RESUMO
To determine the antagonization of anticoagulant and lipolytic effects of a low molecular weight [LMW] heparin preparation protamine chloride was given intravenously after i.v. injection of LMW or normal heparin. The effects of normal heparin on factor Xa, thrombin, aPTT, lipoprotein [LPL] and hepatic triglyceride lipase [HTGL] activities were neutralized immediately by i.v. protamine. The inhibition of thrombin and aPTT by LMW heparin were also abolished, whereas the effects on LPL and HTGL were counteracted to 80% and on factor Xa only to 40% by i.v. protamine chloride. No rebound of the anticoagulant or lipolytic effect was detected. It is assumed that haemorrhagic complication during therapy can be antagonized by protamine chloride. The incomplete inhibitory effect of protamine chloride on LPL, HTGL and factor Xa activities of LMW heparin indicate that protamine chloride requires more than 14 saccharide units in the heparin molecule for interaction.
Assuntos
Antagonistas de Heparina/farmacologia , Protaminas/farmacologia , Adulto , Cromatografia Líquida de Alta Pressão , Fator X/fisiologia , Fator Xa , Heparina , Humanos , Lipase/metabolismo , Lipoproteínas/metabolismo , Fígado/enzimologia , Masculino , Peso Molecular , Tempo de Tromboplastina Parcial , Tempo de TrombinaRESUMO
The lipolytic and anticoagulant actions of a 4000 dalton low molecular weight (LMW) heparin were compared with unfractionated mucosal heparin after intravenous and various subcutaneous doses in man. I.v. injection of 100 USP units/kg body weight lipoprotein lipase (LPL) activity, and inhibition of factor Xa decreased with a half life twice as long after LMW heparin compared to normal heparin (p less than 0.05). There were no differences in half lives for HTGL activity, thrombin inhibition and on aPTT. The area under the activity time curve (AUC) of LPL and factor Xa was double with LMW heparin (p less than 0.05). S.c. administration showed that the AUC of LMW heparin on the factor Xa inhibition was 10 times larger compared to normal heparin. LPL activity was released comparable to normal heparin. The effects on HTGL were three times larger compared to normal heparin. There were no differences in half lives. The data show that in contrast to normal heparin LMW heparin is rapidly and completely absorbed from the subcutaneous depots. The pharmacodynamic data of LPL activity and factor Xa inhibition suggest similar release mechanisms.
Assuntos
Anticoagulantes , Heparina/farmacologia , Lipólise/efeitos dos fármacos , Adulto , Fator X/antagonistas & inibidores , Fator Xa , Feminino , Humanos , Lipase/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Trombina/antagonistas & inibidoresRESUMO
Hepatic metabolism of the uricosuric drug benzbromarone results in the formation of two hydroxilated main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxybenzbromarone). As urinary excretion of benzbromarone and its metabolites is very low, we investigated biliary and plasma concentrations of the parent drug and the metabolites after oral administration of a single 100 mg dose of benzbromarone in 6 patients requiring diagnostic gastroduodenoscopy. Benzbromarone, M1 and M2 were detectable in bile samples 12 hours after drug application. No dehalogenated derivatives (bromobenzarone, benzarone) were present in the bile. 12h, 24h, and 36h plasma concentrations of the parent drug and the main metabolites varied substantially. Our data provide direct evidence of biliary excretion of benzbromarone and its hydroxilated main metabolites 1'-OH-bzbr (M1) and 6-OH-bzbr (M2) and demonstrate the lack of excretion of debrominated products.
