Search

Stroke is the third leading cause of global death and disability. Cyclooxygenase-2 mRNA has been shown to be up-regulated after stroke and also the time window of its expression extends from 4 to 12 h. The objective of this study was to elucidate the protective effect of Etoricoxib (a selective Cyclooxygenase-2 inhibitor) against transient middle cerebral artery occlusion induced behavioral, biochemical and histological alterations. Transient ischemia reperfusion significantly caused behavioral (neurological deficits, decreased locomotor activity and rotarod performance), biochemical (increased lipid peroxidation and nitrite concentration, while decreased superoxide dismutase and catalase activity) and histological (increased infarct volume) changes. Etoricoxib (3 and 10 mg/kg, i.p.) significantly reversed the alterations caused by cerebral ischemia however, 1 mg/kg dose was not found effective in any of the parameters. Finally, we can conclude that Etoricoxib has beneficial effects against transient middle cerebral artery occlusion model in rats. The present study indicates that Etoricoxib may be considered as a potential candidate in the treatment of stroke, clinically., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To evaluate an ethanolic extract of seeds of Linum usitatissimum (Linn.) (EELU) for its renoprotective role in rats through its antihypertensive effect and conservation of biological oxidation enzymes., Materials and Methods: Male Wistar rats (200-250 g) underwent uninephrectomy on day 0; after 2 weeks of recovery, the nephrectomised rats were divided into four groups of eight each: (I) sham (II); renal ischaemia reperfusion (RIR); (III) RIR + EELU 200 mg/kg; and (IV) RIR + EELU 400 mg/kg. In group II, III and IV the renal artery was occluded for 45 min and reperfused for 4 weeks; the sham group did not undergo RIR., Results: EELU (400 mg/kg) significantly decreased the haemodynamic changes after 4 weeks of RIR injury. EELU treatment significantly restored the levels of renal endogenous antioxidant enzymes and membrane-bound enzymes. EELU 400 mg/kg restored the levels of blood urea nitrogen and serum creatinine. EELU also decreased the levels of tumour necrosis factor-α and myeloperoxidase activity. A flow-cytometric study confirmed a significant decrease in cellular necrosis and increase in viability after RIR in EELU-treated rats. The anti-apoptotic role of EELU was evident from the decrease in DNA fragmentation. Renal tissue damage as assessed by histopathology was decreased in groups III and IV (200 and 400 mg/kg EELU)., Conclusion: We conclude that EELU protected the kidney against RIR-induced renal injury, probably by inhibiting reactive oxygen species that have a causal role in such cases. It also inhibits apoptotic cell death and inflammation, and improves haemodynamic changes.

The objective of the study was to evaluate the cardioprotective activity of flax lignan concentrate (FLC) in isoprenalin (ISO) induced cardiotoxicity in rats. Male Wistar rats (200-230 g) were divided into three groups. Group I: control, Group II: isoprenalin, Group III: FLC (500 mg/kg, p.o.) orally for 8 days and in group II and III isoprenalin 5.25 mg/kg, s.c. on day 9 and 8.5 mg/kg on day 10. On day 10 estimation of marker enzymes in serum and haemodynamic parameters were recorded. Animals were sacrificed, histology of heart was performed. Isoprenalin showed cardiotoxicity, manifested by increased levels of marker enzymes and increased heart rate. FLC treatment reversed these biochemical changes significantly compared with ISO group. The cardiotoxic effect of isoprenalin was less in FLC pretreated animals, which was confirmed in histopathological alterations. Haemodynamic, biochemical alteration and histopathological results suggest a cardioprotective protective effect of FLC in isoprenalin induced cardiotoxicity.

Context: Cardioprotective effects of various plants are generally attributed to their antioxidant activity. The whole fruit extract of pomegranate (WFEP), Punica granatum L. (Punicaceae), has a potent antioxidant activity., Objective: To investigate cardioprotective effect of WFEP against doxorubicin (Dox)-induced cardiotoxicity in rats., Materials and Methods: Male Wistar rats were divided randomly into three groups of eight rats each: control (water, 5 mL/kg); Dox (10 mg/kg i.v.) and WFEP (100 mg/kg). Dox was administered in Dox and WFEP groups. After anesthetizing the animals on the last day, electrocardiogram was recorded and blood was analyzed for creatine kinase-MB isoenzyme (CK-MB), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activities. Determinations of superoxide dismutase (SOD), reduced glutathione (GSH), lipid peroxidation (LPO) and histopathology of the heart tissues were carried out., Results: The WFEP group showed decreased QT and increase in heart rate (p < 0.05) compared to the Dox group. Significant decrease in CK-MB (p < 0.01), LDH (p < 0.05) and no such significant decrease in AST were observed as compared to the Dox group. There was significant increase in the level of GSH (p < 0.05), whereas inhibition of LPO and increase in SOD concentration was not significant in the WFEP group compared to the Dox group. Histopathological study of the WFEP-treated group showed slight protection against myocardial toxicity induced by Dox., Conclusion: Results indicate that WFEP has cardioprotective effect against Dox-induced cardiotoxicity in rats.

Context: Macrotyloma uniflorum (Lam.) Verdc. (Leguminosae) seeds, known as the poor man's pulse crop in India, have been used as a food and also used in the traditional method for treatment of kidney stones, diabetes, obesity, etc., Objective: To investigate the antidiabetic effect of α-amylase inhibitor isolated from the seeds of Macrotyloma uniflorum seeds in streptozotocin-nicotinamide induced diabetic mice., Materials and Method: α-Amylase inhibitor was purified using a carboxymethyl cellulose (CMC) column. Kinetic studies were done using mouse pancreatic and human salivary α-amylase. Its antidiabetic effect was studied in streptozotocin-nicotinamide-induced diabetic mice. Biochemical parameters such as serum total cholesterol, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined. Histopathological investigation was performed on the pancreas, kidney, and liver tissue samples., Results: Macrotyloma uniflorum α-amylase inhibitor (MUAI) inhibited both the mouse pancreatic and human salivary α-amylase in a non-competitive manner with K(i) values of 11 and 8.8 µM and IC(50) value of 30 and 12.5 µg/mL, respectively. It decreased the serum glucose level in the treated diabetic mice. Histological findings suggested minimum pathological changes in the treated diabetic mice as compared to the diabetic control., Discussion and Conclusion: The results suggest that MUAI has an antihyperglycemic activity and therefore can be used in the dietary treatment of non-insulin dependent diabetes mellitus.

