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PubMed2000

Primary cutaneous cryptococcosis in a patient with systemic immunosuppression after liver transplantation.

We report a 36-year-old woman who slowly developed an ulceration on the left thigh 2 years after transplantation for Budd-Chiari syndrome. At this time point, the patient was treated with prednisone, tacrolimus and azathioprine for immunosuppression and with phenprocoumon and low-dose aspirin for anticoagulation in the presence of polycythemia vera. A biopsy of the skin lesion was obtained and revealed encapsulated yeast that was identified by microbiological and serological methods as Cryptococcus neoformans serotype D. The patient had no signs of systemic infection and a therapy with fluconazole (200 mg/day) was started. The lesion healed within 8 weeks and fluconazole was stopped after 3 months. Due to interactions between fluconazole, tacrolimus and phenprocoumon, the latter drugs were decreased to prevent toxicity. So far, 1 month after stopping fluconazole, no recurrence of skin lesions has been observed.

Adult↗
PubMed2006

Contribution of CYP2C9 to variability in vitamin K antagonist metabolism.

CYP2C9 is the third most important cytochrome P450 (CYP) in terms of number of drugs metabolised. A considerable amount of information on this isoform is now available with respect to its structural biology, the mechanisms by which it can be induced and the existence of a range of variant alleles, which are often functionally significant. CYP2C9 makes a very important contribution to metabolism of vitamin K antagonist anticoagulants, and is the main oxidising enzyme for S-warfarin and S-acenocoumarol as well as contributing to phenprocoumon metabolism. A large number of studies have now shown that CYP2C9 genotype predicts dose requirement for both warfarin and acenocoumarol, with a possible contribution for phenprocoumon. Patients with variant alleles are likely to require a lower dose and may be at risk of overcoagulation and resultant bleeding, especially during the induction phase of therapy. Although CYP2C9 genotype is clearly a predictor of vitamin K antagonist dose requirement, especially in Caucasian populations in whom variant alleles are common, a number of recent studies have shown that age, genotype for the gene encoding the target gene vitamin K epoxide reductase and concomitant drugs are equally important factors in determining dose. There is a need for prospective studies to assess the value of predicting dose requirement on the basis of all these factors, including the CYP2C9 genotype.

Alleles↗
PubMed2000

Heparin-free DALI LDL-apheresis in hyperlipidemic patients: efficacy, safety and biocompatibility.

BACKGROUND AND AIM OF STUDY: In routine DALI apheresis--the first technique for direct adsorption of lipoproteins from whole blood--heparin plus citrate (ACD-A) is used as anticoagulation regimen. However, recently several publications have warned of heparin-induced thrombocytopenia as a rare but potentially life-threatening complication of heparin administration (HIT type 2). The aim of the present study was therefore to test the efficacy and biocompatibility of DALI using a heparin-free anticoagulation regimen consisting exclusively of citrate. METHODS: Four symptomatic hypercholesterolemic patients on regular DALI apheresis were switched to the heparin-free protocol for two sessions each. Two of the patients were on oral anticoagulation using phenprocoumon. In the weekly sessions, 1.3 patient blood volumes were processed at a blood flow rate of 60 ml/min using ACD-A at a ratio of 1:20 (v/v) during adsorber priming and the session. RESULTS: Clinically, all sessions were essentially uneventful. Uncorrected lipoprotein reductions amounted to 65% for LDL-C, 62% for Lp(a), 53% for VLDL-C, 24% for HDL-C, 17% for triglycerides and 19% for fibrinogen. Cell counts remained virtually constant. No signs of hemolysis or clotting could be detected. Thromboplastin time (Quick) was slightly prolonged and partial thromboplastin time (PTT) moderately elevated in all patients. In contrast, whole blood coagulation time acc. to Lee-White and activated clotting times were increased only in orally anticoagulated patients. Biocompatibility in terms of complement, leukocyte and thrombocyte activation was excellent. Bradykinin activation was moderate peaking at 3038 pg/ml in the efferent line. Systemic thrombin-antithrombin complex (TAT) reflected perfect anticoagulation in orally anticoagulated patients and adequate anticoagulation in the patients without phenprocoumon. CONCLUSION: In this pilot study, heparin-free DALI apheresis was safe and effective and may thus be performed in LDL-apheresis dependent patients who suffer from heparin intolerance.

