Current Issue : January - March Volume : 2011 Issue Number : 1 Articles : 7 Articles
Background: Increased functionality of efflux transporters at the blood-brain barrier may contribute to decreased\r\ndrug concentrations at the target site in CNS diseases like epilepsy. In the rat, pharmacoresistant epilepsy can be\r\nmimicked by inducing status epilepticus by intraperitoneal injection of kainate, which leads to development of\r\nspontaneous seizures after 3 weeks to 3 months. The aim of this study was to investigate potential changes in Pglycoprotein\r\n(P-gp) expression and functionality at an early stage after induction of status epilepticus by kainate.\r\nMethods: (R)-[11C]verapamil, which is currently the most frequently used positron emission tomography (PET)\r\nligand for determining P-gp functionality at the blood-brain barrier, was used in kainate and saline (control) treated\r\nrats, at 7 days after treatment. To investigate the effect of P-gp on (R)-[11C]verapamil brain distribution, both groups\r\nwere studied without or with co-administration of the P-gp inhibitor tariquidar. P-gp expression was determined\r\nusing immunohistochemistry in post mortem brains. (R)-[11C]verapamil kinetics were analyzed with approaches\r\ncommon in PET research (Logan analysis, and compartmental modelling of individual profiles) as well as by\r\npopulation mixed effects modelling (NONMEM).\r\nResults: All data analysis approaches indicated only modest differences in brain distribution of (R)-[11C]verapamil\r\nbetween saline and kainate treated rats, while tariquidar treatment in both groups resulted in a more than 10-fold\r\nincrease. NONMEM provided most precise parameter estimates. P-gp expression was found to be similar for kainate\r\nand saline treated rats.\r\nConclusions: P-gp expression and functionality does not seem to change at early stage after induction of\r\nanticipated pharmacoresistant epilepsy by kainate....
Drug hypersensitivity reactions are a serious problem in the management of the HIV-positive patient, and antiretroviral drugs are currently the main cause of these reactions. We report a case of cutaneous hypersensitivity associated with a new protease inhibitor Darunavir. Patient had a maculopapular rash and fever after the second dose of the antiretroviral. After withdrawal of the drug and use of hydrocortisone, the patient had a good outcome, being released in good general condition after 3 days of hospitalization....
Background: Acid-sensing ion channels (ASICs) have a significant role in the sensation of pain and constitute an\r\nimportant target for the search of new antinociceptive drugs. In this work we studied the antinociceptive\r\nproperties of the BM-21 extract, obtained from the sea grass Thalassia testudinum, in chemical and thermal models\r\nof nociception in mice. The action of the BM-21 extract and the major phenolic component isolated from this\r\nextract, a sulphated flavone glycoside named thalassiolin B, was studied in the chemical nociception test and in\r\nthe ASIC currents of the dorsal root ganglion (DRG) neurons obtained from Wistar rats.\r\nResults: Behavioral antinociceptive experiments were made on male OF-1 mice. Single oral administration of\r\nBM-21 produced a significant inhibition of chemical nociception caused by acetic acid and formalin (specifically\r\nduring its second phase), and increased the reaction time in the hot plate test. Thalassiolin B reduced the licking\r\nbehavior during both the phasic and tonic phases in the formalin test. It was also found that BM-21 and thalassiolin B\r\nselectively inhibited the fast desensitizing (t < 400 ms) ASIC currents in DRG neurons obtained from Wistar rats, with\r\na nonsignificant action on ASIC currents with a slow desensitizing time-course. The action of thalassiolin B shows no\r\npH or voltage dependence nor is it modified by steady-state ASIC desensitization or voltage. The high concentration\r\nof thalassiolin B in the extract may account for the antinociceptive action of BM-21.\r\nConclusions: To our knowledge, this is the first report of an ASIC-current inhibitor derived of a marine-plant\r\nextract, and in a phenolic compound. The antinociceptive effects of BM-21 and thalassiolin B may be partially\r\nbecause of this action on the ASICs. That the active components of the extract are able to cross the blood-brain\r\nbarrier gives them an additional advantage for future uses as tools to study pain mechanisms with a potential\r\ntherapeutic application....
Background: Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major\r\ntherapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the\r\neffects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor a/g (PPARa/g) agonist, on both\r\nlipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.\r\nMethods: A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment\r\n(vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout\r\nperiod. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the\r\ndosing period, and at the end of the washout period.\r\nResults: Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average\r\nof 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein\r\ncholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein\r\ncholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved\r\ninsulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar\r\nat this dose (P = 0.043).\r\nConclusions: Aleglitazar, a dual PPARa/g agonist, has beneficial effects on both lipid and glucose parameters and\r\nmay have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients\r\nwith T2DM....