Assuntos
Benzobromarona/metabolismo , Bile/metabolismo , Uricosúricos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Hidroxilação , Pessoa de Meia-IdadeRESUMO
A 49 year old female patient with anorexia nervosa was admitted to the hospital because of treatment-refractory hyperuricemia and gout. Medical history and clinical findings were compatible with primary gout and uric acid nephropathy. The patient stated that she regularly took allopurinol. In the hospital she initially received 300 mg allopurinol daily after breakfast. In order to ensure allopurinol ingestion and absorption the plasma concentrations of both allopurinol and its active metabolite oxipurinol were determined in addition to serum uric acid and further clinical chemistry data. Despite allopurinol treatment no decrease of serum uric acid was observed for three days. Therefore the head nurse was instructed to supervise the intake of allopurinol carefully. During the following days serum uric acid decreased and plasma oxipurinol concentrations rose. On day 9 of treatment serum uric acid fell into the upper normal range. Therefore the patient was allowed to leave the hospital within a few days. However serum uric acid thereafter increased again while plasma oxipurinol declined. Later on it became evident that the patient had vomited self-induced approximately 15 minutes after allopurinol intake. In the meantime her husband had urged her to return home. Starting with day 18 benzbromarone treatment was added. Combined therapy with 400 mg allopurinol and 50 mg benzbromarone daily finally resulted in a serum uric acid concentration of 4.5 mg/dl at discharge from the hospital. About three weeks later the private physician again diagnosed hyperuricemia with serum uric acid values between 10 and 12 mg/dl. Meanwhile the patient needs to be dialysed due to end stage renal disease. Our observations show that self-induced vomiting to prevent effective treatment may be a disease-specific pattern of noncompliance with drug therapy in anorexia nervosa.
Assuntos
Anorexia Nervosa/psicologia , Gota/tratamento farmacológico , Cooperação do Paciente , Ácido Úrico/sangue , Alopurinol/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Falha de Tratamento , Vômito/etiologiaRESUMO
The effects of preceding food intake on the plasma concentrations of R(-)-ibuprofen and the pharmacologically active enantiomer S(+)-ibuprofen were investigated in healthy subjects. A single oral dose of 400 mg racemic ibuprofen was administered either fasting or following a standardized meal. As compared to fasting administration postprandial drug intake resulted in a clear reduction of R(-) and S(+)- ibuprofen plasma concentrations mainly during the initial three hours. The ratio of S(+)/R(-)-ibuprofen postprandially was increased for Cmax and AUC o-tmax as well as for AUC o-infinity. These data are compatible with a meal-induced enhancement of chiral inversion of R(-) to S(+)-ibuprofen. The significant reduction of plasma concentrations of ibuprofen mainly during the initial three hours suggests that the analgesic efficacy is diminished when the drug is taken after a meal. This may to a slight extent be compensated for by a small increase of the metabolic inversion of the R(-)-enantiomer into the active S(+)-form of the drug.
Assuntos
Anti-Inflamatórios não Esteroides/farmacocinética , Jejum , Ibuprofeno/farmacocinética , Período Pós-Prandial , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Estudos Cross-Over , Ingestão de Alimentos , Feminino , Humanos , Ibuprofeno/administração & dosagem , Masculino , EstereoisomerismoRESUMO
The disposition of benzbromarone and its uric acid lowering effect were investigated in 8 patients with compensated liver cirrhosis in order to obtain evidence whether dose requirements differ from subjects with normal liver function. Following a single oral dose of 100 mg benzbromarone, the plasma concentrations of the parent drug and the two hydroxylated main metabolites M1 and M2 as well as uric acid were determined up to at least 72 h. All patients were found to be rapid benzbromarone eliminators. In patients 2-8 the extent of systemic availability of benzbromarone, as estimated by the average AUC(0-infinite), was similar to previous observations in healthy individuals, whereas the values of both metabolites M1 and M2 tended to be lower in patients with liver cirrhosis. Cmax of benzbromarone and M1 also were lower in patients, M2 was equivalent to the data in subjects with normal liver function. tmax and the plasma elimination half-life t(1/2) varied within the same range as previously observed in healthy individuals. One patient exhibited much higher values in AUC(0-infinite); and Cmax of benzbromarone and both metabolites, and in addition of the elimination half-life of M1 and M2, whereas the plasma elimination of benzbromarone itself was not delayed. An effect of altered liver function cannot be excluded in this patient. Ten hours after benzbromarone administration the mean plasma uric acid in patients 2-8 was reduced by 31.5% and in patient 1 by 44.2% as compared to pretreatment values. Baseline levels were not regained until 72 h. These data are compatible with a prolonged uric acid lowering effect of an active benzbromarone metabolite. Altogether, the present observations do not suggest dose adjustment to be necessary in patients with compensated liver cirrhosis Child A and B.
