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

Boer, A. de; Stiekema, J. C. J.; Danhof, Meindert; Dinther, T. G. Van; Boeijinga, J. K.; Cohen, Adam F.; Breimer, D. D.

doi:10.1128/aac.35.10.2110

Cited by 4 publications

(1 citation statement)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some of these were selected on the basis of their mechanism of action, which could predict an interaction with Orgaran (i.e. drugs that by themselves may effect haemostasis such as acetylsalicylic acid, acenocoumarol, ticarcillin and cloxacillin) [10][11][12]. Others were se lected on the basis of the frequency of their use (digoxin, chlorthalidone) [13,14].…”

Section: Drug Interactionsmentioning

confidence: 99%

Pharmacokinetic Considerations on Orgaran (Org 10172) Therapy

Danhof¹,

Boer²,

Magnani³

et al. 1992

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

Pharmacokinetic investigations on Orgaran (Org 10172) have been conducted by monitoring the following biological effects: plasma anti-Xa, anti-IIa and Ila-generation-inhibiting (IlaGI) 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 IlaGI activites 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 IlaGI 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 IlaGI 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. It is concluded that the studies on the pharmacokinetics of Orgaran on the basis of its biological effects have been helpful in the development of guidleines for the optimal dosing in thrombosis prophylaxis.

show abstract

Section: Drug Interactionsmentioning

confidence: 99%

Pharmacokinetic Considerations on Orgaran (Org 10172) Therapy

Danhof¹,

Boer²,

Magnani³

et al. 1992

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

show abstract

In vitro susceptibility of Pasteurella multocida subspecies multocida strains isolated from swine to 42 antimicrobial agents

Gutiérrez-Martín

Ferri

1993

Zentralblatt für Bakteriologie

View full text Add to dashboard Cite

Danaparoid

Wilde¹,

Markham²

1997

Drugs

100

View full text Add to dashboard Cite

Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has low cross-reactivity with HIT-associated antibodies. Further comparative trials are needed to confirm these promising findings.

show abstract

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

Cited by 4 publications

References 18 publications

Pharmacokinetic Considerations on Orgaran (Org 10172) Therapy

Pharmacokinetic Considerations on Orgaran (Org 10172) Therapy

In vitro susceptibility of Pasteurella multocida subspecies multocida strains isolated from swine to 42 antimicrobial agents

Danaparoid

Contact Info

Product

Resources

About