[Serious surgical complications associated with chronic anticoagulant therapy]. / Závazné chirurgické komplikace chronické antikoagulacní lécby.

Chronic anticoagulant treatment is administered mostly for cardiological reasons. Cumarin derivatires are used in the majority of cases (Warfarin, Pelentan). It is necessary to monitor this treatment regularly and to control the dose according to the INR value. Different complications can occur; the haemorrhage represents a serious one. The authors discuss several aspects of anticoagulant therapy and possible prevention of the complications. The importance of the problems is demonstrated on the authors' clinical experience--two cases of haemorrhage after Warfarin administration simulating an acute surgical event.

[Use of hypoprothrombinemia provocation test for early diagnosis of liver disease caused by harmful environmental agents]. / Zastosowanie próby hipoprotrombinemii prowokowanej we wczesnej diagnostyce chorób watroby wywolanych przez czynniki srodowiskowe.

The aim of this work has been to assess the feasibility of using Prothrombin Time (PT) Assay before and after administration of Pelentan (Hypoprothrombinemia Provocation (HPP) Test) for early detection of subclinical toxic hepatic injuries. The proposed modification of PT Assay is based on the observation that people with slight hepatic injury receiving small doses of Pelentan (diethylcoumarol) display remarkably longer PT than healthy people receiving similar doses of the chemical. The test group comprised 37 people occupationally exposed to hepatotoxic agents, 85 males permanently abusing alcohol, while 24 clinically healthy people, not exposed occupationally to the toxic agents served as the control. In addition, 26 hepatitis B and/or C virus carriers were also examined. The results show that: 1. HPP test enables assessment of hepatic function in patients with suspected hepatic injury and in people permanently abusing alcohol; 2. low value of serum prothrombin index 24 h and 48 h after the administration of Pelentan is indicative of the positive result of the test; 3. HPP test provides more information on the functional condition of liver than single PT determination by the Quick assay.

Pharmacokinetics of ethyl biscoumacetate and its metabolite 7-hydroxy ethyl biscoumacetate in healthy volunteers.

Disposition kinetics of ethyl biscoumacetate and its metabolite 7-hydroxy ethyl biscoumacetate were evaluated in ten healthy volunteers, after a single 300 mg oral dose of ethyl biscoumacetate. Serum concentrations of parent compound and its metabolite were measured by HPLC. The maximum serum ethyl biscoumacetate concentrations were reached 1.0-4.0 hours after drug dosing. From 3 hours after drug administration the concentration of the metabolite was always higher than the concentration of the parent compound. Geometric mean of elimination half-life was 0.66 hours for ethyl biscoumacetate and 2.03 hours for the 7-hydroxy ethyl metabolite.

[Breast feeding and oral anticoagulants]. / Borstvoeding en orale anticoagulantia.

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.

[Effect of dimethicone on pharmacokinetics and pharmacodynamics of ethyl biscoumacetate]. / Effet du diméticone sur la pharmacocinétique et la pharmacodynamie du biscoumacétate d'éthyle.

The influence of dimeticone (Gel de Polysilane Midy) on the pharmacokinetics and pharmacodynamics of oral ethyl biscoumacetate was studied in 6 healthy volunteers in a randomised single dose, two-way cross-over study. Each volunteer received at one week interval a single dose (300 mg) of ethyl biscoumacetate, either alone or with dimeticone. Ethyl biscoumacetate levels were measured in plasma for 24 hours. Pharmacodynamic parameters were measured for 96 hours. Ethyl biscoumacetate peak concentration was significantly higher when administered with dimeticone (40.3 +/- 25.3 mg/l vs 31.0 +/- 25.7 mg/l; p = 0.031), without significant change in the area under curve. Other pharmacokinetic and pharmacodynamic parameters did not differ significantly. The slight increase of the ethyl biscoumacetate bioavailability with dimeticone in repeated dosing might have pharmacodynamic consequence; a clinical trial should address this question.

Phytomenadione improves red cell deformability in laboratory animals.

