M. Danhof

Pharmacokinetic considerations on Orgaran (Org 10172) therapy

Pharmacokinetic investigations on Orgaran (Org 10172) have been conducted by monitoring the following biological effects: plasma anti-Xa, anti-IIa and IIa-generation-inhibiting (IIaGI) activities. In addition, a limited number of studies were conducted on the basis of concentrations of the No-affinity glycosaminoglyc(uron)an (NoA-GAG) fraction as determined by a competitive binding assay. In humans, widely different pharmacokinetic profiles for various biological effects were observed, with relatively short elimination half-lives for the anti-IIa and IIaGI activities of 4.3 +/- 3.5 and 6.7 +/- 3.2 h, respectively, but a relatively long elimination half-life of anti-Xa activity of 24.5 +/- 9.6 h. These differences in half-life mainly reflect differences in the rate of elimination of individual components of Orgaran. Rapid elimination of some of these components may explain why twice daily dosing is required for optimal thrombosis prophylaxis with Orgaran. In a comparative study in healthy male volunteers, the pharmacokinetics of the following low molecular weight heparin(oid)s were determined after intravenous administration: Orgaran (3,750 anti-Xa units), Fragmin (5,000 anti-Xa units), Fraxiparine (7,500 IC units) and Clexane (40 mg). Between these products, wide differences in pharmacokinetics were observed. Particularly, the half-lives of anti-Xa activity and IIaGI activity were much longer for Orgaran than for the other products. At the same time, a relatively low area under the curve of anti-IIa activity was observed. The absolute bioavailability of Orgaran following subcutaneous administration was determined on the basis of plasma anti-Xa and IIaGI activities and the NoA-GAG fraction concentrations. Absorption from subcutaneous tissues was found to be close to 100%, which is significantly higher than of heparin; a finding which indicates that the subcutaneous route is reliable for the administration of Orgaran. The elimination of Orgaran components occurs by renal and possibly non-renal routes. With respect to anti-Xa activity, about 50% of the total clearance can be accounted for by urinary excretion. Therefore, in severe renal failure, a reduction of the maintenance dose of Orgaran would seem to be indicated. Studies on the influence of enzyme induction as a result of treatment with pentobarbital suggest that the pharmacokinetics of Lomoparan are relatively insensitive to changes in hepatic function. In a number of studies, the influence of conditions such as age, body weight and drug interactions were studied. Generally, only minor changes in the pharmacokinetic parameters of Orgaran were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

The Use of Intracerebral Microdialysis for the Determination of Pharmacokinetic Profiles of Anticancer Drugs in Tumor-Bearing Rat Brain

AbstractPurpose. The use of intracerebral microdialysis as a tool to measure the penetration of anticancer agents in brain tumor was investigated.nMethods. Following intravenous (iv) administration of 75 mg/kg. concentration-time profiles of methotrexate (MTX) were determined in brain cortical dialysate and in plasma. The individual ratio of the area under the curve of MTX in brain dialysate over that in plasma (MTX penetration) was determined in normal brain, in tumor-bearing brain and in brain after sham tumor implantation. Individual brains were examined histologically on the presence of tumor, as well as for other factors that might influence local MTX penetration. Histological scores were related to the individual data on penetration of MTX.nResults. MTX penetration values were higher in cortical brain at the site of the tumor, as compared to the levels measured in normal or sham implanted brain (mean increase to 250 %). In the cortical brain contralateral to the tumor, MTX penetration values were found to be lower than in normal brain (mean reduction of 65 %). Furthermore, it appeared that in the absence of tumor tissue, the presence of exudate around the probe was independently associated with increased penetration of MTX into the brain.nConclusions. Tumor tissue appeared to be the most important parameter in changing local MTX penetration in brain after tumor implantation. In general, it is anticipated that intracerebral microdialysis combined with histological examination can be used to investigate effects of brain tumor presence on regional (periprobe) penetration of anticancer drugs into the brain.

Hemodynamic effects and histamine release elicited by the selective adenosine A3 receptor agonist 2-CL-IB-Meca in concious rats

The hemodynamic effects of the novel, selective adenosine A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5-N-methylcarboxamide (2-Cl-IB-MECA) were investigated in conscious rats. Intravenous administration of 200 micrograms/kg 2-Cl-IB-MECA resulted in a short-lasting hypotension, which was accompanied by a 50-100-fold increase in plasma histamine concentrations. Administration of a second dose of 2-Cl-IB-MECA did not elicit any hemodynamic effects. Also no histamine release was observed after the second dose. The observation of rapid tachyphylaxis in combination with histamine release suggests that mast cell mediator release plays a key role in the hemodynamic effects of adenosine A3 receptor agonists.