VMNS2e is a novel biphenyl compound, which in previous studies had showed most favourable interactions with the active site of protein tyrosine phosphatase 1B (PTP1B). The effect of acute and chronic treatment of VMNS2e (30mg/kg) was investigated in ob/ob mice. Plasma glucose was measured after acute administration of VMNS2e (30mg/kg) in both lean and ob/ob mice. In the chronic study, VMNS2e (30mg/kg) was given orally, once daily for 60days. Metformin (300mg/kg) was taken as standard therapy. Body weight, food intake and blood glucose was measured weekly while glycosylated hemoglobin A(1c) (HbA(1c)), insulin, triglyceride, total cholesterol, low density lipoprotein (LDL), fructosamine, non esterified fatty acid and organ weight were estimated after the completion of treatment period. Oral glucose tolerance test was performed on the last day of treatment. Liver and epididymal fat weights were taken. Acute dose of VMNS2e elicited an anti hyperglycemic effect. It reduced blood glucose by 14% (0.5h) and 35.6% (6h). Chronic VMNS2e treatment improved glucose tolerance by 25.3%. It decreased blood glucose levels. Hyperinsulinemia was reduced (19.6%). VMNS2e treatment had no significant effect on body weight and food consumption. VMNS2e treatment exhibited significant reduction (28.2%) in HbA(1c), plasma triglyceride (49%), LDL (24%) and fructosamine (13%) levels. VMNS2e treatment did not alter total cholesterol and non esterified fatty acid levels. Epididymal fat/body weight ratio was reduced (26.3%). VMNS2e exhibited both acute and chronic anti hyperglycemic effect, insulin sensitivity along with improvement in various lipid parameters and glycemic control., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aim: To study the effect of a new biphenyl synthetic compound showing interactions with the active site of protein tyrosine phosphatase 1B by docking and molecular dynamics, VMNS2e in streptozotocin-induced diabetic nephropathy in rats with various renal function parameters and renal ultrastructure., Methods: Streptozotocin (55 mg/kg)-induced diabetic rats were orally treated once daily with VMNS2e (30, 60, and 120 mg/kg) for 8 weeks. The body weight and blood glucose levels of the rats were recorded during the study period. After 8 weeks of treatment creatinine clearance, urinary protein, blood urea nitrogen, urinary albumin excretion rate, and insulin levels were measured. An ultrastructure study of the kidney tissue was performed and the glomerular basement membrane thickness was measured., Results: Eight weeks of VMNS2e treatment significantly reduced the fasting blood glucose level, attenuated elevating blood urea nitrogen levels, and reduced glomerular basement membrane thickness., Conclusion: It is concluded that VMNS2e treatment at 30 and 60 mg/kg, when given for 8 weeks, partly ameliorated early diabetic nephropathy in diabetic rats., (© 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.)

Trigonella foenum (TF) has long been used in the traditional Indian systems of medicine for the treatment of various ailments. The objective was to study the anabolic and androgenic activity of the furostanol glycosides fraction of Trigonella foenum-graecum (Fenu-FG) in immature castrated male Wistar rats. It was also aimed to investigate the effect of Fenu-FG on testicular histology in non-castrated immature rats. The animals (55 ± 5 g) were castrated. The rats were treated with either vehicle, testosterone (10 mg/kg s.c. bi-weekly) or Fenu-FG (10 and 35 mg/kg p.o.) once daily for 4 weeks. At the end of the study, blood was withdrawn, serum testosterone and BUN were measured. Animals were killed and reproductive organs were excised and weighed.Fenu-FG (35 mg/kg p.o.) and testosterone (10 mg/kg, s.c. biweekly) increased the weight of the levator ani muscle as well as body weight. Fenu-FG (10 or 35 mg/kg p.o.) did not change the testosterone level in castrated rats. Histopathological examination of the testis of non-castrated rats treated with Fenu-FG (10, 35 mg/kg p.o.) showed normal architecture of the testis. Fenu-FG (35 mg/kg p.o.) showed anabolic activity without androgenic activity., (Copyright © 2010 John Wiley & Sons, Ltd.)

Women experience menopause differently across the world, in terms of their symptomology. Many experience symptoms of menopause like hot flashes, joint pain and loss of libido. Estrogen replacement is the prescribed therapy for most of the sexual dysfunction observed in menopausal women. Many women are reluctant to use exogenous hormone therapy for treatment of menopausal symptoms and are turning to botanical and dietary supplements for relief. In the present study IND-HE (friedelin rich fraction) was studied for estrogenic activity as well as its effect on sexual behavior in overiectomized female Wistar rats.The rats were divided into 4 groups of six rats each. The Group 1 received distilled water, Group II - IND-HE (75 mg/kg p. o.), Group III - IND-HE (100 mg/kg p. o.) and Group IV received estrogen (estradiol) (1 mg/kg in olive oil suspension, s.c. bi-weekly). The treatment period was 8 weeks. On 1 day, one month and two month of treatment the sexual behavior was studied. At the end of the treatment the blood was withdrawn from retro-orbital plexus. The animals were sacrificed and uterus was removed, weighed and histology was studied. In different group of rats estrous cycle was studied which indicate estrogenic activity and for progestogenic activity of deciduoma formation was studied.The result indicated that IND-HE (75 and 100 mg/kg p.o.) improved sexual behavior parameters. IND-HE (75 and 100) significantly (P< 0.01) decreased darting and hopping latency. The darting frequency and hopping frequency was significantly (P< 0.01) improved in IND-HE (75 and100 mg/kg p.o.) as well as estrogen group. Lordosis interval (LI) was increased significantly in estrogen group after 1(st) month (P< 0.05), and after 2(nd) month (P< 0.01). IND-HE (100) treatment showed increase in LI after 1(st) month (P< 0.05) remained during 2(nd) month (P< 0.01). While IND-HE (75) treatment increased LI only after 2(nd) month (P< 0.05).IND-HE (75 and 100 mg/kg p.o.) showed estrogenic activity as indicated by vaginal cornification, increase in uterine weight and rise in serum estrogen.

