Shyam S. Agrawal

Current concepts in the pathophysiology of glaucoma

Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized. The literature available in the National Medical Library and online Pubmed search engine was used for literature review.

Indazole: a medicinally important heterocyclic moiety

This article reveals the various biological activities of the heterocyclic compound, indazole, including anti-inflammatory, antimicrobial, antiHIV, anticancer, hypoglycemic, antiprotozoal, antihypertensive, and other activities. From the observed biological activities of the indazole moiety, it is concluded that the medicinal properties of indazole have to be explored in the near future for the treatment of various pathological conditions.

Evaluation of hepatoprotective activity of aerial parts of Tephrosia purpurea L. and stem bark of Tecomella undulata.

ETHNOPHARMACOLOGICAL RELEVANCE The aerial parts of Tephrosia purpurea (L.) pers. (Fabaceae) and stem bark of Tecomella undulata seem. (Bignoniaceae) are used for liver disorders in the traditional system of medicine. AIM OF THE STUDY To evaluate the hepatoprotective activity of aerial parts of Tephrosia purpurea and stem bark of Tecomella undulata against thioacetamide-induced hepatotoxicity. MATERIALS AND METHODS Hepatotoxicity was induced in albino rats of either sex by subcutaneous injection of thioacetamide. Aqueous-ethanolic extract of aerial parts of Tephrosia purpurea (100, 300 and 500 mg/kg/day and ethanolic extract of stem bark of Tecomella undulata (200, 500 and 1000 mg/kg/day were evaluated. RESULTS Oral administration of Tephrosia purpurea at 500 mg/kg and Tecomella undulata at 1000 mg/kg resulted in a significant reduction in serum aspartate aminotransaminase (35% and 31%, respectively), alanine aminotransaminase (50% and 42%, respectively), gamma glutamyl transpeptidase (56% and 49%, respectively), alkaline phosphatase (46% and 37%, respectively), total bilirubin (61% and 48%, respectively) and liver MDA levels (65% and 50%, respectively), and significant improvement in liver glutathione (73% and 68%, respectively) when compared with thioacetamide damaged rats. Histology of the liver sections of the animals treated with the extracts also showed dose-dependent reduction of necrosis. CONCLUSIONS The present study demonstrates the hepatoprotective activity of the aerial parts of Tephrosia purpurea and stem bark of Tecomella undulata against thioacetamide-induced hepatotoxicity.

Evaluation of anticataract potential of Triphala in selenite-induced cataract: In vitro and in vivo studies

Triphala (TP) is composed of Emblica officinalis, Terminalia chebula, and Terminalia belerica. The present study was undertaken to evaluate its anticataract potential in vitro and in vivo in a selenite-induced experimental model of cataract. In vitro enucleated rat lenses were maintained in organ culture containing Dulbecco’s Modified Eagles Medium alone or with the addition of 100μM selenite. These served as the normal and control groups, respectively. In the test group, the medium was supplemented with selenite and different concentrations of TP aqueous extract. The lenses were incubated for 24 h at 37°C. After incubation, the lenses were processed to estimate reduced glutathione (GSH), lipid peroxidation product, and antioxidant enzymes. In vivo selenite cataract was induced in 9-day-old rat pups by subcutaneous injection of sodium selenite (25 μmole/kg body weight). The test groups received 25, 50, and 75 mg/kg of TP intraperitoneally 4 h before the selenite challenge. At the end of the study period, the rats’ eyes were examined by slit-lamp. TP significantly (P < 0.01) restored GSH and decreased malondialdehyde levels. A significant restoration in the activities of antioxidant enzymes such as superoxide dismutase (P < 0.05), catalase (P < 0.05), glutathione peroxidase (P < 0.05), and glutathione-s-transferase (P < 0.005) was observed in the TP-supplemented group compared to controls. In vivo TF 25mg/kg developed only 20% nuclear cataract as compared to 100% in control. TP prevents or retards experimental selenite-induced cataract. This effect may be due to antioxidant activity. Further studies are warranted to explore its role in human cataract.