On the reliability of affinity and efficacy estimates obtained by direct operational model fitting of agonist concentration-effect curves following irreversible receptor inactivation

Recently, Zernig and colleagues (1996) (J Pharmacol Toxicol Meth 35: 223-237) suggested that for the estimation of agonist affinity and efficacy, the method of simultaneously fitting of concentration-effect curves from control and irreversible antagonist-treated tissues to the operational model of agonism is superior to other analytical approaches. In the present study, we have evaluated the limitations of this simultaneous curve fitting method. Simulation studies showed that this method can be only employed with confidence when the upper asymptotes of the control curves display minimal variation between tissues, which makes its practical utility rather limited. The unreliability of the simultaneous fitting procedure was further underscored with the analysis of experimental data obtained from the interaction between noradrenaline and phenoxybenzamine in rat isolated aorta. The lack of robustness of the parameter estimates showed that under standard experimental conditions the outcomes of simultaneous model fitting are highly dependent on between-tissue variations of the upper asymptotes of the control curves and, therefore, may be unreliable. Therefore, whenever possible, a multiple curve design should be adopted, in which control and treated curves are obtained in one tissue and provide enough information for an independent estimation of affinity and efficacy that is free of intertissue differences.

Drug transport across the blood — brain barrier: II. Experimental techniques to study drug transport

This is part II of a review on the transport of drugs across the blood-brain barrier. In this part, the emphasis is on the various experimental techniques that can be used to characterize the blood — brain barrier transport of drugs. Generally speaking, three approaches can be distinguished:in vitro techniques using isolated brain capillaries, cerebrovascular endothelial cells in primary culture or endothelium-derived cell lines;in vivo techniques (both single-passage and multi-passage techniques) andin situ perfusion techniques. Each of these techniques has specific advantages and disadvantages associated with it. Therefore, in many instances, a combination of different approaches is needed to study the fundamental aspects of drug transport across the blood-brain barrier.

Understanding the Behavior of Systems Pharmacology Models Using Mathematical Analysis of Differential Equations: Prolactin Modeling as a Case Study

In this tutorial, we introduce basic concepts in dynamical systems analysis, such as phase‐planes, stability, and bifurcation theory, useful for dissecting the behavior of complex and nonlinear models. A precursor‐pool model with positive feedback is used to demonstrate the power of mathematical analysis. This model is nonlinear and exhibits multiple steady states, the stability of which is analyzed. The analysis offers insight into model behavior and suggests useful parameter regions, which simulations alone could not.

Interaction of the Combined Medication with the New Low-Molecular-Weight Heparinoid Lomoparan® (Org 10172) and Acenocoumarol

A high intravenous dose of the low-molecular-weight heparinoid Lomoparan (Org 10172) was administered to 6 healthy males in a steady state of anticoagulation (Thrombotest) by acenocoumarol. Prothrombin time, activated partial thromboplastin time and Stypven time were prolonged to a degree which was greater than that expected on the base of the summation of the effects by each drug alone. This effect was observed for a period of up to 1 h. The Thrombotest was affected for up to 5 h after the intravenous administration of Org 10172, therefore it is deemed unsuitable for monitoring the combined effects of these two anticoagulants during this period. Acenocoumarol did not affect the pharmacokinetic parameters of Org 10172 with the exception of a slight reduction of the clearance of plasma anti-Xa activity.

Studies of interaction of a low-molecular-weight heparinoid (Org 10172) with cloxacillin and ticarcillin in healthy male volunteers.

Pharmacokinetic and pharmacodynamic interactions between Org 10172 (intravenous bolus injection of 3,250 anti-Xa units), which is a low-molecular-weight heparinoid, cloxacillin (500 mg orally four times daily for 3 days), and ticarcillin (4,000 mg intravenously four times daily for 2 days) were evaluated in two separate studies with healthy male volunteers (n = 18). Both cloxacillin and ticarcillin caused a significant increase in elimination half-life of anti-Xa activity, i.e., from 31 +/- 10 to 54 +/- 23 h and from 27 +/- 6 to 42 +/- 13 h, respectively (P less than 0.05). Ticarcillin decreased clearance (11%) and increased apparent volume of distribution (35%) (P less than 0.05), while for cloxacillin, these differences did not reach statistical significance. These changes in disposition of Org 10172 by the penicillins were not accompanied by important pharmacodynamic changes as evaluated by coagulation tests, platelet aggregation, and bleeding time. Cloxacillin appeared to influence blood coagulation (prolongation of the activated partial thromboplastin time and shortening of thrombin time; P less than 0.05) and facilitated thrombin-induced platelet aggregation, which coincided with a shorter bleeding time during the combined treatment in comparison with the time during treatment with Org 10172 alone (P less than 0.05). In conclusion, the disposition of Org 10172 was slightly changed by cloxacillin and ticarcillin, and, unexpectedly, cloxacillin appeared to have mild procoagulant effects.