The aim of the present investigation was to evaluate the antidiabetic activity of cycloart-23-ene-3beta, 25-diol (called as B2) isolated from stem bark of Pongamia pinnata in streptozotocin-nicotinamide induced diabetic mice. Diabetes was induced in mice by injecting streptozotocin (200mg/kg, i.p.) after 15 min nicotinamide (110 mg/kg, i.p.). The mice were divided into following groups; I - nondiabeteic, II - diabetic control, III - glybenclamide (10mg/kg, p.o.), IV - B2 (1mg/kg, p.o.) and V - B2 (3mg/kg, p.o., only for acute study). Serum glucose was determined periodically. Body weight, food and water intake were recorded daily. Oral glucose tolerance test was performed on day 28. Biochemical and enzyme antioxidant parameters were determined. Histology of pancreas was performed. B2 and glybenclamide treatment reduced serum glucose in acute study. However in chronic study, increase in body weight and decrease in food and water intake was observed. Increased glucose utilization was observed in oral glucose tolerance test. Both glybenclamide and B2 increased serum and pancreatic insulin. Glycosylated haemoglobin, serum cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, globulin, bilirubin, lactate dehydrogenase, urea and uric acid were decreased significantly after B2 treatment. B2 treatment decreased liver malondialdehyde but increased superoxidase dismutase and reduced glutathione. Histologically, focal necrosis was observed in the diabetic mouse pancreata but was less obvious in treated groups. The mechanism of B2 appears to be due to increased pancreatic insulin secretion and antioxidant activity., (2010 Elsevier B.V. All rights reserved.)

The interonium distance plays a major role in neuromuscular blocking activity of bis-quaternary ammonium compounds. In this study we tried to alter the distance between two quaternary nitrogens in some of the steroidal derivatives synthesized and evaluated them for neuromuscular blocking activity using in vivo (in chicks) and in vitro models (rectus abdominus and chick biventer cervis muscle) for their mechanism of action. All the synthesized compounds have shown to possess good depolarizing, competitive neuromuscular blocking activity, particularly the 17-acetoxy derivative and the increase in the distance between two quaternary nitrogens decreased the activity.

Our previous studies have shown that early administration of vitamin E acetate (50 mg/kg, ip (VEA)) and methylcobalamin (500 microg/kg, ip (MCA)) for 30 days improved conduction velocity and neuropathic pain behavior. Here, we evaluated the effect of early co-administration of VEA and MCA (MVE) on thermal hyperlagesia (TH) and motor nerve conduction velocity (MNCV) in rats with sciatic nerve crush injury (SNCI). Fifteen days post-surgery, a reduction in paw withdrawal latency (PWL) was observed in untreated (UNTR) rats. However, latency improved in MVE-treated animals, comparable to the placebo. On day 15, a decrease in MNCV was observed in the UNTR group of animals, and this effect was not observed for the MVE and placebo groups of animals. The results of this study indicate that early exposure to MVE attenuates the progression of TH and improves MNCV in rats with SNCI.

The present study was performed to evaluate the cardioprotective effects and pharmacological characterization of newly synthesized β-adrenoreceptor antagonists 3-(3-tert-butylamino-2-hydroxypropoxy)-4-methoxybenzaldehyde (PP-36) in the rat model of coronary artery occlusion and reperfusion. Pre-ischemic administration (20 minutes before coronary occlusion) of PP-36 showed cardioprotective effects against ischemia/reperfusion injury in rats. PP-36 (6 mg kg(-1)) significantly reduced arrhythmia score (6.33 ± 0.55, P < 0.05), infarct size/left ventricle size (38.9 ± 3.2, P < 0.05) and no mortality compared to vehicle-treated control group (14.17 ± 1.83, 44.9 ± 4.6 and 17% respectively). In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations, were carried out to investigate the potency of PP-36 towards different β-adrenoceptor subtypes. pA2/pKB values of PP-36 for β1-β2-and β3-adrenoceptors were 6.904 ± 0.190, 6.44 ± 0.129 and 5.773 ± 0.129, respectively. In conclusion, PP-36 is a β-adrenoceptor antagonist possessing potent anti-arrhythmic and cardioprotective effects against ischemia/reperfusion injury in rats.

Aim of the Study: The aim of the study was to evaluate the antihyperglycaemic activity of aqueous (PPSB-AQE) and petroleum ether (PPSB-PEE) extract of stem bark Pongamia pinnata in alloxan induced diabetic mice., Materials and Methods: Diabetes was induced in mice by alloxan (80 mg/kg, i.v.). After acute and subacute treatment serum glucose was determined. OGTT was performed in PPSB-PEE pretreated animals., Results: PPSB-PEE (25, 50, 100, 200 and 400mg/kg) showed significant reduction in serum glucose level in acute and subacute studies. The antihyperglycaemic effects of PPSBPE (100, 200 and 400mg/kg) showed onset at 2h and peak effect at 6h and the effect was sustained until 24 th h with 400mg/kg. In subacute study, antihyperglycaemic effect was observed on 21st day. In PPSBPE treated mice the body weight was not reduced in contrast to that in vehicle group. In OGTT, increased glucose utilization was observed., Conclusions: It is concluded that PPSB-PEE but not PPSB-AQE showed antihyperglycaemic activity.

