Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis.

The pharmacokinetics of cefpiramide, a new cephalosporin, were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers, respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower, the dosage regimen of cefpiramide would probably be modified in cirrhosis.

Clopidogrel--a platelet inhibitor which inhibits thrombogenesis in non-anticoagulated human blood independently of the blood flow conditions.

The goal of the present study was to investigate the effect of 7 and 14 days of daily oral administration of 75 mg clopidogrel on collagen-induced thrombogenesis in flowing non-anticoagulated human blood. Blood was drawn directly from an antecubital vein over immobilised collagen type III fibrils positioned in a parallel-plate perfusion chamber. The wall shear rates at the collagen surface were those characteristic for veins (100 s-1), and for medium sized (650 s-1) and moderately stenosed (2600 s-1) arteries. Clopidogrel ingestion reduced the thrombus volume significantly (p < 0.05) at 100 and 2600 s-1 (39 and 51% respectively). The beta-thromboglobulin plasma levels were reduced concomitantly. However, it was not possible to measure accurately the thrombus volume at 650 s-1, due to loose packing of the platelet thrombi. Transmission electron microscopy substantiated this observation and showed that clopidogrel profoundly reduced the platelet degranulation process (p < 0.005). The inhibitory effect of clopidogrel on platelet consumption by the growing thrombi resulted apparently in higher platelet concentration at the collagen surface, which enhanced the platelet-collagen adhesion at all three shear rates (p < 0.05). Despite the low deposition of fibrin on collagen, clopidogrel reduced significantly the fibrinopeptide A plasma levels and the fibrin deposition at shear rates below 650 s-1. This was apparently a consequence of the reduced platelet recruitment and the lower activation of platelets, since activated platelets in thrombi promote deposition of fibrin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man.

This paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. This study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses < 1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16,000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (Cmax) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (CI) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t 1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major roles in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9, Cmax, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the "steady state" was obtained 2 to 3 days after the first injection at which the mean Cmax was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20,000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8,000 anti-Xa IU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 micrograms.ml-1 (2 and 2.5 anti-Xa IU.ml-1).

Placental transfer of SR49059 in the human dually perfused cotyledon in vitro.

SR49059 is an antagonist of vasopressin V(1a)receptors currently developed as a tocolytic drug. We investigated the transplacental transfer of SR49059 in vitro using the single pass dually perfused human cotyledon model. Thirteen placentae were collected from normal term pregnancies immediately after delivery. The placental transfer of SR49059 was tested at steady state at three different concentrations (100 ng/ml, 200 ng/ml and 500 ng/ml) along with that of antipyrine 20 mg/l as a reference substance. Concentrations were assayed by liquid chromatography with UV (antipyrine) or mass spectrometry (SR49059) detection. At steady state, the mean+/-s.d. fetal transfer rate of SR49059 was 10.80+/-4.33 per cent, 9.34+/-4.41 per cent, and 11.78+/-3.26 per cent at 100 ng/ml, 200 ng/ml and 500 ng/ml, respectively. The corresponding clearance indices were 0.29+/-0.14, 0.25+/-0.08, and 0.31+/-0.06, respectively. The absence of saturation kinetics is consistent with a passive mechanism of transfer. Moderate amounts of SR49059 are transferred from the maternal to the fetal circulation. The clearance index of SR49059 appeared to be very similar to that of ritodrine, which is currently used as a tocolytic.

Isolation and characterization of a cDNA encoding a chicken beta thyroid hormone receptor.

We have isolated and characterized a cDNA encoding a chicken beta homolog of c-erbA, or thyroid hormone receptor (TR). Chicken liver cDNA libraries were screened with a rat TR beta-1 cDNA probe, and several cDNA inserts were isolated and characterized. The sequence of one cDNA predicts a 369-amino-acid open reading frame (ORF), with a protein sequence that possesses 96% identity with that of rat TR beta-1, but only 88% identity with chicken TR alpha. These data indicate that the cDNA likely encodes a beta form of TR that has the expected putative DNA and T3 binding domains. The chicken TR beta (chTR beta) in vitro translated protein binds T3 with high affinity, and binds both the thyroid hormone response element (TRE) from the rat growth hormone gene and the Xenopus vitellogenin A2 gene estrogen response element (ERE), similarly to that of the rat TR beta-1. Northern blot analysis revealed the expression of a 7.0-kb RNA in several tissues including cerebellum, pituitary, kidney, and liver. This chicken liver TR beta cDNA sequence varies in both the 5' and 3' untranslated regions from the chicken kidney TR beta cDNA sequence recently reported (Forrest et al., 1990). The 5' untranslated cDNA sequence divergence occurs near a potential splice site junction of the human TR beta gene, suggesting that this chicken liver cDNA may represent an alternatively spliced RNA product of the chicken TR beta gene.

Gastroesophageal reflux in neonates with congenital abdominal wall defect.

