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V Fischer

Publications and source records attributed to V Fischer.

At least 55 records · Page 3Linked to original sources
PubMed1994

Triple valve surgery with triple aorto-coronary bypass and endarterectomy of the right coronary artery.

This paper presents the case report of a 50-year-old woman with a triple valve lesion of rheumatic origin and ischemic coronary disease. The patient underwent successful simultaneous triple valve surgery; the aortic and mitral valves were replaced by mechanical prostheses, and the tricuspid valve was repaired by annuloplasty, together with three aorto-coronary bypasses and endarterectomy of the right coronary artery. The peri- and postoperative courses were uneventful and the patient was discharged from hospital in good clinical condition 12 days after surgery.

Aortic Valve↗
PubMed1994

[Dysfunction of valvular prostheses].

Implantation of artificial mechanic valvular prostheses significantly improves and prolong the life of patients with valvular defects with a haemodynamic impact. This therapeutic method does not cure the patients and operation switches the problem of a natural dysfunctional valve to that of a functional artificial valve with improvement of the quality of life and its prolongation. The long-term effect and thus the general prognosis--the patient's "fate" depends above all on complications such as infections and haemocoagulation which are the main cause of dysfunction of artificial prostheses. The authors describe in the submitted paper basic principles of prevention of these undesirable events and decisive steps which must be taken to ensure a rapid and accurate diagnosis of imminent of already developed dysfunction of the prosthesis and its solution under the given conditions.

Heart Valve Prosthesis↗
PubMed1992

Possible role of free radical formation in drug-induced agranulocytosis.

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1 to 2% incidence of drug-induced agranulocytosis. Many other drugs, including paracetamol (acetaminophen), can cause agranulocytosis, although with a much lower incidence. Metabolic activation of these drugs by neutrophils or stem cells could be the molecular mechanism underlying this adverse effect. Drug oxidation by myeloperoxidase leads to free radical metabolite formation; these reactive free radicals can oxidise glutathione to a thiyl free radical, which in the presence of oxygen forms oxygen-derived free radicals. In contrast to glutathione, when these free radical metabolites oxidise ascorbate an unreactive free radical is formed, which does not even react with oxygen. In both reactions, the free radical metabolite is reduced to the original drug, although ascorbate is the more effective reducing agent. Thus ascorbate, when coadministered with agranulocytosis-causing drugs, may inhibit free radical chain reactions and other free radical-mediated reactions, such as protein adduct formation, and thereby prevent drug-induced agranulocytosis.

Agranulocytosis↗
PubMed1992

The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6.

A large interindividual variability for clozapine bioavailability and plasma steady-state concentrations and clearance exists. The enzymatic system which is involved in clozapine metabolism has not been fully characterized, yet structurally related tricyclic drugs have been found to be metabolized by cytochrome P450 2D6 (CYP2D6), which is polymorphically expressed in humans. The involvement of CYP2D6 in clozapine and fluperlapine metabolism was studied with human liver microsomes and in recombinant RT2D6 7-8 (RT2D6) cells, which specifically express human CYP2D6. Clozapine and its structural analog fluperlapine both bind to the active site of CYP2D6, as demonstrated by the competitive inhibition of dextromethorphan metabolism at inhibitor concentrations up to 40 microM. The inhibition constants (Ki) for both clozapine and fluperlapine were about 4 microM in microsomes from human liver. Clozapine exhibited a higher inhibition constant of 18.7 microM in microsomes from RT2D6 cells, but the difference was not statistically significant (P less than .05). These concentrations are close to the plasma concentrations of 0.3 to 3 microM achieved during clozapine therapy. Both clozapine and fluperlapine are also metabolized by CYP2D6. RT2D6 cells produced a number of metabolites from clozapine, whereas only a single metabolite was obtained from fluperlapine. The clozapine metabolites were not identified; however, they were different from N-oxide and N-demethyl clozapine. The fluperlapine metabolite was found to be the 7-hydroxy fluperlapine, which is also a major metabolite in vivo. In conclusion, both drug-drug interactions on the binding site of CYP2D6 and polymorphic metabolism of clozapine by CYP2D6 could contribute to the observed variability in clozapine kinetics in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1992

[Endarterectomy of the coronary arteries].