Argyreia speciosa commonly known as Vridha daraka in Sanskrit is one of the important plants used in indigenous system of medicine. The root is regarded as an alternative tonic and useful in the diseases of nervous system. To confirm the veracity of aforementioned claim, we have evaluated the anticonvulsant effect of the extract. In this investigation, the mice were pretreated with different doses of Argyreia speciosa extract (100, 200, 400 mg/kg) for 10 days and then, they were subjected to either pentylenetetrazole (80 mg/kg) or maximal electroshock seizures (50 mA, 0.2 s) treatment. The hydroalcoholic extract of Argyreia speciosa at the dose of 200 and 400 mg/kg significantly delayed the latency to the onset of first clonus as well as onset of death in unprotected mice and exhibited protection in 16.66% and 33.33% of pentylenetetrazole treated mice respectively. Whereas in case of maximal electroshock-seizures, the dose of 200 and 400 mg/kg significantly reduced the duration of hind limb extension and both the doses were statistically found to be equipotent. The reference standards, clonazepam (0.1 mg/kg) and phenytoin (20 mg/kg) provided complete protection. Thus, present study revealed anticonvulsant effect of Argyreia speciosa against pentylenetetrazole- and maximal electroshock-induced convulsions in mice.

Objectives: The objective of this study was to evaluate the acute and chronic diuretic effect of the ethanolic extract of the leaves of Cocculus hirsutus (L.) Diles., Methods: The ethanolic extract was administered (100, 200 and 400 mg/kg, p.o.) in Wistar rats. In the acute study, rats received drugs orally and urine was collected after 1, 2, 3, 4, 5 and 6 h. The chronic study involved repeated administration of ethanolic extract for 28 days and urine was collected on day 1, 7, 14, 21 and 28. The parameters were total urine volume, concentration of Na+, K+ and Cl- ions, creatinine in urine and serum. Urine output, electrolytes (Na+, K+ and Cl- ions) and creatinine were determined on day 7, 14, 21 and 28., Key Findings: The highest dose (400 mg/kg) of the ethanolic extract significantly (P < 0.01) enhanced urine output. Excretion of cations (Na+ and K+ ions) and anions (Cl- ions) increased significantly with respect to the control (gum acacia 2% dissolved in saline, 10 ml/kg) group. The increase of cations in the urine after treatment with ethanolic extract was dose dependent. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) did not significantly change the concentration of Na+, K+ and Cl- ions in serum. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) increased the excretion of creatinine in urine but with a corresponding decrease in serum., Conclusions: It was concluded that the ethanolic extract of the leaves of C. hirsutus (400 mg/kg) had significant diuretic effect in rats.

PP-24 is a newly synthesized putative beta-adrenoceptor antagonist. The objective of the study was to the evaluate beta-adrenoceptor blocking activity of PP-24 on isolated rat preparations: right atria, uterus and colon. Effects on the rat ECG and renal hypertension (induced by left renal artery ligation) were also investigated. Treatment with PP-24 (3 and 10 mg kg(-1)) for 7 days in rats with renal hypertension significantly reduced the mean atrial blood pressure. Single i.v. injections of isoprenaline (0.3, 1 and 3 microg kg(-1)) alone in normal anaesthetized rat caused hypotension and tachycardia, while PP-24 alone produced dose-dependent falls in mean aterial pressure and bradycardia. Pretreatment of anaesthetized rats with test compounds significantly blocked the hypotension response but not the tachycardia induced by isoprenaline (0.3, 1 and 3 microg kg(-1)). The pA(2) of PP-24 to beta(1)-, beta(2)- and beta(3)-adrenoceptors was 7.72 +/- 0.082, 7.40 +/- 0.082 and 6.39 +/- 0.16, respectively. The beta(1)/beta(2) selectivity ratio was 2.08, compared with 1.27 for propranolol and 39.17 for atenolol. It is concluded that PP-24 possesses beta-adrenoceptor blockade activity but with non-specific affinity for beta(1)- and beta(2)-adrenoceptor subtypes. The rank order of potency of the antagonists for beta(1)-adrenoceptors was atenolol > PP-24 > propranolol. The antihypertensive activity of PP-24 in rats with renal hypertension appears to be due to blockade of beta-adrenoceptors.

Insulin resistance and subsequent insulin secretory defect are two main features of type 2 diabetes and associated metabolic disorders. The animal models of type 2 diabetes are very complex and are as heterogeneous as the disease. We have evaluated the effect of various antidiabetic and lipid lowering agents (fenofibrate, rosiglitazone, glimepiride, metformin and simvastatin) on the metabolic abnormalities induced by combining a high-fat diet and multiple low-dose streptozocin (MLDS) in mice. Male Swiss albino mice were orally treated with the above agents and fed with a diet containing high fat for 28 days. On day 15 the animals were injected intraperitoneally with low-dose streptozocin (40 mg kg(-1)), which was administered for five consecutive days. At the end of the 28-day treatment plasma metabolic parameters (glucose, triglyceride and immunoreactive insulin) were estimated. The antidiabetic and hypolipidaemic agents exhibited differential effects on these metabolic parameters. With the exception of fenofibrate all these agents reduced the plasma glucose levels, and the effects of metformin and rosiglitazone on glucose were found to be statistically significant. Although the effect of the test drugs on cholesterol was modest, a significant decrease in triglyceride levels was observed with sub-chronic treatment with these agents. Interestingly, glimepiride mildly elevated the insulin levels while the other antidiabetics and hypolipidaemics reduced the insulin levels, with metformin and rosiglitazone exhibiting statistically significant effects on insulin. To our knowledge this is the first report on the effect of various peroxisome proliferator-activated receptor modulators and newer antidiabetics on the metabolic effects induced by the combined high-fat diet and MLDS model of type 2 diabetes in Swiss albino mice. The results suggested the complexity of the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia induced by the high-fat diet and MLDS mouse model, and their correction by various antidiabetics and antihyperlipidaemics may have involved diverse mechanisms.

