Prevalence of CYP2C9 and CYP2C19 variants and the impact on clopidogrel efficacy in patients having CYPC19*2 variant.

OBJECTIVE: Human cytochrome p450 enzymes play an important role in the metabolism of various substances. The CYP2C subfamily consists of various important drug-metabolizing enzymes such as CYP2C9 and CYP2C19. The objectives of the study include the determination of the frequency of genetic variants (CYP2C9*2, CYP2C9*3, and CYP2C19*2) of selected enzymes using allele-specific polymerase chain reaction (ASPCR) and its comparison with Indian as well as global past frequencies. We also aimed to study the impact of genetic mutation on clopidogrel efficacy and compare the efficacies between patients with and without CYP2C19*2 genetic variant. METHODOLOGY: In this study, the prevalence of variants CYP2C19*2, CYP2C9*2, and CYP2C9*3, the most popular variants of the respective enzymes, was determined using the ASPCR method. The correlation between the CYP2C19*2 variant and the antiplatelet activity of clopidogrel was studied using platelet aggregation assay (PAA). RESULTS: The determined frequencies of CYP2C19*2, CYP2C9*2, and CYP2C9*3 are 46%, 9%, and 12%. These frequencies are indicative of homozygous as well as heterozygous mutations. Reduced clopidogrel efficacy was observed in patients with a heterozygous mutation of CYP2C19*2 variant. CONCLUSIONS: The observed frequencies are not significantly different from that observed in earlier reported studies conducted across India and the world. Antiplatelet activity, as measured using the PAA method, was significantly lesser in patients having the CYP2C19*2 variant. The therapy failure in these patients can lead to serious cardiovascular consequences, and we propose determining the presence of the CYP2C19*2 variant before initiation of clopidogrel therapy.

Unveiling the modulation of Nogo receptor in neuroregeneration and plasticity: Novel aspects and future horizon in a new frontier.

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Multiple Sclerosis, Hereditary Spastic Paraplegia, and Amyotrophic Lateral Sclerosis have emerged as the most dreaded diseases due to a lack of precise diagnostic tools and efficient therapies. Despite the fact that the contributing factors of NDs are still unidentified, mounting evidence indicates the possibility that genetic and cellular changes may lead to the significant production of abnormally misfolded proteins. These misfolded proteins lead to damaging effects thereby causing neurodegeneration. The association between Neurite outgrowth factor (Nogo) with neurological diseases and other peripheral diseases is coming into play. Three isoforms of Nogo have been identified Nogo-A, Nogo-B and Nogo-C. Among these, Nogo-A is mainly responsible for neurological diseases as it is localized in the CNS (Central Nervous System), whereas Nogo-B and Nogo-C are responsible for other diseases such as colitis, lung, intestinal injury, etc. Nogo-A, a membrane protein, had first been described as a CNS-specific inhibitor of axonal regeneration. Several recent studies have revealed the role of Nogo-A proteins and their receptors in modulating neurite outgrowth, branching, and precursor migration during nervous system development. It may also modulate or affect the inhibition of growth during the developmental processes of the CNS. Information about the effects of other ligands of Nogo protein on the CNS are yet to be discovered however several pieces of evidence have suggested that it may also influence the neuronal maturation of CNS and targeting Nogo-A could prove to be beneficial in several neurodegenerative diseases.

Assessment of potential drug-drug interactions among outpatients in a tertiary care hospital: focusing on the role of P-glycoprotein and CYP3A4 (retrospective observational study).

Background: Selecting a medicine has a significant impact on the quality of therapy including efficacy and safety. P-glycoprotein and CYP3A4 share several common substrates known as bi-substrates. Both play major role in the pharmacokinetics and pharmacodynamics when over or under expressed. Objective: The study aimed to assess the Drug-Drug Interaction (DDI) related to P-glycoprotein (P-gp) and Cytochrome P450-3A4 (CYP3A4), to predict their clinical outcomes and also to discover prospective predictors of pDDIs. Methods: The subjects in this retrospective study ranged in age from 18 to 95 years with polypharmacy prescriptions. Information was gathered through patient medical records. Based on Micromedex and previous literature studies, medications prescribed to the patients were observed for pDDIs according to risk rating scale for drug interactions. Results: A total of 504 patients (160 males and 344 females) were included in the study. The mean of pDDI seen in the patients was 1.66 ± 1.48 and total 825 pDDIs were discovered. The factors significantly associated with having ≥1 pDDIs included: taking ≥5 medicines (OR 1.747), increased age (OR 1.026) increased comorbidities (OR 1.73). Conclusion: In prescriptions, a considerable number of probable DDI were discovered. Therefore, careful selection of drugs and identification of mechanisms for DDI is needed to lower the frequency of pDDI.

