RESUMO
Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Glucose/metabolismo , Hipoglicemiantes/uso terapêutico , Doenças Cardiovasculares/etiologia , Hemoglobinas Glicadas/metabolismo , Glicina/análogos & derivados , Regulamentação Governamental , Humanos , Hipoglicemiantes/efeitos adversos , Oxazóis , Fenilbutazona/análogos & derivados , Guias de Prática Clínica como Assunto , Risco , Rosiglitazona , Tolbutamida , Estados Unidos , United States Food and Drug AdministrationRESUMO
REASONS FOR PERFORMING STUDY: In horses, it has been demonstrated that suxibuzone (SBZ) has a lower gastric ulcerogenic effect than phenylbutazone (PBZ). However, no field trials have been reported comparing the efficacy of the drugs in alleviating lameness. OBJECTIVES: To compare the therapeutic effect of SBZ to that of PBZ when administered orally in lame horses. Acceptability of both products was also compared. METHODS: Lame horses (n = 155) were used in a multicentre, controlled, randomised and double-blinded clinical trial. Horses were treated orally with either SBZ or PBZ at equivalent therapeutic dosages. PBZ was given to 79 horses at a dose of 4.4 mg/kg bwt/12 h for 2 days, followed by 2.2 mg/kg bwt/12 h for 6 days. SBZ was given to 76 horses at 6.6 mg/kg bwt/12 h for 2 days, followed by 3.3 mg/kg bwt/ 12 h for 6 days. Efficacy of treatments was evaluated by clinicians in equine practices according to lameness progression throughout the study. Product ingestion was checked daily to evaluate product acceptability. RESULTS: Although SBZ showed a statistically significant tendency to have a better efficacy than PBZ (Odds ratio = 2.7; P = 0.016), significance dissipated once the analysis was adjusted for some imbalanced baseline covariates, confirming that they were actually related to the apparent advantage of SBZ over PBZ. Product acceptability was significantly higher in the SBZ group than in the PBZ group (96.1% vs. 77.2%; P = 0.001). CONCLUSIONS: SBZ and PBZ did not show significant differences in alleviating lameness in horses. However, SBZ had better product acceptability when administered orally with some food. POTENTIAL RELEVANCE: SBZ is a good therapeutic alternative to PBZ in horses since there is no significant difference in alleviating lameness between the 2 therapies.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças dos Cavalos/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Fenilbutazona/análogos & derivados , Fenilbutazona/uso terapêutico , Animais , Método Duplo-Cego , Feminino , Cavalos , MasculinoRESUMO
Eighteen mature, healthy horses were divided into three groups (six per group) receiving either no treatment, 15 consecutive days of phenylbutazone (PBZ), or 15 consecutive days of suxibuzone (SBZ) at recommended label doses. Horses underwent endoscopy before and after the treatment period and were assigned gastric ulcer scores. Gastric ulcer number and severity scores were similar across treatment groups. These findings suggest that when administered at the recommended label dose for 15 days, neither PBZ nor SBZ causes an increase in the number or severity of gastric ulcers over what would be expected with traditional stabling and intermittent feeding patterns. Also, PBZ-treated horses did not have more severe gastric ulcers than SBZ-treated horses, indicating that SBZ does not appear to offer an advantage over PBZ in preventing gastric ulcers when used at recommended label doses. However, ulcers in other regions of the gastrointestinal tract (e.g., right dorsal colon, duodenum) were not evaluated in horses in this study.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças dos Cavalos/induzido quimicamente , Fenilbutazona/análogos & derivados , Fenilbutazona/efeitos adversos , Úlcera Gástrica/veterinária , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Química Farmacêutica , Feminino , Doenças dos Cavalos/patologia , Cavalos , Masculino , Fenilbutazona/administração & dosagem , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologiaRESUMO
The efficacy of top-dress antiinflammatory drugs ultimately depends on a patient's willingness to consume treated feed. The current study compares the palatability of two phenylbutazone top-dress formulations (Equipalazone Powder, Dechra Pharmaceuticals, and Pro-Dynam, VetXX, Ltd.) and a suxibuzone top-dress formulation (Danilon Equidos, Janssen Animal Health). Results of a three-period, crossover study on 18 healthy horses showed that Pro-Dynam was significantly less palatable, with significantly less consumption of treated feed compared with either Equipalazone Powder or Danilon Equidos. There was no statistically significant difference in terms of consumption of treated feed and palatability scores between Equipalazone Powder and Danilon Equidos.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças dos Cavalos/tratamento farmacológico , Fenilbutazona/análogos & derivados , Fenilbutazona/administração & dosagem , Paladar , Administração Oral , Ração Animal , Animais , Estudos Cross-Over , Feminino , Cavalos , Masculino , Paladar/fisiologiaAssuntos
Coxeadura Animal/etiologia , Mononeuropatias/veterinária , Animais , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios , Dimetil Sulfóxido/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Membro Posterior/patologia , Cavalos , Masculino , Mononeuropatias/complicações , Fenilbutazona/análogos & derivados , Fenilbutazona/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Vitamina E/uso terapêuticoRESUMO
Recent reports of serious concern regarding the safe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives. Earlier reports have claimed reduced toxicity among similar derivatives. These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives. Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity. Although none of the reported nonbutylated malonamides was as potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity. PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives. Of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.
