Current Issue : July - September Volume : 2014 Issue Number : 3 Articles : 6 Articles
The ability to deliver drug molecules effectively\nacross the bloodââ?¬â??brain barrier into the brain is\nimportant in the development of central nervous system\n(CNS) therapies. Cerebral microdialysis is the only existing\ntechnique for sampling molecules from the brain extracellular\nfluid (ECF; also termed interstitial fluid), the\ncompartment to which the astrocytes and neurones are\ndirectly exposed. Plasma levels of drugs are often poor\npredictors of CNS activity. While cerebrospinal fluid (CSF)\nlevels of drugs are often used as evidence of delivery of\ndrug to brain, the CSF is a different compartment to the\nECF. The continuous nature of microdialysis sampling of\nthe ECF is ideal for pharmacokinetic (PK) studies, and can\ngive valuable PK information of variations with time in\ndrug concentrations of brain ECF versus plasma. The\nmicrodialysis technique needs careful calibration for relative\nrecovery (extraction efficiency) of the drug if absolute\nquantification is required. Besides the drug, other molecules\ncan be analysed in the microdialysates for information\non downstream targets and/or energy metabolism in\nthe brain. Cerebral microdialysis is an invasive technique,\nso is only useable in patients requiring neurocritical care,\nneurosurgery or brain biopsy. Application of results to \nwider patient populations, and to those with different\npathologies or degrees of pathology, obviously demands\ncaution. Nevertheless, microdialysis data can provide\nvaluable guidelines for designing CNS therapies, and\nplay an important role in small phase II clinical trials. In\nthis review, we focus on the role of cerebral microdialysis\nin recent clinical studies of antimicrobial agents,\ndrugs for tumour therapy, neuroprotective agents and\nanticonvulsants....
This study was undertaken to assess the in vitro dissolution and in vivo bioavailability of six brands of ciprofloxacin oral tablets\navailable in the UAE market using rabbits. The in vitro dissolution profiles of the six ciprofloxacin products were determined using\nthe USP dissolution paddle method. Pharmacokinetic modeling using compartmental and noncompartmental analysis was done\nto determine the pharmacokinetic parameters of ciprofloxacin after single-dose oral administration. In vitro release study revealed\nthat the amount of ciprofloxacin released in 20 minutes was not less than 80% of the labeled amount which is in accordance\nwith the pharmacopoeial requirements. All tested products are considered to be very rapid dissolving except for formulae A and\nD. Ciprofloxacin plasma concentration in rabbits was best fitted to a two-compartment open model. The lowest bioavailability\nwas determined to be for product A (93.24%) while the highest bioavailability was determined to be for product E (108.01%).\nPostmarketing surveillance is very crucial to ensure product quality and eliminating substandard products to be distributed and,\nconsequently, ensure better patient clinical outcome. The tested ciprofloxacin generic products distributed in the UAE market were\nproven to be of good quality and could be used interchangeably with the branded ciprofloxacin product....
Background: The prevalence of childhood obesity and insulin resistance is rising, increasing the risk of diabetes\nmellitus type 2. To prevent these complications, lifestyle intervention is the corner stone in treatment. However,\nlong-term efficacy of lifestyle intervention is questionable. In addition to lifestyle intervention, pharmacological\ntreatments have been explored. Metformin has been shown to be moderately effective to reduce BMI in obese\nadolescents with hyperinsulinemia. However, data on pharmacokinetics and long-term efficacy and safety are\nlacking as well as an evidence-based dosing regimen for this age group. The primary objective of the METFORMIN\nstudy is to determine the effect of adding metformin treatment to lifestyle intervention in reducing BMI in obese\nadolescents with insulin resistance. In addition, the pharmacokinetics of metformin in obese adolescents will be studied.\nMethods/design: The METFORMIN study is a multi-centre prospective study that consists of two 18-month phases: a\ndouble-blind randomized placebo-controlled trial (part 1) and an open-label follow-up study (part 2). During part 1, the\nparticipants will be given metformin 1,000 mg or placebo twice daily and will be offered a lifestyle intervention\nprogramme; 144 participants will be included, 72 in each arm. Primary endpoints are reduction in body mass index,\ninsulin resistance, and percentage body fat.\nDiscussion: This study will provide data on short- a...
