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PubMed2003

Oral anticoagulation for ECG tremor artefact simulating atrial fibrillation.

That tremor simulates atrial fibrillation and causes oral anticoagulation has not been reported. In a 69-year-old patient with diabetes, arterial hypertension and recurrent strokes, hand tremor developed since 1998. In September 2000 atrial fibrillation was diagnosed upon a routine and 24-hour ambulatory ECG. Because of the additional risk factors for stroke/embolism, phenprocoumon was begun. The diagnosis was changed to paroxysmal AF upon the following ECGs, showing sinus rhythm. Not earlier than 1 year after establishing the diagnosis,"atrial fibrillation" was identified as being due to a tremor artefact. Phenprocoumon was discontinued. Neurological investigations revealed Parkinson's disease as the cause of the tremor. Three weeks after initiation of pramipexol, the tremor artefact was no longer visible on ECG. Misinterpreting an ECG-artefact due to Parkinsons's tremor as atrial fibrillation may be followed by unnecessary diagnostic and therapeutic procedures, including long-term oral anticoagulation. Upon adequate treatment of Parkinson's disease, the tremor artefact immediately disappears from the ECG.

Aged↗
PubMed2003

Life threatening bleeding under adequate oral anticoagulation. Cases 4a, b.

We report on two men with severe and recurrent bleeding episodes under well performed phenprocoumon therapy. Both patients showed an INR value within the therapeutic/subtherapeutic range with an inappropriately prolonged activated partial thromboplastin time (aPTT). The vitamin K-dependent coagulation factors were in the expected range, except for factor IX, which was as low as in moderate haemophilia B. After substitution of vitamin K, factor IX and the aPTT recovered completely in one case. In the other case factor IX was not measured but aPTT normalized. Diagnosis of an increased sensitivity of factor IX to phenprocoumon was assumed and proven in both cases by the demonstration of a missense mutation at ALA-10 in the factor IX propeptide.

Administration, Oral↗
PubMed2004

[Extent and quality of anti-coagulation treatment with coumarin derivatives by the Dutch Thrombosis Services].

OBJECTIVE: To obtain an impression of the extent and quality of the anti-coagulation treatment with coumarin derivatives carried out by the Thrombosis Services in the Netherlands. DESIGN: Descriptive. METHOD: Data were drawn from the medical annual reports of 62 of the 63 Thrombosis Services in the Netherlands over the period 1998-2002. In 2002 the Thrombosis Services treated 325,072 patients and performed 4,469,730 INR laboratory tests. The half-yearly figures produced by the Thrombosis Services were calculated as an average percentage per year per thrombosis service and then recalculated as a percentage per year. RESULTS: Seventy-three per cent of the patients were treated for an arterial and 27% for a venous indication. Depending on the required intensity of anticoagulation a mean of 74-78% of the long-term treated patients fell within the therapeutic range and a mean of 6-10% below. The mean number of major bleedings per 100 treatment years was 1.0. A mean of 79% of the patients was treated with acenocoumarol and 21% with phenprocoumon. When acenocoumarol was used, a mean of 72-77% fell within the therapeutic range and in the case of phenprocoumon 79-82%. In the last few years the number of patients had increased due to a growing number of patients treated for atrial fibrillation. The percentages of INR within the therapeutic range were unchanged or showed a slight increase. CONCLUSION: The quality of the anticoagulation therapy with coumarin derivatives was good or acceptable.

Acenocoumarol↗
PubMedDate not supplied

Liquid chromatographic determination of coumarin anticoagulants in tablets: collaborative study.

