Current Issue : April - June Volume : 2012 Issue Number : 2 Articles : 8 Articles
Various a2,3 subtype selective partial GABA-A agonists are in development to treat anxiety disorders. These compounds are\r\nexpected to be anxiolytic with fewer undesirable side effects, compared to nonselective GABA-A agonists like benzodiazepines.\r\nSeveral a2,3 subtype selective and nonselective GABA-A agonists have been examined in healthy volunteers, using a battery\r\naddressing different brain domains. Data from five placebo-controlled double-blind studies were pooled. Lorazepam 2mg was\r\nthe comparator in three studies. Three a2,3-selective GABAA agonists (i.e., TPA023, TPACMP2, SL65.1498), one a1-selective\r\nGABAA agonists (zolpidem), and another full agonist (alprazolam) were examined. Pharmacological selectivity was assessed by\r\ndetermination of regression lines for the change from baseline of saccadic-peak-velocity- (?SPV-) relative effect, relative to changes\r\nin different pharmacodynamic endpoints (?PD). SPV was chosen for its sensitivity to the anxiolysis of benzodiazepines. Slopes\r\nof the ?SPV-?PD relations were consistently lower with the a2,3 selective GABA-A agonists than with lorazepam, indicating that\r\ntheir PD effects are less than their SPV-effects. The ?SPV-?PD relations of lorazepam were comparable to alprazolam. Zolpidem\r\nshowed relatively higher impairments in ?PD relative to ?SPV, but did not significantly differ from lorazepam. These PD results\r\nsupport the pharmacological selectivity of the a2,3-selective GABA-A agonists, implying an improved therapeutic window....
Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD.\nCopper promotes the non-amyloidogenic processing of APP and thereby lowers the A�Ÿ production in cell culture systems, and\nit increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients,\nthe decline of A�Ÿ levels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day), indicating a\nbeneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at\nnormalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in\nmetal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically....
We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet\r\ncontaining tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing\r\nwith TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting\r\nstate. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug\r\nconcentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios\r\n(GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for\r\nCmax, AUC0-24, and C24 were 1.47 (1.24ââ?¬â??1.75), 1.13 (1.03ââ?¬â??1.23), and 1.01 (0.91ââ?¬â??1.11), respectively. Corresponding GMRs were\r\n1.04 (0.84ââ?¬â??1.27), 1.19 (1.10ââ?¬â??1.29), and 0.99 (0.82ââ?¬â??1.19) for tenofovir, 0.83 (0.76ââ?¬â??0.92), 0.87 (0.78ââ?¬â??0.97), and 0.91 (0.73ââ?¬â??1.14) for\r\nemtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients\r\nexperiencing central nervous system toxicities....
The objective of proposed work was to develop, formulate and evaluate bi-layer tablet containing Metoprolol succinate as extended release form and Ramipril as immediate release form. Acting by different mechanisms, metoprolol succinate and ramipril in combination would produce an additive antihypertensive effect. Although an enhanced antihypertensive effect can be obtained by using a larger dose of a single drug, this may increase the incidence of side effects. Using low doses of the two drugs in combination would achieve better reduction in BP without compromising tolerability. Both extended release and immediate release part were formulated by wet granulation method. The granules were evaluated and compressed by using Bilayer compression machine. The prepared bilayer tablets were evaluated and in vitro dissolution test was carried out separately for Ramipril and Metoprolol succinate. Different formulations were developed for Metoprolol succinate and Ramipril separately, based on trial and error basis and evaluated. The optimized formulation was found to be comparable in drug release profile as per USP 2007 in case of metoprolol succinate layer and as per IP 2007 in case of ramipril layer. A broad range of drug release pattern could be achieved by varying polymer ratio in extended release part; binder and disintegrant ratio in immediate release part. Utilizing the experimental design concept, an effective formulation has been developed with extended release Metoprolol succinate and immediate release Ramipril in the form of Bilayer tablet to optimize therapy of Hypertension and Myocardial Infarction....