The authors analyze 50 patients with endarterectomy of the coronary arteries during the periods of 1972-1974 and 1988-1990. The results of endarterectomy of the right and left coronary artery provide evidence of its justification in indicated cases whereby contrary to some departments the results of endarterectomy of the left coronary artery are comparable with endarterectomy of the right coronary artery.

Coronary Disease↗
PubMed1991

Cyclosporine A metabolism by cytochrome P-450III occurs in microsomes from rat liver but not from normal epidermis or psoriatic lesions.

Cyclosporine A is efficacious in the treatment of psoriasis when taken orally or injected intralesionally but not topically. Lack of penetration to necessary locations or rapid metabolism during passage through the epidermis may account for the ineffectiveness. Cytochromes P-450III in the liver are known to be involved in cyclosporine metabolism and inactivation. This study was undertaken to determine if an epidermal cytochrome P-450III exists that can inactivate topical cyclosporine A. Rats were treated with the macrolide antibiotic erythromycin to induce the cytochrome P-450III family of enzymes. Microsomal fractions were prepared from liver and epidermis of rats and from lesional areas of psoriasis patients. NADPH cytochrome C reductase activity was determined as a positive control for microsomal enzymatic activity. Formation of metabolite 1, the predominant metabolite of cyclosporine A, by liver microsomes was increased 193% after 10 d erythromycin treatment. The cytochrome P-450 dependent activity in microsomes from the epidermis of control and erythromycin-treated rats and in microsomes from psoriatic tissue was at the detection limits of the assay system. Cytochrome P-450III gene family mRNA were detectable by polymerase chain reaction in liver but not in psoriatic or normal epidermis. The lack of detectable P-450III mRNA and the absence or minimal conversion of cyclosporine A to inactive metabolites by epidermal microsomes suggest that the ineffectiveness of topical cyclosporine A in psoriasis may not be due to inactivation of cyclosporine A by cytochrome P-450 in the skin.

Animals↗
PubMed1991

Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis.

The use of clozapine, a unique antipsychotic drug, has been restricted due to a 1-2% incidence of drug-induced agranulocytosis. Metabolic activation of clozapine in neutrophils or stem cells could be the molecular mechanism underlying this side effect. Clozapine oxidation by human myeloperoxidase and horseradish peroxidase was evident from the disappearance of the UV absorbance at 290 nm. High performance liquid chromatography analysis revealed the formation of at least four radioactive peaks as a result of clozapine metabolism, including radioactivity coeluting with the protein. The tight association of radioactivity with the enzymatic protein was metabolism-dependent. This protein binding, which correlates with the total metabolism of clozapine, was reduced in the presence of glutathione and was absent in the presence of ascorbate. Similarly, in the presence of both reducing agents, the metabolite peaks in the high performance liquid chromatography radiogram, which are not associated with protein, disappeared. In contrast, in the presence of glutathione, two additional metabolites were found that could be isolated and identified by NMR and mass spectroscopy as clozapine glutathionyl adducts. Evidence for one-electron transfer reactions or the intermediate formation of a clozapine radical during the peroxidase-mediated metabolism of clozapine stems from the observation of thiyl and ascorbyl radicals in the presence of glutathione and ascorbate, respectively. The ascorbyl radical was detected by direct ESR spectroscopy in a peroxidase system. Its steady state concentration was significantly increased in the presence of clozapine. Glutathionyl radical formation was demonstrated by radical trapping with 5,5-dimethyl-1-pyrroline N-oxide in a peroxidase system. Again, the radical adduct concentration was significantly increased in the presence of clozapine. Similarly, when oxygen consumption was measured in peroxidase systems in the presence of glutathione or NADPH, the rate of oxygen uptake was markedly enhanced upon addition of clozapine. Thus, the data support the possibility of clozapine activation to free radical metabolites, which may cause oxidative stress or lead to adduct formation. Further, it can be concluded from these data that radical scavengers such as ascorbic acid, when coadministered with clozapine to patients, may reduce oxidative stress and protein adduct formation.

