RESUMO
Use of non-steroidal anti-inflammatory drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in patients with cirrhosis have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty-nine patients with cirrhosis were included in an observer-blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500 mg; N = 15) or dipyrone (575 mg; N = 14) for 72 hr. Serum and urine samples were obtained at baseline, 48 and 72 hr, and cystatin C, creatinine, aldosterone, 6-keto-Prostaglandin-F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72 hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72 hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis.
Assuntos
Dipirona/efeitos adversos , Rim/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Prostaglandinas/metabolismo , Acetaminofen/administração & dosagem , Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Adulto , Idoso , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Analgésicos não Narcóticos/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Ascite/tratamento farmacológico , Dipirona/administração & dosagem , Dipirona/uso terapêutico , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Fatores de TempoRESUMO
OBJECTIVE: The diagnosis of drug-induced hepatotoxicity is based on circumstantial evidence and is often inaccurate. We have designed a method based on published data to assign causality to suspected cases of drug-induced hepatotoxicity. DESIGN: Forty-seven published cases of ticlopidine-induced hepatotoxicity were identified by a Medline-based literature search. Data regarding abnormal liver function in patients receiving ticlopidine were obtained from the only published placebo-ticlopidine clinical trial (the Canadian American Ticlopidine Study; CATS). Thus, we calculated the maximum number of expected hepatotoxicity cases in patients exposed to ticlopidine and those not exposed to the drug by means of the Poisson distribution. The calculated odds ratio was used as a prior odd for subsequent quantification, using a Bayesian-based approach, of individual ticlopidine-induced hepatotoxicity likelihood. Concretely, the prior odd is modified by several separate likelihood ratios: age; sex; AST level; ALT level; alkaline phosphatase level; total bilirubin level; latent period of adverse reaction appearance; and period of remission of adverse reaction. This methodology was applied to two new cases of suspected ticlopidine-induced hepatotoxicity. RESULTS: The prior probability of ticlopidine-induced hepatotoxicity derived from CATS data is 61.29%. This is in contrast with the 28.83% incidence rate of drug-induced liver alterations in the general population. Alkaline phosphatase levels and total bilirubin levels were six times the normal values among individuals with ticlopidine-induced hepatotoxicity than in the general population. They were the most relevant likelihood ratios of the Bayesian model to establish a high level of causality relationship between a hepatotoxicity event and ticlopidine use. CONCLUSIONS: The proposed method, which links information from clinical trials with the profile of clinical hepatotoxicity of a drug defined from published cases reported after a drug is marketed, can be a useful tool for drug postmarketing surveillance research.
Assuntos
Teorema de Bayes , Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias/etiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Distribuição de Poisson , Ticlopidina/efeitos adversos , Adulto , Idoso , Ensaios Clínicos como Assunto , Feminino , Humanos , Incidência , Hepatopatias/diagnóstico , Hepatopatias/enzimologia , MEDLINE , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de TempoRESUMO
The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. The natural history, characteristics and limitations of this exclusion process are revised. Also, the numerous published attribution algorithms for evaluation of drug-related liver abnormalities are described and their characteristics and differences are illustrated with true patients from our clinical experience. Situations that complicate the diagnosis such as age, sex, concomitant use of other drugs, genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs and drug-drug interactions are described. Finally, developing approach to diagnosis of drug-induced liver injury, different of attribution algorithms, are evaluated and explained using a new method based in a Bayesian approach developed and published by the authors. The authors' vision of all these potential advances and their clinical utility is provided.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias/diagnóstico , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Teorema de Bayes , Feminino , Humanos , Masculino , Polimorfismo GenéticoRESUMO
BACKGROUND: In the last 20 years, some cases of agranulocytosis associated with calcium dobesilate consumption in Spain have been reported. A high risk of dobesilate-associated agranulocytosis (121 cases per million per year) calculated using both a case-control and a case-population strategy has been published. However few spontaneous reports have been noted in the same period of time. No explanation exists for this disagreement. METHODS: Estimated incidence rates of agranulocytosis in the IAAAS study and the calculated risk of dobesilate-associated agranulocytosis were used as background risks in a Poisson-based methodology, to calculate the number of coincidental reports of agranulocytosis among patients treated with dobesilate. The influence of treatment duration, notification rate and population characteristics were calculated. RESULTS: During the period 1978-2000, a total of 23 cases would have taken place if the background risk of agranulocytosis were 4.7 per million per year (IAAAS's risk); however, only 9 spontaneous cases of agranulocytosis associated to dobesilate were noted. A simulation showed that with notification rates equal to or higher than 17%, it was not possible to exclude that the 9 cases were false-positives. With notification rates equal or inferior to 16%, it would be unlikely that cases of agranulocytosis were noted in this population with a risk of 4.7 per million per year; therefore, it is necessary to assume a higher agranulocytosis risk. More than 1 case per year could be a false-positive if the background risk of agranulocytosis is 9.5 per million per year, this being the appropriate risk for a population of patients older than 60 years. The duration of treatment beyond 30 days increases the probability of a random coincidence of the intake of drug and an agranulocytosis event. CONCLUSIONS: The disagreement between calculated dobesilate-associated agranulocytosis risk and the number of noted spontaneous reports may be explained by at least three different factors: under-reporting, duration of treatment and age of patients. It is possible, with the methodology presented, to estimate the influence of these factors to avoid confusion with possible false-positive cases and then to design the correct prospective trial that can provide the true agranulocytosis risk.