Group II metabotropic glutamate receptors (mGluRs) couple to the inhibitory G-protein Gi. The group II mGluRs\r\ninclude two subtypes, mGlu2 and mGlu3, and their pharmacological activation produces analgesic effects in\r\ninflammatory and neuropathic pain states. However, the specific contribution of each one of the two subtypes has\r\nnot been clarified due to the lack of selective orthosteric ligands that can discriminate between mGlu2 and mGlu3\r\nsubtypes.\r\nIn this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the\r\nendogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3\r\nreceptor agonists.\r\nOur results showed that mGlu2-/- mice display a significantly greater pain response compared to their wild type\r\nlittermates. Interestingly the increased pain sensitivity in mGlu2-/- mice occurred only in the second phase of the\r\nformalin test. No differences were observed in the first phase. In contrast, mGlu3-/- mice did not significantly differ\r\nfrom their wild type littermates in either phase of the formalin test.\r\nWhen systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a\r\nsignificant reduction of both phases in wild-type mice and in mGlu3-/- but not in mGlu2-/- mice. However tolerance\r\nto the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-/- mice developed following 5 consecutive days of\r\ninjection.\r\nTaken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors\r\nin the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely\r\nmediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of\r\nmGlu2/3 agonists develops despite the lack of mGlu3 receptors....
Background: Benign prosatic hyperplasia(BPH) is a major health problem world wide many herbal and synthetic drugs are used to treat our intention is to investigation of different doses of stearic acid and palmitic acid on testosterone induced prostatic hyperplasia in rats. Method: Animals were divided into seven groups (n=6). Group- I received vehicle served as negative control, Groups-II to Group-VII treated with subcutaneous testosterone (3 mg kg-1) injection for 14 days to induce prostatic hyperplasia(PH). Among six, one group served as positive control, and remaining 5 groups treated with low dose of steric acid (SA1) and, high dose of steric acid (SA2); low dose of palmitic acid (PA1), high dose of palmitic acid (PA2) and Finasteride (FT) groups. All drugs treatment given orally for period of 14 days. Rats were weighed before initiation and after completion of an experiment. Rats were sacrificed under light ether anaesthesia and isolated prostates were weighed and their Histopathological studies were carried out. Results: There was no change in body weight of rats before and after treatment. Both doses of steric acid and palmitic acid have significantly inhibited the elevation in prostate weight (PW) and PW to body weight (BW) ratio. As expected finasteride inhibited the elevation in prostate weight (PW) and PW to body weight (BW). Histopathological finding finasteride and both doses steric acid and palmitic acid showed protective effect against testosterone induced prostate cell growth. Conclusion: All doses of steric acid and palmitic acid showed protective against on testosterone induced prostatic hyperplasia in rats...
Background: An ever growing body of evidences is emerging concerning metabolism hormones,\r\nneurotransmitters or stress-related biomarkers as effective modulators of eating behavior and body weight in\r\nmammals. The present study sought at examining the density and affinity of two proteins related to\r\nneurotransmission and cell metabolism, the serotonin transporter SERT and the cholesterol import-benzodiazepine\r\nsite TSPO (translocator protein), in a rodent leptin-lacking mutant, the obese ob/ob mouse. Binding studies were\r\nthus carried out in brain or peripheral tissues, blood platelets (SERT) and kidneys (TSPO), of ob/ob and WT mice\r\nsupplied with a standard diet, using the selective radiochemical ligands [3H]-paroxetine and [3H]-PK11195.\r\nResults: We observed comparable SERT number or affinity in brain and platelets of ob/ob and WT mice, whilst a\r\nsignificantly higher [3H]-PK11195 density was reported in the brain of ob/ob animals. TSPO binding parameters\r\nwere similar in the kidneys of all tested mice. By [3H]-PK11195 autoradiography of coronal hypothalamichippocampal\r\nsections, an increased TSPO signal was detected in the dentate gyrus (hippocampus) and choroids\r\nplexus of ob/ob mice, without appreciable changes in the cortex or hypothalamic-thalamic regions.\r\nConclusions: These findings show that TSPO expression is up-regulated in cerebral regions of ob/ob leptindeficient\r\nmice, suggesting a role of the translocator protein in leptin-dependent CNS trophism and metabolism.\r\nUnchanged SERT in mutant mice is discussed herein in the context of previous literature as the forerunner to a\r\ndeeper biochemical investigation....
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