Objectives: Ellagic acid (EA) has shown antinociceptive and anti-inflammatory effects. Inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) enzymes and also cytokines play a key role in many inflammatory conditions. This study was aimed to investigate the mechanisms involved in the anti-inflammatory effect of EA. Materials and Methods: Carrageenan-induced mouse paw edema model was used for induction of inflammation. Results: The results showed that intraplantar injection of carrageenan led to time-dependent development of peripheral inflammation, which resulted in a significant increase in the levels of tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) β, nitric oxide (NO) and prostaglandin E ₂ (PGE ₂ ) and also iNOS and COX-2 protein expression in inflamed paw. However, systemic administration of EA (1-30 mg/kg, intraperitoneal [i.p.]) could reduce edema in a dose-dependent fashion in inflamed rat paws with ED50 value 8.41 (5.26-14.76) mg/kg. It decreased the serum concentration of NO, PGE ₂ , aspartate aminotransferase and alanine aminotransferase, and suppress the protein expression of iNOS, COX-2 enzymes, and attenuated the formation of PGE _2, TNF-α and IL-1 β in inflamed paw tissue. We also demonstrated that EA significantly decreased the malondialdehyde (MDA) level in liver at 5 h after carrageenan injection. Moreover, histopathological studies indicated that EA significantly diminished migration of polymorphonuclear leukocytes into site of inflammation, as did indomethacin. Conclusions: Collectively, the anti-inflammatory mechanisms of EA might be related to the decrease in the level of MDA, iNOS, and COX-2 in the edema paw via the suppression of pro-inflammatory cytokines (TNFα, IL1 β), NO and PGE ₂ overproduction.

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Aims: Envenomation with poisonous snakes is associated with considerable morbidity and mortality. The present study was undertaken with the objectives of assessing anti-snake venom (ASV) use, early adverse reactions to ASV, premedication and clinical outcomes in snake bite patients. Association of various risk factors (age, gender, dose of ASV, time gap between snake bite and ASV administration, use of mechanical ventilation and type of snake bite) with mortality was also assessed. Settings and Design: This retrospective study was conducted at two Tertiary Care Teaching Hospitals. Subjects and Methods: The medical records of 176 patients of snake bite with documented use of ASV were retrospectively analyzed to retrieve relevant data. Statistical Analysis: Descriptive statistics was used to express results about ASV use, early adverse reactions to ASV, premedication and clinical outcomes. Univariate and multivariate analysis was performed to find out significant risk factors associated with mortality. Results: The main indication for ASV was vasculotoxic snake bite (75%) followed by neurotoxic snake bite (16%). Mean dose of ASV was 18.63 ± 14.52 vials. Prophylactic premedication with corticosteroids alone or in combination with antihistaminic was used in more than 70% patients. Early adverse reactions to ASV were seen in 4% patients. Neurotoxic snake bite was a significant risk factor associated with mortality in multivariate analysis. Conclusions: Neurotoxic snake bite is an independent predictor of mortality in snake bite patients. Currently used polyvalent ASV may be less effective in treating neurotoxic snake bite.

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Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV.

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Objective: The present study was undertaken to evaluate the protective effects of the fruit extract of Tribulus terrestris (TT) on the metronidazole (MTZ)-induced alterations in spermatogenesis, sperm count, testicular functions, and oxidative stress. Materials and Methods: Thirty adult Swiss strain mice were divided into six groups. Animals of Groups I and II served as untreated and vehicle-treated controls, while that of Groups III and IV were administered with MTZ (500 mg/kg BW/day) and TT (200 mg/kg BW/day) alone for 28 days, respectively. Low (100 mg/kg BW/day) and high (200 mg/kg BW/day) doses of TT along with MTZ (500 mg/kg BW/day) were administered for 28 days in the mice of Groups V and VI, respectively.Twenty four hours after the last treatment, all the animals were euthanized to study the histological changes in the testis and sperm count in the epididymis. Testicular functional markers, lipid peroxidation (LPO) and the activities of antioxidant enzymes, e.g., superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, were also assessed in the mice of all the groups. Results: Metronidazole caused marked alterations in the testicular weight, spermatogenesis, activities of antioxidant enzymes, lactate dehydrogenase, alkaline phosphatase, and the level of LPO. The epididymal sperm count also declined significantly in MTZ-treated group. These changes were partially restored following co-administration of 500 mg/kg BW/day of MTZ and 100 mg/kg BW/day of TT. However, in the mice co-administered with 500 mg/kg BW/day of MTZ and 200 mg/kg BW/day of TT, the changes reverted back completely, similar to that of the controls. Conclusion: The fruit extract of TT ameliorates the MTZ-induced alterations in the testis.