A liquid chromatographic method for the determination of coumarin anticoagulants in tablets was collaboratively studied by 7 laboratories. The method uses an octadecylsilane-bonded microparticulate column, tetrahydrofuran-methanol-water-acetic acid mobile phase, and photometric detection at 311 nm. Each collaborator received samples of warfarin sodium, phenprocoumon, and dicumarol as a synthetic composite and as commercial individual and composited tablets. Pooled average assay values for synthetic and commercial tablet samples of warfarin sodium were 101.6 and 99.5%, respectively, with a combined reproducibility SD of 2.38% (CV = 2.37%) and combined repeatability SD of 1.49% (CV = 1.49%). Pooled average (SD) assay values for dicumarol and phenprocoumon commercial samples were 98.0 (2.27) and 101.3% (4.00), respectively. The content uniformity determinations of 2 mg warfarin sodium and 25 mg dicumarol tablets indicated average tablet contents (range) of 99.5% (91.0-116.0) and 98.0% (89.8-108.8), respectively. The method has been approved interim official first action.

Chromatography, Liquid↗
PubMed1988

Circulating osteocalcin during oral anticoagulant therapy.

In this paper we present the following observations: 1) In sheep vitamin K-antagonists like phenprocoumon induce a decrease of the serum levels of osteocalcin (bone Gla-protein) and of the affinity of the circulating osteocalcin for hydroxyapatite. 2) In sheep vitamin K counteracts the effect of phenprocoumon on the blood coagulation system, but not that on the osteocalcin production. 3) In human subjects vitamin K-antagonists also lead to decreased levels of serum osteocalcin and a low affinity of the protein for hydroxyapatite. 4) These two variables reached steady-state levels within 24 h after the start of oral anticoagulant treatment and--at continuation of the therapy--they remained low for at least several years.

Acenocoumarol↗
PubMed1979

[Drug interaction during therapy with tolbutamide. The influence of some commonly used drugs on plasma level and half life in diabetic out-patients (author's transl)].

Tolbutamide belongs to those drugs responsible for the majority of drug interactions. E.g. Tolbutamide metabolism has been shown to be inhibited by coumarole derivatives. We determined plasma-tolbutamide levels in diabetic out-patients for one year. The results obtained indicate no difference in patients additionally treated with either digoxin or digoxin and alpha-methyldopa, or buformin and phenprocumone as compared with control groups. Interactions with respect to biotransformation should not be expected as far as digoxin, alpha-Methyldopa, or buformine were concerned, since these compounds do not share a common metabolic pathway with tolbutamide. In a different group of patients the elimination half life of tolbutamide under the influence of phenprocoumone was additonally determined. Differences could not be detected. This finding can be explained by means of enzyme-kinetic considerations, since phenprocumone, in contrast to dicoumarole, becomes metabolized according to a first order reaction. Competitive enzyme inhibition with tolbutamide which is metabolized similarly to phenprocoumone, therefore appears improbable.

Buformin↗
PubMed1994

Heart transplantation under coumarin therapy: friend or foe?

Thirty-six patients were included in a retrospective study of the effect of pre-operative anticoagulant therapy on peri-operative blood loss and haemostatic changes after heart transplantation. Eleven patients (group H) had received intravenous heparin for at least 3 weeks before cardiac transplantation. Twelve patients (group P) had been transplanted when fully anticoagulated with phenprocoumon. A control group of 13 patients (group C) had undergone bypass grafting of their coronary arteries with no pre-operative anticoagulant therapy. Post-operative drainage from the chest drains was 700 ml (median) in group H, 425 ml in group P, and 360 ml in group C (group H vs. group C: P < 0.05). After heparinization for cardiopulmonary bypass, activated clotting time was 462 s (median) in group H, 1500 s in group P, and 727 s in group C (P < 0.003 vs. groups H and P). Post-operatively, patients in group P were given more units of fresh frozen plasma (median 2.5 units; P < 0.01), prothrombin complex concentrate (median 1000 I.U.; P < 0.05) and vitamin K (median 10 mg; P < 0.05) than groups H and C. Heart transplantation under full phenprocoumon therapy does not increase the likelihood of complications caused by peri-operative bleeding.

Adult↗
PubMed1994

Assessment of therapeutic quality control in a long-term anticoagulant trial in post-myocardial infarction patients.