Assuntos
Benzobromarona/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Ácido Úrico/sangue , Uricosúricos/administração & dosagem , Adulto , Benzobromarona/farmacocinética , Feminino , Humanos , Cirrose Hepática/sangue , Pessoa de Meia-Idade , Uricosúricos/farmacocinéticaAssuntos
Actinas , Oligopeptídeos , Faloidina , Fenômenos Químicos , Química , Ligação Proteica , Espectrofotometria UltravioletaRESUMO
High-performance liquid chromatography (HPLC) of heparins was carried out with on-line photodiode-array detection. Average molecular weights and molecular weight distribution were calculated using computer data acquisition and handling; size-exclusion chromatography was performed using different selective microparticulate columns and narrow molecular weight distribution heparin standards for calibration; heparin peak purity was investigated using several methods for evaluation. Additional UV-absorbing compounds present in heparin preparations were characterized and quantitated by reversed-phase HPLC. These methods are useful for the analysis of the molecular weight distribution and peak purity of heparins and for the determination of additional drugs, additives or impurities.
Assuntos
Heparina/análise , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Peso Molecular , Espectrofotometria UltravioletaRESUMO
The enantiomers of the chiral coumarin-type anticoagulants phenprocoumon, warfarin and p-chlorophenprocoumon were separated by high-performance liquid chromatography on a chiral stationary phase (Nucleosil-Chiral 2) and normal-phase conditions. Chromatographic peak identification was performed with authentic reference compounds of the enantiomers and on-line UV spectra comparison. This method was applied to the determination of the enantiomeric ratio of phenprocoumon in plasma and urine extracts from patients under racemic drug therapy. The limit of detection (50 and 80 ng/ml) and precision (less than 5%) of the method are adequate for pharmacokinetic and enantioselective disposition studies, respectively, of phenprocoumon. No racemization was detected during the extraction procedures.
Assuntos
4-Hidroxicumarinas/metabolismo , Femprocumona/metabolismo , Varfarina/metabolismo , Cromatografia Líquida de Alta Pressão , Humanos , Femprocumona/sangue , Femprocumona/urina , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Estereoisomerismo , Varfarina/sangue , Varfarina/urinaRESUMO
The diuretic drug hydrochlorothiazide (HCT) is used mainly for treatment of mild to moderate hypertension and is usually administered with other drugs. An assay for the determination of HCT in human plasma and urine by high performance liquid chromatography (HPLC) has been developed. Samples were purified by solvent extraction and analysed by reversed phase HPLC with ultraviolet detection, using hydroflumethiazide as the internal standard; plasma was eluted using gradient elution and urine was analysed isocratically. The method is simple to perform, is sensitive (detection limit 0.01 micrograms/mL in plasma and 0.2 micrograms/mL for urine); it showed good reproducibility (3-8%). A great number of drugs did not interfere with the assay and the method was used for pharmacokinetic studies in healthy subjects, but samples from patients can also be analysed with high selectivity.
Assuntos
Hidroclorotiazida/análise , Adulto , Cromatografia Líquida de Alta Pressão , Humanos , Hidroclorotiazida/sangue , Hidroclorotiazida/urina , Masculino , Espectrofotometria UltravioletaRESUMO
The analysis of extracts from the South American plant Justicia pectoralis Jacq. permitted the identification, among other compounds, of coumarin, dihydrocoumarin, umbelliferone and 3-(2-hydroxyphenyl)propionic acid by gas chromatography/mass spectrometry (GC/MS); the acids and phenolic compounds were derivatized with diazomethane. GC/MS of simple coumarins, phenylpropionic acids and their hydroxylated isomers was performed after derivatization through methylation and trimethylsilylation; these results may be useful for the identification and quantification of these compounds in other biological materials.
Assuntos
Cumarínicos/isolamento & purificação , Fenilpropionatos/isolamento & purificação , Plantas/análise , Cromatografia Gasosa-Espectrometria de Massas , Indicadores e ReagentesRESUMO
The coumarin anticoagulant phenprocoumon (PH) and metabolites (6-, 7- and 4'-hydroxyphenprocoumon) were analysed in plasma and urine samples from anticoagulated patients using solid-phase extraction and high-performance liquid chromatography with reversed-phase columns and ultraviolet and fluorescence detection; a simpler handling of samples, higher selectivity, precision, accuracy and analytical recovery were obtained compared to analysis using liquid-liquid extraction. Similarly, a method for the analysis of PH in human breast milk was developed to assess the passage of anticoagulants into breast milk in anticoagulated lactating women.
