Effect of gastric emptying and entero-hepatic circulation on bioequivalence assessment of ranitidine.

The aim of study was to compare the bioavailability of ranitidine obtained from either Ranitidine (300 mg tablet; LPH® S.C. LaborMed Pharma S.A. Romania: the test formulation) and Zantac® (300 mg tablet; GlaxoSmithKline, Austria: the reference formulation). Twelve, Romanian, healthy volunteers were enrolled in the study. An open-label, two-period, crossover, randomized design was used. Plasma levels of ranitidine were determined using the validated, high-pressure liquid chromatography (HPLC) method. The physiologically motivated time-delayed model was used for the data evaluation and a paired Student's t-test and Schuirmann's two one-sided tests were carried out to compare parameters. Nonmodeling parameters (AUC(t), AUC, C(max), T(max)) were tested by the paired Student's t-test and the 90 confidence intervals of the geometric mean ratios were determined by Schuirmann's tests. Paired Student's t-test showed no significant differences between nonmodeling and modeling parameters. The results of the Schuirmann's tests however indicated significant statistical differences with reference to AUC(t), AUC, C(max), T(max) and other modeling parameters, especially MT(c) and τ(c). Schuirmann's tests revealed significant bioequivalence between ranitidine formulations using the modeling parameters MRT and n. The presented model can be useful as an additional tool to assess drug bioequivalence, by screening for disruptive parameters.

Liquid extraction and HPLC-DAD assay of hydrochlorothiazide from plasma for a bioequivalence study at the lowest therapeutic dose.

The main parameters considered in optimizing the liquid extraction and quantitative assay were the yield, precision, limit of quantification, time required for extraction and concentration, and quantity of solvent. The influence on these parameters of the following factors was examined: nature of the extracting solvent, quantity of solvent, co-extraction solvent, and duration of stirring. Instead of equilibrium parameters of the involved thermodynamic system, a kinetic approach was preferred in terms of the effective partition 'constant', which is not really constant but a function of time and extraction conditions. The final selected method, considered to be rapid and simple, was applied to determine the pharmacokinetics of hydrochlorotiazide (HCT) after administration of Capozide (Bristol-Myers Squibb) tablets containing 50 mg Captopril and 25 mg HCT, to 4 healthy volunteers. The results obtained were in accordance with the pharmacokinetic parameters of HCT reported in the literature.

Pharmacokinetic based adjustment of lidocaine antiarrhythmic schedule.

Administration of lidocaine, 200 mg/day i.m. or 275 mg orally, decreased sudden death after myocardial infarct (from 20.7% to 10.3%) although such schedules are not considered adequate to guarantee efficient plasma levels. Inclusion of lidocaine in a polyethylene matrix assured a slow release and complete disappearance of known side effects. Lidocaine was administered 200 mg intramuscularly to hospitalized patients every 6 h or 275 mg oral tablets to healthy volunteers every 8 h and plasma levels evaluated. Plasma levels after oral administration to healthy volunteers showed a great variability, so that it was not possible to draw a statistically significant conclusion about the accumulation of lidocaine in a period of 1 week. In coronary artery disease patients, plasma levels slowly increased with time, but clinical signs indicated, in some cases, a much more rapid accumulation. The therapeutic efficiency at low repeated doses was explained as a consequence of a slow accumulation on the one hand and of the addition of the action of MEGX, the major metabolite of lidocaine, on the other hand.

Pharmacokinetics of progesterone in postmenopausal women: 2. Pharmacokinetics following percutaneous administration.

Progesterone was administered percutaneously to postmenopausal women in topical applications on the breast and chest areas in a hydrophilic (gel), lipophilic and an emulsion type base. Venous blood samples were taken 2, 4, 6, 24, 48 and 72 h following administration. The plasma levels were evaluated by radioimmunoassay. Time of maximum concentration (tmax) was, in all cases, in the neighborhood of 4 h. Mean peak plasma concentrations were: 1 ng/ml for the lipophilic, 1.24 ng/ml for the hydrophilic and 2.26 ng/ml for the emulsion type base. The areas under the curves (AUCs) were practically equivalent for the first two methods, but higher values were obtained for administration in the emulsion type base. The elimination was slow, with a half-time varying in the range of 3040 h for all three types of base, a value that was much higher than those obtained after administration of progesterone via vaginal suppositories. The AUCs were parallel with the peak plasma concentrations: almost 2-fold higher for emulsion than for the gel and lipophilic base. Fit for plasma levels using mono-, bi- and tricompartmental models furnished acceptable results only in the case of monocompartmental model, which raises a number of physiological and physico-chemical considerations. A 'pseudomonocompartmental' model was constructed to explain this 'anomaly'.