Adsorption↗
PubMed1992

[Reliable Quick value management by self determination].

Because of the considerably increased risk of thrombembolic complications after implantation of mechanical heart valves, lifelong anticoagulation is required. In the face of frequently unsteady prothrombin-time (PT)-values, a stable anticoagulation is one of the most difficult tasks in attending patients with heart-valve-prosthesis. If PT is out of the therapeutic range, the risk of bleeding or of thrombembolism increases disproportionately. Two differently trained groups of phenprocoumon-treated patients monitored their PT themselves for 6 months by means of a coagulometer, and they also determined their weekly dose of phenprocoumon. PTs were therapeutic 80.5% resp. 93.8% of the time. Intensive training and care maximized safety of anticoagulation.

Coumarins↗
PubMed1965

[Effect of the activity of an indirect anticoagulant by a monoamine oxidase inhibitor].

The combinations of some anticoagulants (phenindione, chlorphenadione, diphenadione, phenprocoumon, 3-[1-(p-chlorophenyl)propyl]-4-hydroxycoumarin, cumachlor and acenocoumarol) with MAO-inhibitors (phenylcyclopropylamino hydrochloride, isocarboxazid, iproniazid, nialamide and p-chloro-N'-[2-(isopropylcarbamoyl)-1-methylethyl]benzohydrazide) were investigated with regard to modification of the anticoagulant activity in the rat. The activity of some anticoagulants like phenindione may be enhanced by the addition of MAO-inhibitors, whereas others (chlorphenadione, phenprocoumon) are only slightly or not at all influenced. The MAO-inhibitors phenylcyclopropylamino hydrochloride and nialamide show enhancement of activity in most combinations whereas iproniazid never does. The other MAO-inhibitors lie between these two extremes.

Animals↗
PubMed1991

The influence of preoperative anticoagulation on heparin response during cardiopulmonary bypass.

The effect of preoperative anticoagulant therapy on intraoperative heparin response in patients undergoing cardiac operations was examined in a prospective study. The study included 45 patients with different preoperative anticoagulant treatments: 10 patients received treatment with phenprocoumon (a warfarin analogue) (group M), 12 patients received treatment with intravenous heparin (group Hiv), and 13 patients received treatment with subcutaneous heparin (group Hsc). The control group consisted of 10 patients who did not receive anticoagulant therapy before operation (group C). Preoperative antithrombin III activity was highest in group M (85% +/- 6%) and lowest in group Hiv (70% +/- 15%, p less than 0.05). The activated clotting time, determined 10 minutes after bolus injection of 250 IU (group M) or 375 IU heparin (all other groups), was 529 +/- 109 seconds in group C, greater than 1000 seconds in group M, 483 +/- 99 seconds in group Hsc, and 406 +/- 63 seconds in group Hiv (p less than 0.05). Heparin consumption during cardiopulmonary bypass varied between 4.6 +/- 1.4 IU/kg.min (group Hiv) and 2.6 +/- 0.9 IU/kg.min (group M) (p less than 0.05). Despite this increased heparin consumption, the patients who had received heparin before operation demonstrated increased activation of coagulation at the end of cardiopulmonary bypass (thrombin-antithrombin III complex, 19 +/- 4.1 ng/ml in group M and 61 +/- 7 ng/ml in group Hsc, p less than 0.05; cross-linked fibrin fragments, 257 +/- 92 ng/ml in group M and 875 +/- 152 ng/ml in group Hiv, p less than 0.05). Increased platelet activation was also found in patients with preoperative heparin therapy (beta-thromboglobulin at the end of cardiopulmonary bypass was 585 +/- 88 ng/ml in group M versus 1341 +/- 190 ng/ml in group Hsc, p less than 0.05). Drainage from the chest tube 24 hours after operation was 815 +/- 305 ml in group C, 644 +/- 238 ml in group M, 1133 +/- 503 ml in group Hsc, and 950 +/- 505 ml in group Hiv (p less than 0.05 for group M versus group Hsc). This study suggests that patients who receive heparin therapy before operation face a high risk of insufficient anticoagulation during cardiopulmonary bypass if standard heparin doses are used. Therefore, for patients who receive preoperative heparin therapy, a larger (500 IU/kg) initial bolus of heparin is recommended before cardiopulmonary bypass. On the other hand, patients who undergo preoperative treatment with phenprocoumon receive sufficient anticoagulative effect with a heparin bolus of 250 IU/kg.(ABSTRACT TRUNCATED AT 400 WORDS)