In search of RdRp and Mpro inhibitors against SARS CoV-2: Molecular docking, molecular dynamic simulations and ADMET analysis.

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome coronavirus (SARS CoV-2) has been declared a worldwide pandemic by WHO recently. The complete understanding of the complex genomic structure of SARS CoV-2 has enabled the use of computational tools in search of SARS CoV-2 inhibitors against the multiple proteins responsible for its entry and multiplication in human cells. With this endeavor, 177 natural, anti-viral chemical entities and their derivatives, selected through the critical analysis of the literatures, were studied using pharmacophore screening followed by molecular docking against RNA dependent RNA polymerase and main protease. The identified hits have been subjected to molecular dynamic simulations to study the stability of ligand-protein complexes followed by ADMET analysis and Lipinski filters to confirm their drug likeliness. It has led to an important start point in the drug discovery and development of therapeutic agents against SARS CoV-2.

Central and Peripheral Glucagon Reduces Hyperlipidemia in Rats and Hamsters.

Increased lipid levels in blood contribute to increasing the risk of diabetic complications. Glucagon exerts lipid lowering effects in diabetic state. However, the mechanism behind the lipid reduction by glucagon independent of glucose homeostasis is not well understood. We assessed the actions of glucagon on lipid modulation in blood and markers in liver in hyperlipidemic hamsters and rats. Male Sprague Dawley rats and Golden Syrian hamsters on a hyperlipidemic diet for 2 weeks were administered a single dose of glucagon by subcutaneous (SC, 150 and 300 µg/kg) or intracerebroventricular (ICV, 15 and 30 µg/animal) route. Effect of acute treatment was observed on tyloxapol-induced hypertriglyceridemia, corn oil-induced post-prandial lipemia, and bile flow. A repeated dose treatment by subcutaneous (300 µg/kg) or intracerebroventricular (30 µg/animal) route was done for 2 weeks, following which circulating and hepatic lipids, hepatic markers of lipid metabolism and bile flow were assessed. Acute administration of glucagon (SC and ICV) decreased triglyceride absorption, hepatic triglyceride secretion rate and increased excretion of cholesterol in bile fluid in dose related manner. Repeated dose treatment reduced circulating and hepatic lipids and mainly LDL, and enhanced cholesterol excretion in bile. In liver, expression of HMG-CoA reductase was reduced while that of ABCA1 was increased after repeated treatment, whereas pair fed group did not show significant changes when compared to the control group. These findings demonstrate that central as well as peripheral glucagon effectively reduces hyperlipidemia in rat and hamster model, by modulating hepatic lipid metabolism.

Therapeutic potential of coagonists of glucagon and GLP-1.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors reduces body weight without inducing hyperglycemia. In addition, coagonists have demonstrated lipid lowering property, which was independent of their anorectic effect. Similarly, GLP-1 modulates cardiovascular function which is favorable for treatment of myocardial injury, cardiac dysfunction, cardiac arrhythmias, endothelial dysfunction, and blood pressure, while glucagon has a positive impact on heart rate, cardiac output, ventricular contraction and enhances cardiac performance in animals and humans. Hence, researchers focused on combining these attributes of GLP-1 and glucagon in a single molecule, which was termed as a coagonist. Oxyntomodulin is the naturally occurring coagonist of GLP-1 and glucagon. This review focusses on the coagonists under clinical development discussing activities affecting cardiovascular functions, lipid modulation, direct effect on cardiac functions or other related functions. A comparative analysis of the in vitro and in vivo properties of GLP-1, glucagon and the coagonists is also carried out. This review discusses potential of GLP-1 and glucagon coagonists in treatment of cardiovascular and hemodynamic diseases with attention to GLP-1 or glucagon receptor specific properties as well as the interaction between other therapies.