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

Acenocoumarol↗
PubMed1996

[Liver injury caused by coumarin anticoagulants: experience of the IKS (Intercanton Monitoring Station) and the SANZ (Swiss Center for Drug Monitoring)].

Drug-induced liver diseases are potentially avoidable. Hepatotoxic drugs can mimic virtually any form of liver disease. Among all voluntary adverse drug reaction reports to central registries, 4-7% refer to drug-induced liver diseases. We analyze all cases of coumarin-induced hepatic injuries reported on a voluntary basis to the Swiss Drug Monitoring Centre (SANZ) and the Pharmacovigilance Centre (IKS) from 1981 to 1995. During this period the SANZ collected 9720 reports, 674 of which (6.9%) referred to the liver and the biliary tract. In only 11 reports an oral anticoagulant was involved. In 8 cases we assumed at least a possible causal relationship. 2 more cases were reported directly to the IKS. Among these 10 cases 7 were related to phenprocoumon and 3 to acenocoumarol. In 4 cases elevated concentrations of liver enzymes were measured 2-7 days after the beginning of therapy. In the remaining 6 cases the clinical picture was so severe that the patients had to be hospitalized. These 10 cases are discussed and compared with the cases published in the literature. According to our data, hepatic disorders induced by coumarin-anti-coagulants are rare. If hepatitis is diagnosed in a patient treated with oral anticoagulants, the differential diagnosis of a coumarin-induced hepatic injury has to be considered. Crossreactions between the coumarin derivatives phenprocoumon and acenocoumarol are possible.

Acenocoumarol↗
PubMed1997

Restenosis after coronary stent placement and randomization to a 4-week combined antiplatelet or anticoagulant therapy: six-month angiographic follow-up of the Intracoronary Stenting and Antithrombotic Regimen (ISAR) Trial.

BACKGROUND: Platelets and mural thrombus at the lesion site may play a key role in initiating the restenosis process after coronary interventions. The ISAR Trial provides a comparison of the outcomes of patients randomized to two different antithrombotic regimens administered for 4 weeks after successful coronary stent placement: combined antiplatelet therapy (aspirin plus ticlopidine) or a conventional anticoagulant regimen (phenprocoumon with initial overlapping heparin plus aspirin). Within the first 4 weeks after stent placement, combined antiplatelet therapy has been associated with a significant reduction of ischemic complications. In the present study, we examined whether combined antiplatelet therapy administered for 4 weeks after stent placement is able to reduce the process of restenosis at 6 months. METHODS AND RESULTS: Of 517 patients initially randomized, 496 were eligible for 6-month angiographic follow-up. Scheduled angiography was performed in 432 of the eligible patients (87.1%), 216 in each group. In a comparison of the two groups, there were no significant differences in clinical and procedural variables or in qualitative and quantitative lesion characteristics before and after stenting. At 6 months, minimal luminal diameter was 1.95+/-0.86 mm in the group with initial combined antiplatelet therapy and 1.90+/-0.87 mm in the group with initial anticoagulant therapy (P=.55). Late lumen loss was 1.10+/-0.81 and 1.15+/-0.75 mm (P=.54), and the restenosis rate was 26.8% and 28.9%, respectively (P=.70). Target lesion revascularization rate was 14.6% in the antiplatelet therapy group and 15.6% in the anticoagulant therapy group (P=.85). CONCLUSIONS: This study shows that combined antiplatelet therapy (aspirin plus ticlopidine) administered for 4 weeks after coronary Palmaz-Schatz stent placement does not result in a detectable benefit for the prevention of restenosis compared with conventional anticoagulant therapy (phenprocoumon with initial overlapping heparin plus aspirin).

Administration, Oral↗
PubMed1998

Increased fraction of circulating activated platelets in acute and previous cerebrovascular ischemia.