Antithrombin III↗
PubMed1977

[Effect of alclofenac on the prothrombin level in patients under treatment with anticoagulants].

Simultaneous administration of the anticoagulants acenocoumarol, phenprocoumon or chlorindion and the antirheumatic substance alclofenac in long term trials has no observable influence on the prothrombin time of stabilized patients. When the anticoagulant (acenocoumarol or phenprocoumon) and the alclofenac therapy are begun simultaneously, a variation of the dose is necessary. Either a one-third lower initial dosage can be given, or, after attaining the maximal anticoagulation effect on the prothrombin time (48 h after beginning acenocoumarol therapy, 72 h with phenprocoumarol), a lower daily dosage must be administered once, in comparison to the other group without alclofenac therapy. The maintenace dosage is not influenced by alclofenac.

Aged↗
PubMed1987

[Binding of drugs to artificial plasma substitutes].

The binding of different drugs to plasma proteins as well as the binding to other structures (e.g. dialysis membranes, i.v. delivery sets) is well documented and of therapeutic importance. Colloid solutions of macromolecules are widely used as plasma substitutes and plasma expanders. A possible binding of drugs to these macromolecules was investigated by means of equilibrium dialysis. Benzodiazepines, beta-blockers, cardiac glycosides, local anesthetics, non steroidal antiinflammatory drugs, glibenclamide, phenobarbitone and phenprocoumon (10(-7) in 50 mM tris buffer, pH 7.4) were dialyzed against tris buffer diluted (1:5) commercially available plasma substitutes consisting of hydroxyethyl starch (HES), dextran, gelatine and polyvinylpyrrolidone (PVP). Binding to plasma substitutes was observed with the highest values for penbutolol and oxypolygelatine (41%), digitoxin and HES 200 (35%), phenprocoumon and PVP (43%). It is concluded that the binding of drugs to plasma substitutes is in most cases negligible and not of clinical relevance. Since some drugs seem to bind to some extent to different macromolecules this should be borne in mind and could be of some influence e.g. in perfusion experiments with isolated organs.

Chemical Phenomena↗
PubMedDate not supplied

Liquid chromatographic determination of coumarin anticoagulants in tablets.

A simple and rapid liquid chromatographic method is described for the qualitative and quantitative determination of 5 coumarin anticoagulants in tablet composites and individual tablets. Analyses are carried out on a C18 reverse phase column using tetrahydrofuran-methanol-water-acetic acid (35 + 10 + 65 + 0.1) as mobile phase and photometric detection at 311 nm. The coefficients of variation for 10 consecutive injections of a mixed standards solution ranged from 0.28% for ethyl biscoumacetate to 0.78% for acenocoumarol. Standard recoveries were as follows: acenocoumarol, 99.3%; dicumarol, 99.6%; phenprocoumon, 101.6%; and warfarin sodium, 99.0%. The method was linear between 2 and 8 micrograms of drug injected. Assay results agreed favorably with those of the USP XX methods for dicumarol, phenprocoumon, and warfarin, and the NF XIV method for acenocoumarol. In addition, close correspondence was found with the results previously reported for the same drugs by a semiautomated spectrophotometric method. The content uniformity testing of individual 50 mg dicumarol tablets and 5 mg warfarin sodium tablets by the proposed method gave average (SD) values of 100.32% (0.64) and 101.00% (0.14), respectively, whereas these values were 101.60% (1.81) and 101.80% (0.18), respectively, by the method of USP XX.

Anticoagulants↗
PubMed1984

[Effect of metronidazole on phenazone metabolism].

