Current Issue : October - December Volume : 2013 Issue Number : 4 Articles : 6 Articles
Background: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents\r\ntreated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes.\r\nMethods: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day.\r\nAnakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions.\r\nThe data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix.\r\nResults: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic\r\nevaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics.\r\nTaking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F)\r\nsignificantly reduced the associated between-subject and between-occasion variabilities. The final estimates were\r\n6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the\r\nCRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline\r\nand large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP\r\nlevels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for\r\nwhich the development of a resistance to treatment was significant was 62% and the corresponding time was\r\napproximately 60 days.\r\nConclusions: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css\r\ntarget in order to obtain a CRP decrease to 10 mg/L or below....
Purpose: Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest\r\nduring the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity\r\nproperties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP).\r\nMaterial from some of the plant sources are currently employed in African Traditional Medicine.\r\nMethods: Computer-based methods are slowly gaining ground in this area and are often used as preliminary\r\ncriteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable\r\nlevels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug.\r\nIn the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library\r\ncontaining ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin\r\nforests and savannas, which have been published in the literature. In this analysis, we have used 46 computed\r\nphysico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and\r\nelimination and toxicity (ADMET) of the compounds.\r\nResults: This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are\r\ncompliant, having properties which fall within the range of ADME properties of 95% of currently known drugs,\r\nwhile about 69% of the compounds have = 2 violations. Moreover, about 73% of the compounds within the\r\ncorresponding ââ?¬Å?drug-likeââ?¬Â subset showed compliance.\r\nConclusions: In addition to the verified levels of ââ?¬Å?drug-likenessââ?¬Â, diversity and the wide range of measured\r\nbiological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and\r\nhence could represent an important starting point for hit/lead discovery...
Ezetimibe belongs to BCS class II drug and selectively inhibits the selection of cholesterol and related phytosterols. The tablets of ezetimibe are prepared by direct compression with different disintegrants and lubricates. Influence of disintegrants and lubricants on dissolution rate of the drug was studied. Various physical parameters like weight variation, friability, hardness, drug content, disintegration time, wetting time were also studied and dissolution parameters such as dissolution rate constant, and dissolution efficiency were calculated from the dissolution data. Most of the tablets complied with the pharmacopeial standards. In vitro dissolution studies were carried out in 500ml of 0.45% SLS in 0.05M acetate buffer as dissolution medium. Among all the super disintegrants, sodium starch glycolate showed a greater release and the tablets formulated with the lubricant PEG4000 showed a higher release compared to the tablets formulated with other lubricants....
In India, Ayurveda has made a major contribution in drug discovery process with new means of identification of active compounds. Recent advancement in bioavailability enhancement of drugs by compounds of herbal origin has developed a revolutionary shift in the field of therapeutics. Herbal bio-enhancers have been shown to enhance bioavailability and bio-efficacy of different classes of drugs, such as antibiotics, anti-tuberculosis, antiviral, antifungal, and anti-cancerous drugs at low doses. They have also improved oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds. These molecules enhance the systemic availability of drugs through various possible mechanisms but this paper emphasizes on the two major mechanisms such as inhibition of drug metabolizing cytochrome enzymes and P-glycoprotein efflux pump which have not been described in detail earlier as reviewed through literature. Further this review clearly indicates that scientific researchers and pharmaceutical industries have to give emphasis on experimental studies to find out novel active constituents from such a vast array of unexploited plants having a role as a bioavailability and bio-efficacy enhancer....
Unlike traditional anticoagulants, the more recently developed agents rivaroxaban, dabigatran and apixaban target\r\nspecific factors in the coagulation cascade to attenuate thrombosis. Rivaroxaban and apixaban directly inhibit Factor\r\nXa, whereas dabigatran directly inhibits thrombin. All three drugs exhibit predictable pharmacokinetic and\r\npharmacodynamic characteristics that allow for fixed oral doses in a variety of settings. The population\r\npharmacokinetics of rivaroxaban, and also dabigatran, have been evaluated in a series of models using patient data\r\nfrom phase II and III clinical studies. These models point towards a consistent pharmacokinetic and\r\npharmacodynamic profile, even when extreme demographic factors are taken into account, meaning that doses\r\nrarely need to be adjusted. The exception is in certain patients with renal impairment, for whom pharmacokinetic\r\nmodelling provided the rationale for reduced doses as part of some regimens. Although not routinely required, the\r\nability to measure plasma concentrations of these agents could be advantageous in emergency situations, such as\r\noverdose. Specific pharmacokinetic and pharmacodynamic characteristics must be taken into account when\r\nselecting an appropriate assay for monitoring. The anti-Factor Xa chromogenic assays now available are likely to\r\nprovide the most appropriate means of determining plasma concentrations of rivaroxaban and apixaban, and\r\nspecific assays for dabigatran are in development....
Background: The sodium-dependent glucose co-transporter-2 (SGLT2) is expressed in absorptive epithelia of the\r\nrenal tubules. Remogliflozin etabonate (RE) is the prodrug of remogliflozin, the active entity that inhibits SGLT2. An\r\ninhibitor of this pathway would enhance urinary glucose excretion (UGE), and potentially improve plasma glucose\r\nconcentrations in diabetic patients. RE is intended for use for the treatment of type 2 diabetes mellitus (T2DM) as\r\nmonotherapy and in combination with existing therapies. Metformin, a dimethylbiguanide, is an effective oral\r\nantihyperglycemic agent widely used for the treatment of T2DM.\r\nMethods: This was a randomized, open-label, repeat-dose, two-sequence, cross-over study in 13 subjects with\r\nT2DM. Subjects were randomized to one of two treatment sequences in which they received either metformin\r\nalone, RE alone, or both over three, 3-day treatment periods separated by two non-treatment intervals of variable\r\nduration. On the evening before each treatment period, subjects were admitted and confined to the clinical site for\r\nthe duration of the 3-day treatment period. Pharmacokinetic, pharmacodynamic (urine glucose and fasting plasma\r\nglucose), and safety (adverse events, vital signs, ECG, clinical laboratory parameters including lactic acid)\r\nassessments were performed at check-in and throughout the treatment periods. Pharmacokinetic sampling\r\noccurred on Day 3 of each treatment period.\r\nResults: This study demonstrated the lack of effect of RE on steady state metformin pharmacokinetics. Metformin\r\ndid not affect the AUC of RE, remogliflozin, or its active metabolite, GSK279782, although Cmax values were slightly\r\nlower for remogliflozin and its metabolite after co-administration with metformin compared with administration of\r\nRE alone. Metformin did not alter the pharmacodynamic effects (UGE) of RE. Concomitant administration of\r\nmetformin and RE was well tolerated with minimal hypoglycemia, no serious adverse events, and no increase in\r\nlactic acid.\r\nConclusions: Coadministration of metformin and RE was well tolerated in this study. The results support continued\r\ndevelopment of RE as a treatment for T2DM....
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