Determination of alinidine in human plasma by high-performance liquid chromatography.

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…

Interruption of the enterohepatic circulation of phenprocoumon by cholestyramine

The effect of cholestyramine (12 gm/day divided into 3 doses) on the pharmacokinetics and pharmacodynamics of a single intravenouse dose (30 mg) of phenprocoumon was studied in 6 normal subjects. Cholestyramine treatment led to an increase in the rate of elimination of phenprocoumon in all. Total clearance increased 1.5- to 2-fold. The total anticoagulant effect per dose was considerably reduced during treatment with cholestyramine. Binding studies in vitro showed that phenprocoumon is strongly bound to cholestyramine and that at a given cholestyramine concentration the percentage of phenprocoumon bound remained constant over a large concentration range of phenprocoumon. The results suggest…

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 (…

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

Evidence for Impaired Hepatic Vitamin K1 Metabolism in Patients Treated with N-Methyl-Thiotetrazole Cephalosporins

SummaryIn 8 patients on no oral intake and with parenteral alimentation, administration of cephalosporins with N-methyl-thiotetrazole side chain (moxalactam, cefamandole), was associated with prolongation of prothrombin time, appearance in the circulation of descarboxy-prothrombin (counter immunoelectrophoresis and echis carinatus assay) and diminution of protein C. Acute administration of 10 mg vitamin Ki was followed by the transient appearance of vitamin K1 2,3-epoxide, indicating an impaired hepatocellular regeneration of vitamin K1 from the epoxide. Impaired hepatic vitamin K1 metabolism, tentatively ascribed to the N-methyl-thiotetrazole group, is one (but possibly not the only) cause…

Pharmacokinetic analysis of the interaction between dicoumarol and tolbutamide in man

The effect of repeated administration of tolbutamide on the elimination and anticoagulant action of a single oral dose of dicoumarol 600 mg was studied in four healthy male subjects using a crossover design. In all subjects the plasma concentration of dicoumarol in the postabsorptive phase was lower during concomitant tolbutamide treatment. However, the subjects differed with respect to the elimination kinetics of dicoumarol and the effect of tolbutamide on some of the measured pharmacokinetic paramaters. In two subjects dicoumarol was eliminated by apparent first-order kinetics. Tolbutamide led to a pronounced increase in the elimination rate and a shift in the plasma concentration-respons…

Quantitative analysis of vitamin K1 and vitamin K1 2,3-epoxide in plasma by electron-capture gas-liquid chromatography.

Rapid gas chromatographic determination of underivatized phenprocoumon in plasma.

Azapropazone binding to human serum albumin

Azapropazone, a new non-steroidal antiinflammatory drug, is strongly bound to human serum albumin. As revealed by Scatchard analysis, one high-affinity binding site with an association constant of about 1.2 x 10(6)M-1 and two low-affinity binding sites with association constants of about 0.05 x 10(6)M-1 were found. While the high-affinity binding site of azapropazone is clearly not identical with the diazepam or digitoxin binding sites of human serum albumin, contradictory evidence was found by optical measurements and displacement studies for the similarity of the azapropazone and the warfarin binding site of human serum albumin. At present, it is suggested that both drugs bind to differen…

Anticoagulant Activity of the Enantiomers of Acenocoumarol in Man

For the mono-coumarin derivatives warfarin and phen-procoumon it was shown that in man and rats the S(−) enantiomer is several times more potent as anticoagulant than the R(+) enantiomer. These stereoselective differences in the anticoagulant potency reflect differences in the affinity for the receptor site rather than differences in the pharmacokinetics.

PLASMA CONCENTRATION-EFFECT RELATIONSHIP OF THE ANTIARRHYTHMIC AGENT LORCAINIDE

The enantiomers of phenprocoumon: pharmacodynamic and pharmacokinetic studies.

The pharmacodynamics and pharmacokinetics of the optical enantiomers of phenprocoumon were studied in 5 normal subjects and compared to the racemic mixture. Each subject received a single oral dose of 0.6 mg/kg of racemic, S(-), and R(+) phenprocoumon. S(-) phenprocoumon was 1.6 to 2.6 times as a potent as R(+) phenprocoumon when the area under the effect/time curve was used to quantify the total anticoagulant effect per dose. Comparing the plasma concentrations that elicited the same anticoagulant effect, S(-) phenprocoumon was 1.5 to 2.5 times as potent as R(+) phenprocoumon. The anticoagulant activity of the racemic mixture was between that of the enantiomers. There was no distinct diffe…

Determination of bupivacaine in human plasma by high-performance liquid chromatography.

Lorcainid — Pharmakokinetik und Pharmakodynamik

Nutzen und Notwendigkeit der heute praktizierten antiarrhythmischen Therapie sind umstritten. Gerade lebensbedrohliche Arrhythmien erweisen sich einer Standardtherapie mit konventionellen Antiarrhythmika gegenuber haufig als refraktar, wahrend eine erfolgreiche Therapie mit z. T. erheblichen Nebenwirkungen erkauft werden mus. Eine Verbesserung des Therapieerfolges erhofft man sich sowohl aus der Innovation neuer, wirksamerer und nebenwirkungsarmerer Antiarrhythmika, als auch aus der Anderung der therapeutischen Strategie (Ersatz der Standardtherapie durch eine individuell angepaste Dosierung).

