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PubMed1984

[Clinical, immunological and therapeutic research in mesangial immunoglobulin-A glomerulonephritis].

Forty seven patients with IgA glomerulonephritis (GN) were studied. The males predominated among them--the ratio males-female--2,9:1. The first clinical manifestations were macroscopic hematuria (in 2/3 of the cases) or only urine changes--low-degree proteinuria and microscopic erythrocyturia. As early as the establishment--38,2 per cent of the patients had elevated arterial pressure, and it reached, 59,5 per cent during the follow-up period. Anemia was rare. Manifestations of nephrotic syndrome were absent. ESR was normal in 1/3 of the employees or slightly accelerated. Chronic renal insufficiency developed 6,31 per cent of the patient all of them males. Terminal renal insufficiency developed 8 patients. The elevated arterial pressure, proteinuria over 2g/24 h, accelerated ESR, high serum levels of IgA, the longer duration of the disease and higher age of the patients to a certain extent--were unfavourable prognostic criteria. The basic immune deviations of IgA GN are the high serum levels of IgA (in 53,1% of the patients) and to a lower extent of IgG (in 17% of the patients) as well as the reduced serum levels of C3 (in 31,9% of the patients). CIC are not a frequent finding. The percentage of ERF is lower than in the healthy subjects. The treatment with a combination of azathioprine (acenocoumarol, indomethacin or levamisole) has no effect on the clinical manifestations and evolution.

Acenocoumarol↗
PubMed1982

[Controlled therapeutic trial in IgA glomerulonephritis].

A controlled therapeutic study was carried out on 38 patients with IgA glomerulonephritis. According to the data from the light microscopy, 15 patients were with minimum histological deviations, 21 patients--with focal-segmental glomerulonephritis, and 2 patients--with diffuse. The patients with the minimum histological deviations and focal-segmental glomerulonephritis were grouped into three groups. The first group of 13 patients was treated with indomethacin, 75 mg daily in the course of 8.5 months on the average (6-13 months). The second group of 5 patients was treated with levamisole--3 days with 150 mg daily--two times a month, in the course of 14 months on the average (6.5-30 months). The control group, without any treatment, covered 13 patients. There were no discrepancies in the clinical manifestations, laboratory data and renal function among the patients from the three groups. In an additional group of 7 patients with focal-segmental and diffuse mesangioproliferative glomerulonephritis, five of them with renal insufficiency, a combined immuno-suppressive and anticoagulant treatment with azathioprin, heparin and acenocoumarol was carried out in the course of 15 months on the average (6-35 months). Indomethacin and levamisole treatment had no effect on the clinical manifestations and evolution of the disease. The combined immuno-suppressive and anticoagulant treatment had also no effect on the progress in the terminal renal insufficiency.

Acenocoumarol↗
PubMed1982

Repeated occurrence of skin necrosis twice following coumarin intake and subsequently during decrease of vitamin K dependent coagulation factors associated with cholestasis.

A female patient is described who developed skin and subcutaneous fat necrosis on two occasions after intake of acenocoumarol. Several months later identical skin changes occurred during an episode of cholestasis associated with a prolongation of the prothrombin time to an extent comparable with therapeutic anticoagulation; intake of oral anticoagulants could be excluded. This association gives new insights in the pathogenetic mechanisms responsible for the so-called coumarin necrosis and indicates that it may be not due to drug toxicity or allergy.

Acenocoumarol↗
PubMed1982

[Possibilities of combined treatment of diffuse collagenous glomerulonephritis].

Combined corticosteroid, immunosuppressive and anticoagulant treatment was performed to 17 patients with various histological forms of collagenous glomerulonephritis, 14--with disseminated lupus erythematodes, 1--with periartheritis nodosa and 2--with Schönlein-Henoch disease. The immunosuppressive treatment was carried out for an average of 14.62 months, the corticosteroid treatment--an average of 17 months and the anticoagulant--18.12 months. In 6 patients the corticosteroid treatment was initiated with a pulse of 30 mg methylprednisolone in the course of 3-10 days, and in the rest of the patients--with an initial dose of 60 mg prednisolone. The anticoagulant treatment was, at first, carried out with heparin 30,000 U daily, and later with acenocoumarol and the immunosuppressive--with azathioprin--100 mg daily. The term of treatment and observation is from 6 to 63 months, an average of 25-82 months. The treatment was discontinued in eight patients. Very good effect (complete clinical and laboratory remission) was obtained in seven patients--41.18 per cent, good effect (clinical remission but incomplete laboratory) in 7 patients--41.18 per cent, one patient with no change--5.88 per cent. Two patients--11.76 per cent, died of the complications of the treatment. Grave complications resulting from the treatment were obtained in seven patients.