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In the family of gas transmitters, hydrogen sulfide (H ₂ S) is yet not adequately researched. Known for its rotten egg smell and adverse effects on the brain, lungs, and kidneys for more than 300 years, the vasorelaxant effects of H ₂ S on blood vessel was first observed in 1997. Since then, research continued to explore the possible therapeutic effects of H ₂ S in hypertension, inflammation, pancreatitis, different types of shock, diabetes, and heart failure. However, a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of H ₂ S, such as nitric oxide-dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy. More than a decade of good repute among researchers, H ₂ S research has certain results that need to be clarified or reevaluated. H ₂ S produces its response by multiple modes of action, such as opening the ATP-sensitive potassium channel, angiotensin-converting enzyme inhibition, and calcium channel blockade. H ₂ S is endogenously produced from two sulfur-containing amino acids L-cysteine and L-methionine by the two enzymes cystathionine γ lyase and cystathionine β synthase. Recently, the third enzyme, 3-mercaptopyruvate sulfur transferase, along with cysteine aminotransferase, which is similar to aspartate aminotransferase, has been found to produce H ₂ S in the brain. The H ₂ S has interested researchers, and a great deal of information is being generated every year. This review aims to provide an update on the developments in the research of H ₂ S in hypertension amid the ambiguity in defining the exact role of H ₂ S in hypertension because of insufficient number of research results on this area. This critical review on the role of H ₂ S in hypertension will clarify the gray areas and highlight its future prospects.

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Objective: Lead (Pb) is a long-known poison of environment and industrial origin. Its prolonged exposure affects cellular material and alters cellular genetics and produces oxidative damages. In this study, we investigated the exposure of chronic sustained hypoxia or lead acetate alone or in combination with or without supplementation of α-tocopherol on hepatic oxidative and nitrosative stress in rats. Materials and Methods: The rats weighing 165 ± 5 g were exposed to chronic sustained hypoxia (10% oxygen) or lead acetate (25 mg/kg of body weight, intraperitoneally) alone or in combination with or without supplementation of α-tocopherol (10 mg/100 g b.wt, intramuscularly). The body weight of all the rats was recorded on the day 1 of the treatment and the day of sacrifice. Serum lipid profile was estimated by using a biochemical analyzer. Oxidant and enzymatic antioxidants status was evaluated by using spectrophotometer. Serum levels of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were measured by using ELISA technique. Histopathological assessments of hepatic tissue were also done. Results: Exposure of both lead and hypoxia showed decreased body weight, altered serum lipid profile, oxidant and enzymatic antioxidants status, serum HIF-1α and VEGF concentrations. Simultaneous α-tocopherol supplementation showed beneficial effects to all these alterations. Histopathological observations also showed hepatic degenerative changes after lead or hypoxia exposure either alone or in combination, but remarkable improvement has been noticed after α-tocopherol supplementation. Conclusion: Supplementation of α-tocopherol is beneficial to counter both lead acetate and hypoxia induced hepatic cytotoxicities possibly by reducing oxidative and nitrosative stress.

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Objectives: To investigate the effect of DMSO on cisplatin induced cytotoxicity (invitro) against K562 (Human mylogenous leukemia) cell line and to study the cisplatin-DMSO adduct formation using UV-spectrophotometer. Materials and methods: Effect of DMSO on the cytotoxicity of cisplatin was studied in K562 (Chronic mylogenous leukemia) cell line by MTT assay. Cisplatin-DMSO adduct formation was studied by continuously monitoring the increase in absorption peaks for 30 minutes using UV-spectrophotometer. Results: 0.1-0.3% DMSO markedly reduced the cytotoxic activity of cisplatin in K562 cells. Cisplatin-DMSO adduct formation was detected using UV-spectrophotometer. Continuous increase in UV absorbance between 250nm-290nm was observed when cisplatin (0.5mg/ml) and DMSO (10%) were mixed. Conclusion: Present study revealed that DMSO inactivates the cytotoxicity of cisplatin. Cisplatin-DMSO mixture showed increased absorbance at 250-290nm.Therefore, using DMSO in invitro assays might result in misinterpretation of actual efficacy of drugs.