Synthesis, antimicrobial activity and QSAR studies of new 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazoles

Antimicrobial activity of synthesized 2,3-disubstituted-3,3a,4,5,6,7-hexahydro-2H-indazole derivatives indicated that 3-(4-chlorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (6) and 3-(4-fluorophenyl)-2-(4-nitrophenylsulfonyl)-3,3a,4,5,6,7-hexahydro-2H-indazole (20) were the most active compounds. Further, the results of QSAR studies indicated the importance of topological parameters (2)chi and (2)chi(v) in defining the antimicrobial activity of hexahydroindazoles.

Anti-implantation activity of H2 receptor blockers and meloxicam, a COX-inhibitor, in albino Wistar rats

Objective To evaluate the anti-implantation activity of H2 receptor blockers ranitidine and famotidine, and Cox-inhibitor meloxicam, alone and in combination, considering the role of histamine and prostaglandins in implantation. Method The drugs were administered orally to female albino Wistar rats at different dose levels for 1 to 7 days, immediately after confirming copulation by observing sperm in the vaginal smear. A laparotomy was done on the 10th day of pregnancy, the implants and corpora lutea were counted, and the pre- and post implantation losses determined. The mast cell stabilising activity was studied using both in vitro and in vivo methods. Results Ranitidine 70 mg/kg (75.41%; p < 0.01), and famotidine 80 mg/kg (74.30%; p < 0.001) showed significant anti-fertility activity. No increase in activity was seen at higher doses. Meloxicam showed significant activity at doses of 3, 4, and 5 mg/kg. The combination of meloxicam (4 mg/kg) with ranitidine (70 mg) and famotidine (80 mg/kg) showed 100% anti-fertility activity. Conclusion Our results indirectly confirm the combined involvement of histamine and prostaglandins in the implantation process. The mast cell stabilising property of H2 blockers appears to be a possible mechanism for their anti-implantation activity.

Antifertility activity of methanolic bark extract of Aegle marmelos (l.) in male wistar rats

BackgroundAegle marmelos leaf, seed and fruit from earlier studies is known to affect male fertility in reversible manner. However they had delayed onset and recovery was found to be prolonged. The present study was undertaken with an aim to evaluate the effect of Aegle marmelos bark extract on rats as the extract is found to be a rich source of marmin and fagarine known for reducing male fertility. Three different concentration of methanolic bark extracts of Aegle marmelos (L.) were evaluated for male antifertility activity on albino wistar rats. Methanolic bark extract of Aegle marmelos at the dose of 200, 400, and 600 mg/Kg b.w was administered orally for 60 days. Treatments were stopped thereafter and animals were sacrificed after a recovery period of 30 days. Control animal were administered vehicle (0.5% CMC for 60 days). Lonidamine was used as standard drug to compare the effect of extract.ResultsMethanolic extract causes a dose & duration dependent infertility via reducing reproductive organ weight and serum testosterone levels. Sperm analysis results showed reduction in sperm density, motility, viability and sperm acrosomal integrity without interfering libido and vital organ body weight. Histopathological studies of testes revealed exfoliation of elongated spermatids, nuclear chromatin condensation, degeneration and prominent spaces detected within the germinal epithelium signifying testicular cytotoxicity and necrosis. Time dependent complete infertility was observed in all dose levels. Animals after the withdrawal from treatment, for 30 days showed restoration of the morphological as well as physiological parameters in extract treated rats. Methanolic extract showed lipid lowering activity compared to control, suggestive good candidature of this plant for further studies.ConclusionsOur studies suggested Aegle marmelos barks methanolic extract as strong candidate for male contraceptive via its ability to produce complete inhibition of pregnancy, rapid restoration of fertility after withdrawal from treatment and its lipid correcting ability proving further beneficial effects.