The deformability of red blood cells (RBC) is one of the factors that determine whole blood rheology. Derivatives of vitamin K (phytomenadione, menadione, menadione bisulfite) are electron-transporting substances. The aim of this study was to investigate the possible influence of derivatives of vitamin K on erythrocyte deformability in studies in vivo--on rats and rabbits. The influence of vitamin K antagonist on erythrocyte deformability (ethylbiscumacetate) was also determined. Pentoxifylline known to affect RBC deformability was also included in the study as the control treatment. The study was performed on white laboratory rats and domestic rabbits. The blood was obtained from animals after single and multiple dosing of drugs. Blood sample was prepared and RBC filterability was assayed with a gravity driven filtration technique. Pentoxyfylline did not change erythrocyte deformability after single dose, but significantly improved erythrocyte deformability of laboratory animals after multiple application. Filterability values of the RBCs of the rats and rabbits increased significantly after single and multiple treatment with phytomenadione, while the two other derivatives, menadione and menadione bisulfite, did not change RBC deformability. Ethylbiscumacetate did not change erythrocyte deformability in rats after single dose.

[The effect of vicasol and pelentan on the biopolymers of the periodontium]. / O vliianii vikasola i pelentana na sostoianie biopolimerov periodonta zubov.

Vitamin K (vikasol) and pelentan were examined for their effects of periodontal tissue levels of collagen, hexosamine-containing biopolymers and sialoglycoproteins. During tooth replantation in dogs, vitamin K was demonstrated to elevate the levels of collagen, hexosamine-containing polymers in periodontal tissue by 25.8, 19.9, and 36.1%, respectively, whereas pelentan lowered the above parameters.

[Activity of menadione reductase and level of cytochrome B5 and P-450 in liver with varying supplies of vitamin K and administration of pelentan to rats]. / Aktivnost' menadionreduktazy i soderzhanie tsitokhormov B5 i P-450 v pecheni pri razlichnoi obespechennosti krys vitaminom K i vvedenii pelentana.

Content of cytochromes b5 and P-450 as well as activity of soluble menadione reductase were estimated in liver microsomes of rats deprived of vitamin K or maintained both on a diet containing excess of vicasol or antivitamin K-pelentan. Deficiency of vitamin K led to an increase in the specific activity of menadione reductase and in content of the cytochrome P-450. Administration of antivitamin K did not alter these parameters but caused an increase in the content of cytochrome b5, which was not changed in vitamin K deficiency. Dissimilar effects of alimentary deficiency in vitamin K and of pelentan administration suggest that administration of antivitamins K (although it allowed to discover alterations developed via the system of vitamin K-dependent carboxylation) could not be completely identified with alimentary vitamin K deficiency.

Determination of ethyl biscoumacetate and its metabolite 7-hydroxyethyl biscoumacetate in human serum by high-performance liquid chromatography and mass spectrometry.

An efficient reversed-phase high-performance liquid chromatographic method has been developed for the determination of ethyl biscoumacetate (EBA) and its metabolite in human serum, using the mu Bondapak C18 column and methanol-water-phosphoric acid (56:46.8:0.2, v/v/v) as the mobile phase. This method permitted the determination of both EBA and a metabolite in human serum. The latter has been mentioned by other authors only in urine samples, where significant concentrations were found. Identification of the metabolite as 7-hydroxyethyl biscoumacetate was based on its chromatographic separation, followed by isolation from the eluate and direct mass spectrometric identification. It has been found that the higher EBA concentrations in human serum described by Brodie et al. [J. Pharmacol. Exp. Ther., 106 (1952) 453] were caused by the insufficient resolving power of the spectrophotometric method used, leading to overlapping of the UV spectra of the parent drug and its metabolite.

[Kinetic characteristics of creatine kinase and hexokinase from rat skeletal muscles during dietary deficit of vitamin K and administration of pelentane]. / Kineticheskie kharakteristiki kreatinkinazy i geksokinazy skeletnykh myshts krysy pri pishchevom defitsite vitamina K i vvedenii pelentana.

Kinetic parameters of rat creatine kinase isozymes at different vitamin K supply and treatment with antivitamin K--pelentan have been determined. MM-isozyme (skeletal muscle) has selective sensitivity to the vitamin K deficit, while BB and MB-isozymes (brain, kidney and heart) have not. The value KM for ATP of MM-isozymes increases, while maximal activity decreases. Pelentan treatment does not lead to the change of MM-creatine kinase affinity to ATP. Soluble hexokinase of skeletal muscle in rats with vitamin K deficiency and treated with pelentan has higher affinity to glucose as compared to normal rat enzyme. It has been supposed that skeletal muscle hexokinase exists in a particular molecular form under vitamin K deficiency.