Mushrooms are low calorie food with very little fat and are highly suitable for obese persons. With no starch and very low sugars, they are the 'delight of the diabetics'. Combination of herbal drugs (or isolated phytochemicals) is found to be beneficial in certain diseases when given along with conventional drugs. The aim of the present study was to evaluate the effects of aqueous extract of Pleurotus pulmonarius (Lentinaceae) (called as PP-aqu) and its interaction with glyburide in alloxan induced diabetic mice. The diabetic mice treated were with PP-aqu (500 mg/kg, p.o.) alone or combination with glyburide (10 mg/kg, p.o.) for 28 days. Blood samples were collected by orbital sinus puncture using heparinized capillary glass tubes and were analyzed for serum glucose on 0, 7th, 14th, 21st and 28th days. Body weights and mortality were noted during the study period. In oral glucose tolerance test (OGTT), glucose (2.5 g/kg, p.o.) was administered with either vehicle, PP-aqu alone or in combination with glyburide and serum glucose level analyzed at 0, 30, 60 and 120 min after drug administration. Administration of PP-aqu (500 mg/kg) and its combination with glyburide (10 mg/kg) significantly (P < 0.001) decreased serum glucose level in diabetic mice. In OGTT, glyburide or PP-aqu treatment alone or their combination produced significant (P < 0.001) increase in glucose threshold. Thus we suggest that P. pulmonarius showed potent and synergistic antihyperglycemic effect in combination with glyburide.

Sibutramine is one of the very few drugs that are approved for long-term treatment of obesity. Sibutramine is a racemic mixture (RS) containing two equal forms of the R(+) and S(-) enantiomers. In this paper, we have investigated comparative anorexic effect of sibutramine enantiomers and their recemate form in rats. After obtaining two days of baseline results, rats were administered orally either with (RS)-sibutramine or its enantiomers (R)- or (S)-sibutramine at dose levels of 5, 10, 20 mg/kg each for 4 days and body weight, food intake and water intake were measured daily. Locomotor activity score of each rat was also recorded on each day. R-Sibutramine and (RS)-sibutramine produced dose dependant decrease in the body weight and food intake. On the other hand, (S)-sibutramine was shown to increase in these parameters. Neither sibutramine nor it's enantiomers showed any consistent effects on spontaneous motor activity (SMA) scores. In conclusion, (R)-sibutramine is better anorexic than or (RS)-sibutramine or it's (S)-enantiomers.

Beta-adrenoceptor antagonists are widely used in cardiovascular medicine. However, the main side effect of these drugs is due to antagonism of beta(2)-adrenoceptors in the airways, resulting in bronchospasm. Therefore, more cardioselective beta-blockers have been developed to offer a lower side effect profile. We have studied a new aryloxypropanolamine derivative (PP-34) with more cardioselectivity and efficacy against ischaemia/reperfusion injury in rats. Oxalate salts of 1-(tert-butylamino)-3-(5-tert-butylaminomethyl-2-methoxyphenoxy) propan-2-ol (PP-34) is a novel beta-adrenoceptor antagonist. In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations were carried out to investigate the potency of PP-34 towards different beta-adrenoceptor subtypes. pA(2)/pK(B) values of PP-34 for beta(1), beta(2), and beta(3) adrenoceptor were 7.89+/-0.15, 6.13+/-0.09 and 6.30+/-0.19, respectively. The beta(1)/beta(2) selectivity ratio calculated was in the order of PP-34 > atenolol > propranolol. Pre-ischaemic administration (20 min before coronary occlusion) of PP-34 (0.3 or 1 mg kg(-1)) showed cardioprotective effects against ischaemia/reperfusion injury in rats and significantly reduced arrhythmias, infarct area and necrosis induced by ischaemia/reperfusion injury. The efficacy of PP-34 was found to be greater then atenolol. In conclusion, PP-34 is a cardioselective beta-adrenoceptor antagonist, possessing potent anti-arrhythmic and cardioprotective effects against ischaemia/reperfusion injury in rats.

The anti-diarrhoeal effect of aqueous and alcoholic extracts of Triphala and Triphala Mashi were studied employing castor oil-induced-diarrhoeal model in rats. The gastrointestinal transit rate was expressed as the percentage of the longest distance travelled by the charcoal divided by the total length of the small intestine. All the extracts, at various doses 200, 400 and 800 mg/kg displayed remarkable anti-diarrhoeal activity as evidenced by a significant increase in first defecation time, cumulative fecal weight and intestinal transit time. Aqueous and alcoholic extracts of Triphala and Triphala Mashi were considered safe up to a dose of 1750 mg/kg when evaluated for acute oral toxicity in accordance with the OECD (Organization for Economic Cooperation and Development) guidelines. In conclusion, the remarkable anti-diarrhoeal effect of Triphala and Triphala Mashi extracts against castor oil-induced diarrhoea suggest its potential for application in a wide range of diarrhoeal states.