Nine volunteers received in random order on three occasions either 15 mg/kg phenazone (antipyrine; in the following called phenazone, INN), 15 mg/kg phenazone and 1000 mg cimetidine or 15 mg/kg phenazone and 1000 mg metronidazole. Cimetidine prolonged phenazone half-life from 12.7 +/- 1.0 h to 15.5 +/- 1.0 h (p less than 0.05) and decreased total plasma clearance of phenazone from 40.9 +/- 3.9 ml/min to 33.9 +/- 2.9 ml/min (p less than 0.05). When metronidazole was given with phenazone to the volunteers no change of phenazone pharmacokinetics in plasma occurred. Urinary excretion of the main oxidative metabolites of phenazone (4-hydroxyphenazone, 3-hydroxymethylphenazone and norphenazone) was unaffected during cimetidine as well as metronidazole treatment. Both metronidazole and cimetidine potentiate the anticoagulant effect of warfarin. In contrast it could be shown that cimetidine does not interact with the metabolism of phenprocoumon. Whether metronidazole interferes with the pharmacokinetics of phenprocoumon should be studied in further investigations.

Adult↗
PubMed1993

The pharmacology of oral anticoagulants: implications for therapy.

All oral anticoagulants act by producing a functional deficiency of vitamin K, thereby impairing the normal synthesis of factors II, VII, IX and X. All, except dicumarol, are well absorbed after oral administration. They are highly protein bound and are mainly metabolized in the liver. A number of factors such as altered absorption, distribution, elimination, genetic factors, aging, vitamin K excess or deficiency, alterations in the level of vitamin K-dependent coagulation factors and drug interactions may affect response to oral anticoagulants. Adverse effects include hemorrhage, skin necrosis and teratogenicity. Phenindione can also cause serious hypersensitivity reactions. Five oral anticoagulants are available in Europe, although warfarin, phenprocoumon and nicoumalone (acenocumarol) are the most commonly used agents. The choice of oral anticoagulant is often influenced by previous experience and familiarity, but in a survey of 22 clinical pharmacologists in 12 countries of Europe, warfarin (57%) or phenprocoumon (24%) were the agents recommended most often in clinical practice.

Administration, Oral↗
PubMed1998

[Influence of various antithrombotic therapy methods on the incidence of subacute coronary stent occlusions, hemorrhagic complications and length of hospitalization].

BACKGROUND: The clinical benefit of coronary stenting is reduced by the risk of thrombotic stent occlusion as well as hemorrhagic complications of intensive antithrombotic therapy. We compared the influence of different antithrombotic therapies on the incidence of post-interventional complications and in-hospital stay duration. METHODS: After successful placement of a coronary stent, 334 consecutive patients were given different antithrombotic treatments in addition to aspirin 100 mg/d indefinitely: (1) phenprocoumon for 3 months (n = 47), (2) low molecular weight heparin 2 x 100 U/kg/d s.c. for 4 weeks (n = 90), (3) ticlopidine 2 x 250 mg/d and low molecular weight heparin 2 x 100 U/kg/d s.c. for 4 weeks (n = 72) and (4) ticlopidine 2 x 250 mg/d for 4 weeks (n = 125). RESULTS: Major events were subacute stent thrombosis in 17 patients (5%), and severe hemorrhagic complication in 20 patients (5.9%). The incidence of subacute stent thrombosis in groups 1 to 4 was 10.6%, 11%, 1.4% and 0.8% respectively. The use of ticlopidine was associated with a significant lowering of stent occlusions in univariate and multivariate analysis (p = 0.0013). Additional uni- and multivariate predictors were stent placement as a "bail-out" procedure (p = 0.033) and in patients with acute coronary syndrome (p = 0.049). Anticoagulant therapy was associated with a higher incidence of severe hemorrhagic complications (p < 0.01) and a prolonged in-hospital stay (p = 0.01). CONCLUSIONS: These results confirm that anti-thrombotic therapy with aspirin and ticlopidine combines low rates of subacute stent occlusion and hemorrhagic complications. Treatment with phenprocoumon and low molecular weight heparin does not improve the rate of subacute stent occlusion but increases hemorrhagic complications. Very low rates of stent occlusion permit short in-hospital stays with concomitant reduction in cost.