Acenocoumarol↗
PubMed1993

[Breast feeding and oral anticoagulants].

Oral anticoagulants are frequently prescribed during lactation. Because these drugs could affect the hemostasis of the newborn, we did a literature search to find out whether precautions should be taken. It appeared that acenocoumarol and warfarin are not detectable in human milk. Besides the usual daily supplementation of 25 micrograms vitamin K for every breast-fed infant, precautions are not necessary. Phenprocoumon, ethylbiscoumacetate and phenindione are excreted in human milk and could affect neonatal hemostasis.

Acenocoumarol↗
PubMed1993

Experience with moderate intensity anticoagulation and aspirin after mechanical valve replacement. A retrospective, non-randomized study.

A selected group of patients who underwent valve replacement were analyzed to evaluate the feasibility, effectiveness and safety of combined treatment with moderate intensity anticoagulation plus aspirin. One hundred ninety-six patients who received a total of 204 mechanical valve prostheses between 1985 and 1991 were selected according to rigid criteria. The prostheses included 124 valves of caged ball design, 62 St. Jude valves and 18 others. The follow up of the whole population was 581.8 patient years, with an average of 2.97 patient years, and was complete by the definition criteria. All patients received moderate intensity anticoagulation with acenocoumarol (target International Normalized Ratio 2.5 to 3.5) and daily aspirin (100 mg or 325 mg). The incidence of thromboembolic events for the whole group was 3.26% per patient year, but only 1.6% in patients "compliant" with treatment. Preoperative embolism and non-compliance with treatment had a strong correlation with postoperative thromboembolism. The INR values had a strong correlation with both thromboembolic and hemorrhagic events. The incidence of serious hemorrhagic events was 4.12% patient years although only two cases (0.34%/pty) were fatal (cerebral hemorrhages). There was no difference in hemorrhagic incidence between patients receiving either 325 mg or 100 mg daily. A low incidence of thromboembolic complications was attained with the use of combined antithrombotic and antiplatelet therapy, even in the first generation caged ball type prostheses. However, the combination of moderate intensity anticoagulation with either 325 mg or 100 mg aspirin was associated with a risk of bleeding similar to high intensity anticoagulation alone. The risk of bleeding appeared to be greater in the presence of gastric pathology, and the combination of anticoagulants and aspirin should be avoided in patients with these conditions.

Acenocoumarol↗
PubMed1998

[Safety of oral anticoagulation in aged patients with heart diseases].

BACKGROUND: Anticoagulation therapy in the elderly poses some doubts on the possible increase in hemorrhagic risk. The hemorrhagic complications in a population of patients over 70 years of age anticoagulated with acenocoumarol by heart disease were studied. MATERIALS AND METHODS: A study was made of seventy-two patients (43 females and 29 males; mean age: 73 years) anticoagulated for one year and controlled on an outpatient basis by means of INR (international normalized ratio) measurement with a maximal interval of four weeks. INR values above 4.5 or below 2.0 were considered out of range. RESULTS: Nineteen patients had an INR above the recommended value on one occasion and eleven patients on two or more occasions. Sixteen patients had hemorrhagic complications, five were admitted on account of hemorrhages although none of them required transfusional therapy. No cases of brain hemorrhage or peripheral embolism occurred. CONCLUSIONS: Most anticoagulated elderly patients were within their therapeutic range. The percentage of severe hemorrhagic complications was low. Advanced age had did not prove to be a factor against therapy with oral anticoagulants.

Acenocoumarol↗
PubMed1993

Bleeding complications in oral anticoagulant therapy. An analysis of risk factors.