Determination of circulating activated platelets may be helpful to estimate the prognosis and to stratify therapies in arterial vascular disorders including stroke. We used flow cytometry and phase contrast microscopy to study whether the fraction of platelets expressing p-selectin and CD63 and the fraction of platelets with shape change are increased in patients with acute and previous cerebrovascular ischemia. The proportion of platelets expressing activation dependent antigens was higher in patients with acute (n = 24; p-selectin: 8.23 +/- 4.21%; CD63: 3.53 +/- 2.53%) and with previous cerebrovascular ischemia (n = 46; 3.86 +/- 1.98%; 2.80 +/- 1.79%) as compared to age- and sex-matched control subjects (n = 35; 2.17 +/- 0.96%; 1.79 +/- 0.75%; p < or = 0.005, respectively). In patients with previous ischemia, there was no difference between treatment with aspirin (n = 25) or phenprocoumon (n = 21). Hypertension, diabetes mellitus and smoking were not associated with increased antigen expression (analysis of variance). The fraction of discoid platelets and platelet counts were not significantly different between groups. Our results indicate increased expression of platelet neoantigens in acute and to a less degree in previous cerebrovascular ischemia. Ongoing platelet activation after cerebrovascular ischemia despite therapy with aspirin or phenprocoumon indicates that new anti-platelet drugs may be of benefit for these patients. Flow cytometry appears to be a useful tool to assess platelet function in cerebrovascular ischemia.

Aged↗
PubMed1988

Basilar artery disease--clinical outcome and Doppler sonographical follow-up.

In the past 5 years we have investigated 29 patients with symptomatic basilar artery stenoses (14 cases) and occlusions (14) and a patent primitive trigeminal artery with thin-calibered basilar and vertebral arteries (1) using directional continuous-wave Doppler sonography of the vertebral arteries. A total of 19 patients survived, and 17 of them were clinically and sonographically reexamined after 40.4 +/- 15.8 months (mean +/- SD). Among the 8 patients with basilar stenoses, 6--with no further transient ischemic attacks (TIAs) in the interval--exhibited an increase in the summed modified Pourcelot indices (relative end-diastolic flow velocities) of the vertebrals by 0.18 +/- 0.16; the other 2 showed a decrease by 0.26 each, in 1 case temporally related to a TIA, in the 2nd case without further clinical deterioration. In the 8 survivors with basilar occlusions, 5 remained--by sonographic criteria--unchanged with summed modified Pourcelot indices of the vertebrals of 0.00, while 3 patients exhibited a slight increase in the summed modified Pourcelot indices of 0.13 +/- 0.03. While the difference between the outcome of subsets of patients treated with regimens of 30,000-40,000 units heparin/day or phenprocoumon and less radical drugs were statistically not significant, the former regimen appeared clinically more efficacious in preventing further deterioration in approximately two-thirds of the patients affected. Due to the potential recurrence of neurological symptoms, a treatment period with phenprocoumon of 6 months after discharge from hospital appears justified. Due to these therapeutic efforts, approximately half of the patients initially affected survived with no or only a mild neurological deficit.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1981

Anticoagulants and experimental metastases-evaluation of antimetastatic effects in different model systems.

Intravenous tumor cell injection and spontaneously metastasising transplantable tumors have been used as models for haematogenous tumor spread. To evaluate the validity of these two experimental approaches for the study of blood coagulability and metastases, the effect of anticoagulants on "secondary" tumor growth was investigated in both models and the results were compared. The B16 melanoma and the Lewis lung carcinoma in C57BL mice were employed throughout the study, and anticoagulation was rendered through the use of phenprocoumon, heparin and ancrod. All anticoagulants were capable of reducing lung colonies after i.v. tumor cell injection, whereas only phenprocoumon significantly diminished the formation of spontaneous metastases. A review of the current literature on anticoagulants and tumor dissemination and the observations described lead to the following conclusions: (1) Results from studies with i.v. introduced tumor cells cannot be extrapolated to spontaneously metastasising tumors. (2) Spontaneously metastasising tumors represent the preferable model for the study of antimetastatic effects of anticoagulants. (3) Little evidence exists to support the concept of the pathogenetic role of fibrin formation in the establishment of spontaneous metastases from blood-borne tumor cells. (4) Coumarin derivatives are potent antimetastatic drugs, their mode of action appears to be independent of their anticoagulant activity.