Pharmacokinetics of progesterone in postmenopausal women: 1. Pharmacokinetics following intravaginal administration.

Progesterone was administered to postmenopausal women in a form of vaginal suppositories containing 100 and 200 mg active substance in Butyrum cacao (BC) and Massa estarinum (ME), a base with emulsifying properties. In the case of single doses, blood samples were taken at 2, 4, 6, 24, 48 and 72 h. Another group of patients received vaginal suppositories (100 mg progesterone) once a day for a 6 day period, with blood samples taken 12 h after each administration. The plasma levels of progesterone were evaluated by radioimmunoassay. The time of maximum concentration (tmax) was 4 h in most cases, and 6 h in the others. The plasma levels were not dose-proportional. Peak plasma concentrations were in the range of 10-15 ng/ml with a mean of 10.5 ng/ml for the 100 mg and 12 ng/ml for the 200 mg doses. The ratio of the mean area under the curve (AUC) for 200 mg and the mean AUC for the 100 mg dose was found to be 1.37. Replacing BC with ME resulted in the lowering of cmax and AUC, and an increase in tmax following a reducing in the rate and extent of adsorption. In the case of ME suppositories, the variability in AUC, cmax and tmax was greater compared to that observed with the BC suppositories. Elimination half-time was in the range of 9-10 h for BC and 14 h for ME suppositories. In vitro assessment of the release kinetics from a hydrophobic and an emulsion type base confirmed previous findings: the latter base assured better pharmaceutical availability. The repeated doses did not seem to produce an accumulation of progesterone in the plasma. On the contrary, a small decrease in plasma levels over time appeared during the 6 day period. Numerical analysis revealed an excellent goodness of fit for the in vivo experimental data via biexponential curves, i.e. a pseudomonocompartmental model.

Pharmacometabonomics, pharmacogenomics and personalized medicine.

The development of genomics in the last decade opened new perspectives to fulfill the permanent ideal of therapy, namely personalization of therapy (of medicine) by using of adage: "the right drug to the right patient". The pharmacogenomics, developed in these 10 years, already permitted the identification of the patients with side drug effects risk by detection of the presence of single nucleotide polymorphisms (SNPs) from enzymatic systems implied in drugs metabolism such as CYP450. More recently, the emergence of pharmacometabonomics permitted the appreciation of the influence of the metabolic factors (and of the environment) on the genes expression. The combination of these sciences can permit a better individualization of drug therapy concerning both the genetic background of individual and exterior interventions. Actual studies seem to confirm this supposition.

Dissolution of pentoxifylline from extended release formulations. Researches concerning development of a biorelevant test.

This paper presents results of a pharmacokinetics study concerning pentoxifylline and its main metabolites after administration of extended release formulation of Trental 400 mg and correlation of this pharmacokinetics with in vitro dissolution test results of parent drug. In order to establish most relevant in vitro test, dissolution was performed in different experimental conditions (stirring rate and dissolution medium). Correlation was linear and very good. Generalization of correlation to rate of appearance of metabolites in plasma proved that this process could be well correlated with dissolution. Most relevant test was finally found to be the release in water medium, in conditions of a high stirring rate - 100 rpm.

[Practical aspects of the treatment of Darrow's syndrome]. / Aspecte practice in tratamentul sindromului Darrow.

An analysis is made of a group of 30 patients who, in the course of the evolution of their basic disease,have also presented, at a certain time, lowered potassium concentrations in the blood and metabolic alkalosis. As etiological factors the frequency is stressed, of conditions in the course of which stasis gastric juice is lost, the chronical lack of potassium import, as well as corticoid therapy. Special attention is given to circumstances imposed by oedema of the anastomosis opening. Interpretation and monitoring of the treatment were carried out on the basis of sophisticated, as well as current laboratory methods, but the importance of the clinical signs is stressed, when a well-equiped laboratory department is not available.