Current Issue : January - March Volume : 2014 Issue Number : 1 Articles : 6 Articles
Alprazolam immediate release (IR) tablets are currently approved for the management of anxiety disorder or \r\nthe short-term relief of symptoms of anxiety. A sublingual (SL) formulation of alprazolam, which disintegrates in \r\nthe mouth without the need for additional fluids, has been developed. The aim of this study was to determine if the \r\nalprazolam SL 1 mg tablet was bioequivalent to the alprazolam IR 1 mg tablet in healthy volunteers.\r\nIn this randomized, open label, two-way crossover, single dose study, subjects were randomized to receive a \r\nsingle alprazolam 1 mg IR tablet during one dosing period and a single 1 mg SL tablet during the other dosing period. \r\nThe primary pharmacokinetic endpoints were area under the plasma concentration-time profile from time zero to the \r\ntime of the last quantifiable concentration AUC(0-t) and maximum plasma concentration (Cmax). Adverse events (AEs) \r\nwere monitored throughout the study. Bioequivalence was concluded if the 90% confidence intervals (CI) for the ratio \r\nof adjusted geometric means for both AUC(0-t) and Cmax were wholly within 80%-125%.\r\nParticipants were mostly male (27/28 [96.4%]) and had a mean (standard deviation) age of 35.9 (8.2) years. For \r\nthe alprazolam 1 mg SL tablet relative to the alprazolam 1 mg IR tablet, the ratio of adjusted geometric means (90% \r\nCI) for AUC(0-t) and Cmax were 95.43% (91.74%, 99.27%) and 88.27% (83.68%, 93.11%), respectively. The incidence \r\nof AEs was similar during both treatment periods: 24 participants reported 39 AEs during the alprazolam 1 mg IR \r\ntreatment period, and 23 participants reported 38 AEs during the alprazolam 1 mg SL treatment period.\r\nBioequivalence was demonstrated between the alprazolam IR and SL 1 mg tablets, suggesting that the clinical \r\nperformance of the SL tablet will be similar to that of the IR tablet....
Background: Artemether-lumefantrine (CoartemW; AL) is a standard of care for malaria treatment as an oral\r\nsix-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on\r\npatient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two\r\nnovel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for\r\nbioequivalence with their respective number of standard tablets.\r\nMethods: A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study\r\ncomparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets,\r\nand the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed\r\nconditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS.\r\nPharmacokinetic (PK) parameters were determined by non-compartmental analyses.\r\nResults: Adjusted geometric mean AUClast for artemether were 345 and 364 ng�·h/mL (geometric mean ratio (GMR)\r\n0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 �µg�·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg\r\ntablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL\r\n(GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 �µg/mL (GMR 0.97; 90% CI 0.89-1.05). For the\r\n60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and\r\n231 ng�·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 �µg�·h/mL (GMR 0.89; 90%\r\nCI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90%\r\nCI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 �µg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for\r\nCmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence\r\nacceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion.\r\nConclusion: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their\r\nrespective standard CoartemW tablet doses. These novel formulations are easy to administer and may improve\r\nadherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum....
Metformin is a biguanide antihyperglycemic agent often used for the treatment of non-insulin dependent diabetics (NIDDM). In this study, the pharmacokinetics and pharmacodynamics ofmetformin were investigated in Indianhealthy volunteers during a fasting state for over 10 h. In order to evaluate the amount of glucose-lowering effect of metformin, the plasma concentrations of glucose were measured for a period of 10 h followed by the administration of 500 mg test or reference metformin tablets with control group. In addition, the concentration of metformin in blood samples was determined by HPLC assay for the drug. All volunteers were consumed with 12 g of sugar after drug administration to maintain initial plasma glucose concentration while control group administered with 12 g sugar only. The time courses of the plasma concentration of metformin and the glucose-lowering effect were analyzed. It was found that no relation between effect-concentration of metformin was observed but it was found there was no increase in blood sugar after breakfast and meal which could be related to decreased absorption of glucose from gastrointestinal tract caused by metformin....
