat kidney and this decrease is overcome by IF. Moreover, we provide evidence for involvement of mitogen activated protein kinases (MAPK) cascade in mediating the effects of IF as there is reduction in the expression of p38 which gets induced under diabetic condition. This was further accompanied by the concomitant decrease in cleavage of caspase3 and p53 expression. These findings suggest that IF significantly improves biochemical parameters associated with development of DN and changes the expression of Sir2 and p53.Item Differential effects of tannic acid on cisplatin induced nephrotoxicity in rats(Elsevier, 2007-05) Gaikwad, Anil BhanudasCisplatin is a widely used antineoplastic drug. Major drawback of cisplatin therapy is its nephrotoxicity. The objective of this study was to check the effect of tannic acid on cisplatin induced nephrotoxicity. Post-treatment of tannic acid prevents cisplatin (5 mg/kg) induced nephrotoxicity and decreases poly(ADP-ribose) polymerase cleavage, phosphorylation of p38 and hypoacetylation of histone H4. In contrast, co-treatment of tannic acid potentiates the nephrotoxicity. Comparative nephrotoxicity studies show that co-treatment of tannic acid with reduced dose of cisplatin (1.5 mg/kg) developed almost similar nephrotoxicity. MALDI protein profiling of plasma samples provides indirect evidence that tannic acid co-treatment increases bioavailability of cisplatin.Item PPARγ agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance(Elsevier, 2007-05) Gaikwad, Anil BhanudasAltered vascular responses to various vasopressors in animal models of insulin resistance (IR) and diabetes have been well documented. However, the precise mechanisms about vascular responses in IR with or without frank hyperglycemia (prediabetic state) are not available. Moreover, recently the role of peroxisome proliferators activated receptor-γ (PPARγ) has been linked to influence the vascular responses in hypertensive and diabetic state. Hence, the present study was conceived to determine the role of hyperglycemia on angiotensin II (Ang II) mediated vascular responses in the high fat diet (HFD) induced insulin resistance either with mild or frank hyperglycemia [induced by injection of low dose streptozotocin (STZ) to HFD fed rats (HFD + STZ)]. In addition, insulin-sensitizing agent such as rosiglitazone and pioglitazone were also studied on biochemical and vascular responses. Ang II-induced contractions were studied isometrically in thoracic aortic rings isolated from 4 weeks of normal pellet diet (NPD) fed control, HFD and HFD + STZ fed insulin resistant rats. Specific binding of Ang II receptors were carried out using radioligand ([3H]–Ang II) binding studies. After 4 weeks of HFD feeding, rats exhibited characteristics features of insulin resistance such as mild hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and hypertension; whereas HFD + STZ treated rats showed all above parameters along with frank hyperglycemia. Maximal contractile response (Emax) to Ang II is increased in HFD fed rats as compared to control rats. Moreover, Emax values are further elevated in HFD + STZ group where the frank hyperglycemia was induced by low dose of streptozotocin. Rosiglitazone (5 mg kg−1, p.o.) and pioglitazone (10 mg kg−1, p.o.) treatment significantly lowered the plasma glucose, triglycerides, insulin and cholesterol levels in insulin resistance rats. In addition, it also restored the elevated systolic, mean arterial, diastolic blood pressure and attenuated the enhanced contractile responses to Ang II in thoracic aortic rings obtained from both HFD and HFD + STZ treated rats. Specific binding of [3H]–Ang II is upregulated in HFD-fed and HFD + STZ treated rats. Treatment with pioglitazone and rosiglitazone significantly decreased the AT1R specific binding in HFD fed rats. Our results indicate the role of hyperglycemia in the elevation of Ang II induced vascular responses in thoracic aorta isolated from insulin resistant rats and PPARγ agonists can attenuate these responses.Item In vitro hemolysis and lipid peroxidation-inducing activity of the tentacle extract of the sea anemone (Paracondylactis indicus Dave) in rat erythrocytes(Wolters Kluwer, 2007-06) Roy, AniruddhaIn vitro hemolytic activity of the tentacle extract of Paracondylactis indicus (Dave), a sea anemone found in the eastern coastal region of West Bengal (India), was determined in rat erythrocytesItem HPLC method for the determination of carboplatin and paclitaxel with cremophorEL in an amphiphilic polymer matrix(Elsevier, 2007-08) Chitkara, Deepak; Mittal, AnupamaSimple and rapid reversed phase HPLC methods for individual as well as simultaneous analysis of paclitaxel and carboplatin with cremophorEL (CrEL) in an amphiphilic polymer matrix were developed. Different analytical performance parameters such as linearity, accuracy, precision, specificity, limit of detection (LOD) and limit of quantification (LOQ) were determined according to ICH guidelines. All the analytical methods were developed by reverse phase HPLC on C-18 column with a mobile phase comprising of water–acetonitrile run on isocratic mode for the analysis of carboplatin and gradient mode for individual analysis of paclitaxel and for simultaneous analysis of the two drugs at a flow rate of 1 ml/min at 227 nm. The proposed methods for independent analysis of the drugs elute out carboplatin in 4.3 min and paclitaxel in 10.5 min while in simultaneous analysis carboplatin shows Rt at 4 min and paclitaxel at 18 min with a continuous run for 17 more minutes to elute out CrEL. These methods were found to be specific as none of the components of the media, i.e. polymer, CrEL and buffer interfered with the drug peaks. The linearity of the calibration curves for each analyte in the desired concentration range was found to be good (r2 > 0.9995). The methods were accurate and precise with recoveries ranging from 98 to 101% for each drug and relative standard deviation (%RSD) <2%. Peaks corresponding to each of the drug showed positive value for the minimum peak purity index over the entire range of integrated chromatographic peak thus indicating the purity of the peaks. Stability analysis of the two drugs revealed that the drugs remain stable during the period of study.Item Evaluation of Proinflammatory Cytokine Pathway Inhibitors for p38 MAPK Inhibitory Potential(ACS, 2007-11) Paul, Atish TulshiramThe target for the anti-inflammatory natural products like amentoflavone (2), which act by interfering with the proinflammatory cytokine pathway (e.g., TNF-α, IL-1β, and NO synthase), is not yet well-defined. Data obtained from docking, electronic, and surface analyses shed some light on steric and electronic complementarity of these molecules to p38 MAPK, thereby suggesting a possible mechanism by which they might reduce the production of proinflammatory cytokines.Item Metformin and glitazones: does similarity in biomolecular mechanism originate from tautomerism in these drugs?(Wiley, 2007-11) Sundriyal, SandeepThis theoretical study attempts to find out similarity between metformin and glitazone class of antidiabetic drugs. It was found that some tautomeric forms of both metformin and thiazolidinedione ring of glitazones have similar molecular electrostatic potential (MESP) surface and may bind to a common complementary surface. Complexation and docking studies were also carried out in order to support this hypothesis.