Acute Disease↗
PubMed1998

Comparative results of thrombolysis treatment with rt-PA and urokinase: a pilot study.

BACKGROUND: The aim of the following prospective study was to investigate whether patients benefited from locoregional lysis treatment of recent deep leg vein thrombosis after 1 year. PATIENTS AND METHODS: The prospective study included 69 patients aged between 22 and 58 years, in whom recent lower leg vein and popliteal vein thromboses were diagnosed by phlebography. Patients were randomized to one of three treatment groups: one group was treated for a maximum of 7 days with full heparinization and daily dose of 20 mg rt-PA administered locoregionally over a period of 4 hours; a second group received 100,000 IU/h urokinase locoregionally for a maximum of 7 days, in addition to full heparinization; and in the third group (control group), intravenous heparin infusions after PTT constituted the only form of treatment. All patients were given phenprocoumon from day 7 and received compression treatment. Before treatment began and before the course of phenprocoumon started, phlebography and colour duplex sonography examinations were carried out. After 12 months, follow-up duplex sonography was conducted to evaluate the reflux times over the popliteal vein and the degree of patency of the deep leg veins. RESULTS: Complete lysis was achieved in 6 of 22 patients in the recombinant tissue plasminogen activator (rt-PA) group and in 11 of 22 patients in the urokinase group. At follow-up examination after 12 months, there were serious post-thrombotic changes in 14 of 22 patients in the rt-PA group, in 9 of 22 patients in the urokinase group and in 15 of 22 patients in the group of patients who received no lysis treatment. CONCLUSION: Patients with recently formed thromboses in the lower leg and popliteal veins who underwent 7 days of locoregional lysis treatment with urokinase demonstrated significantly fewer clinical symptoms of post-thrombotic syndrome after 1 year than those who received locoregional treatment with rt-PA over a similar period or a control group treated with anticoagulants only.

Adult↗
PubMed1992

A decade of oral anticoagulant treatment to maintain autologous vein grafts for femoropopliteal atherosclerosis.

To determine whether long-term oral anticoagulant treatment was effective in improving graft performance and preventing major amputation following vein bypass surgery for femoropopliteal atherosclerosis, a clinical trial was conducted in one single center and continued during 10 years. After 130 patients had electively received a femoropopliteal vein graft, they were randomly assigned to a therapy group (treatment with phenprocoumon [n = 66]) or to a control group (n = 64) that remained without any anticoagulant treatment. Primary end points of the study were graft reocclusion and limb loss. The median durations of primary patency and limb salvage were significantly longer for treated patients than that for controls. In addition, survival in the therapy group was longer. Following autologous vein bypass surgery in the treated group, the results were superior in terms of graft patency, limb salvage, and survival.

Administration, Oral↗
PubMed1994

Nitric oxide production depends on preceding tetrahydrobiopterin synthesis by endothelial cells: selective suppression of induced nitric oxide production by sepiapterin reductase inhibitors.

Using murine vascular endothelial cells expressing both constitutive and inducible nitric oxide synthases (cNOS and iNOS), we explored the feasibility of suppressing cytokine-induced nitric oxide (NO) production without affecting constitutive NO production by inhibition of the tetrahydrobiopterin (BH4) biosynthesis. We show in this study that in endothelial cells cytokine/endotoxin-activated BH4 synthesis precedes the induction of NO generation. Using the sepiapterin reductase inhibitors phenprocoumon or dicumarol as BH4 synthesis inhibitors, we achieved a pronounced and selective suppression of induced NO production in cytokine-activated endothelial cells. Addition of exogenous BH4, but not sepiapterin, restored NO production in the presence of the inhibitors. Despite profound inhibition of the BH4 biosynthesis, constitutive NO synthesis was not affected, thereby demonstrating the selectivity and specificity of the inhibitors. Suppression of enhanced NO production by sepiapterin reductase inhibitors such as cumaroles could provide pharmacologic means for therapeutic interventions in NO-mediated pathophysiologic events.