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Objective: The aim was to evaluate the effect of the polyphenolic fraction of Desmostachya bipinnata Stapf (PFDB) (Poaceae) on tamoxifen (TAM)-induced liver damage in female Sprague-Dawley rats. Materials and Methods: The roots of Desmostachya bipinnata were extracted in 70% methanol, and the polyphenolic fraction was isolated. Protection of BRL3A cells against ethanol-induced damage was determined by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Hepatotoxicity was induced in rats by oral administration of TAM (45 mg/kg/day) for 21 days. The PFDB was administered to experimental animals at two selected doses (100 and 200 mg/kg/day) during the treatment. The serum levels of various biochemical parameters and the antioxidant enzymes were examined by standard procedures. Results: A dose-dependent increase in percentage viability was observed when ethanol-exposed BRL3A cells were treated with PFDB. Both the treatment groups upon pretreatment with PFDB exhibited a significant (P ≤ 0.05) protective effect by lowering serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, triglycerides, cholesterol, urea, uric acid, bilirubin and creatinin levels and improving protein level in serum in dose-dependent manner, which was comparable to that of silymarin group. In addition, PFDB prevented elevation of reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase in the TAM-intoxicated rats in concentration-dependent manner and significantly (P < 0.05) reduced the lipid peroxidation in the liver tissue. The biochemical observations were supplemented with histopathological reports, which showed the attenuation of hepatocellular necrosis. Conclusions: The results of this study strongly indicate that the polyphenolic fraction of the plant roots has a potent hepatoprotective action against TAM-induced hepatic damage in rats.

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Aims: The aim of the study was to perform a systematic review and meta-analysis to determine the association between antidepressants use and risk of myocardial infarction (MI), and whether this association differs between tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Methods: A PubMed/MEDLINE search was conducted for studies published up to December 2013. Included studies were evaluated for publication bias and heterogeneity. Depending on the presence of heterogeneity, a random or fixed effects model was used to identify the pooled relative risk (RR) with 95% confidence intervals (CIs). Cumulative meta-analysis, subgroup and sensitivity analyses were also performed. All analyses were performed using comprehensive meta-analysis software. Results: Fourteen (five cohort and nine case-control) studies were included. There was heterogeneity among the studies (P_{heterogeneity} = 0.02; I² = 68%) but no publication bias (Begg's P = 0.30 and Egger's P = 0.45). Antidepressants use significantly increases the risk of myocardial infarction (MI) (RR = 2.03; 95% CI = 1.30-3.18; P < 0.01). On subgroup analysis by study design, cohort studies show significant positive association (RR = 2.16; 95% CI = 1.42-3.29; P < 0.01), but not case-control studies (RR = 2.47; 95% CI = 0.69-8.90; P = 0.17). Sensitivity analysis and cumulative meta-analysis confirmed the stability of results. TCAs users are having 36% increased risk of MI after excluding one outlier (RR = 1.36; 95% CI = 1.10-1.67; P < 0.01), but SSRIs showing no association (RR = 0.84; 95% CI = 0.57-1.22; P = 0.35). Conclusions: We found evidence that the use of antidepressants was associated with elevated risk of MI. Further research is needed to identify the underlying biological mechanisms.

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The quality of individual case safety reports (ICSRs) generated under Pharmacovigilance Programme of India (PvPI) plays a pivotal role in detecting a signal from Indian drug safety data. Currently, more than hundred thousand ICSRs were generated under PvPI and reported to Uppsala Monitoring Centre. The documentation grading and completeness score of Indian ICSRs were rapidly increasing, and the current score was 0.94 out of 1.0. Periodical training on emphasizing the quality ICSRs is need of the hour.