BACKGROUND: Insufficient data are available about the safety of oral anticoagulant therapy. The specialized organization of thrombosis services in the Netherlands can provide important information on the bleeding risk and various risk factors for bleeding in patients receiving oral anticoagulant therapy. METHODS: In a follow-up study over a 12-month period beginning in January 1988 on all patients treated by the Leiden Thrombosis Service, the frequency of bleeding complications was assessed. A Poisson regression model was used to assess the relative contribution to the bleeding risk of age, sex, target zone (intensity of anticoagulant effect aimed at), achieved intensity of anticoagulant therapy (International Normalized Ratio), and the type of coumarin derivative used. RESULTS: Six thousand eight hundred fourteen patients experienced 1003 bleeding complications (16.5 per 100 treatment-years), 162 of which were major bleeds (2.7 per 100 treatment-years). Bleeding increased significantly with age (32% increase for all bleeding, 46% for major bleeding for every 10-year increase in age in comparison with age < 40 years). Women had more minor bleeding complications than men, whereas both sexes experienced major bleeding in an equal frequency. There was no influence of target zone, while every one-point increase in International Normalized Ratio gave 42% more major bleeding (54% more regarding all bleeding). Use of acenocoumarol resulted in fewer bleeds (26% less regarding all bleeding and 46% less regarding major bleeding) than use of phenprocoumon. CONCLUSIONS: The risk of anticoagulant therapy in a routine, real-life situation is similar as in the setting of several well-organized clinical trials. The risk of bleeding complications rises significantly with age and with the achieved intensity of anticoagulation, and is dependent on the type of coumarin derivative that is used.

Administration, Oral↗
PubMed1997

Brachial, radial, or femoral approach for elective Palmaz-Schatz stent implantation: a randomized comparison.

UNLABELLED: From October 1994 to November 1995, 150 male eligible patients were randomly assigned to Palmaz-Schatz stent implantation through 6 French catheters using the femoral (puncture) (n = 56), radial (puncture) (n = 56), or brachial (cutdown) (n = 38) approach at 6 participating Belgian centers. Acenocoumarol was given for 1 month after stenting. END POINTS: Primary-entry site complications (bleeding, haematoma, transfusion, occlusion, surgery) poststent implantation. Secondary-success rate, stent thrombosis, Q or non Q wave MI, repeat PTCA, CABG, CVA, haemorrage, death. There were no statistically significant differences between the three groups for base line and angiographic patient characteristics, procedural characteristics, in hospital outcome, average hospitalisation time after stenting, events during the month after stenting, or local complications at 1 month follow-up. The only statistically significant difference was the arterial time of the procedure: mean +/- SD (minutes) brachial 31.0 +/- 10.02 *P < 0.001, femoral 42.2 +/- 21.8, radial 55.8 +/- 31.3 **P < 0.0001 (*brachial vs. femoral, **brachial vs. radial). There was a clear trend toward more technical difficulties and more problems with the radial approach. In each group: vascular surgery at entry site: 0%, blood transfusion: 0%. In our study, local complications and length of hospital stay were similar with the three possible approaches, and brachial approach was associated with a shorter arterial time.

Adult↗
PubMed2001

Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin.

BACKGROUND: Patients who are entered in clinical trials after a transient ischaemic attack (TIA) or non disabling ischaemic stroke have an annual risk of important vascular events (death from all vascular causes, non-fatal stroke, or non-fatal myocardial infarction) of between 4 and 11 percent. Aspirin, in a daily dose of 30mg or more, offers only modest protection after cerebral ischaemia: it reduces the incidence of major vascular events by 20 percent at most. Secondary prevention trials after myocardial infarction indicate that treatment with oral anticoagulants is associated with a risk reduction approximately twice that of treatment with antiplatelet therapy. OBJECTIVES: 1) To compare the efficacy of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin. 2) To compare the safety of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin. SEARCH STRATEGY: This review draws on the search strategy developed for the Stroke Group as a whole. Relevant trials were identified in the Specialised Register of Controlled Trials (last searched: June 2000). Authors of published trials were contacted for further information and unpublished data. SELECTION CRITERIA: Randomised trials with concealed treatment allocation on long term (> 6 months) secondary prevention after recent (< 6 months) TIA or minor ischaemic stroke of presumed arterial origin were selected. The oral anticoagulant therapy was to be of specified intensity (by means of the International Normalised Ratio (INR)) with warfarin, phenprocoumon or acenocoumarol versus a single antiplatelet drug (or combination of antiplatelet agents). DATA COLLECTION AND ANALYSIS: Two reviewers selected trials meeting the inclusion criteria and extracted details of randomisation methods, blinding of treatments and assessments, whether intention-to-treat analysis is possible from the published data, whether treatment groups are comparable with regard to major prognostic risk factors for outcomes, the number of patients who are excluded or lost to follow-up, definition of outcomes, and entry and exclusion criteria. The methodological quality of each trial was assessed by the two reviewers using these extracted data. In addition, target INR for anticoagulant treatment and dose and type of antiplatelet drug, duration of follow-up and the numbers of defined outcome events was recorded. The data were analysed according to the intention-to-treat principle. Subgroup analyses with treatment INR 2.1 - 3.6 versus INR 3.0 - 4.5 was performed. Relative and absolute risk reductions were calculated by means of the statistical software provided by the Cochrane Collaboration. MAIN RESULTS: Four trials, with a total of 1870 patients were selected. In the prevention of ischaemic stroke after cerebral ischaemia of presumed arterial origin, the available data do not allow a robust conclusion on whether anticoagulants (in any intensity) are more efficacious than antiplatelet therapy (low intensity anticoagulation RR 0.96, 95% CI 0.38 to 2.42, high intensity anticoagulation RR 1.02, 95% CI 0.49 to 2.13). Treatment with anticoagulation INR 2.1 - 3.6 does not give an importantly higher bleeding risk than treatment with antiplatelet agents (RR 1.19, 95% CI 0.59 to 2.41). It is clear that oral anticoagulants INR 3.0 - 4.5 are not safe, because they yield a higher risk of major bleeding complications (RR 9.0, 95% CI 3.9 to 21). REVIEWER'S CONCLUSIONS: For the secondary prevention of further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin, there is insufficient evidence to justify the routine use of low intensity oral anticoagulants (INR 2.0 - 3.6). More intense anticoagulation (INR 3.0 - 4.5) is not safe and should not be used in this setting.