Lorcainide; II. Plasma concentration-effect relationship

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…

Haemodynamic effects of a single intravenous dose of lorcainide in patients with heart disease

The cardiovascular effects of a single i.v. dose (2 mg/kg over 5 min) of lorcainide were studied in 14 patients with heart disease. In the haemodynamic part of the study (6 patients), the aortic and pulmonary systolic, diastolic and mean pressures, left ventricular systolic and end-diastolic pressures, cardiac output and the rate of rise of left ventricular pressure were measured before and for 30 min after administration of the drug. Lorcainide produced a slight and short-lasting decrease in the aortic and pulmonary systolic pressures, and all other pressure values remained unchanged. The cardiac output and systemic vascular resistance were not altered by lorcainide. It consistently depres…

Differential effect of the enantiomers of phenprocoumon and warfarin on the vitamin K1-epoxide/vitamin K1 ratio in rat plasma.

Disposition of azapropazone in chronic renal and hepatic failure.

The disposition of azapropazone 600 mg i.v. was investigated in 6 healthy subjects, 13 patients with cirrhosis and 8 patients with renal failure. In healthy subjects the elimination half-life was 12.2±2.1 h (mean ± SD), the volume of distribution 10.6±3.31 and the total clearance was 597±135 ml·h−1. Renal clearance accounted for about 62% of the total clearance. The free fraction of azapropazone in the plasma was 0.0045±0.0006. The patients with cirrhosis were divided into Group I with modest and Group II with severe impairment of liver function. In Group I the total clearance of azapropazone was not significantly different from that in healthy subjects. There was a 2.5-fold increase in its…

Stereoselective drug distribution and anticoagulant potency of the enantiomers of phenprocoumon in rats

Abstract The elimination, distribution and anticoagulant activity of S(—)-, R(+)-, and R,S(±)-phenprocoumon were determined in male Wistar-Lewis rats after intravenous injection of a single dose of 0·6 mg kg−1. From the plasma concentrations which elicited the same anticoagulant effect, S(—)-phenprocoumon was 4 to 5 times more potent than R(+)-phenprocoumon. The potency of the racemate was between those of the enantiomers. The mean biologic half-life of the S(—)-enantiomer was shorter (12·5 h) than that of R(+)-phenprocoumon (17·8 h). No differences were observed in the apparent volume of distribution. However, the mean liver: plasma concentration ratio was higher for the S(—)-(6·9) than fo…

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…

Displacement of phenprocoumon (Marcumar) from albumin by sulfonylurea compounds, suramin, and ioglycamic acid.

The technique of Sephadex gel filtration was employed to characterize the effect of some sulfonylurea compounds, ioglycamic acid, and suramin on the binding of phenprocoumon to bovine serum albumin.

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…

SATURABLE PRESYSTEMIC ELIMINATION OF THE ANTIARRHYTHMIC DRUG LORCAINIDE

Interaction of phenylbutazone with racemic phenprocoumon and its enantiomers in rats.

The interaction of phenylbutazone with the enantiomers and racemic [ 3 H]phenprocoumon was studied in male inbred Wistar-Lewis rats following a single i.v. dose of the three forms of phenprocoumon and chronic oral treatment with phenylbutazone (average plasma concentration of about 60 Μg/ml). Phenylbutazone augmented the anticoagulant effect of R(+), S(−), and R, S (±) phenprocoumon to a similar extent. The free fraction of drug in the plasma of the enantiomers and racemic phenprocoumon increased in the presence of phenylbutazone. However, the rate of elimination of total drug from plasma and liver and the distribution between liver and plasma of all three forms of phenprocoumon remained ne…

Kardiovaskuläre Effekte von Lorcainid, einer neuen antiarrhythmischen Substanz

Wir untersuchten die kardiovaskularen Effekte eines neuen und sehr wirksamen Antiarrhythmicums vom Lokalanasthetika-Typ. Folgende Parameter wurden wahrend einer diagnostischen Herzkatheteruntersuchung gemessen: Aortendruck, Pul- monalarteriendruck, Herzminutenvolumen, linksventrikularer Druck und dp/dt max. Nach i.v. Gabe von Lorcainid (2 mg/kg) kam es zu einer zeit- und dosisabhangigen Verminderung aller Kontraktilitatsindizes: dp/dt max. wurde maximal um 18.75% gegenuber der Ausgangslage reduziert. Alle Veranderungen waren bis zur 15. min nach Infusionsende maximal und zeigten innerhalb von 30 min eindeutige Ruckbildungstendenz. Der systolische Aortendruck, der linksventrikulare Druck, da…

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.

Lorcainide. I. Saturable presystemic elimination.