OBJECTIVE: To study the effect of shilajit (a herbomineral preparation) on blood glucose and lipid profile in euglycemic and alloxan-induced diabetic rats and its effects on the above parameters in combination with conventional antidiabetic drugs. MATERIAL AND METHODS: Diabetes was induced in albino rats by administration of a single dose of alloxan monohydrate 5% (125 mg/kg, i.p.). Effects of three different doses of shilajit (50, 100 and 200 mg/kg/day, orally), alone for 4 weeks and a combination of shilajit (100 mg/kg/day, orally) with either glibenclamide (5 mg/kg/day, orally) or metformin (0.5 g/kg/day, orally) for 4 weeks were studied on blood glucose and lipid profile. RESULTS: In the diabetic rats, all the three doses of shilajit produced a significant reduction in blood glucose levels and also produced beneficial effects on the lipid profile. The maximum effect was observed with the 100 mg/kg/day dose of shilajit. Combination of shilajit (100 mg/kg) with glibenclamide (5 mg/kg/day) or metformin (0.5 gm/kg/day) significantly enhanced the glucose-lowering ability and improvement in lipid profile than any of these drugs given alone. CONCLUSION: Shilajit is effective in controlling blood glucose levels and improves the lipid profile.

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OBJECTIVE: To evaluate the effects of Centella asiatica (CA) upon pain (antinociception) and inflammation in rodent models. MATERIAL AND METHODS: The antinociceptive activity of the water extract of CA (10, 30, 100 and 300 mg/kg) was studied using acetic acid-induced writhing and hot-plate method in mice. The antiinflammatory activity of CA was studied in rats by prostaglandin E2-induced paw edema. RESULTS: Water extract of CA revealed significant antinociceptive activity with both the models. The activity was statistically similar to aspirin but less potent than morphine. The CA extract also revealed significant antiinflammatory activity. This effect was statistically similar to the non-steroidal antiinflammatory drug, mefenamic acid. CONCLUSION: These results suggest that the water extract of CA possesses antinociceptive and antiinflammatory activities.

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OBJECTIVE: To induce immunosuppression in rats by pyrogallol and to develop a novel model to screen the immunomodulatory activity of a known agent. MATERIAL AND METHODS: In order to induce immunosuppression, pyrogallol was daily administered to rats for 7 days in different doses (10, 25, 50 and 100 mg/kg, i.p.). On Day 7 and 13, the rats were sensitized with sheep red blood cells (SRBC) to assess the humoral immune response. On Day 20, SRBC were injected in the subplantar region of the hind paw, and an increase in the paw volume was recorded on Day 22 to assess the cell-mediated immune responses. The phagocytosis in the peritoneal macrophages was assessed on the last day. The parameters of oxidative stress such as lipid peroxidation (LPO), reduced glutathione (GSH) content, superoxide dismutase (SOD) and catalase (CAT) activities were assessed on the last day. In another set of experiment, the immunomodulatory activity of Rubia cordifolia (RC) (50, 100, and 200 mg/kg, p.o., daily from Day 1 to Day 22) was screened in rats in whom immunosuppression was induced by a minimum effective dose of pyrogallol (50 mg/kg). RESULTS: The dose of 25 mg/kg of pyrogallol suppressed only the humoral immunity (P<0.05), while 50 and 100 mg/kg dose significantly (P<0.01) impaired all the parameters i.e. humoral immunity, cell-mediated immunity and phagocytosis (P<0.01). It also caused a dose-dependent increase in the LPO levels, depletion of GSH, and decrease in activities of SOD and CAT. The treatment with the alcoholic extract of Rubia cordifolia significantly prevented the influence of the minimum effective dose of pyrogallol (50 mg/kg) on all immunological parameters and concurrently prevented the changes in the marker parameters of oxidative stress. The dose of 100 mg/kg was found to be optimum for this purpose. CONCLUSION: Fifty mg/kg (i.p., daily for 7 days) appears to be the minimum dose of pyrogallol, which can induce significant immunosuppression in rats. The correlation analysis indicated that pyrogallol-induced immunosuppression is related to oxidative stress. In addition, it was found that the immunomodulatory activity of a known agent could be successfully screened by this method. Thus, pyrogallol can be used as an experimental tool to induce immunosuppression while screening the immunomodulatory activity of any agent.