Effect of GLP-1 based therapies on diabetic dyslipidemia.

Glucagon-like peptide-1 (GLP-1), is a hormone secreted by small intestine. Consumption of food or glucose stimulates synthesis and secretion of GLP-1 in the bloodstream, which in turn stimulates insulin secretion from pancreas and delays gastric emptying. Owing to the favorable spectrum of effects on reduction of hyperglycemia and body weight, GLP-1 mimetics are intensely pursued as therapies for the treatment of type 2 diabetes (T2DM). Even after intensive control of hyperglycemia, the propensity for cardiovascular disease cannot be totally negated in diabetic patients. A major reason for the cardiovascular disease risk in diabetic patients is underlying dyslipidemia, also termed as diabetic dyslipidemia. It is characterized by high concentrations of triglycerides and LDL cholesterol, and lowered HDL cholesterol in plasma, which are associated with hyperglycemia. Increased insulin resistance gives rise to increased free fatty acids in bloodstream, which is the main reason for the lipid changes appearing in diabetic dyslipidemia. The secondary complications like atherosclerosis and other cardiovascular diseases may be predicted with the blood concentrations of triglycerides and cholesterol, due to the correlation proven in clinic. Hence, new drugs that target diabetic dyslipidemia will always be useful in therapy. Apart from its actions on body weight and glucose, GLP-1 can also regulate cholesterol and triglycerides by numerous ways. Acute and long term treatment with either GLP-1 or its stable analogs reduced fasting as well as postprandial lipids in healthy as well as T2DM patients. GLP-1R signaling reduces VLDL-TG production rate from liver, reduces hepatic TG content by modulating key enzymes of lipid metabolism in liver, and impairs hepatocyte de novo lipogenesis and ß-oxidation. GLP-1 can also modulate reverse cholesterol transport. Apart from these direct effects on lipid metabolism, GLP-1 also reduces atherosclerotic events by inhibiting expression of atherogenic inflammatory mediators, suppressing smooth muscle cell proliferation and stimulating NO production. This review mainly deliberates the association of GLP-1 in lipid regulation via lipid absorption, hepatic cholesterol metabolism, reverse cholesterol transport and progression of atherosclerosis.

Chemopreventive effect of a novel, selective TACE inhibitor on DMBA- and TPA-induced skin carcinogenesis.

UNLABELLED: Abstract Context: Tumor necrosis factor (TNF)-α, a potent proinflammatory cytokine, plays a major role in the pathogenesis of cancer. TNF-α converting enzyme (TACE) mediates processing and release of biologically active TNF-α. OBJECTIVE: We aimed to investigate the effect of a novel, selective TACE inhibitor (compound 11p) on skin inflammation and associated tumorigenesis in mice. METHODS: Skin edema was induced in mice by dermal application 12-O-tetradecanoylphorbol-13-acetate (TPA) solution in acetone on to the ear and the effect of post-treatment of compound 11p (topical application) was evaluated. Edema and inflammation was assessed by measuring ear thickness, weight of skin punch and cytokine levels. Skin cancer in mice was initiated by single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by repeated TPA application for 20 weeks. The effect of compound 11p on papilloma incidence and multiplicity was evaluated. RESULTS: Treatment with compound 11p strongly suppressed TPA-induced elevation in skin thickness and weight. A dose-dependent suppression in TPA-mediated TNF-α, IL-6, IFN-γ, IL-17 and PGE2 levels which was associated with a decrease in infiltration of inflammatory cells was also observed with the treatment. Moreover, compound 11p treatment delayed the onset, markedly reduced the papilloma incidence and multiplicity persuaded by DMBA and TPA. DISCUSSION AND CONCLUSION: These findings suggest that selective blockade of TACE suppresses TPA-induced epidermal hyperplasia, inflammatory cell infiltration and cytokine level. Inhibition of inflammatory events related to tumor growth might have led to the anti-tumor effect in mouse skin cancer model induced by DMBA and TPA.

Physicochemical and structural characterization of iron-sucrose formulations: a comparative study.