Administration, Oral↗
PubMed2006

Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin.

BACKGROUND: Patients with limited cerebral ischaemia of arterial origin have an annual risk of major vascular events between 4% and 11%. Aspirin reduces this risk by 20% at most. Secondary prevention trials after myocardial infarction indicate that treatment with oral anticoagulants is associated with a risk reduction approximately twice that of treatment with antiplatelet therapy. OBJECTIVES: To compare the efficacy and safety of oral anticoagulants and antiplatelet therapy in the secondary prevention of vascular events after cerebral ischaemia of presumed arterial origin. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (searched 16 September 2004). Authors of published trials were contacted for further information and unpublished data. SELECTION CRITERIA: Randomised trials examining long-term secondary prevention after recent ischaemic stroke of presumed arterial origin were selected. The oral anticoagulant therapy had to be of specified intensity with warfarin, phenprocoumon or acenocoumarol versus antiplatelet therapy. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, assessed trial quality and extracted data. Subgroup analyses with treatment International Normalized Ratio (INR) 1.4 to 2.8 (low intensity), INR 2.1 to 3.6 (medium intensity) and INR 3.0 to 4.5 (high intensity) were performed. MAIN RESULTS: Five trials, with 4076 patients were selected. The data do not allow a robust conclusion on whether anticoagulants are more or less efficacious in the prevention of vascular events than antiplatelet therapy (medium intensity anticoagulation relative risk (RR) 0.96, 95% confidence intervals (CI) 0.38 to 2.42; high intensity anticoagulation RR 1.02, 95% CI 0.49 to 2.13). There is no evidence that treatment with low or medium intensity anticoagulation gives a higher bleeding risk than treatment with antiplatelet agents. The relative risk for major bleeding complications for low intensity anticoagulation was 1.27 (95% CI 0.79 to 2.03) and for medium intensity anticoagulation 1.19 (95% CI 0.59 to 2.41). However, it was clear that high intensity oral anticoagulants with INR 3.0 to 4.5 were not safe, because they yielded a higher risk of major bleeding complications (RR 9.0, 95% CI 3.9 to 21). AUTHORS' CONCLUSIONS: For secondary prevention of further vascular events after limited ischaemic stroke of arterial origin, there is insufficient evidence to justify the routine use of medium-intensity oral anticoagulants; such treatment should only be used as part of a clinical trial. More intense anticoagulation is not safe and should not be used in this setting. Low-intensity anticoagulation is not likely to be more or less efficacious than aspirin.