Assuntos
Inibidores de Ciclo-Oxigenase , Malonatos/síntese química , Fenilbutazona/análogos & derivados , Fenilbutazona/síntese química , Amidas/síntese química , Amidas/farmacologia , Animais , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Malonatos/farmacologia , Espectrometria de Massas , Microssomos/enzimologia , Fenilbutazona/farmacologia , Glândulas Seminais/enzimologia , Ovinos , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
The chemical syntheses and biological evaluation of several potential irreversible inhibitors for prostaglandin (PGH) synthase are described. These inhibitors were modeled after the nonsteroidal antiinflammatory (NSAI) drug phenylbutazone (4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an alpha-bromoacetamide, an alpha-chloroacetamide, a phenylurethane, a propargyl chloride, and several alpha,beta-unsaturated Michael acceptors were incorporated at the 4-position of the pyrazolidinedione ring structure. None of the derivatives showed evidence of irreversible inhibition of PGH synthase, although several were nearly as potent inhibitors of this enzyme as phenylbutazone. The nitrile obtained from 1,4-conjugate addition of cyanide to one of the unsaturated derivatives was considerably more potent as an inhibitor of PGH synthase than was phenylbutazone.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Inibidores de Ciclo-Oxigenase , Fenilbutazona/síntese química , Animais , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Microssomos/enzimologia , Fenilbutazona/análogos & derivados , Fenilbutazona/farmacologia , Glândulas Seminais/enzimologia , Ovinos , Relação Estrutura-AtividadeRESUMO
Among phenylbutazone (PZ) and its related compounds, suxibuzone (SUX) caused the most extensive decrease in pyruvate kinase (PK) activity with lower toxicity. Therefore, we studied the effect of SUX on rat hepatocarcinogenesis to confirm our assumption that an agent which causes a prolonged decrease in PK activity in rat liver promotes hepatocarcinogenesis. For initiation rats were fed a diet containing 0.06% 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) for 4 weeks. At the end of 53 weeks of the experiment the incidences of liver tumors were 14.3 and 70.0% in the rats fed basal diet and in the rats fed 0.5% SUX diet, respectively, after the initiation. No tumors were observed in rats fed the SUX diet without the initiation. The result shows that SUX promotes hepatocarcinogenesis and supports the above assumption.
Assuntos
Carcinógenos , Neoplasias Hepáticas/induzido quimicamente , Fígado/efeitos dos fármacos , Metildimetilaminoazobenzeno/toxicidade , Fenilbutazona/análogos & derivados , Piruvato Quinase/metabolismo , p-Dimetilaminoazobenzeno/análogos & derivados , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Interações Medicamentosas , Fígado/enzimologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Fenobarbital/toxicidade , Fenilbutazona/toxicidade , Ratos , Ratos EndogâmicosRESUMO
The radiographic contrast agent sodium diatrizoate (DTR) reportedly inhibits f-Met-Leu-Phe-induced chemotaxis in human neutrophils. DTR is also an ingredient of Ficoll-Paque, a density centrifugation medium widely used to purify human polymorphonuclear leukocytes (PMNs). Exposure of PMNs to DTR during preparation had no detrimental effect on subsequent binding characteristics of tritiated f-Met-Leu-Phe, probably owing to a rapid dissociation of DTR from the PMN receptors. DTR competed directly with f-Met-Leu-Phe for receptor binding, but was 160- and 640-fold less potent than phenylbutazone and 1,2-diphenyl-4-[3-(1-naphthyl)-propyl]-3,5-pyrazolidinedione (DPN; an analog of phenylbutazone), respectively. Iohexol and the methylamide of DTR did not compete with [3H]f-Met-Leu-Phe in receptor binding, supporting the existence of a definite interaction between iodinated aromatic molecules and the f-Met-Leu-Phe receptor. DTR did not inhibit prostaglandin synthesis, as did DPN. Both drugs inhibited chemotactic peptide-induced release of superoxide anion in a concentration-dependent manner, and were relatively selective for f-Met-Leu-Phe, as opposed to C5a. Both drugs at 10 microM interfered non-selectively with chemotactic peptide-induced beta-glucuronidase release from PMNs. Available non-peptide antagonists of f-Met-Leu-Phe exhibited other pharmacodynamic properties that could make them unsuitable for future in vivo studies designed to probe the physiological role of the receptor.