3,4-Disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thiones: Synthesis, Antimicrobial Evaluation and QSAR Investigations Using Hansch Analysis

The 3,4‐disubstituted‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione derivatives were synthesized and characterized by physicochemical and spectral means, and the results of antimicrobial study of these compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans by tube dilution method indicated that 4‐(4‐chlorophenyl)‐3‐(4‐nitrophenylsulfonyl)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione 6 and 4‐(4‐fluorophenyl)‐3‐(4‐nitrophenylsulfonyl)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2‐thione 12 were the most potential ones. Further, the QSAR studies by Hansch analysis applied to find out the correlation between physicochemical characteristics of synthesized compounds with antimicrobial activity demonstrated the contribution of electronic parameter, total energy (Te) and the topological parameter (valence second order molecular connectivity index (2χv)). Excellent statistically significant models were developed by Hansch approach (r2 = 0.828–0.898) for the three microorganisms under study. The cross‐validated r2 (q2), which is an indication of the predictive capability of the model for all cases was also very good (q2 = 0.776–0.875).

Anti-ovulatory activity of H2 receptor blockers in albino rabbits--a preliminary study.

Objective To evaluate the anti-ovulatory activity of H2 receptor blockers (ranitidine, famotidine and roxatidine) in albino rabbits considering the role of histamine in ovulation. Method The drugs were orally administered once daily for three days to adult female rabbits weighing between 1.3–2.0 kg (four groups of three animals). The control group received the 1% weight/volume gum acacia suspension. Thirty minutes after the administration of the last dose, a freshly prepared 0.4 % solution of cupric acetate was administered to each animal intravenously via the marginal ear vein (4 mg/kg body weight) to induce ovulation. To assess ovulation, laparotomy was carried out 48 h after cupric acetate injection. The ovaries were exposed, bleeding points on each ovary were counted, and the ovaries and uteri were subjected to histopathological evaluation. Results Based on the number of bleeding points (ovulation sites) observed on the ovary, H2 blockers showed varying degrees of anti-ovulatory activity. Roxatidine exerted the most pronounced activity. Histopathological observations of uterus and ovary confirmed the aforementioned observations. Conclusion H2 receptor blockers appeared to inhibit the cupric acetate-induced ovulation in albino rabbits. Our results seem to confirm the role of histamine in ovulation reported by other authors.

Randomised, cross-over, comparative bioavailability trial of matrix type transdermal drug delivery system (TDDS) of carvedilol and hydrochlorothiazide combination in healthy human volunteers: A pilot study

The present study deals with transdermal drug delivery system (TDDS) of Carvedilol (CRV) and Hydrochlorothiazide (HCTZ). It compares the bioavailability of these two study drugs from a TDDS with conventional immediate release oral tablets in healthy volunteers. The TDDS was also evaluated for any adverse drug reaction. This was an open-label, randomised, single centre, two-treatment, two period, single dose, crossover pilot study of two formulations of cardiovascular agents. Subjects (n=10) were randomised to have a TDDS applied to their abdominal skin for 72h or receive one oral tablet each of CRV and HCTZ respectively in period I, followed by 1-week washout period. They received the alternative treatment in period II. A significant improvement in bioavailability was observed with the transdermal patches over oral tablets as observed by the mean AUC((0)(-)(t)) values 4004.37+/-180.98 and 1824.30+/-17.43ngh/mL respectively for CRV and HCTZ as compared to 753.46+/-53.34 and 392.89+/-34.23ngh/mL respectively, with the oral tablets. The TDDS possesses significant potential for skin irritation. The TDDS developed in our laboratory produced therapeutically effective plasma concentrations of the cardiovascular agents up to a range of 60 to 72h (in different volunteers with a mean=66h). It could be concluded from these observations that the TDDS meets the intended goal of at least 2day management of stage II hypertension with application of a single transdermal patch, hence improving patient compliance over the inconvenience seen with frequent oral administration.