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Aims: The bark of Taxus wallichiana is widely used for preparing a decoction and consumed as a tea by several tribal communities of the Indian subcontinent. The sedative, motor coordination, anxiolytic, and antidepressant effects of the hydroalcoholic extract of T. wallichiana bark and its ethylacetate fraction were evaluated in mice models of behavior analysis. Materials and Methods: The effects were evaluated on diazepam-induced sleeping time, elevated plus maze and light and dark box, and on the forced swimming test. General locomotor activity and motor coordination effects were evaluated in the actophotmeter and rota-rod tests respectively. Statistical Analysis: Results are expressed as mean ± standard error of the mean. Statistical analysis was performed using ANOVA, followed by post-hoc Dunnett's test. *P < 0.05, **P < 0.01, ***P < 0.001 were considered as significant. Results: Both the hydroalcoholic extract and ethylacetate fraction showed a marked decrease in latency of sleep onset, prolonged the diazepam-induced sleeping time, decreased spontaneous locomotor activity; whereas ethylacetate fraction produced anxiolytic and antidepressant activity. Conclusions: Both hydroalcoholic extract and its ethylacetate fraction of the bark of T. wallichiana have bioactive principles, which induce neuropharmacological changes.

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A 33-year-old multidrug-resistant tuberculosis female patient diagnosed as cycloserine-induced psychosis developed several neuroleptic side effects such as extrapyramidal reaction, neuroleptic malignant syndrome, and drug-induced parkinsonism while she was being treated with initially haloperidol and then olanzapine over a period of 2 months . Patient's antipsychotic medications were withdrawn, and treatment with bromocriptine showed prompt recovery. The multiple neurological adverse effects which the patient developed had implications on the management of the complications as well as her illness.

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Osteonecrosis of the jaws is an adverse reaction associated with the use of bisphosphonates. Although the diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is based on symptomatology, it is often detected late because the patients become symptomatic only after osteonecrosis is well established. We describe a case of early oral BRONJ detected by magnetic resonance imaging (MRI) accidentally. Head MRI revealed low signal of T1-weight images in left mandibula. Patient had been treated with minodronate for osteoporosis during 18 months. Based on the MRI findings and medication history, early stage BRONJ could be considered. Therefore minodronate was switched to teriparatide. Thereafter mandible pares-thesias, odontalgia and exposed bone were not observed. This case suggests that MRI is useful for the early detection of BRONJ.

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Irrational antibiotic usage has led to vast spread resistance to available antibiotics, but we refuse to slide back to "preantibiotic era." The threat is serious with the "Enterococcus, Staphylococcous, Klebsiella, Acinetobacter, Pseudomonas and Enterobacter" organisms causing nosocomial infections that are difficult to treat because of the production of extended spectrum β-lactamases, carbapenamases and metallo-β-lactamases. Facing us is a situation where soon multidrug resistance would have spread across the globe with no antibiotics to withstand it. The infectious disease society of America and Food and Drug Administration have taken initiatives like the 10 × '20 where they plan to develop 10 new antibiotics by the year 2020. Existing classes of antibiotics against resistant bacteria include the carbapenems, oxazolidinones, glycopeptides, monobactams, streptogramins and daptomycin. Newer drugs in existing classes of antibiotics such as cephalosporins, aminoglycosides, tetracyclines, glycopeptides and β-lactamase inhibitors continue to get synthesized. The situation demands newer targets against bacterial machinery. Some of them include the peptidoglycantransferase, outer membrane protein of Pseudomonas, tRNA synthase, fatty acid synthase and mycobacterial ATP synthase. To curb the irrational and excessive usage of presently available antibiotics should be a priority if they are still to be kept in usage for the future.

