Factors responsible for interindividual differences in the dose requirement of phenprocoumon

The total and unbound plasma concentrations of phenprocoumon and the prothrombin complex activity were determined in 51 patients on phenprocoumon. A 7-fold difference in the dosing rate (10-70 micrograms/kg/day) was required to maintain the prothrombin complex activity at 11-30% of normal. The variation in dosing requirement was mainly due to interindividual differences in the intrinsic clearance of phenprocoumon and only to a minor degree to differences in sensitivity to it. On average patients with myocardial infarction required only 2/3 of the daily dose of phenprocoumon of post cardiac surgery patients and patients with thrombosis and emboli. That difference appeared to be due to higher…

Effect of serum protein binding on pharmacokinetics and anticoagulant activity of phenprocoumon in rats.

The relationship among serum protein binding, kinetics of elimination, distribution, and anticoagulant activity of phenprocoumon was investigated in 25 selected outbred Sprague-Dawley rats which differed in the extent of serum protein binding of this drug. In addition, the serum protein binding of phenprocoumon was altered in inbred Lewis rats by continuous treatment with tolbutamide. This drug was found to displace phenprocoumon from serum proteins without affecting its intrinsic clearance. The serum free fraction values (fs)of the selected Sprague-Dawley rats ranged from 0.0053 to 0.0145. There were positive and linear correlations between fsand the first-order elimination rate constant (…

Dose-dependent metabolism and hepatic distribution of phenprocoumon in rats

The dose-dependency of phenprocoumon disposition was determined in rats by iv administration of 0.1 and 1.0 mg/kg doses to separate groups of animals. The intrinsic clearance (unbound clearance) was 33% lower in the animals given 1.0 mg/kg dose than in the animals given 0.1 mg/kg dose. The apparent unbound volume of distribution was 55% lower and the elimination rate constant 54% higher in the high dose group than in the lower dose group. Binding of phenprocoumon to liver showed saturability with a two- to threefold higher apparent unbound fraction of phenprocoumon in liver in animals given the high dose in comparison to animals given the low dose.

Improved method for quantitative analysis of vitamin K1i and vitamin K1 2,3-epoxide in human plasma by electron-capture gas-liquid capillary chromatography

Platelet micro-RNA expression in type 2 diabetes mellitus

Large platelets but not putative endothelial progenitor cells are associated with low strut coverage after drug-eluting stent implantation

Objectives This study assessed whether different subsets of circulating endothelial and putative endothelial progenitor cells (CEC and EPC) correlate with stent strut coverage (SSC) using second generation optical coherence tomography (OCT). Background Due to the lack of imaging modalities with a resolution down to the magnitude of a few cells, the influence of EPC on endothelialisation of drug-eluting stents has not been assessed in patients. Methods In 37 patients, SSC of everolimus-eluting stents was assessed by OCT 5-7months after stent implantation. Different subsets of EPC (CD34(+)KDR(+), CD34(+)KDR(+)CD45(dim), CD133(+), CD3(+)CD31(+)), CEC (CD31(+)CD45(-)CD146(+)), and CD31(+)CD45(-…

Age-dependent differences in the effect of phenprocoumon on the vitamin K1-epoxide cycle in rats

Abstract The anticoagulant activity and the pharmacokinetics of phenprocoumon as well as the effect of phenprocoumon on the vitamin K1-epoxide cycle in younger (12 weeks) and older (36 weeks) male inbred Lewis rats has been examined in a study of the mechanism responsible for the increase in the responsiveness to oral anticoagulant drugs (OAD's) with increasing age. After a single i.v.-dose of phenprocoumon (0†355 mg kg−1 the anticoagulant effect obtained was greater in older than in younger rats. There were no differences between younger and older rats in the rate of elimination, volume of distribution and in the free fraction and free concentration values of phenprocoumon in plasma and li…

Klinische Pharmakologie I

Rifampicin (RMP) induziert nach mehrtagiger Gabe die mischfunktionellen Oxygenasen in der Leber, so das auch sein eigener Metabolismus beschleunigt wird (Eigeninduktion, Acocella 1978a). Wie wir beobachteten, nahmen die RMP-Plasmaspiegel unter oraler Dauertherapie starker ab als bei intravenoser Applikation (Musch et al. 1982; Loos et al. 1983). Klinisch zeigten 30 initial mit RMP intravenos behandelte Patienten mit offener Lungentuberkulose eine schnellere Sputumnegativierung und Rontgenbefundbesserung im Vergleich zu 48 oral therapierten Patienten (Kombinationstherapie: RMP-Isoniazid-Ethambutol). So war z. B. die Sputumkulturkonversion nach dem 1. Behandlungsmonat bei intravenoser RMP-Gab…

TYPE II DIABETES MELLITUS HAS NO MAJOR INFLUENCE ON PLATELET MICRO–RNA EXPRESSION: RESULTS FROM MICRO–ARRAY PROFILING IN A COHORT OF 60 PATIENTS

Blood platelets represent pro–inflammatory mediators in the development of atherosclerosis. Diabetes mellitus as a major contributor to cardiovascular disease burden induces dysfunctional platelets. Platelets contain abundant miRNAs, which recently have been linked tightly to inflammation. While

Possible coumarin-like mechanism of action for cephalosporins.

In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K1 was injected to investigate whether this was followed by an increase in vitamin K1 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K1-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K1-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K1-epoxide plasma concentrations following injection of 10 mg vitamin K1, whereas in normal subjects only tr…

Sex-related Differences in Disposition and Response to Phenprocoumon in Rats

Abstract The pharmacokinetics and the pharmacological response to phenprocoumon have been studied in female and male inbred Lewis-Wistar rats. A significantly lower clearance was found in female than in male rats (7.9 ± 1.4 vs 24.5 ± 2.5 mL h−1 kg−1, respectively; t = 15.09, P < 0.001) as well as a lower apparent volume of distribution (288 ± 46 vs 617 ± 105 mL kg−1; t = 7.58, P < 0.001) and a longer half-life (25.5 ± 3.4 vs 17.5 ± 1.8 h; t = 5.16, P < 0.001). The binding of phenprocoumon was higher in female than in male rats (fu: 0.0096 ± 0.0008 vs 0.0124 ± 0.0007, respectively; t = 6.66, P < 0.001). The total (C) as well as the unbound concentration (Cu) neede…

Klinische Pharmakologie II

1963 beschrieb Ommaya ein subkutanes Plastikreservoir, das nach Implantation unter die Kopfhaut einen direkten, sterilen, wiederholbaren Zugang zum Ventrikelliquor ermoglichte. Nach okzipitaler Bohrlochtrepanation des Schadels wurde ein Siliconkatheter in das Hinterhorn des Seitenventrikels eingefuhrt und an das Reservoir angeschlossen.