The characteristics of aristolochic acid nephropathy (AAN) are interstitial fibrosis and atrophy of the proximal tubules, but with\r\nno change in glomeruli. To investigate the effects of AA on renal functions and the pharmacokinetics (PKs) of p-aminohippuric\r\nacid (PAH) and inulin, New Zealand white rabbits were used in this study. The plasma concentrations of PAH and inulin were\r\ndetermined by validated HPLC methods. After a single intravenous administration of 0.5 mg/kg aristolochic acid sodium (AANa),\r\nrabbits exhibited mild to moderate nephrotoxicity on the 7th day. Significant tubulointerstitial damage to kidney specimens\r\nwas found, but there were no remarkable glomerular changes. Clearance rates of PAH and inulin both significantly decreased\r\nin AANa-treated rabbits. In addition, there was a significant correlation among the degree of tubulointerstitial changes and PK\r\nparameters of PAH after AANa administration, but no correlation was noted with the PKs of inulin.With mild to moderate AAN\r\nin rabbits, the renal plasma flow significantly decreased by 55%, and the glomerular filtration rate also significantly decreased by\r\n85%. In conclusion, major renal lesions were found on proximal tubules after AANa administration. The PKs of PAH and inulin\r\nsignificantly changed, and kidney functions, including the RPF and GFR, were reduced....
We illustrated the development of a simple pharmacokinetic (SPK) model aiming to estimate the absorbed chlorpyrifos doses\r\nusing urinary biomarker data, 3,5,6-trichlorpyridinol as the model input. The effectiveness of the SPK model in the pesticide\r\nrisk assessment was evaluated by comparing dose estimates using different urinary composite data. The dose estimates resulting\r\nfrom the first morning voids appeared to be lower than but not significantly different to those using before bedtime, lunch or\r\ndinner voids.We found similar trend for dose estimates using three different urinary composite data. However, the dose estimates\r\nusing the SPK model for individual children were significantly higher than those from the conventional physiologically based\r\npharmacokinetic (PBPK) modeling using aggregate environmental measurements of chlorpyrifos as the model inputs. The use of\r\nurinary data in the SPK model intuitively provided a plausible alternative to the conventional PBPK model in reconstructing the\r\nabsorbed chlorpyrifos dose....
The essential oil extracted from the seeds of dill (Anethum graveolens L.) was demonstrated in this study as a potential source of an eco-friendly antifungal agent. To elucidate the mechanism of the antifungal action further, the effect of the essential oil on the plasma membrane and mitochondria of Aspergillus flavus was investigated. The lesion in the plasma membrane was detected through flow cytometry and further verified through the inhibition of ergosterol synthesis. The essential oil caused morphological changes in the cells of A. flavus and a reduction in the ergosterol quantity. Moreover, mitochondrial membrane potential (MMP), acidification of external medium, and mitochondrial ATPase and dehydrogenase activities were detected. The reactive oxygen species (ROS) accumulation was also examined through fluorometric assay. Exposure to dill oil resulted in an elevation of MMP, and in the suppression of the glucose-induced decrease in external pH at 4 �µl/ml. Decreased ATPase and dehydrogenase activities in A. flavus cells were also observed in a dose-dependent manner. The above dysfunctions of the mitochondria caused ROS accumulation in A. flavus. A reduction in cell viability was prevented through the addition of L-cysteine, which indicates that ROS is an important mediator of the antifungal action of dill oil. In summary, the antifungal activity of dill oil results from its ability to disrupt the permeability barrier of the plasma membrane and from the mitochondrial dysfunction-induced ROS accumulation in A. flavus....
Bioavailability (BA) and bioequivalence (BE) studies play a major role in the drug development phase for both new drug products and their generic equivalents, and thus attract considerable attention globally. BE is a strategy to introduce generic equivalents of brand-name drugs (innovator drugs) to lower the cost of medication through proper assessment as directed by the international regulatory authorities. There are several approaches to assess BE and each regulatory authority has its own regulations/guidance for conducting BA/BE studies before approving generic products for marketing in their country. Therefore, a thorough understanding is required of these BA/BE concepts and basic regulatory considerations for conducting BA/BE studies. This article briefly reviews the BA/BE concepts, approaches, designs, and various basic regulatory considerations and prospects for conducting BA/BE studies....
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