Gastroesophageal reflux (GER), not yet described as a real complication, takes place very often in neonates with congenital abdominal wall defect. Our aim was to determine whether it is due to abdominal hyperpressure alone, or if another factor is involved in this occurrence. Thus we studied one group of 80 gastroschises and one of 67 omphaloceles, treated in our department between December 82 and December 92. Overall occurrence was found to be about 50% in both groups. The main feature is the particular severity of GER in neonates with wide omphalocele who required staged closure, leading to further surgical antireflux procedure. We suggest that this procedure could be performed earlier, at the time of closure, for these babies in whom moreover the anatomic approach is favorable.

[Progressive multifocal leukoencephalopathy. Contribution of nuclear magnetic resonance imaging]. / La leucoencéphalopathie multifocale progressive. Apport de l'imagerie par résonance magnétique nucléaire.

Progressive multifocal leucoencephalopathy is a white matter infection caused by a papovavirus. Immunocompromised patients are predominantly affected. We report the case of a 74-year old woman with abdominal lymphoma resistant to chemotherapy. The diagnosis was suggested by cerebral CT and NMR images and was confirmed at postmortem pathological examination. The contribution of complementary examinations to the diagnosis is discussed in the light of recently published studies.

Single-dose pharmacodynamics of clopidogrel.

The inhibition of platelet aggregation by clopidogrel, a novel platelet ADP-receptor antagonist, was evaluated in healthy male volunteers in two single-dose studies. In one study, 10 subjects received, in increasing order, single doses of 100, 200, 400 and 600 mg of clopidogrel or placebo in five study periods, according to a randomized, doubleblind, protocol design. In the second study, 12 subjects received a single 400 mg dose of clopidogrel as capsules and as tablets, according to an open-label, randomized, crossover design. The interval between the two administrations was seven days. Platelet aggregation induced by ADP (2, 5 and 10 microM) and by collagen (0.5 and 1 microg/mL; rising-dose study only) was assessed from blood samples collected over a period of 24 hours to 72 hours postdose. The inhibition of platelet aggregation was expressed as the mean percent change from baseline in maximum platelet aggregation. The effect of clopidogrel on bleeding time was also assessed. Clopidogrel induced a statistically significant inhibition of ADP-induced platelet aggregation at all doses. With 5 microM of ADP, the inhibition was dose-related up to a dose of 400 mg, with no further increase at a dose of 600 mg. At 2 hours, mean inhibition ranged from 12+/-6% (100 mg) to 42 +/-6% (400 mg), and at 24 hours, it ranged from 17+/-7% (100 mg) to 43+/-9% (400 mg). After 400 mg, the inhibition of platelet aggregation remained stable from 2 hours up to 72 hours, with mean percentages of inhibition ranging from 49 to 39%. Clopidogrel only showed a slight-to-moderate inhibitory effect on collagen-induced platelet aggregation. A mean bleeding time prolongation of 1.7 was observed 5 hours after the 400 mg and 600 mg doses; it was statistically significant only following the higher dose. Individual bleeding time prolongations ranged from 1 to 2.85. Clopidogrel was well tolerated at all doses. The results of these studies were part of the rational for the choice of the loading dose.

Repeated-dose pharmacodynamics of clopidogrel in healthy subjects.

The effect of repeated doses of clopidogrel, a novel platelet ADP-receptor antagonist, on platelet aggregation and its tolerance were assessed in two randomized, double-blind studies in healthy male adults. In each of the four successive dose groups in Study I, 6 subjects received either clopidogrel 25, 50, 100, or 150 mg once daily and 2 received placebo for 16 days, according to a rising dose design. In each of the three successive treatment groups of Study II, 9 subjects received clopidogrel (50, 75, or 100 mg once daily) in the morning, 3 received triclopidine 250 mg twice daily and 3 received placebo for 14 days. In both studies, the inhibition of platelet aggregation induced by 5 microM of ADP was measured before dosing (baseline), then at regular intervals during and after treatment. Bleeding time was generally assessed at the same time points as platelet aggregation. In both studies, the inhibition of platelet aggregation reached steady state after day 6 dosing. Mean steady-state percent inhibition of platelet aggregation was 30%, 46%, 53%, and 73% for clopidogrel 25, 50, 100, and 150 mg, respectively, in Study I; and 54%, 52%, 47%, and 43% for clopidogrel 50, 75, 100 mg, and for ticlopidine, respectively, in Study II. After treatment discontinuation, statistically significant inhibition of platelet aggregation persisted for up to 8 days. In Study I, up to 75 mg repeated doses, mean bleeding time prolongation factor did not exceed 2, but increased further to 3.5 and 5.5 at a clopidogrel dose of 100 mg and 150 mg, respectively. In study II, prolongation factors during treatment did not exceed 2.2 for clopidogrel (in the 75 mg dose group) and 1.6 for ticlopidine 500 mg. Recovery of bleeding time was observed within 7-8 days. Treatments were well tolerated, and no serious clinical events or important changes in laboratory parameters were recorded. These data were consistent with those obtained in atherosclerotic patients and showed that the plateau response for the inhibition of platelet aggregation was reached at the 75 mg dose, for which bleeding time prolongation was approximately 2.

