OBJECTIVE: To investigate whether the placental expression of P-glycoprotein shows a quantitative difference during pregnancy. STUDY DESIGN: Villous tissue was collected from chorionic villus samples (13-14 weeks of gestation; n = 3 and 20-25 weeks of gestation; n = 4) and from full-term placentas (38-41 weeks of gestation; n = 28). P-glycoprotein was detected by western blot analysis and quantified by densitometry. RESULTS: We showed for the first time a significant and progressive two-fold decrease in the mean expression of P-glycoprotein between early and late samples, with a major overlap of values. CONCLUSION: As P-glycoprotein appears to be involved in drug extrusion, these data suggest that the placenta's ability to protect the fetus from xenobiotics is greater in early pregnancy than at term.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Decrease of intestinal P-glycoprotein activity by 2n-propylquinoline, a new oral treatment for visceral leishmaniasis.

Drugs currently available for visceral leishmaniasis treatment are potentially toxic, have to be administered by parenteral route and frequently give rise to drug resistance, due to the involvement of P-glycoproteins (P-gp) in Leishmania. The purpose of this study was to investigate a possible inhibitory effect of 2n-propylquinoline (2nPQ) on P-gp activity. 2nPQ is a new oral anti-leishmanial drug that has demonstrated its efficacy in BALB/c infected mice with Leishmania donovani [Antimicrob. Agents Chemother. 37 (1993) 859]. Rat everted gut sacs and human intestinal Caco-2 cell lines were used to study the effect of 2nPQ on P-gp activity. Our results demonstrate an inhibitory effect of 2nPQ on the P-gp activity with two P-gp substrates (rhodamine 123 and digoxin), two P-gp inhibitors (cyclosporin A and verapamil), and in two different species. Alone or associated with other active drugs, 2nPQ would be very useful to control Leishmania Multi-Drug-Resistance and intestinal P-gp in humans with kala-azar.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

[Pharmacokinetics of ofloxacin administered orally in elderly subjects with bronchial or urinary tract infections].

The pharmacokinetics of ofloxacin orally administered were investigated at the steady-state in sixteen elderly patients older than 65 years. Patients with either urinary tract of respiratory tract mild infectious were divided into two age-dependent groups A and B. Group A: eight patients (65-80 years) received 200 mg of ofloxacin by the oral route every 12 hours and group B: eight patients older than 80 years, received 200 mg of ofloxacin by the oral route every 24 hours. The pharmacokinetic study was performed on treatment day 5. Plasmatic levels and urinary excretion of ofloxacin during 12 or 24 hours were assayed by means of high pressure liquid chromatography. Wide variations in plasma ofloxacin concentrations were observed within each group (Cmax range, group A: 1.9-9.2 mg/l, group B: 1.6-10.0 mg/l). Similar variability was observed for ofloxacin elimination parameters (CI/F, renal CI(R)/F) and half-life. In contrast, within-group and between-group differences in the volume of distribution adjusted for weight were not significant (group A: 1.22 +/- 0.44 l.kg; group B: 1.49 +/- 0.53 l.kg), but these values were approximately half those observed in the young adult. Plasmatic [CI/F] and renal clearance [CI(R)/F] of ofloxacin were correlated with creatinine clearance in both groups and in the overall population studied. Then the overall population was classified in terms of creatinine clearance [group 1: greater than 50 ml/min; group 2: less than or equal to 50 (minimum 20) ml/min]. The pharmacokinetics of ofloxacin in the elderly are characterized by a decrease in the volume of distribution and in plasmatic and renal clearances.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMedDate not supplied

[Topical digestive drugs with a clay base. Influence on the absorption of cimetidine].

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Adult↗

PubMedDate not supplied

[Bioavailability of oral and rectal indomethacin].

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Administration, Oral↗

PubMedDate not supplied

[Unexpected interactions of some psychotropic drugs with barbital and pentobarbital effects in mice (author's transl)].