Animals↗
PubMed2006

Systemic mechanical heart valve replacement in children under 16 years of age.

UNLABELLED: We report the early and late outcome following left-sided mechanical heart valve replacement in children. Between 10/1981 and 02/2001, 27 children (13 male, mean age 7.2 +/- 5.2 years, range 0.53-15.7 years) underwent mechanical mitral (MVR 16), aortic (AVR 9) or double valve replacement (DVR 2) with St. Jude Medical valves. Eighteen children (66.7%) had undergone previous cardiac surgery. Valve disease was congenital in 23, due to endocarditis in 2 and rheumatic in 2 patients. Concomitant cardiac surgery was performed in 12 patients (44.4%). Operative mortality was 3.7% (1/27). Perioperative complications were complete heart block (5) and myocardial infarction (1). Mean follow-up was 6.5+/-5.9 years (range 0.4-19 years, total 169.9 patient-years). There was one valve-related late death due to mitral valve thrombosis without phenprocoumon. Actuarial survival after 1, 5 and 10 years was 93, 93 and 93%. Late complications included endocarditis (2), minor hemorrhagic event (1) and stroke (1). Overall 10-year freedom from any anticoagulation-related adverse event under phenprocoumon was 91% (1.3%/patient year). Eight patients required reoperations: re-MVR (5; outgrowth of the prostheses (3), pannus overgrowth (2)), closure of paravalvular leak after AVR (2), and re- DVR (1; endocarditis). Actuarial freedom from reoperation after 1, 5 and 10 years was 96, 88 and 76%. CONCLUSION: Mechanical valve prostheses are a valuable option for left-sided heart valve replacement in pediatric patients with good results. Operative mortality and the incidence of any valve-related events as endocarditis, reoperation, thromboembolism or anticoagulation related bleeding is acceptable.

Adolescent↗
PubMed1995

Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors.

The low oral bioavailability and rapid biliary excretion of peptide-derived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidic HIV protease inhibitors had previously identified compound II (phenprocoumon, K(i) = 1 muM) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I (1-(naphthoxyacetyl)-L-histidyl-5(S)-amino-6-cyclohexyl-3 (R),4(R)-dihydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) and nonpeptidic inhibitors, such as phenprocoumon (compound II), provided a rational basis for the structure-based design of more active analogues. This investigation reports on the important finding of a carboxamide functionally appropriately added to the 4-hydroxycoumarin and the 4-hydroxy-2-pyrone templates which resulted in a new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding affinity. The most active diastereomer of the carboxamide-containing compound XXIV inhibited HIV-1 protease with a K(i) value of 0.0014 muM. This research provides a new design direction for the discovery of more potent HIV protease inhibitors as potential therapeutic agents for the treatment of HIV infection.

4-Hydroxycoumarins↗
PubMed1999

[Severe pulmonary hypertension in systemic lupus erythematosus. The successful therapy of an unusual manifestation].