Background: Fluralaner is a novel systemic insecticide and acaricide. The purpose of these studies was to\r\ninvestigate the pharmacokinetic properties of fluralaner in Beagle dogs following single oral or intravenous\r\n(i.v.) administration.\r\nMethods: Following the oral administration of 12.5, 25 or 50 mg fluralaner/kg body weight (BW), formulated as\r\nchewable tablets or i.v. administration of 12.5 mg fluralaner/kg BW, formulated as i.v. solution to 24 Beagles, plasma\r\nsamples were collected until 112 days after treatment. Plasma concentrations of fluralaner were measured using\r\nHPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods.\r\nResults: After oral administration, maximum plasma concentrations (Cmax) were reached within 1 day on average.\r\nFluralaner was quantifiable in plasma for up to 112 days after single oral and i.v. treatment. The apparent half-life\r\nof fluralaner was 12ââ?¬â??15 days and the mean residence time was 15ââ?¬â??20 days. The apparent volume of distribution of\r\nfluralaner was 3.1 L/kg, and clearance was 0.14 L/kg/day.\r\nConclusions: Fluralaner is readily absorbed after single-dose oral administration, and has a long elimination half-life,\r\nlong mean residence time, relatively high apparent volume of distribution, and low clearance. These pharmacokinetic\r\ncharacteristics help to explain the prolonged activity of fluralaner against fleas and ticks on dogs after a single oral dose....
In the development of central nervous system\n(CNS)-targeted drugs, the prediction of human CNS target\nexposure is a big challenge. Cerebrospinal fluid (CSF) concentrations\nhave often been suggested as a ââ?¬Ë?good enoughââ?¬â?¢\nsurrogate for brain extracellular fluid (brainECF, brain target\nsite) concentrations in humans. However, brain anatomy and\nphysiology indicates prudence. We have applied a multiple\nmicrodialysis probe approach in rats, for continuous measurement\nand direct comparison of quinidine kinetics in brainECF,\nCSF, and plasma. The data obtained indicated important differences\nbetween brainECF and CSF kinetics, with brainECF\nkinetics being most sensitive to P-gp inhibition. To describe the\ndata we developed a systems-based pharmacokinetic model.\nOur findings indicated that: (1) brainECF- and CSF-to-unbound\nplasma AUC0ââ?¬â??360 ratios were all over 100 %; (2) P-gp also\nrestricts brain intracellular exposure; (3) a direct transport route\nof quinidine from plasma to brain cells exists; (4) P-gp-mediated\nefflux of quinidine at the bloodââ?¬â??brain barrier seems to\nresult of combined efflux enhancement and influx hindrance;\n(5) P-gp at the bloodââ?¬â??CSF barrier either functions as an efflux\ntransporter or is not functioning at all. It is concluded that in\nparallel obtained data on unbound brainECF, CSF and plasma\nconcentrations, under dynamic conditions, is a complex but\nmost valid approach to reveal the mechanisms underlying the\nrelationship between brainECF and CSF concentrations. This\nrelationship is significantly influenced by activity of P-gp.\nTherefore, information on functionality of P-gp is required for\nthe prediction of human brain target site concentrations of P-gp\nsubstrates on the basis of human CSF concentrations....
The objective of this work was to facilitate the\ndevelopment of nonlinear mixed effects models by establishing\na diagnostic method for evaluation of stochastic\nmodel components. The random effects investigated were\nbetween subject, between occasion and residual variability.\nThe method was based on a first-order conditional estimates\nlinear approximation and evaluated on three real\ndatasets with previously developed population pharmacokinetic\nmodels. The results were assessed based on the\nagreement in difference in objective function value\nbetween a basic model and extended models for the standard\nnonlinear and linearized approach respectively. The\nlinearization was found to accurately identify significant\nextensions of the modelââ?¬â?¢s stochastic components with\nnotably decreased runtimes as compared to the standard\nnonlinear analysis. The observed gain in runtimes varied\nbetween four to more than 50-fold and the largest gains\nwere seen for models with originally long runtimes. This\nmethod may be especially useful as a screening tool to\ndetect correlations between random effects since it substantially\nquickens the estimation of large varianceââ?¬â??\ncovariance blocks. To expedite the application of this\ndiagnostic tool, the linearization procedure has been automated\nand implemented in the software package PsN....
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