Clopidogrel and drug metabolism: absence of effect on hepatic enzymes in healthy volunteers.

The influence of clopidogrel 75 mg, given once daily for 10 days on hepatic P-450 mixed function oxidases, was examined by assessing its effect on the disposition of antipyrine, on urinary 6-betahydroxycortisol (6beta-OHC) and on the plasma activity of gamma-glutamyl transpeptidase. This double-blind, randomized, placebo-controlled study was conducted in two parallel groups of 10 healthy young volunteers. Subjects were required to fast for 12 hours before and for 4 hours after dosing. Antipyrine 10 mg/kg was administered in the morning, two days before treatment (day -2) and 24 hours after the last dose of clopidogrel or placebo. Plasma levels of antipyrine, and urinary excretion of antipyrine, 3-hydroxymethyl-antipyrine and nor-antipyrine were measured over 36 hours post-drug for pharmacokinetic determinations. Bleeding time and platelet aggregation induced by 5 microM of ADP were measured before treatment (baseline) and at regular intervals after dosing during treatment. Clopidogrel treatment had a marked effect on platelet aggregation and bleeding time. No significant change in the disposition of antipyrine was observed after the ingestion of clopidogrel over 10 days: mean AUC ratio (+/-SEM) for plasma antipyrine was 1.021+/-0.023 for the clopidogrel group versus 1.001+/-0.019 for the placebo group; mean day 10/day -2 t 1/2 ratios were 1.019+/-0.018 and 1.027+/-0.023, respectively. Urinary excretions of antipyrine and metabolites were unchanged by clopidogrel compared to placebo. The changes in plasma cortisol concentrations, 6beta-OHC excretion and serum gamma-glutamyl transpeptidase activities observed at the end of treatment were fully comparable between the two treatment groups. Thus, the different tests showed no evidence of hepatic enzyme induction by clopidogrel in a pharmacologically effective dose regimen.

Clopidogrel compatibility with concomitant cardiac co-medications: a study of its interactions with a beta-blocker and a calcium uptake antagonist.

The safety and pharmacodynamic compatibility of clopidogrel with medications commonly used in patients with atherosclerosis, such as, a beta-adrenergic receptor antagonist (atenolol) and a calcium uptake inhibitor (nifedipine) were assessed. Atenolol and nifedipine interactions with clopidogrel were studied in patients with peripheral arterial obstructive disease taking a well-established regimen of nifedipine (N group of 6 patients) and in patients with coronary artery disease taking a well-established regimen of either atenolol (A group of 8 patients) or of atenolol and nifedipine (AN group of 8 patients). The study was conducted as a double-blind, randomized, crossover comparison of clopidogrel, 75 mg once daily, and placebo treatment for 7 days, with a 14-day washout between treatments. Pharmacodynamic interactions between atenolol and nifedipine, either alone or in combination, and clopidogrel were assessed primarily on the clinical control of angina or hypertension and, secondarily, by comparing the extent of inhibition of ADP (5 microM)-induced platelet aggregation achieved between the 3 groups. The mean number of anginal episodes per patient during the placebo week was 1.50, 9.0 and 11.5 in the A, N and AN groups, respectively; during the week of clopidogrel treatment, it was 1.39, 7.3 and 9.0, respectively, indicating no change in occurrence. Likewise, review of the use of nitrates (long or short acting) did not suggest any major change in usage during any period of the study. ECGs did not change between the three recording times (at screening and at the end of each treatment period). Vital signs were also unchanged throughout. Percent inhibition of platelet aggregation on day 7 was 31% in the N group, 39% in the A group, 28% in the AN group, and 33% overall. In conclusion, the coadministration of clopidogrel did not interfere with the clinical control of hypertension or angina established with atenolol or nifedipine, or both. Clopidogrel retained its full antiplatelet effect, and there were no safety problems caused by the coadministration.

Cefpiramide kinetics and plasma protein binding in cholestasis.

Cefpiramide is a new parenteral cephalosporin mainly excreted in the bile. Eight patients with cholestasis and 11 healthy subjects received a single 1 g i.v. dose. Cefpiramide concentrations in plasma and urine were measured by h.p.l.c. and plasma binding was determined by ultrafiltration. Total clearance of cefpiramide (mean +/- s.d.) was 15.5 +/- 7.1 ml min-1 in patients and 25.6 +/- 4.6 ml min-1 in healthy subjects. As a result, the terminal elimination half-life was longer in patients (12.0 +/- 2.9 h vs 5.3 +/- 0.9 h). Owing to impaired biliary elimination of cefpiramide in cholestasis, the urinary recovery of unchanged drug in patients was about five times greater than in healthy subjects (85.1 +/- 10.3% vs 16.2 +/- 3.9%). Plasma binding was significantly lower in cholestasis (fu = 0.23 +/- 0.13 vs 0.02 +/- 0.004 in healthy subjects). Accordingly, the dosage regimen of cefpiramide should be modified in patients with cholestasis.