Some of the substances studied modified the effects of the two barbiturates as expected and in the same direction: --chlorpromazine and diazepam increased the effects; --amphetamine and caffeine decreased them. Barbital, unlike pentobarbital, undergoes almost no metabolic transformation. This explains why pentobarbital is potentiated in the presence of proadifen, an inhibitor of liver microsomial enzymes, whereas the effect of barbital is unchanged, and probably explains similar results obtained with iproniazide and imipramine. For the same reason, rifampicine, an enzyme inducer, antagonizes the effect of pentobarbital without affecting that of barbital. The dissociated effects obtained with other substances are more difficult to explain: --increased effects of barbital without modification of the effects of pentobarbital (sulpiride); --decreased effects of barbital without modification of the effects of pentobarbital (methylphenidate, nomifensine, amineptine, oxolinic acid, methysergide); --decreased effects of barbital with increased effects of pentobarbital (viloxazine). Two hypotheses may be considered: 1. The study of barbital and pentobarbital concentrations in blood and brain would allow to exclude a pharmacokinetic interaction; 2. Barbital does not act through the same mechanism as pentobarbital.

Amphetamine↗

PubMedDate not supplied

Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers.

The disposition of the enantiomers of zopiclone and its two chiral metabolites was investigated after oral administration of a single dose of 15 mg of a racemic mixture (twice the usual therapeutic regimen) in 12 adult Caucasian volunteers. Determination of concentrations of zopiclone enantiomers in plasma showed that zopiclone pharmacokinetics is stereoselective with AUC0-->infinity values of 691.3 and 209.5 ng.ml-1.hr (p < 0.001), Cmax values of 87.3 and 44.0 ng.ml-1 (p < 0.001), oral CLtot/F values of 195.5 and 659.8 ml.min-1 (p < 0.001), Vd/F values of 98.6 and 192.8 liters (p < 0.01) and elimination half-life of 399.2 and 225.6 min (p < 0.01) for (+)-zopiclone and (-)-zopiclone, respectively. On the contrary, absorption half-life and Tmax values were not significantly different. In 48-hr urine, 3.6% of unchanged zopiclone was excreted, whereas 14.2% and 13.8% of both metabolites, N-desmethylzopiclone and N-oxidezopiclone, respectively, were found. Quantities of (+)-zopiclone excreted in urine were always higher compared with its antipode (-)-zopiclone for the 12 volunteers (p < 0.001). For the metabolites, quantities of both enantiomers were either equal or different and when different, it was always in favor of the (+)-enantiomer.

Administration, Oral↗

PubMedDate not supplied

[Antacid activity of citrate-bicarbonate complex of effervescent formulations of ranitidine. In vitro analysis using 'artificial stomach-duodenum' model].

Antacid activity supported by citrate-bicarbonate complex of four effervescent ranitidine forms has been assessed in vitro using an 'artificial stomach-duodenum' model controlled by microcomputer. This model allows (i) maintenance of constant the rates of the fluxes throughout the experiments or (ii) simulation of gastroduodenal flux regulation, in the normal subject (NS) or in the duodenal ulcer patient (DU) situation. The four forms developed a theoretical maximal antacid capacity between 61 and 81 mmol with a maximum intragastric pH between 3.2 and 4.8. In the gastroduodenal flux regulation simulation, antacid activity duration was rapid and included between 85 and 118 min in NS situation (50 to 56 mmol H+ consumed) and between 75 and 93 min in DU situation (43 to 47 mmol H+ consumed). The reduction of acid load penetrating into the duodenum was contained between 36 and 50 per cent. Effervescent compounds exerted a neutralising activity and a buffering capacity close to pH 6.0 (5 per cent of total antacid capacity), related to antacid potency.

Antacids↗

PubMedDate not supplied

In vitro assessment of antacid efficacy using a computer-controlled 'artificial stomach-duodenum' model reproducing gastroduodenal flux regulation.

We have developed an artificial stomach-duodenum model made up of three compartments representing the stomach, (including a fragment of hog gastric mucosa), the proximal duodenum, and the distal duodenum. Gastroduodenal flow rates are controlled by a microcomputer capable of (1) adjusting gastric emptying and alkaline secretion in the proximal duodenum according to intragastric pH; (2) adjusting pancreatic alkaline secretion according to proximal duodenum pH; and (3) simulating acid response to food ingestion. Antacid drugs were added 90 min after simulated food ingestion in near-physiological or duodenal ulcer conditions. Aluminum phosphate-containing antacids resulted in a persistent antacid effect, due to their adsorption to the gastric mucosa; this prolonged the buffering capacity at pH 2.4 to 120 min. Aluminum+magnesium hydroxides and calcium+magnesium carbonate combinations mainly exerted neutralizing activity, inducing an increase in the gastric emptying rate. In the duodenal ulcer simulation, the pH of the gastric contents was lower and the antacid effect was shorter than in the 'physiological' simulation.

Aluminum↗