Alcohol Oxidoreductases↗
PubMed1986

A simplified functional assay for protein C in plasma samples.

The important role of protein C (PC) in the regulation of hemostasis has been appreciated since the description of patients who were deficient in PC and presented with severe thromboembolic events. The potentially fatal complications associated with PC-deficiency require an early and reliable identification of those patients affected with this inherited disorder. The present study introduces a test procedure for the functional assessment of PC in plasma samples. The test utilizes the thrombin/thrombomodulin complex to achieve complete and rapid formation of activated PC whose proteolytic capacity is subsequently determined with a chromogenic substrate. Homogenate obtained from rabbit lung effectively substituted the purified component thrombomodulin in the assay system. This new approach simplifies the test procedure without losing specificity and accuracy. Proteases, such as plasmin, streptokinase and urokinase did not influence the assay and the inhibitory effect of heparin on the PC-activation could easily be overcome by the addition of protamine sulphate. The PC-activity in a group of unselected patients (n = 50), who did not reveal any abnormalities in global coagulation tests, amounted to 100 +/- 12% (mean +/- SD) with a range from 54 to 143% when analyzed in comparison to a plasma pool constituted from healthy volunteers. Since the synthesis of PC depends on the availability of vitamin K, patients receiving phenprocoumon have also been analyzed. These patients (n = 103) presented 40 +/- 11% residual PC-activity accompanied by a concomitant decrease in PC-antigen levels to 43 +/- 10% (mean +/- SD). The test described is specific, sensitive, less time-consuming and can be performed on a routine basis.

Adult↗
PubMed1978

Successful prevention of coumarin-induced hemorrhagic skin necrosis by timely administration of vitamin k1.

Successful prevention of the progression of incipient hemorrhagic skin necrosis by timely administration of vitamin K1 in a woman treated with phenprocoumon is presented. From a critical review of the literature strong evidence emerges that coumarin necrosis does only occur in cases with severe initial drug induced hypocoagulability. Non- recognition thusfar of its importance is due to insufficient knowledge of the biological activities of thromboplastin preparations presently used in the laboratory control of oral anticoagulation. All well documented cases with apparently adequate Quick values were monitored with Faktor VIII insensitive thromboplastin. Therefore, such preparations should no longer be used in anticoagulant control.

4-Hydroxycoumarins↗
PubMed1992

Monitoring prothrombin fragment 1 + 2 during initiation of oral anticoagulant therapy after intracoronary stenting.

Patients with intracoronary stent implantation are treated with aggressive anticoagulant and antiplatelet therapy consisting of high-dose heparin, phenprocoumon, acetylsalicylic acid, dipyridamole, and the infusion of dextran to prevent a subacute thrombotic occlusion of the stented segment. In an effort to optimize this treatment by reducing both imminent bleeding complications and subacute thrombotic occlusion, the concentrations of prothrombin fragment 1 + 2 (F 1 + 2) were determined after intracoronary Palmaz-Schatz stent implantation in 19 consecutive patients. The F 1 + 2 concentrations after stent implantation and before the initiation of oral anticoagulant therapy (OAT) were 0.35 nm/l and 0.25-0.53 nm/l (median and 25th-75th percentile), versus 0.74 nm/l and 0.52-0.78 nm/l, in healthy subjects and 0.61 nm/l and 0.30-1.02 nm/l in 15 patients with ongoing proximal DVT. Nine days after initiation of OAT, F 1 + 2 concentrations in both patient groups had not yet reached levels observed in patients with OAT in the stable state (0.16 nm/l, 0.12-0.26 nm/l; n = 76; P less than 0.0001 compared with healthy subjects; INR 2.0-4.5). Despite an INR greater than 2.0, accompanying heparinization was terminated on day 9. In two stented patients a minor bleeding complication arose after the removal of the arterial catheter. Subacute thrombotic occlusions were not observed. Since F 1 + 2 concentrations did not exceed the upper limit of normal range (1.11 nm/l) in any of the 19 patients, the therapeutic regimen was not changed. Monitoring F 1 + 2 may thus be helpful in introducing a more individual treatment if aggressive anticoagulation has to be performed.

Administration, Oral↗