Intravenous polynuclear iron formulations are vital components in the treatment of iron deficiency anemia associated with chronic kidney disease as well as other diseases associated with gastro-intestinal and cardio-vascular system. Intravenous iron preparations consist of iron-carbohydrate nanoparticles with iron-oxyhydroxide as a core covered by carbohydrate shell. These preparations should be very well characterized in terms of their physicochemical properties and pharmacological profile in order to establish safety and efficacy. The present research work was aimed to physicochemically characterize a new generic iron-sucrose preparation (IS-Claris) and establish its equivalency with the reference product (Venofer®). Various analytical techniques including gel permeation chromatography (GPC), mass spectroscopy (MALDI-TOF), absorption spectroscopy, X-ray diffraction analysis (XRD), nuclear magnetic resonance spectroscopy (proton and (13)C NMR), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis (TGA) were employed. It was observed that the specifications of IS-Claris obtained through these analyses reflect those of Venofer® and hence the two formulations were considered comparable.

Anti-nociceptive and anti-allodynic activity of aliskiren in various pain models.

In the present study, we have investigated the anti-nociceptive and anti-allodynic activity of the renin inhibitor, aliskiren, in various pain models. The anti-nociceptive activity of aliskiren was investigated in chemically-induced pain, orofacial pain and centrally mediated pain models. Anti-allodynic activity was evaluated in post-operative and neuropathic pain models. The levels of TNF-α and IL-6 were measured in homogenates of hind paw as markers of inflammation in formalin injected mice. Intraperitoneal administration of aliskiren (1-50mg/kg) showed anti-nociceptive activity in the writhing test, formalin hind paw test, capsaicin induced pain, and orofacial pain tests in ICR mice in a dose dependent manner. Aliskiren (50mg/kg, i.p.) reduced levels of TNF-α and IL-6 in hind paw homogenates of formalin-injected mice. Aliskiren (50mg/kg, i.p.) did not show any analgesic activity in hot-plate and tail-flick tests, indicating the absence of centrally mediated anti-nociceptive effects. On the other hand, intra-plantar administration of aliskiren (0.1, 0.5 and 1mg) showed analgesic activity in rat formalin tests, indicating a locally mediated effect. Aliskiren (30-100mg/kg, i.p.) showed anti-allodynic activity in post-operative pain and chronic constriction injury-induced neuropathic pain in Sprague Dawley rats. This data suggests that aliskiren may have the potential to be used as an anti-nociceptive and anti-allodynic agent.

Discovery of novel acyl coenzyme a: cholesterol acyltransferase inhibitors: pharmacophore-based virtual screening, synthesis and pharmacology.

The present study describes ligand-based pharmacophore modeling of a series of structurally diverse acyl coenzyme A cholesterol acyltransferase inhibitors. Quantitative pharmacophore models were generated using HypoGen module of Discovery Studio 2.1, whereby the best pharmacophore model possessing two hydrophobic, one ring aromatic, and one hydrogen bond acceptor feature for inhibition of acyl coenzyme A cholesterol acyltransferase showed a very good correlation coefficient (r = 0.942) along with satisfactory cost analysis. Hypo1 was also validated by test set and cross-validation methods. Developed models were found to be predictive as indicated by low error values for test set molecules. Virtual screening against Maybridge database using Hypo1 was performed. The two most potent compounds (47 and 48; predicted IC50 = 1 nM) of the retrieved hits were synthesized and biologically evaluated. These compounds showed 86% and 88% inhibition of acyl coenzyme A cholesterol acyltransferase (at 10 µg/mL) with IC50 value of 3.6 and 2.5 nM, respectively. As evident from the close proximity of biological data to the predicted values, it can be concluded that the generated model (Hypo1) is a reliable and useful tool for lead optimization of novel acyl coenzyme A cholesterol acyltransferase inhibitors.

Giant ventricular myxoma obstructing right ventricular outflow tract / Mixoma ventricular direito gigante obstruindo via de saída do ventrículo direito

Intracardiac myxoma is predominantly located in the left atrium but their location in the right ventricle is quite unusual. We present a case in which successful excision of the tumor was done through bicameral approach.

Mixoma intracardíaco localiza-se predominantemente no átrio esquerdo, e sua localização no ventrículo direito é bastante incomum. Apresentamos um caso no qual excisão bem sucedida do tumor foi feita por meio de abordagem bicameral.

Effect of piperine in the regulation of obesity-induced dyslipidemia in high-fat diet rats.