UNLABELLED: OBJECTIVE AND CLINICAL FINDINGS: A 48-year-old woman was hospitalized because of haemoptysis. Until shortly before admission she had been on phenprocoumon after pulmonary embolism sustained 18 months previously. Six months before admission systemic lupus erythematodes (SLE) had been diagnosed and treatment with cortisone initiated. Physical examination revealed jugular venous congestion, tachycardia, dyspnoea on even minimal physical activity and pretibial oedema. INVESTIGATIONS: Lung scintigraphy showed a perfusion deficiency in the right lung, unchanged since a test 18 month before. Doppler echocardiography recorded an estimated pulmonary artery systolic pressure of 110 mm Hg. Angiography showed a fully patent superior vena cava and nearly complete occlusion of the main right pulmonary artery by a thrombus. DIAGNOSIS, TREATMENT AND COURSE: The haemoptyses ceased after 5 days of treatment with methylprednisolone, 130 mg daily for 5 days, reduced after 5 days to 80 mg i.v. every other day, plus cyclophosphamide, 50 mg daily by mouth. The pulmonary hypertension remained unchanged so that pulmonary thrombendarterectomy was indicated. Surgery revealed extensive mediastinal fibrosis and almost complete occlusion of the thick-walled right pulmonary artery by thrombus adherent to the wall. Histology showed vasculitis of the pulmonary arterial intima and of the small pulmonary vessels. After thrombectomy the pulmonary arterial systolic pressure fell to an remained at below 40 mm Hg. Phenprocoumon was continued (at an INR of 2.5-3.5) as was immunosuppressive treatment. The patient has remained free of symptoms and is able to be physically active. CONCLUSION: Pulmonary hypertension is a serious complication of SLE. Echocardiography is recommended for both the original diagnosis and serial follow-up, complemented by other imaging methods if indicated.

Acute Disease↗
PubMed1993

[Pulmonary thromboembolism in antiphospholipid syndrome].

A 37-year-old woman in acute right heart failure had experienced systemic venous thromboses for 17 years, five miscarriages and repeated pulmonary emboli. For the last 7 years she had been treated symptomatically for pulmonary hypertension. The platelet count was 62,000/microliters, thromboplastin time under phenprocoumon was 22%, partial thromboplastin time was 72 s. Despite anticoagulation with phenprocoumon and heparin (7,500 IU two times daily subcutaneously) new pulmonary emboli occurred and platelet count fell to 12,000/microliters. An increased titre for anticardiolipin antibodies (IgG > 320 GPL U/l, IgM 8 MPL U/l), antinuclear (1:640) and anti-ds-DNA antibodies (> 200 IU/ml) with simultaneous complement consumption suggested secondary antiphospholipid syndrome associated with lupus erythematodes. Treatment with prednisolone (150 mg/d), immunoglobulins (20 mg/d intravenously for 5 days) and heparin (25,000 IU/24 h intravenously) achieved an increase in platelet count to 200,000/microliters within 10 days, but fell again when the prednisolone dose was reduced, recovering under azathioprine, 150 mg/d. Four weeks later the patient died of renewed acute right heart failure.

Acute Disease↗
PubMed1993

Vitamin K metabolism and vitamin K1 status in human liver samples: a search for inter-individual differences in warfarin sensitivity.

Vitamin K-dependent parameters in human liver samples were investigated to find a clue to the inter-individual differences in sensitivity for oral anticoagulants. Vitamin K epoxide reductase and vitamin K-dependent carboxylase activity differed 2-3-fold between the samples. Microsomal warfarin binding correlated significantly with the reductase activity. Microsomal vitamin K epoxide reductase of the different samples showed equal sensitivity for warfarin inhibition, I50 about 0.1 microM. Vitamin K epoxide reductase activity stimulated by NADH/lipoamide and microsomal lipoamide dehydrogenase activity showed higher inter-subject variability than the reductase activity by itself. Liver vitamin K1 levels varied 4-5-fold. Total and liver microsomal vitamin K1 levels were correlated. One of the liver samples was obtained from a donor anticoagulated with phenprocoumon and additionally treated with vitamin K1. High levels of the vitamin and its epoxide were present. Phenprocoumon was essentially irreversibly bound to the microsomes. In general the results confirm inter-individual differences in the hepatic vitamin K-dependent systems; the differences as such were found to be small. However, as the various parameters can work synergistically in the same direction, they may well account for the wide dose range observed in oral anticoagulant therapy.

Adolescent↗