The effect of mefloquine on artesunate pharmacokinetics was assessed in 20 volunteers given artesunate for 3 days, followed >21 days later by combination therapy for 3 days. The areas under the concentration-time curve from 0 h to infinity for dihydroartemisinin, the active metabolite of artesunate, were similar on day 3 of the two dosing periods (P ؍ 0.12), implying no interaction.Mefloquine-artesunate was one of the first artemisinin combination therapies used clinically, and it remains an effective treatment for uncomplicated malaria (2, 9). While the influence of artesunate on the pharmacokinetics of mefloquine has been investigated (12, 16), with seemingly inconsistent results (11), the effect of mefloquine on artesunate disposition has not. The active metabolite of artesunate, dihydroartemisinin (DHA), is itself an antimalarial drug that has been partnered with mefloquine as a form of artemisinin combination therapy (2, 9). Mefloquine does not influence DHA pharmacokinetics in patients with falciparum malaria (13-15), but extrapolation of this finding to artesunate-mefloquine may be invalid. Artesunate and DHA have different chemical and pharmacologic properties (5), and between-subject variability and changes in drug disposition and metabolism during recovery from malaria complicate assessment of previously published parallel-group DHA-mefloquine patient studies. We have therefore evaluated the effects of mefloquine on artesunate and DHA pharmacokinetics in healthy males, using a crossover study design.The study was approved by the South Metropolitan Health Service Human Research Ethics Committee, Western Australia, and all subjects provided informed consent. Twenty of the 25 volunteers recruited met eligibility criteria and provided complete valid data for analysis. Their mean age was 28.9 (range, 19.0 to 57.1) years and their mean body weight 77 (48 to 130) kg. Each subject received 200 mg artesunate (Mepha Ltd., Switzerland) by mouth after an overnight fast on three consecutive mornings (period 1). After a washout phase of Ն21 days, this schedule was repeated, but mefloquine (Mepha) at 250 mg daily was given at the same time as artesunate (period 2). On days 1 and 3 of each period, blood samples were drawn for drug assay under a predetermined schedule from immediately before (0 h) to 8 h postdose. Additional samples were taken for mefloquine assay on the mornings of days 2, 4, 5, and 6 during and after period 2.Drug assays were by high-performance liquid chromatography. For mefloquine, extracted plasma (with clomipramine as an internal standard) was injected onto a RP Select B column (E. Merck, Darmstadt, Germany) run on a 1100 high-performance liquid chromatograph (Agilent Technologies, Waldbronn, Germany), using a mobile phase of 40% (vol/vol) acetonitrile in 45 mM KH 2 PO 4 (pH 3) at 1.3 ml/min with UV detection at 225 nm. Within-and between-day relative standard deviations over 50 to 2,000 g/liter were Յ9.4% and Յ8.8%, respectively. The lower limit of quantitation was 10 g/liter. For artesunate a...
Fluoxetine hydrochloride (CAS 59333-67-4) is a selective serotonin reuptake inhibitor (SSRI) widely used as antidepressant drug. The aim of the present trial was to assess the bioequivalence of a new formulation of the drug (test formulation) as compared to a reference product from the Swiss market. Both drugs were available as 20 mg dispersible tablets. The trial was performed according to a two-period, two-sequence, balanced, randomised, single-dose design with a wash-out phase of at least 56 days. The two formulations were tested in 30 male healthy volunteers. A specific highly sensitive bioassay in tandem mass spectrometry allowed to set the limit of quantification to 100 pg/ml for fluoxetine and norfluoxetine. Average t(max) was 5.4 h for fluoxetine and 71-80 h for norfluoxetine. The peak concentration was on average 14 ng/ml for fluoxetine and 10.5 ng/ml for norfluoxetine. Half-life was on average 48-50 h for fluoxetine and 130-138 h for norfluoxetine. AUC infinity for fluoxetine and norfluoxetine were on average 790 and 2800 ng x ml(-1) x h, respectively. All these figures demonstrate that plasma concentration-time profiles of fluoxetine and norfluoxetine are quite different. Applied statistical tests, suggested by operating guidelines, demonstrated bioequivalence of the test formulation and the reference formulation. The conclusion on bioequivalence was based on both fluoxetine and norfluoxetine results. 90 % confidence Intervals for Cmax, AUCt and AUC infinity (fluoxetine and norfluoxetine) were within the acceptance range (0.80-1.25) and t(max), processed with a non-parametric test, did not show any statistically significant difference between test and reference formulation. Safety and tolerability proved to be similarly good with both test and reference formulation. In conclusion, the present trial has demonstrated bioequivalence of the test and the reference formulation, both consisting of fluoxetine hydrochloride dispersible tablets.
Studies of roof monitor emissions are conducted for two reasons: (1) to obtain design data necessary to engineer control systems to meet existing regulations, and (2) to determine projected control costs which can influence present day proposals for process change. Heated wire anemometers and rotating vane anemometers have been selected for velocity measurements, and high-volume air samplers have been selected to collect the particulate sample. Evaluation of other types of velocity sensing devices are described in the paper.Roof monitor studies must be preceded by a preliminary survey to allow the project engineer to determine the test sampling locations and specific methodology necessary for the given study, and to allow the engineer to determine the type of safety equipment, scaffolds, and power requirements necessary to complete the study.Field tests are conducted by operating a number of high-volume air samplers simultaneously while at the same time measuring the velocity of the gas through the monitor opening. Curves of particulate concentration and velocity as a function of monitor length are constructed. The concentration and velocity curves are then integrated together and the resultant curve is multiplied by the monitor width to determine a curve of mass emission rate as a function of monitor length. The total mass emission rate is represented by the area under the mass emission rate curve.Procedures for calibrating the anemometers and correcting for the effect of power fluctuation on the high-volume sampler operation are described. Data evaluation procedures and discussion of test error are also described.A study can cost between 10 and 20 thousand dollars, including the cost of manpower and the cost of scaffolds, power, cables, etc. It can take four months or more to conduct a study, from the preliminary survey phase through the report phase.
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