OBJECTIVE: The present study was undertaken to explore the effect of piperine in obesity-induced dyslipidemia. MATERIALS AND METHODS: Male Sprague Dawley rats were fed high-fat diet (HFD) for the first eight weeks, to develop obesity-induced dyslipidemia. Later on piperine (40 mg / kg) and sibutramine (5 mg / kg) were administered for three weeks along with the continuation of HFD to two separate groups, which served as the test and standard groups, respectively. Body weight, food intake, serum triglyceride, total cholesterol, LDL, VLDL, and HDL were measured at the end of the fourth, eighth (before treatment), and eleventh (after treatment) week, while the fat mass was measured at the end of the eleventh week in the normal, HFD-control, test, and standard groups. RESULTS: Supplementing piperine with HFD significantly reduced not only body weight, triglyceride, total cholesterol, LDL, VLDL, and fat mass, but also increased the HDL levels, with no change in food intake. CONCLUSION: The above results suggest that piperine possesses potential fat reducing and lipid lowering effects, without any change in food appetite, at a small dose of 40 mg / kg. The mechanism of action for such an activity needs to be determined. However, looking to structural similarity with the presently known Melanocortin-4 (MC-4) agonists, involvement of MC-4 receptors in its activity can be guessed.

Giant ventricular myxoma obstructing right ventricular outflow tract.

Intracardiac myxoma is predominantly located in the left atrium but their location in the right ventricle is quite unusual. We present a case in which successful excision of the tumor was done through bicameral approach.

Role of estrogen receptor- α in an experimental model of bronchial asthma.

BACKGROUND: Use of hormone replacement therapy (HRT) may increase the risk of adult-onset asthma in women. Various in vitro studies have reported that estradiol stimulates human mast cell lines causing release of allergic mediators which was not observed in estrogen receptor-alpha (ER-alpha) knockout mice. Thus, estrogen might be a key element in occurrence of asthma. In the present study, we proposed to determine the role of ER-alpha in an experimental model of bronchial asthma. METHODS: Trypsin and egg albumin induced chronic model of asthma were used. On the 28th day, various parameters such as pO2 level, serum bicarbonate level, tidal volume, respiratory rate, air flow rate, differential white blood cells count in the bronchoalveolar lavage (BAL) fluid and serum cholesterol level were measured as well as lung histopathological examination and uterine weight measurement were carried out. RESULTS: Estradiol treatment resulted in lower pO2 level, tidal volume and air flow rate. Also, serum bicarbonate level, respiratory rate and eosinophil rate and eosinophil count in BAL fluid were higher as compared to asthmatic control group. These effects were not observed in methyl-piperidino-pyrazole (MPP) co-treated group. Histopathological data suggested that the destruction of alveolar and muscular layers was more prominent in estradiol-treated group than asthmatic control and MPP co-treated groups. Estradiol-treated group showed lower total serum cholesterol levels and higher uterine weight as compared to asthmatic control group which was not observed in MPP co-treated group; indicating antagonism of estradiol by MPP at ER-alpha receptor. CONCLUSION: Estrogen seems to have a strong promoting effect on pathogenesis of bronchial asthma via ER-alpha receptors.

Antiasthmatic property of polyherbal preparation E-721 B.

E-721B and its aqueous extract were studied for its antiasthmatic effect in various experimental models using rats and guinea pigs. E-721B produced significant and dose-dependent inhibition of peritoneal mast-cell degranulation induced by compound 48/80 and egg-albumin in sensitised rats. The inhibition was comparable to that with disodium cromoglycate, ketotifen, and prednisolone. E-721B administered 2 h before the experiment and once daily for seven days significantly increased the preconvulsion time of acetylcholine and histamine aerosol-induced bronchospasm. It also significantly reduced mortality in guineapigs produced by egg albumin-induced anaphylactic shock and also reduced bronchoalveolar fluid eosinophil count in the same animals. E-721B significantly inhibited the acetylcholine and histamine-induced contraction of different isolated smooth muscle preparations from rats and guinea pigs. Contrary to these findings E-721B produced dose-dependent contraction of the rat anococcygeus muscle which was blocked by prazosin. Thus our observations establish the antiasthmatic potential of this herbal formulation.