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OBJECTIVE: To investigate the anorectic effect of the methanol extract of Benincasa hispida (MEBH) in Swiss albino mice. MATERIAL AND METHODS: Fasted mice were administered with various doses of MEBH (0.2-1 g/kg, i.p.), and the food intake was measured hourly for a period of 7 h. In another experiment, the percentage of gastric emptying at 4th h was determined after the administration of MEBH (0.2-1 g/kg, i.p.) in different set of mice which had free access to preweighed food for either 1, 2 or 4 h. RESULTS: MEBH significantly reduced the cumulative food intake over a 7 h period in a dose-dependent manner. The percentage reduction of cumulative food intake at 7th h for MEBH with 0.2, 0.6 and 1 g/kg was 27%, 38% and 54% respectively. The 4 h gastric emptying was not significantly influenced by MEBH when compared to control. CONCLUSION: The present study reveals for the first time a possible anorectic activity of Benincasa hispida, most probably mediated through the CNS without affecting the gastric emptying. However, further studies are required to find its potential as an antiobesity agent.

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OBJECTIVE: To evaluate the role of calcium channel blockers and their mechanisms of action on acute inflammation of rat paw. MATERIAL AND METHODS: The study was conducted using carrageenan-induced rat paw inflammation model. Two different doses of nifedipine and verapamil (25 and 400 µg/kg, i.p.) were used. Edema was assessed by calculating the volume changes and by extravasation of Evans blue dye. RESULTS: Nifedipine reduced edema dose-dependently, whereas verapamil was effective only at low dose. Adrenalectomy prevented the effect of nifedipine and verapamil. With low dose of nifedipine 66% of antiinflammatory effect was observed. Pretreatment with -helical corticotropin releasing factor (CRF 9-41), a corticotropin-releasing hormone (CRH) receptor antagonist, had the same effect as that of adrenalectomy for either doses of verapamil, but only the effect of low-dose nifedipine was prevented completely. CONCLUSION: Our data suggest that verapamil and nifedipine exerts a potent antiinflammatory action possibly through pituitary adrenocortical activation.

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OBJECTIVE: To study the probable site of the antinociceptive action of fluoxetine and its interaction with morphine and naloxone. MATERIAL AND METHODS: The antinociceptive activity of fluoxetine was studied using tail-flick method in the absence and presence of naloxone in mice. Different doses of fluoxetine (2, 5 and 10 mg/kg) and morphine (0.5 mg/kg and 1 mg/kg) were administered subcutaneously to select the subanalgesic doses for both. Subanalgesic doses of both the drugs were administered simultaneously to study their interaction on tail-flick latency. RESULTS: Fluoxetine and morphine produced a dose-dependent antinociceptive action. Combination of the subanalgesic dose of both fluoxetine (2 mg/kg) and morphine (0.5 mg/kg) produced an additive effect. Naloxone in a dose of 1 mg/kg produced a significant (P<0. 001) hyperalgesia at time intervals of 15, 30 and 60 min while in a dose of 2 mg/kg it produced significant (P<0. 001) hyperalgesia at time intervals of 30, 60 and 120 min. Naloxone (2 mg/kg) pretreatment significantly reduced the antinociception produced by fluoxetine. CONCLUSION: Analgesia produced by fluoxetine may be mediated by 'micro' opioid receptor, however, mechanisms involving other endogenous opioid peptides could not be ruled out. Fluoxetine as a monotherapy or in combination with other opioids could be useful in the management of pain.