Agranulocytosis↗
PubMed1991

[Implantation of artificial heart valve prostheses in the mitral position using continuous sutures--our initial experience].

Heart valve replacement using continuous suture is the method of choice in many cardiosurgical centers. Our experience with this method is presented in this report on our first nine patients. In seven of them the Björk-Shiley and in two the Sorin type of prosthesis was applied without occurrence of paravalvular leak. Suture in continuous fashion can be performed under the following conditions: moderate thickening of the annulus fibrosus, absence of calcifications, and acute bacterial endocarditis. (Ref. 7).

Female↗
PubMed1990

Metabolism of fluperlapine by cytochrome P450-dependent and flavin-dependent monooxygenases in continuous cultures of rat and human cells.

The metabolism of fluperlapine, a neuroleptic dibenzazepine derivative with a N-methyl-piperazinyl substituent, was investigated in continuous cultures of rat and human cells which express various cytochrome P450-dependent monooxygenase activities. The differentiated rat hepatoma cells H4IIEC3/G- and their variants 2sFou and FGC-5 metabolized fluperlapine predominantly by N-oxygenation and only to a minor degree by N-demethylation or glucuronidation of primary phenolic products. Total fluperlapine metabolism in dedifferentiated rat hepatoma cells H5 and partially differentiated human hepatoma cells HepG2 was much smaller than in the differentiated rat hepatoma lines. This was primarily attributable to their low capacity for N-oxygenation. Human lung adenocarcinoma lines NCI-H322 and NCI-H358 formed only trace amounts of fluperlapine N-oxide. Pretreatment of 2sFou cells with benz(a)anthracene, phenobarbital or dexamethasone markedly increased the formation of N-demethylated and glucuronidated products but did not affect the rate of N-oxide formation. Guanethidine and cysteamine, inhibitors of flavin-dependent monooxygenase activity, reduced fluperlapine N-oxidation more strongly than aldrin epoxidation, a marker for cytochrome P450 activity. In contrast, n-octylamine inhibited aldrin epoxidation but was without effect on fluperlapine N-oxygenation. The results suggest that certain cells in continuous culture are capable of expressing flavin-dependent monooxygenase(s) in addition to cytochrome P450-containing monooxygenases. Such cells may offer useful systems for studying the oxidative metabolism of a broad spectrum of xenobiotics and analysing the importance of the two oxygenation reactions for the biological effects of their substrates.

Animals↗
PubMed1990

Effect of enzyme induction on Sandimmun (cyclosporin A) biotransformation and hepatotoxicity in cultured rat hepatocytes and in vivo.