Assuntos
Meios de Contraste/farmacologia , N-Formilmetionina Leucil-Fenilalanina/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Fenilbutazona/análogos & derivados , Receptores Imunológicos/efeitos dos fármacos , Ligação Competitiva , Diatrizoato/farmacologia , Dinoprostona/metabolismo , Glucuronidase/metabolismo , Humanos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , Neutrófilos/metabolismo , Fenilbutazona/farmacologia , Ensaio Radioligante , Receptores de Formil Peptídeo , Receptores Imunológicos/antagonistas & inibidores , Superóxidos/metabolismoRESUMO
The effect of prednisolone and non-steroid anti-inflammatory drugs on PMNL (polymorphonuclear leucocytes) oxidative metabolism was quantified with a newly standardized NBT test, and it was investigated whether these effects correlate with phagocytosing capacity of PMNL. Prednisolone inhibits NBT reduction in dose dependency already at concentrations, which do not interfere with phagocytosis. Thus prednisolone dissociates phagocytosis and phagocytosis-associated oxidative metabolism. High doses of prednisolone also inhibit phagocytosis. These effects of prednisolone are still demonstrable when PMNL are washed after pre-incubation with the drug. The non-steroid anti-inflammatory drugs (indomethacin, phenylbutazone and pyrazinobutazone) inhibit phagocytosis and NBT reduction at equivalent doses. When PMNL are washed after incubation with the drugs, they regain normal capacity to phagocyse and to reduce NBT. It is suggested that these drugs inhibit phagocytosis directly, and consequently the phagocytosis-associated oxidative metabolism is suppressed.
Assuntos
Anti-Inflamatórios/farmacologia , Neutrófilos/efeitos dos fármacos , Fagocitose , Prednisolona/farmacologia , Humanos , Indometacina/farmacologia , Microesferas , Nitroazul de Tetrazólio , Oxirredução , Fenilbutazona/análogos & derivados , Fenilbutazona/farmacologiaRESUMO
Chemically defined haptenic reagents and haptenic conjugates were synthesized to be used for skin tests in allergic patients and for serological tests. One series of reagents is based on an open-chain derivative which is formed by reaction of the oxidation product of phenylbutazone, 4-hydroxyphenylbutazone, with amino functions. A second series uses the intact 1,2-diphenyl-pyrazolidine-3,5-dione molecule which is substituted in the 4-position with acetic acid. Both haptens are used in conjunction with spacer molecules which provide considerable distances between haptenic moiety and carriers. The skin test reagents are hexavalent conjugates based on the bis-penta-L-lysine carrier "PAL". Rabbit and guinea-pig antisera against the haptens were obtained by immunizations with human serum albumin conjugates. Data obtained from passive cutaneous anaphylaxis and from ELISA tests show that there is generally only slight cross-reactivity between the two series of haptenic reagents. Also, there is only modest cross-reactivity between intact drugs and haptenic reagents. No measurable crossreactions were noted between 1-phenyl-2,3-dimethyl-3-pyrazolin-5-one derivatives and haptenic reagents of the 1,2-diphenyl-pyrazolidinedione series.