Parkinson's disease (PD) is characterized clinically by resting tremor, rigidity, bradykinesia and postural instability due to progressive and selective loss of dopamine neurons in the ventral substantia nigra, with the presence of ubiquitinated protein deposits called Lewy bodies in the neurons. The pathoetiology of cell death in PD is incompletely understood and evidence implicates impaired mitochondrial complex I function, altered intracellular redox state, activation of proapoptotic factors and dysfunction of ubiquitinproteasome pathway. Now it is believed that genetic aberration, an environmental toxin or combination of both leads to a cascade of events culminating in the destruction of myelinated brainstem catecholaminergic neurons. Also the role of production of significant levels of abnormal proteins, which may misfold, aggregate and interfere with intracellular processes causing cytotoxicity has recently been hypothesized. In this article, the diverse pieces of evidence that have linked the various factors responsible for the pathophysiology of PD are reviewed with special emphasis to various candidate genes and proteins. Furthermore, the present therapeutic strategies and futuristic approaches for the pharmacotherapy of PD are critically discussed.

Aqueous extract of leaves of M. oleifera was investigated and rationalised for its wound healing activity. The aqueous extract was studied at dose level of 300 mg/kg body weight using resutured incision; excision and dead space wound models in rats. Significant increase in wound closure rate, skin-breaking strength, granuloma breaking strength, hydroxyproline content, granuloma dry weight and decrease in scar area was observed. The prohealing actions seem to be due to increased collagen deposition as well as better alignment and maturation. From the results obtained, it may be concluded that the aqueous extract of M. oleifera has significant wound healing property.

Abnormalities in glucose and lipid regulation have been reported in schizophrenia during antipsychotic medications. The objectives of the present study were to evaluate the effect of various peroxisome proliferator-activated receptor modulators viz. glimepiride, rosiglitazone and fenofibrate on chlorpromazine, clozapine and ziprasidone induced hyperglycemia and hyperlipidemia in mice. Male Swiss albino mice were orally treated with chlorpromazine, clozapine and ziprasidone concurrently with the antidiabetic medications for 7 days. Plasma glucose, insulin and triglyceride levels were determined at the end of the study. Chlorpromazine and clozapine elevated the glucose and triglyceride levels in normal mice, with no effect on insulin but ziprasidone increased the basal triglyceride and insulin levels and did not have any effect on glucose. Glimepiride and rosiglitazone showed beneficial glucose and triglyceride lowering effects in chlorpromazine and clozapine animals and no effect on insulin levels. Fenofibrate significantly reduced the glucose levels only in animals treated with clozapine, and exhibited significant reduction of triglyceride levels in chlorpromazine, clozapine and ziprasidone treated animals. All three antidiabetic/hypolipidemic agents lowered triglyceride and insulin levels in ziprasidone treated animals. The results of the present studies suggest that hyperglycemia, hyperinsulinemia and hypertriglyceridemia induced by various antipsychotics may involve diverse mechanisms.

Migraine is characterized by attacks of intense pulsatile and throbbing headache, typically unilateral in nature with or without aura. Migraine affects a substantial fraction (10-20 %) of the world population (more women than men). With regard to the pathophysiology of migraine, several theories have been proposed; the major three are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing) and neurogenic dural inflammation (release of inflammatory neuropeptides). The drugs used to treat migraine can be divided into two groups: agents that abolish the acute migraine headache and agents aimed at prevention. The acutely acting antimigraine agents (5-HT(1B/1D) receptor agonists) stimulated research interest in the field of migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT(2) receptor antagonists, beta-adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non-specific and not always effective. Despite progress, the complex etiology of migraine requires further research, the condition often remains undiagnosed and available therapies are underused. In this review, the evidence that linked the different theories of migraine with its pathophysiology is considered. Furthermore, the present therapeutic targets and future approaches for the acute and prophylactic treatment of migraine are critically evaluated.

A new class of 4'-methylbiphenyl-2-(substituted phenyl)carboxamide derivatives had been previously evaluated in vivo for their anti-inflammatory activities in animal models of inflammation. In the present study, the most active compound of that series, compound 4e (4'-methylbiphenyl-2-(4-carboxy phenyl)carboxamide), was investigated in detail for its anti-inflammatory, analgesic and ulcerogenic potential. Pretreatment of rats with 4e (100 mg/kg) reduced carrageenan induced rat paw edema at 3 h compared to control group. Dose dependent percent inhibition of granuloma formation, exudate volume, total leukocyte count was observed in 4e (25, 50 and 100 mg/kg) and celecoxib (CAS 169590-42-5; 5 mg/kg) treated groups in the cotton pellet granuloma and granuloma pouch technique, respectively, in rats. C-reactive proteins were absent in the 4e treated group. Compound 4e inhibited acetic acid induced writhing dose dependently (10, 20 and 30 mg/kg). Compound 4e was inactive in the hot plate test. Gastric toxicity screening experiments showed that compound 4e, both after single and repeated oral administration, is devoid of any gastric irritation in rats. The LD50 was found to be more than 2000 mg/kg.

A simple and rapid high-performance thin-layer chromatographic (HPTLC) determination of lamotrigine (LTG) in serum is reported. The method involves extraction of the drug by ethyl acetate followed by separation on TLC silica plates using a mixture of toluene-acetone-ammonia (7:3:0.5), as eluting solvent. Densitometric analysis was carried out at 312 nm with lamotrigine being detected at Rf of 0.54. The analytical method has excellent linearity (r=0.998) in the range of 20-300 ng/spot. This assay range is adequate for analyzing human serum, as it corresponds to lamotrigine concentrations measured in human serum from epileptic patients. The method was validated for sensitivity, selectivity, extraction efficiency, accuracy and intra and inter-day reproducibility. The limit of detection and limit of quantification were found to be 6.4 and 10.2 ng, respectively. Good accuracy is reported in the range of 92.06-97.12% and high precision with %CV in range of 0.53-2.59. The method was applied for determination of serum lamotrigine levels in epileptic patients and in pharmacokinetic study of lamotrigine administered orally to rabbits.