This study was designed to examine the relationship between the extent of Sandimmun (cyclosporin A, SIM) metabolism and SIM-induced hepatotoxicity both in vivo and in primary cultures of rat hepatocytes. Firstly, SIM (50 mg/kg p.o.) was administered daily to male Wistar rats for 10 days with or without co-administration of Aroclor 1254. SIM-induced hepatotoxicity appeared after 4 days of treatment and was enhanced after 10 administrations of SIM. Total plasma proteins were decreased and hyperbilirubinemia as well as increased levels of plasma bile salts were prominent. Aroclor 1254 stimulated total hepatic cytochrome P-450 3.7-fold, and markedly increased the rate of SIM metabolism and plasma elimination as determined by both HPLC and RIA techniques. However, this induction did not change the degree of SIM-induced hepatotoxicity. Secondly, short-term cultures of hepatocytes obtained from normal rats and from rats pretreated with either Aroclor 1254 or dexamethasone, a specific inducer of the cytochrome P-450 III gene family responsible for the formation of the primary SIM metabolites M1, M17 and M21, were incubated with various concentrations of SIM for up to 17 hr. At 1 microM SIM, both inducers greatly increased the rate of SIM metabolism in vitro, producing, however, different metabolite patterns. In the hepatocyte cultures, SIM inhibited the incorporation of amino acids into proteins. In addition, a small fraction of [3H]-labeled SIM was covalently bound to hepatocellular macromolecules. Although the fraction of covalently bound SIM was markedly increased in cells from dexamethasone-treated rats, the degree of inhibition of hepatocellular protein synthesis was not changed in cells from induced rats. In contrast to SIM-induced nephrotoxicity, these results suggest that increased rates of SIM biotransformation by inducers of drug metabolism are not associated with an attenuation of hepatotoxicity both in vivo and in vitro.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1990

Glutathione and ascorbate reduction of the acetaminophen radical formed by peroxidase. Detection of the glutathione disulfide radical anion and the ascorbyl radical.

The acetaminophen phenoxyl radical was generated by the oxidation of acetaminophen by horseradish peroxidase in a fast-flow ESR experiment, and its reaction with glutathione and ascorbate was studied. Glutathione reduces the phenoxyl radical of acetaminophen to regenerate acetaminophen and form the thiyl radical of glutathione. This thiyl radical reacts with the thiolate anion of glutathione to form the disulfide radical anion, which was detected and characterized by ESR spectroscopy. In the presence of ascorbate, the ascorbyl radical was produced by the reduction of the acetaminophen phenoxyl radical by ascorbate. This reaction results in the complete reduction of the free radical of acetaminophen, whereas the glutathione reduction of the phenoxyl radical of acetaminophen was not complete on the fast-flow ESR time scale of milliseconds. This suggests that ascorbate rather than glutathione is more likely to react with the acetaminophen phenoxyl free radical in vivo. In the presence of both ascorbate and higher concentrations of glutathione, the reaction with ascorbate is dominant. When cysteine was used in the place of reduced glutathione in the above assay system, the disulfide radical anion of cystine was observed in a manner similar to glutathione. These reactions may have significance in the detoxification of acetaminophen and the free radical metabolites of xenobiotics in general. Only in cells containing low levels of ascorbate can glutathione play a direct role in the detoxification of the acetaminophen phenoxyl radical.

Acetaminophen↗
PubMed1989

Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine.

Immunoblotting analysis of human liver microsome preparations revealed that human cytochrome P-450 PCN1 (hPCN1, Mr approximately 52,000) was expressed in each of 40 individual specimens examined. In about 10-20% of the livers, an immunologically related protein having a lower electrophoretic mobility (Mr approximately 52,500) was also detected. A single liver was found that expressed only the lower mobility protein, designated hPCN3, and RNA isolated from this liver was used to construct a lambda gt11 library. The library was screened with an hPCN1 cDNA probe resulting in the isolation of a unique full-length cDNA that was sequenced and shown to encode hPCN3. The deduced amino acid sequence of this cDNA contained 502 residues, a calculated molecular mass of 57,115 daltons, and displayed 84% similarity with hPCN1. The deduced amino-terminal sequence of hPCN3 was identical to that of HFLa, a major cytochrome P-450 expressed in human fetal liver that is immunologically cross-reactive with several family III cytochrome P-450s. hPCN1 and hPCN3 cDNAs were expressed in Hep G2 cells using a vaccinia virus expression system and shown to encode active enzymes, both characterized by reduced CO-binding spectra with lambda max at 450 nm. Enzymatic analysis revealed that both cytochrome P-450s were similarly active in catalyzing oxidation of the calcium channel blocking drug nifedipine. Both enzymes also catalyzed 6 beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione, although hPCN1 exhibited several-fold higher expressed activity than hPCN3. Several minor oxidation products of these steroids (e.g. 15 beta-hydroxytestosterone), comprising up to approximately 20% of the total metabolites, were formed by hPCN1 but not hPCN3, indicating that hPCN3 is a more highly regiospecific monooxygenase catalyst with steroid substrates. Clear differences were also detected in their catalytic activities toward the immunosuppressive drug cyclosporine, with two hydroxylated metabolites (M1 and M17) and one demethylated metabolite (M21) formed by hPCN1 but only one metabolite (M1) formed by hPCN3. These studies establish that hPCN3 is a newly described cytochrome P-450 that is differentially expressed in the adult human population and that has overlapping substrate specificity compared to hPCN1 for metabolism of steroid and drug substrates.