Assuntos
Hipersensibilidade a Drogas/diagnóstico , Fenilbutazona/análogos & derivados , Animais , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Epitopos/análise , Epitopos/imunologia , Cobaias , Anafilaxia Cutânea Passiva , Fenilbutazona/síntese química , Fenilbutazona/imunologia , Coelhos , Kit de Reagentes para Diagnóstico , Testes Cutâneos/métodos , Relação Estrutura-AtividadeRESUMO
Nonsteroidal antiinflammatory drugs(NSAIDs) are known as clinically effective agents for treatment of inflammatory diseases. Inhibition of cyclooxygenase has been thought to be a major facet of the pharmacological mechanism of NSAIDs. However, it is difficult to ascribe the antiinflammatory effects of NSAIDs solely to the inhibition of prostaglandin synthesis. Human neutrophil elastase (HNElastase; HNE, EC 3.4.21.37) has been known as a causative factor in inflammatory diseases. To investigate the specific relationship between HNElastase inhibition and specificity of molecular structure of several NSAIDs, HNElastase was purified by Ultrogel AcA54 gel filtration, CM-Sephadex ion exchange, and HPLC (with TSK 250 column) chromatography. HNElastase was inhibited by aspirin and salicylate in a competitive manner and by naproxen, ketoprofen, phenylbutazone, and oxyphenbutazone in a partial competative manner, but not by ibuprofen and tolmetin. HNElastase-phenylbutazone-complex showed strong Raman shifts at 200, 440, 1124, 1194, 1384, 1506, and 1768 cm(-1). The Raman bands 1194, 1384, and 1768 cm(-1) may represent evidences of the conformational change at -N=N-phi radical, pyrazol ring, and -C=O radical of the elastase-drug complex, respectively. Phenylbutazone might be bound to HNElastase by ionic and hydrophobic interaction, and masked the active site. Inhibition of HNElastase could be another mechanism of action of NSAIDs besides cyclooxygenase inhibition in the treatment of inflammatory diseases. Different inhibition characteristics of HNE-lastase by NSAIDs such as aspirin, phenylbutazone-like drugs and ineffective drugs could be important points for drawing the criteria for appropriate drugs in clinical application.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Cromatografia de Afinidade , Simulação por Computador , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/isolamento & purificação , Cetoprofeno/farmacologia , Elastase de Leucócito/isolamento & purificação , Modelos Moleculares , Naproxeno/farmacologia , Fenilbutazona/análogos & derivados , Salicilatos/farmacologia , Análise Espectral RamanRESUMO
Some drugs, including nonsteroidal antiinflammatory compounds, can be hemolytic in glucose-6-phosphate dehydrogenase-deficient patients. We have studied the potential hemolytic activity of feprazone, a nonsteroidal antiinflammatory compound in vitro and in vivo. Agents that may be hemolytic for glucose-6-phosphate dehydrogenase-deficient erythrocytes will stimulate the hexose monophosphate shunt in normal erythrocytes. Eleven normal subjects were treated with feprazone and their erythrocytes were incubated in their own sera (containing active feprazone metabolites) and [1-14C]-glucose. Because no statistically significant increase in 14CO2 evolution was observed, 15 pediatric male patients with glucose-6-phosphate dehydrogenase deficiency who required antiinflammatory treatment were treated with feprazone. No hemolytic crises and no statistically significant changes of hematologic tests were observed.
Assuntos
Feprazona/farmacologia , Deficiência de Glucosefosfato Desidrogenase/sangue , Hemólise/efeitos dos fármacos , Fenilbutazona/análogos & derivados , Adolescente , Adulto , Eritrócitos/efeitos dos fármacos , Feprazona/efeitos adversos , Humanos , MasculinoRESUMO
Long-term safety and efficacy of feprazone (4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione), an antirheumatic drug that is well tolerated in the gastrointestinal tract, were assessed in a noncontrolled multicenter trial. Administered at a daily dosage of 600 mg for a mean duration of 114.1 days, feprazone was well tolerated by 43 (77%) of 56 treated subjects. Thirteen patients reported side effects, but only five discontinued treatment. The side effects were generally mild and occurred in the first weeks of therapy. Feprazone was found effective after one month on both considered indices of disease activity: Ritchie index (articular index for assessment of joint tenderness) and corticosteroid consumption.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Feprazona/uso terapêutico , Osteoartrite/tratamento farmacológico , Fenilbutazona/análogos & derivados , Feminino , Feprazona/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A double-blind trial was carried out in 24 patients with acute gout to compare the efficacy and tolerance of feprazone, a non-steroidal anti-inflammatory drug, with that of phenylbutazone. Patients received 800 mg of either drug daily for 2 days and then 600 mg daily for up to 8 days. The results of patient assessment showed there was no significant difference between the two groups in time taken either to significant improvement or to final resolution of the gout attack. No side-effects were reported with either drug.