A simple reversed-phase high-performance liquid chromatography (HPLC) method was developed for the simultaneous estimation of the antiepileptic drugs (AEDs) lamotrigine (LTG), phenobarbitone (PB), carbamazepine (CBZ) and phenytoin (PHT) in human serum. The procedure involves extraction of the AEDs by mixing 200 microl of serum with 200mul of acetonitrile containing 10 microg/ml of pentobarbitone as internal standard (IS). After centrifugation, 10 microl of the supernatant was injected onto a NOVA PAK C-18 column (250 mm x 4.6mm, 5 microm Hypersil ODS) and eluted with a mobile phase consisting of phosphate buffer (10 mM)-methanol-acetonitrile-acetone in the ratio of 55:22:12:11 (v/v) adjusted to pH 7.0. A UV detector set at 210 nm was employed for detection. The AEDs were well resolved from the human serum constituents and the internal standard. The method can quantify LTG, PB, CBZ, and PHT at concentrations as low as 0.2 microg/ml. The method was quantitatively evaluated in terms of linearity, accuracy, precision, recovery, selectivity, sensitivity, and specificity. The method is simple, convenient, and suitable for the analysis of AEDs from human serum.

Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia, phonophobia, nausea and vomiting. Migraine affects a substantial fraction of world population and is a major cause of disability in the work place. Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing which causes the spreading depression and migraine) and neurogenic dural inflammation (release of inflammatory neuropeptides). The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder. The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention. The last decade has witnessed the advent of Sumatriptan and the 'triptan' class of 5-HT1B/1D receptor agonists which have well established efficacy in treating migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta adrenoceptor blockers and gamma-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non specific and not always effective. Despite such progress, in view of the complexity of the etiology of migraine, it still remains undiagnosed and available therapies are underused. In this article, the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed. Furthermore, the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine, with a special emphasis to calcitonin gene-related peptide, are critically evaluated.

beta-Adrenoreceptor antagonistic activity of a newly synthesized compound was evaluated in vivo by measuring the mean arterial blood pressure and heart rate of urethane-anesthetized rats treated with isoprenaline. In vitro beta(1)-, beta(2)- and beta(3)-antagonism was studied using isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively, in comparison to isoprenaline response. DPJ 904 (1, 3 and 10 mg/kg, i.v.) produced dose-dependent hypotensive and bradycardia response in anesthetized rat. DPJ 904 (1, 3 and 10 mg/kg, i.v.) significantly inhibited both the tachycardial effects and hypotensive response induced by isoprenaline. DPJ 904-antagonized isoprenaline induced positive chronotropic effects of isolated rat right atria and a uterine relaxant effect indicating beta(1)- and beta(2)-blockade. The parallel shift to the right of the concentration-response curve of isoprenaline in the presence of DPJ 904 in KCl (30 mmol/l) induced contraction of the rat colon suggesting that DPJ 904 also possessed beta(3)-adrenoreceptor antagonistic activity. The selectivity to beta(1)-adrenoreceptor was nearly 20.5 times greater than to beta(2)-adrenoreceptor. The present study indicates that DPJ 904 possesses beta-adrenoreceptor antagonistic activity with slightly more affinity to the beta(1)-adrenoreceptor subtype., (Copyright (c) 2005 S. Karger AG, Basel)

The in-vivo beta-adrenoreceptor antagonistic activity of test compounds DPJ 955 and DPJ 890 was assessed against beta-adrenoreceptor agonist (isoprenaline) induced tachycardia in anaesthetized rats. The selectivity to block isoprenaline responses on different &beta-adrenoreceptor subtypes (beta(1), beta(2) and beta(3)) of the test compounds was carried out on isolated rat right atria, isolated rat uterus and isolated rat colon preparations, respectively. Intravenous injection of isoprenaline alone in anaesthetized rats caused hypotension and tachycardia. DPJ 955 or DPJ 890 alone produced a fall in mean arterial pressure and bradycardia in a dose-dependent manner. Administration of isoprenaline to anaesthetized rats pre-treated with test compounds significantly blocked both the tachycardial and hypotensive responses induced by isoprenaline. The test compounds shifted the concentration response curves of isoprenaline towards the right for isolated rat right atrial preparations, rat uterus and rat colon, indicating beta(1), beta(2) and beta(3) adrenoreceptor blockade, respectively. The selectivity ratio for beta(1)/beta-adrenoreceptors to DPJ 955 and DPJ 890 was 64.6 and 83.2, respectively. DPJ 890 was more potent in blocking beta(1)-adrenoreceptors and was more selective towards beta(1) receptors than to other beta-adrenoreceptor subtypes. In conclusion, DPJ 955 and DPJ890 have beta-adrenoreceptor blocking activity with high selectivity for the beta(1)-adrenoreceptor subtype.

The aqueous extract of pericarp of fruits of Sapindus trifoliatus (ST) Linn., family Sapindaceae was evaluated for its potential effects on central nervous system in mice. The extract at doses 20 and 100 mg/kg, i.p. significantly (p < 0.001) reduced the spontaneous locomotor activity and at 100 mg/kg, increased the thiopental-induced sleeping time. In rota-rod motor co-ordination test, ST at 100 mg/kg, i.p. significantly (p < 0.05-0.01) reduced the endurance time. Further ST exhibited no protection against maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced convulsions in mice. In receptor radioligand binding studies, ST exhibited affinity towards dopaminergic, alpha-adrenergic and muscarnic receptors. The findings suggest that, ST may possess principles with potential neuroleptic properties.