Amino Acid Sequence↗
PubMed1989

[Tumors of the heart and arterial embolisms].

Tumors of the heart are a rare cause of embolism of the peripheral arterial system. A series of 26 patients operated on for heart tumor in the Institute of Cardiovascular Diseases in Bratislava over the years 1979-1988 was analyzed. Pseudomyxoma was histologically verified in 24 patients and rhabdomyoma and rhabdomyosarcoma in the other two patients. A total of 12 embolic events was recorded in 9 patients (34.6%). There were 8 instances of embolism in the central nervous system and 4 in the extremities. In all cases pseudomyxoma of the left parts of the heart was the source of embolism. In 21 cases diagnosis was established and operation indicated on the basis of ultrasonographic evidence. The authors recommend the biatrial transseptal approach. Early surgical removal of a heart tumor is the therapy of choice which prevents the development of potential complications from the heart and peripheral arteries.

Adolescent↗
PubMed1989

[Endarterectomy of the coronary arteries].

The authors present an account, based on their clinical material, of 15 endarterectomies of the coronary arteries, which from the chronological aspect are divided into two groups. The first six were performed in 1972-1974 without the use of cardioplegia, total cardias arrest, only with ventricular fibrillation, with a 50% rate of success. The series of the remaining nine patients was operated during the period between October 1987 and the end of 1988 under far more favourable conditions, using cold cardioplegia, hypothermia and total cardias arrest. Only one patient died 24 hours after operation, the remaining eight patients are being followed up for one to 14 months after operation. In six patients endarterectomy of the right coronary artery was performed and in three instances in the area of the r. interventricularis of the left coronary artery. There was no case of perioperative myocardial infarction. The immediate postoperative development of the patients is promising and encourages us to proceed with this surgery (endarterectomy of the coronary artery) which is the only alternative method in the group of patients with diffuse distal arteriosclerosis of the coronary arteries.

Coronary Artery Disease↗
PubMed1988

Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs.

The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid-inducible rat cytochrome P-450 (P-450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P-450 of the P-450III gene family, homologues of rat P-450 PCN and rabbit P-4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P-450 is the major cyclosporine-metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P-450 explain several clinically observed drug interactions with cyclosporine.

Cyclosporins↗
PubMed1988

An ESR study of nonenzymatic reactions of nitroso compounds with biological reducing agents.

The nonenzymatic reduction of nitrosobenzene (I), 2-nitroso-1-naphthol (II) and 2-nitroso-1-naphthol-4-sulfonic acid (III) with reducing agents such as NADPH, L-cysteine and N-acetyl-L-cysteine led to the formation of the corresponding hydronitroxide radicals, as confirmed with ESR spectroscopy. In addition to these radicals, a novel hydronitroxide radical, which was conjugated with GSH at the 4-position, was observed in the reaction of II or III with GSH. The formation of a hydronitroxide conjugated with GSH still retains the radical structure with its related redox chemistry. In this case, the formation of a GSH conjugate does not lead to the formation of chemically less reactive species.

Acetylcysteine↗