Assuntos
Anticoagulantes/análise , Leite Humano/química , Femprocumona/análise , Anticoagulantes/sangue , Anticoagulantes/urina , Cromatografia Líquida de Alta Pressão , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Femprocumona/sangue , Femprocumona/urina , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
Pooled plasma from patients receiving phenprocoumon anticoagulant therapy was extracted and the following substances were characterized: phenprocoumon, and its 7-hydroxy,4'-hydroxy and 6-hydroxy derivatives; they were identified by HPLC and after methylation by quartz capillary GC-MS using the electron impact and selective ion monitoring modes. This is the first occasion when phenprocoumon metabolites have been identified in plasma; they were unconjugated and in much lower concentrations (43.2 and 2 ng/ml for the 7,4' and 6-hydroxy derivatives, respectively) than the original compound (2000 ng/ml).
Assuntos
4-Hidroxicumarinas/sangue , Femprocumona/sangue , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Indicadores e ReagentesRESUMO
Positive ion mass spectra were obtained from several coumarin oral anticoagulants (phenprocoumon, warfarin, acenocoumarol and dicoumarol) and derivatives by liquid chromatography-thermospray mass spectrometry (LC-TSP-MS) and liquid chromatography-electron impact mass spectrometry (LC-EI-MS) to assess the use of LC-MS methods for the determination of these compounds in biological materials. LC-TSP mass spectra showed a single [M + 1]+ ion with no fragmentation; LC-EI mass spectra showed fragment ions which were similar in mass and relative intensities to those obtained by conventional EI-MS. These data should serve as a basis for the development of LC-MS methods for the qualitative and quantitative analysis of coumarin anticoagulants in biological samples. LC-TSP-MS was applied to the determination of phenprocoumon in a plasma extract from an anticoagulated patient.
Assuntos
Anticoagulantes/análise , Cumarínicos/análise , Anticoagulantes/sangue , Anticoagulantes/urina , Cromatografia Líquida , Cumarínicos/sangue , Cumarínicos/urina , Humanos , Espectrometria de Massas , Femprocumona/sangueRESUMO
Benzbromarone is one of the main uricosuric drugs currently used. We determined plasma concentrations of benzbromarone, bromobenzarone, and benzarone and 24 hour uric acid excretion in ten healthy individuals following fasting application of two different non-micronised benzbromarone brands. In addition we explored the influence of adjusting urinary pH to near neutral values and of concomitant food intake. Benzbromarone was more rapidly absorbed from the test preparation than from the reference preparation; the extent of systemic availability did not differ significantly. Urinary pH adjustment had no clearcut effect, whereas food intake retarded drug absorption (even though not significant because of the variability of the data). Binding of benzbromarone to plasma proteins exceeded 99%. Bromobenzarone and benzarone were not detectable and are unlikely to be major metabolites of benzbromarone. Instead we found two other compounds suggestive of metabolites, one of them being monohydroxilated benzbromarone. The plasma concentrations of the parent compound in one subject exceeded those of the rest of the group, possibly indicating genetic differences in drug metabolism. The uricosuric effect was not related to benzbromarone plasma concentrations.
Assuntos
Benzobromarona/farmacocinética , Benzofuranos/farmacocinética , Ácido Úrico/urina , Adulto , Benzobromarona/análogos & derivados , Benzobromarona/farmacologia , Humanos , Hidroxilação , Inativação Metabólica , Masculino , Ligação Proteica , Purinas/administração & dosagemRESUMO
To evaluate phenprocoumon elimination its possible biliary excretion was evaluated in addition to the known pathway of renal elimination. Bile samples were obtained during diagnostic endoscopy in patients receiving chronic phenprocoumon therapy and were analyzed for phenprocoumon and its metabolites by HPLC and GC-MS. The following substances were detected, mainly in conjugated form: unchanged phenprocoumon and the metabolites 7-hydroxy-, 4'-hydroxy-, and 6-hydroxy-phenprocoumon. The data provide direct evidence of the biliary elimination of unchanged phenprocoumon and its metabolites in humans.