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Objective: Charybdotoxin-C (ChTx-C), from the scorpion Leiurus, quinquestriatus hebraeus blocks the calcium-activated potassium channels and causes hyper excitability of the nervous system. Detailed understanding the structure of ChTx-C, conformational stability, and intermolecular interactions are required to select the potential inhibitors of the toxin. Materials and Methods: The structure of ChTx-C was modeled using Modeller 9v7. The amino acid residues lining the binding site were predicted and used for toxin-ligand docking studies, further, selected toxin-inhibitor complexes were studied using molecular dynamics (MD) simulations. Results: The predicted structure has 91.7% of amino acids in the core and allowed regions of Ramachandran plot. A total of 133 analog compounds of existing drugs for scorpion bites were used for docking. As a result of docking, a list of compounds was shown good inhibiting properties with target protein. By analyzing the interactions, Ser 15, Lys 32 had significant interactions with selected ligand molecules and Val5, which may have hydrophobic interaction with the cyclic group of the ligand. MD simulation studies revealed that the conformation and intermolecular interactions of all selected toxin-inhibitor complexes were stable. Conclusion: The interactions of the ligand and active site amino acids were found out for the best-docked poses in turn helpful in designing potential antitoxins which may further be exploited in toxin based therapies.

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Aim: This paper describes how in a problem-based learning (PBL) medical curriculum, having identified the learning outcomes, problems can be developed from real-life events for teaching-learning clinical pharmacology topics for which PBL cases might be inadequate. Such problems can be very interesting and educational. Methodology: Using the story of the development and withdrawal of rofecoxib (Vioxx ^® ), we developed a problem for undergraduate medical students to address important issues related to clinical pharmacology and therapeutics such as new drug development, preclinical testing, clinical trials, adverse drug reactions, professionalism, and critical appraisal of literature. These topics would otherwise be difficult to address in patient-based problems. Results: The evaluation of the problem based on pooled feedback from 57 tutorial groups, each comprising 8-10 students, collected over 5 years, supported the effectiveness of the problem. Conclusion: A systematic approach described in this paper can be used for the development and validation of educational material for introducing focal topics of pharmacology/clinical pharmacology integrated with other disciplines in innovative medical (and other health profession) curricula.

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Proton pump inhibitors are the one of the most widely used drugs in the world. Hypomagnesemic hypoparathyroidism has been reported with different proton pump inhibitors with prolonged oral use. We report the first reported case of possible such effect with intravenous preparation of proton pump inhibitor. This case report raises awareness among physicians worldwide of this often unknown association, as life-threatening cardiac and neuromuscular complications can arise with unrecognized hypocalcemia and hypomagnesemia with proton pump inhibitors.

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Objectives: There are few reports on the effectiveness and safety of intramuscular (IM) antipyretic injections in pediatric patients. This study reports the efficacy and adverse effects of a single IM injection of diclofenac sodium in pediatric patients. Materials and Methods : This was an observational study in which records of febrile pediatric patients presenting to the emergency department were analyzed. Subjects included pediatric patients presenting to the emergency department with a temperature of 38°C or higher. Infants under 12 months of age were excluded. Patients were excluded if they received antipyretics within 4 h prior to presenting to the emergency department. Body temperature was measured at 30-60 min intervals following diclofenac sodium injections. Fever alleviation was defined as the temperature decline to 1°C below the temperature at presentation. Patients who received diclofenac sodium twice or more on different days were observed for side effects such as allergic reaction. Records from the emergency department and outpatient clinics were analyzed. Results : The dose of diclofenac sodium injected was approximately 2 mg/kg. The average time elapsed until antipyresis was 69.1 ± 23.8 min. The average temperature reduction after 1 h was 1.1 ± 0.6°C. The average proportion of temperature change after 1 h was 40.6 ± 22.2%. During the period at the emergency department, there were no reported serious side effects. Conclusions : A single dose of diclofenac sodium provided effective antipyresis in pediatric patients. Serious side effects were not observed.

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Voriconazole-induced psychosis is a rare side effect. It is important that clinicians are made aware of voriconazole-induced potential psychosis. We report a case of voriconazole-induced psychosis that responded to haloperidol.

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Anti-arrhythmic medications are uncommonly used due to their pro-arrhythmic effect. However, just like any other class of medication, they can cause idiosyncratic reactions that may or may not be related to their mechanism of action. Those reactions can be severe enough to warrant discontinuation of a successful therapeutic intervention. In this case, we present a case of trigeminal neuralgia caused by dofetilide.

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