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Hypertension and cancer are two leading diseases in the world. Often they coexist in patients. They share some common predisposing factors e.g., ageing, obesity, alcohol consumption and smoking habit. Abnormal angiogenesis (i.e. the formation of new blood vessels from an existing vasculature) is a common pathological feature, and some pro-angiogenic factors e.g., vascular endothelial growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and few interleukins are common mediators in both the conditions. Among these, the most important is vascular endothelial growth factor, a specific mitogen for vascular endothelium. It increases vascular permeability and induces proteolytic enzymes that are necessary for vascular remodeling. Monocyte/macrophages also have been shown to play a role in angiogenesis by releasing some of the above mediators. Angiogenesis is essential for the growth and metastasis of solid tumors. The essence of impaired angiogenesis (despite high level of angiogenic factors), probably due to signaling defects in the endothelium in hypertension, is not clearly understood. Some anticancer drugs e.g., taxanes, vinblastine, temozolomide and doxorubicin have antiangiogenic activity. Nevertheless, several classes of specific antiangiogenic agents are being evaluated for their anticancer effects and are emerging as new drugs for cancer treatment. COX-2 inhibitors (e.g., celecoxib and rofecoxib), neovastat, thalidomide analogues and some cytokine inhibitors also inhibit angiogenesis. Although certain antihypertensives are found to have antiangiogenic properties, some show pro-angiogenic activity. Also, a number of epidemiological studies have found an association between the use of antihypertensive drugs and risk of cancer. However, a better understanding of common cell biology and the relationship between hypertension and malignancy may be helpful in elucidating more preventive and therapeutic avenues to manage hypertension and cancer.

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OBJECTIVE: To compare the clinical efficacy of three brands of warfarin. MATERIAL AND METHODS: Thirty-six patients (mean age 51.8±12.7 years, 12 males, 24 females) with different indications for anticoagulant therapy were randomly placed in 3 groups. Each group started with one of the three brands of warfarin (Orion from Finland=Brand A, Cipla from India=Brand B and Ferrer from Spain=Brand C) and crossed over to another after 4 weeks. Patients were followed up at weekly visits, checking prothrombin time (PT), International Normalized Ratio (INR) and any complications. The cardiologist and patients were unaware of the warfarin brand used. Number of dose changes, mean dose changes (mg), target INR achievement in the last week and the mean stable dose (mg) were compared between the three brands. RESULTS: Mean number of dose changes throughout the 4-week course was 1.6±1.2 times for brand A, 1.2±1.1 times for brand B and 1.3±0.9 times for brand C (P=0.24). The amount of total dose changes was similar (0.70±0.6 mg for brand A, 0.63±0.9 mg for brand B and 0.72±0.8 mg for brand C, P=0.89). The rate of target INR achievement in the last week was similar (46.9% for brand A, 50% for brand B and 50% for brand C). Thirty-four per cent of patients treated with brand A, 28% with brand B, and 32% with brand C did not achieve target INR. The required dose for the stable target INR was 4.6±2.2 mg, 5.3±2.2 mg and 5.3±2.4 mg in patients treated with brands A, B and C respectively (P=0.61). There were no complications except 2 cases of drug discontinuation by the physician for extreme overdose, (i.e. INR>4.5 that needed drug discontinuation). CONCLUSION: Orion, Cipla and Ferrer warfarin products were similar regarding target INR achievement, the required dose and number of dose changes.

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OBJECTIVE: To examine the effect of nabumetone on the renal function in conscious and anesthetized rats. MATERIAL AND METHODS: For the conscious study, rats were housed individually in metabolic chambers for a duration which consisted of acclimatization, control, experimental and a recovery phase comprising 1, 1, 2 and 1 week respectively. During the experimental phase, one group of rats received nabumetone orally and the controls received an equivalent volume of saline. Water and food intake, body weight, urine output, urine osmolality, osmolal output and electrolyte excretions were estimated. In the second study, rats were anesthetized and saline diuresis in these animals was established with an intravenous infusion of 0.9% saline containing 3H-Inulin. Glomerular filtration rate (GFR) was estimated using standard inulin clearance. The study period consisted of equilibration, control, experimental and a recovery phase comprising 2, 1, 1, and 1 hour respectively. During the experimental phase, one group of rats received a bolus dose of nabumetone intravenously and the controls received the vehicle. Blood and urine samples were collected for analysis of electrolytes, microalbuminuria and GFR estimation. Data was analyzed using ANOVA for repeated measurements. RESULTS: In conscious rats, no significant differences were found between the two groups in any of the measured parameters. In anesthetized rats, however, there was a significant but reversible decrease in GFR and sodium excretion in rats receiving nabumetone. CONCLUSION: In contrast to the suggested renal-sparing effects of COX-2 inhibitors, we have observed renal function being affected with nabumetone during anesthetic stress.

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