[Status of liver mitochondria and rat tissue creatine kinase during administration of antivitamin K]. / Sostoianie mitokhondrii pecheni i aktivnost' kreatinkinazy tkanei krysy pri vvedenii antivitamina K.

It has been shown that 16-18 days administration of antivitamin K (pelentan) leads to two-fold increase of prothrombin time in adult rats but does not influence the soluble brain, renal, heart, muscle and serum creatine kinase activity. No effect on metabolic function of isolated liver mitochondria has been found in contrast to the vitamin K deficient rats. Mitochondria were characterized by high value of respiration control; substance oxidation rates and internal mitochondrial Ca2+ content do not differ in the level from those of control animals. From the obtained results and data published in literature a conclusion can be drawn about only particular similarity (prothrombin time) between the antivitamin K administration and alimentary vitamin K deficit.

[Metabolic function of isolated liver mitochondria during various conditions of vitamin D and K supply and administration of pelentane]. / Metabolicheskie funktsii izolirovannykh mitokhondrii pecheni pri razlichnoi obespechennosti krys vitaminami D i K i vvedenii pelentana.

Alimentary deficiency of vitamin K caused a decrease in the rate of respiration in presence of ADP and in the rate of oxidative phosphorylation in the presence of succinate. Administration of the antivitamin K pelentane, excess of vikasol and deficiency of vitamin D did not affect these parameters. As distinct from controls and rats treated with pelentane, transport of calcium was decreased in presence of all the substrates studied in mitochondria isolated from liver tissue of animals deprived of vitamins K and D as well as of animals treated with vikasol excess. At the same time, accumulation of calcium led to time-dependent inhibition of respiratory chain if NAD-dependent substrates were used. Possible reasons of dissimilarity observed are discussed; the phenomenon found may occur due to exhaustion of the mitochondrial pyridine nucleotides pool. The data obtained suggest that antivitamins K altered only some parameters of body status (prothrombin time) similarly to the alterations observed in alimentary deficiency of vitamin K.

[The effect of supplying rats with vitamin K and administration of pelentane on Na,K- and spectrin-dependent ATPase in erythrocyte ghosts]. / Vliianie obespechennosti krys vitaminom K i vvedeniia pelentana na Na,K- i spektrinzavisimuiu ATPazy tenei éritrotsitov.

It was found that the activity of spectrin-dependent ATPase of erythrocyte ghosts isolated from rats with alimentary deficiency of vitamin K was significantly increased as compared with control animals, whereas in rats kept on a vicasol-rich diet this parameter was unchanged. In vitamin K-deficient rats the amount of proteins loosely bound to erythrocyte membranes was significantly reduced. At the same time, the activity of the integral enzyme (Na, K-ATPase) did not depend on the vitamin K provision despite the fact that in vitamin K-deficient animals kept on a vicasol-rich diet the enzyme affinity for ouabain was strongly decreased as compared with control. It was suggested that this effect might be due to the changes in the lipid and protein environment of the membrane-bound enzyme. Administration of the antivitamin K, pelentane, did not induce any conspicuous changes in the enzyme activities. It was concluded that antivitamin K does not induce any modification of the properties of erythrocyte-linked enzymes observed under conditions of vitamin K deficiency.

[Hypersensitivity vasculitis caused by ethyl biscoumacetate]. / Hipersenzitivni vaskulitis izazvan etilbiskumacetatom.

A case report of a 61-year-old patient with hypersensitive vasculitis caused by ethylbiscumacetate is presented. After the implantation of the artificial aortic valve the patient was treated with medigoxine, furosemide, dipiridamole, disopiramide, potassium chloride and ethylbiscumacetate. Among these drugs furosemide and ethylbiscumacetate are reported to cause hypersensitive vasculitis. On the basis of the past medical history, clinical and histological findings furosemide was ruled out as a causative agent. The diagnosis was confirmed by the skin biopsy and finding of a normal biologic activity of protein C. The discontinuance of all previous drugs and administration of methylprednisolone led to improvement in the skin lesions of the patient. The need for continuous anticoagulant therapy was the reason for fepromarone to be given, achieving good anticoagulant effect, without any side effects. According to the criteria of Karch and Lasagna the degree of connection between drug use and side effects in this case belongs to the category "probable".