Phytotherapies have offered alternative sources of therapy for migraine and gained much importance in prophylactic treatment. Sapindus trifoliatus is a medium-sized deciduous tree growing wild in south India that belongs to the family Sapindaceae. The pericarp is reported for various medicinal properties. A thick aqueous solution of the pericarp is used for the treatment of hemicrania, hysteria or epilepsy in folklore medicine. We have investigated the antihyperalgesic effects of the lyophilized aqueous extract of S. trifoliatus in animal models predictive of experimental migraine models using morphine withdrawal-induced hyperalgesia on the hot-plate test and on 0.3% acetic acid-induced abdominal constrictions in adult male Swiss albino mice. The extract significantly (N = 10, P < 0.05) increased the licking latency in the hot-plate test when administered i.p. at 10 mg/kg (6.70 +/- 0.39 s in saline control vs 18.76 +/- 0.96 s in S. trifoliatus-treated animals) and significantly (N = 10, P < 0.001) reduced the abdominal constrictions when administered i.p. at 2 and 10 mg/kg (40.20 +/- 1.36 in saline control vs 30.20 +/- 1.33 and 23.00 +/- 0.98 for 2 and 10 mg/kg, i.p., respectively, in S. trifoliatus-treated animals). Furthermore, when administered i.p. at 20 and 100 mg/kg, the extract significantly (N = 10, P < 0.05) inhibited the apomorphine-induced climbing behavior in mice (climbing duration 15.75 +/- 5.0 min for saline control vs 11.4 +/- 1.28 and 3.9 +/- 1.71 min for 20 and 100 mg/kg, respectively, in S. trifoliatus-treated animals). In receptor radioligand-binding studies, the extract exhibited affinity towards D2 receptors. The findings suggest that dopamine D2 antagonism could be the mechanism involved in the antihyperalgesic activity of the aqueous extract of S. trifoliatus.

Phytotherapies have offered alternative sources of therapy for migraine and gained much importance in prophylactic treatment. The aqueous extract of pericarp of fruits of Sapindus trifoliatus Linn (ST), family Sapindaceae was evaluated for its affinity for 5-HT(1B/1D) receptors in rabbit saphenous vein, alpha-adrenoceptors in rabbit aorta, GABA receptors in guinea pig ileum, 5-HT(2B) receptors in rat fundus and vanilloid receptors in guinea pig trachea. The calcium blocking effect was studied in rabbit aorta while the modulatory role of ST on platelet serotonin release was evaluated in human platelets. The aqueous extract of Sapindus trifoliatus exhibited significant 5-HT(2B) receptor inhibition and moderate platelet serotonin release inhibition.

The effect of the aqueous extract of Sapindus trifoliatus (ST) on chemical, thermal-induced pain, nitroglycerin-induced hyperalgesia and pain on inflamed tissue was investigated. The extract (20 and 100 mg x kg(-1), i.p.) significantly inhibited acetic-acid-induced abdominal constrictions, formalin-induced pain licking and hotplate-induced pain in mice. Furthermore, the extract significantly increased the response latencies of nitroglycerin-induced hyperalgesia by the tail-flick method and mechanical pain on carrageenan-induced inflamed paw in rats. The data suggest that ST has an inhibitory activity on both peripheral and central pain mechanisms and has a modulatory role in NO-mediated nociceptive transmission.

The compounds 1-isopropylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (5) and 1-tert-butylamino-3-(2-isopropyl-5-methyl-phenoxy)-propan-2-ol oxalate (6) were synthesized from thymol (1), a naturally occurring agent in Thymus vulgaris L. Pharmacological evaluation of 5 and 6 were carried out using mouse ECG and isolated rat uterus models. Pretreatment of 5 (100 microg/kg, i.v.) and 6 (50 microg/kg, i.v.) antagonized isoprenaline (2 microg/kg, i.v.) induced tachycardia, similar to that of atenolol (CAS 29122-68-7, 20 microg/kg, i.v.) pretreatment in mouse ECG experiments as measured by R-R interval. Pretreatment of 5 and 6 blocked isoprenaline and adrenaline induced relaxation of isolated rat uterus (unprimed). Also the compounds 5 and 6 were subjected to in vitro beta1- and beta2-adrenergic receptor binding assay using turkey erythrocyte membrane (beta1) and lung homogenate of rats (beta2). Both 5 and 6 showed beta-adrenergic receptor affinity comparable with that of propranolol (propranolol hydrochloride, CAS 318-98-9) with out selectivity to any one beta-adrenergic receptor. These results suggest that both the compounds possess non-selective beta-adrenergic blocking activity, with the tert-butyl derivative 6 being more active than the isopropyl derivative 5.

The synthesis of 2-substituted-N-(2-diethylaminoethyl)acetamide oxalates (6a, 6b) and the evaluation of their in vivo local anaesthetic activities are described. The compounds 6a and 6b were obtained starting from 4-acetamidophenol and 1-naphthol, respectively. The in vivo local anesthetic activity was evaluated by infiltration anaesthesia, sciatic nerve block and corneal anaesthesia models. N-(2-Diethylaminoethyl)-2-(naphthalen-1-yloxy)acetamide oxalate (6b) was found to have potency, onset and duration of action comparable to that of lidocaine (2) (lidocaine hydrochloride, CAS 6108-05-0). Procaine (1) (procaine hydrochloride, CAS 51-05-8) was also used for comparison. Dissociation constants (pKa) of compounds 5a and 5b (2-substituted-N-(2-diethylaminoethyl)acetamide) have been determined to be 8.9 and 8.6, respectively.

Bacillus thuringiensis var. kenyae (B.t.k.) is a microbial insecticide effective against lepidopteran pest species. Acute oral toxicity in rats and acute dermal toxicity, ocular irritation, skin irritation in rabbits were studied for the wettable powder formulation of B.t.k. In addition, toxicity of the wettable powder formulation was also studied in fresh water fish (Gambussia affinis). The results of these studies indicate that this wettable powder formulation of B.t.k. is nontoxic and nonirritant to rats, rabbits, and fish.