Administration, Oral↗
PubMed1995

Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia is a rare but severe complication of heparin therapy that can result in severe venous or arterial thromboembolic events and whose treatment remains partially unanswered. Recombinant hirudin is potentially effective as an antithrombotic treatment in the management of heparin-induced thrombocytopenia, given its potent antithrombin effects without known interaction with platelets. We report the results obtained with intravenous recombinant hirudin (HBW 023) administered on a compassionate basis to patients suffering from heparin-induced thrombocytopenia. Six patients suffering from heparin-induced thrombocytopenia were submitted to intravenous recombinant hirudin (HBW 023) administered at a dose of 0.05 mg/kg/hr after an initial bolus injection of 0.07 mg/kg in the case of a venous thromboembolic event, and at a dose of 0.15 mg/kg/hr with the same initial bolus injection in the case of an arterial thromboembolic event. Whenever possible, oral anticoagulation with acenocoumarol was introduced at the same time as recombinant hirudin, which was interrupted as soon as the international normalized ratio reached 3. Clinical events, particularly thromboembolism and bleeding, were noted; activated partial thromboplastin time (aPTT), and platelet count were assessed throughout the administration of recombinant hirudin. Heparins responsible for heparin-induced thrombocytopenia were porcine sodium or calcium heparinate in four cases, nadroparin in one case, and enoxaparin in one case. Thrombocytopenia was discovered on routine systematic platelet count in two patients and after the occurrence of arterial and venous thromboembolism in two patients, respectively. After discontinuation of heparin and the onset of recombinant hirudin, clinical evolution was uneventful in all patients, with no recurrence of thromboembolism, limb amputation, or hemorrhagic complication. The aPTT ratio varied from 1.8 to 3.5 (median 2.4) throughout administration of recombinant hirudin. Platelet count rose from nadir (median value 60 x 10(9), 15 to 90) to above 100 x 10(9)/L in every patient within 3-6 days (median 5), after discontinuation of heparin. Intravenous administration of recombinant hirudin ensured safe anticoagulation in patients with heparin-induced thrombocytopenia and made it possible to wait for oral anticoagulation to become efficient and platelet count to return to normal values without occurrence or recurrence of thromboembolism.

Aged↗
PubMed1978

GLC determination of plasma concentrations of gamma-oxo metabolite of phenylbutazone.

A quantitative method for the gamma-oxo metabolite of phenylbutazone from plasma is described. The procedure involved an ethylene dichloride extraction of acidified plasma to which an internal standard, acenocoumarol, had been added. The extracted gamma-oxo metabolite and the internal standard were methylated and analyzed by GLC. Determination of 0.25 microgram of gamma-oxo metabolite/ml with a relative standard deviation of 6.5% was accomplished.

Chromatography, Gas↗
PubMed1998

Congenital and Atherosclerotic (Acquired) Coronary Artery Aneurysms: Coronary Angiographic and Morphologic Observations in 10 Patients

Coronary angiographic observations in 10 patients with coronary artery aneurysms (CAAs) are reported. Four patients had atherosclerotic (acquired) and six had congenital CAAs. The mean age of patients with acquired CAAs was higher (64.7 years) compared with the congenital group (53.2 years). Ipsilateral myocardial infarction (MI) occurred in three of four patients with acquired CAAs but MI was not located on the same side as the aneurysm-bearing coronary artery (contralateral) in two patients with the congenital variety. In the patients with congenital CAAs, an aneurysm predilection site was observed in the proximal portion of the aneurysm-bearing vessel. Dual and multiple aneurysms were more common in the acquired CAAs. Although congenital CAAs were sizeable, the small-sized atherosclerotic CAAs developed complications more frequently. During an average follow-up of 7.9 years, only one patient died of a noncardiac cause and another developed recurrent uncomplicated non-Q wave lateral MI. Both subjects had atherosclerotic CAAs. In our series, no rupture or sudden death occurred. Coronary artery bypass grafting (CABG) was performed in three patients with acquired and in one patient with congenital CAAs. In the latter patient, simultaneous ligation of the congenital aneurysm associated with a coronary arteriovenous fistula was performed. Regarding antiplatelet and anticoagulant policy for the whole group, three patients were on aspirin, four were on acenocoumarol, and in another three subjects with congenital CAAs, a medical regimen was followed. Larger series, however, are required in order to elucidate further angiographic characteristics of acquired vs congenital CAAs.

Journal Article↗
PubMed1990

Arterial stenting with self-expandable and balloon-expandable endoprostheses.