Background: CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was\r\nshown to be 50ââ?¬â??100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the\r\npresent investigation, we have established an analytical method for the quantification of CR8 in biological samples\r\nand evaluated its bioavailability, biodistribution and pharmacokinetics in mice.\r\nMethods: A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was\r\nadministered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points.\r\nBlood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma\r\nand organs.\r\nResults: CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ\r\ndetection was 0.10 Ã?µg/ml and linearity was observed within the 0.10-10 Ã?µg/ml range (r2 > 0.998). The accuracy and\r\nprecision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room\r\ntemperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model\r\nafter oral administration and to a one compartment model after i.v. injection. The elimination half-life was about\r\n3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose\r\ntissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral\r\nbioavailability of CR8 was found to be essentially 100%.\r\nConclusions: We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern\r\nshowed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow\r\nsystemic exposure higher than the IC50 reported for cell death in tumor cell lines. CR8 displays favorable pharmacological\r\nproperties and is therefore a good candidate for future clinical studies....
Background: 1,3-dimethylamylamine (DMAA) has been a component of dietary supplements and is also used\r\nwithin \"party pills,\" often in conjunction with alcohol and other drugs. Ingestion of higher than recommended\r\ndoses results in untoward effects including cerebral hemorrhage. To our knowledge, no studies have been\r\nconducted to determine both the pharmacokinetic profile and physiologic responses of DMAA.\r\nMethods: Eight men reported to the lab in the morning following an overnight fast and received a single 25 mg\r\noral dose of DMAA. Blood samples were collected before and through 24 hours post-DMAA ingestion and analyzed\r\nfor plasma DMAA concentration using high-performance liquid chromatographyââ?¬â??mass spectrometry. Resting heart\r\nrate, blood pressure, and body temperature was also measured.\r\nResults: One subject was excluded from the data analysis due to abnormal DMAA levels. Analysis of the remaining\r\nseven participants showed DMAA had an oral clearance of 20.02 Ã?± 5 LÃ?·hr-1, an oral volume of distribution of 236 Ã?±\r\n38 L, and terminal half-life of 8.45 Ã?± 1.9 hr. Lag time, the delay in appearance of DMAA in the circulation following\r\nextravascular administration, varied among participants but averaged approximately 8 minutes (0.14 Ã?± 0.13 hr). The\r\npeak DMAA concentration for all subjects was observed within 3ââ?¬â??5 hours following ingestion and was very similar\r\nacross subjects, with a mean of ~70 ngÃ?·mL-1. Heart rate, blood pressure, and body temperature were largely\r\nunaffected by DMAA treatment.\r\nConclusions: These are the first data to characterize the oral pharmacokinetic profile of DMAA. These findings\r\nindicate a consistent pattern of increase across subjects with regards to peak DMAA concentration, with peak\r\nvalues approximately 15ââ?¬â??30 times lower than those reported in case studies linking DMAA intake with adverse\r\nevents. Finally, a single 25 mg dose of DMAA does not meaningfully impact resting heart rate, blood pressure, or\r\nbody temperature....
Background: Inter-individual variability in plasma concentration-time profiles might contribute to differences in\r\nanti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of\r\nartemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of\r\nvariability.\r\nMethods: Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin,\r\nlumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60\r\n(dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the\r\npharmacokinetic parameters were assessed and the contribution of demographic and other covariates was\r\nquantified using a nonlinear mixed-effects modelling approach (NONMEM�®).\r\nResults: A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all\r\ndrugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40%\r\nand 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant\r\ntreatment (for artemether only) showed a significant influence on these drugsâ�� pharmacokinetic profiles. Artesunate\r\nand dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled\r\nlumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion\r\nof patients.\r\nConclusion: The marked variability in the disposition of different forms of ACT remained largely unexplained by the\r\navailable covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual\r\nlevels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute\r\nto selecting for drug-resistant parasites....
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