Assuntos
Feprazona/uso terapêutico , Gota/tratamento farmacológico , Fenilbutazona/análogos & derivados , Fenilbutazona/uso terapêutico , Doença Aguda , Adulto , Idoso , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A double-blind crossover study was carried out in 21 patients with osteoarthrosis of the hip to compare the efficacy and tolerance of feprazone (600 mg/day) and ibuprofen (1200 mg/day), each drug being given for 4 weeks. No statistically significant changes were noted in any of the objective parameters measured, but patients' subjective assessments of pain showed a significant improvement in pain levels (p less than or equal to 0.05, day and night) after feprazone. One patient, who had reported a rash at initial assessment, was withdrawn at the end of the first treatment period (on feprazone) when he developed a severe rash, 1 patient was withdrawn because of exacerbation of symptoms (on ibuprofen) and a further patient was lost to follow-up because of intercurrent illness. Both drugs were well tolerated by the other patients and the few side-effects reported were minor in nature.
Assuntos
Feprazona/uso terapêutico , Articulação do Quadril , Osteoartrite/tratamento farmacológico , Fenilbutazona/análogos & derivados , Idoso , Ensaios Clínicos como Assunto , Método Duplo-Cego , Feminino , Feprazona/efeitos adversos , Humanos , Ibuprofeno/efeitos adversos , Ibuprofeno/uso terapêutico , Masculino , Pessoa de Meia-Idade , DorRESUMO
A study was carried out in 10 healthy male subjects to investigate whether mofebutazone, a phenylbutazone derivative, influenced furosemide-induced diuresis and PGE2 excretion as has been shown with other non-steroidal anti-inflammatory agents such as aspirin and indomethacin. The subjects received, at random, a single dose of either 40 mg furosemide or 40 mg furosemide plus 600 mg mofebutazone and were then crossed over to the other regimen after 10 days. Urine was collected for 45 minutes before and then for six 45-minute clearance periods after drug administration. Urine volumes and excretion of sodium, potassium, chloride, magnesium, creatinine and the main metabolite of PGE2 were measured at the end of each period, as were blood levels of creatinine and mofebutazone from samples taken before, during and after administration. The results showed no significant differences between the two groups, indicating no interaction between mofebutazone and the diuretic.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Furosemida/farmacologia , Fenilbutazona/análogos & derivados , Prostaglandinas E/urina , Adulto , Anti-Inflamatórios não Esteroides/sangue , Dinoprostona , Diurese/efeitos dos fármacos , Interações Medicamentosas , Humanos , Masculino , Natriurese/efeitos dos fármacos , Fenilbutazona/sangue , Fenilbutazona/farmacologia , Distribuição AleatóriaRESUMO
The absorption, excretion, and metabolism of a single oral dose of suxibuzone, a new nonsteroidal anti-inflammatory agent, in healthy male volunteers were compared with those of phenylbutazone. After oral administration of either suxibuzone or phenylbutazone, phenylbutazone, oxyphenbutazone, and gamma-hydroxyphenylbutazone were found in the plasma; phenylbutazone was the main metabolite of suxibuzone and phenylbutazone. In the urine, p-gamma-dihydroxyphenylbutazone and several glucuronide conjugates also were found. Spectrometric and/or enzymatic analysis showed that these glucuronide conjugates were suxibuzone glucuronide, 4-hydroxymethylphenylbutazone glucuronide, 4-hydroxymethyloxyphenbutazone glucuronide, oxyphenbutazone glucuronide, and phenylbutazone glucuronides (two types: O-glucuronide and C-4-glucuroxide) after suxibuzone administration, and oxyphenbutazone glucuronide and phenylbutazone glucuronide after phenylbutazone administration. The conjugates specific to suxibuzone administration, suxibuzone glucuronide, 4-hydroxymethylphenylbutazone glucuronide, and 4-hydroxymethyloxyphenbutazone glucuronide, were excreted in the first 6 hr urine. These findings and the pharmacokinetics of these metabolites in the plasma and urine show that suxibuzone is a prodrug of phenylbutazone.
Assuntos
Fenilbutazona/análogos & derivados , Fenilbutazona/metabolismo , Adulto , Biotransformação , Fezes/análise , Humanos , Absorção Intestinal , Cinética , Masculino , Fatores de TempoRESUMO
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.
Assuntos
Fenilbutazona/análogos & derivados , Cromatografia Gasosa/métodos , Humanos , Masculino , Oxirredução , Fenilbutazona/sangue , Fatores de TempoRESUMO
A high-pressure liquid chromatographic method was developed for the quantitative determination of feprazone, a nonsteroidal anti-inflammatory agent, in different pharmaceutical formulations. The results agree with those obtained with GLC and UV spectrophotometric assays.