Coronary angioplasty is complicated by acute occlusion (within 24 hours) and late restenosis (within 6 months) in 2-5% and 20-40% of the cases, respectively. Vascular endoprostheses (stents) may provide the cardiologist with a solution to some of these complications. Several stent-devices are now available for experimental and clinical evaluation. In this study we describe our experience with two metallic stents in normal arteries of swine. Self-expandable, stainless steel stents (3.5 mm diameter) were implanted in 17 peripheral arteries, eight of which were deendothelialized by prior balloon angioplasty. Following implantation, the animals received antithrombotic therapy with acenocoumarol and aspirin (8 stents), or aspirin alone (9 stents). After 1 week repeat angiography was performed, which showed patency of all stented arteries. Microscopy showed complete covering by neointima, 80 microns in thickness. This self-expandable stent (SES) and a balloon-expandable stent (BES), constructed of tantalum, were implanted in normal coronary arteries. SES (3.0 and 3.5 mm) receiving animals were treated with coumadines (10 stents) or received no antithrombotic treatment (16 stents) after implantation. BES receiving animals were also not treated (10 stents). Three untreated animals with SES died suddenly within 48 hours. Postmortem examination showed partial or complete thrombosis of all six stents in these animals, resulting in a patency rate of 62% after 1 week. All animals with SES, which were treated with coumadines, and all animals with BES (untreated) had patent stents after one week. It is concluded that SES implanted in normal coronary arteries of pigs, which do not receive additional antithrombotic treatment, show a 38% occlusion rate within 48 hours, but show 100% patency after 1 week, when the animals are treated with coumadines. BES implanted in normal coronary arteries of pigs, which do not receive antithrombotic drugs, are 100% patent after 1 week.

Angioplasty, Balloon, Coronary↗
PubMed2005

Stereospecific pharmacokinetic characterisation of phenprocoumon metabolites, and mass-spectrometric identification of two novel metabolites in human plasma and liver microsomes.

Phenprocoumon belongs to the group of vitamin K antagonists (VKAs), for example warfarin and acenocoumarol. It is widely used for therapeutic anticoagulation and clinically administered as a racemate. Both enantiomers are partially metabolized by the polymorphic CYP2C9 enzyme. The pharmacokinetics are, however, substantially less dependent on CYP2C9 activity or genotype than for other CYP2C9-metabolised VKAs, and pharmacokinetic differences for the enantiomers are only minor. We have investigated the stereospecific pharmacokinetics of the monohydroxylated phenprocoumon metabolites in human plasma by achiral-chiral LC-LC-MS-MS coupling. In addition to the known metabolites, 4'-, 6-, and 7-hydroxyphenprocoumon, two other monohydroxylated metabolites (M1 and M2) were detected in plasma and human liver microsomal incubations. One of these was identified as 2'-hydroxyphenprocoumon by comparison with synthetic standards; the other seemed to be a side-chain-hydroxylated derivative. Analysis of enantiomeric metabolite ratios after a single oral dose of phenprocoumon revealed changes over time with an overall preponderance of the respective (R) enantiomers. The minor role of CYP2C9 in 4'-hydroxy-PPC formation and the effect of CYP2C9 genotype for (S)-6- and (S)-7-hydroxy-PPC were confirmed. M1 and M2 are formed highly stereoselectively, without dependence on CYP2C9 genotype. These may be interpreted as alternative metabolic pathways that render phenprocoumon less dependent on CYP2C9 activity or genotype.

Anticoagulants↗
PubMed2001

The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro.

INTRODUCTION: The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro. SUBJECTS, MATERIALS AND METHODS: Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes. RESULTS: Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects. CONCLUSION: No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.

Adult↗
PubMed1991

The importance of adequate anticoagulation to prevent early thrombosis after stenting of stenosed venous bypass grafts.

Stent implantation in native coronary arteries may be complicated by acute thrombosis, despite the use of stringent anticoagulation. Thrombotic occlusion of stented venous grafts may occur less frequently, possibly because of the larger caliber of these grafts. We report our experience with 46 stents (Wallstent, Medinvent, Lausanne, Switzerland) implanted in 35 lesions of 24 consecutive patients (mean age 64 years, range 43 to 75). Two overlapping stents were implanted in seven patients, and three overlapping stents were positioned in two. After implantation, activated partial thromboplastin time was maintained at two to three times the control level by intravenous administration of heparin (160 to 550 mg daily) until thrombotest values were reduced 5% to 10% by acenocoumarol. Impending thrombotic occlusion was recognized in two suboptimally anticoagulated patients: patient A after implantation of four stents and patient B after anticoagulation therapy was discontinued because of acute upper gastrointestinal bleeding. Coronary artery bypass grafting was performed successfully in both patients. A third patient had a myocardial infarction on day 7 after stent implantation, in spite of adequate anticoagulation and optimal medical drug therapy. It is concluded that stringent anticoagulation therapy appears mandatory to maintain graft patency after stent implantation.

Blood Vessel Prosthesis↗