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1.
Pharmacol Res ; 203: 107183, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38631619

RESUMO

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Sistema de Registros , Humanos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Estudos Prospectivos , Espanha/epidemiologia , Aspartato Aminotransferases/sangue , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos
2.
Pharmacol Res ; 200: 107046, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38159783

RESUMO

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Europa (Continente) , Previsões , Bases de Dados Factuais
3.
Liver Int ; 36(2): 302-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26104271

RESUMO

BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. METHODS: Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.


Assuntos
Corticosteroides/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas , Acetato de Ciproterona , Fígado/patologia , Neoplasias da Próstata/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Anti-Inflamatórios/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Acetato de Ciproterona/administração & dosagem , Acetato de Ciproterona/efeitos adversos , Humanos , Icterícia/etiologia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Medição de Risco , Índice de Gravidade de Doença
4.
Rev Esp Enferm Dig ; 106(4): 246-54, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25075655

RESUMO

OBJECTIVES: The hepatotoxic potential of statins is controversial. The objectives of this study were to describe the relative frequency of hepatotoxicity caused by statins and the phenotypes found in Spain. PATIENTS AND METHODS: The incidence of hepatotoxicity attributed to statins in the Spanish Hepatotoxicity Registry (REH) were studied and compared with those attributed to other drugs. RESULTS: Between April 1994 and August 2012, the REH included a total of 858 cases of which 47 (5.5 %) were attributed to statins. Of these, 16 were due to atorvastatin (34 %); 13 to simvastatin (27.7 %); 12 to fluvastatin (25.5 %); 4 to lovastatin (8.5 %) and 2 to pravastatin (4.3 %). Statins represented approximately half of the cardiovascular group which occupied 3rd place (10 %), after anti-infectious agents (37 %) and central nervous system drugs (14 %). The hepatocellular pattern was predominant, especially in the simvastatin group (85%), the cholestatic/mixed pattern was more frequent with fluvastatin (66 %) and had a similar distribution to atorvastatin. Patients with statin-induced toxicity were older (62 years versus 53 years, p < 0.001) and more often demonstrated anautoimmune hepatitis phenotype (8.5 % versus 1.4 %, p < 0.003). CONCLUSIONS: Statins are not a common cause of hepatotoxicity in Spain. Atorvastatin is the statin involved in the greatest number of incidents. The liver injury pattern varies among the different statins. The hepatitis phenotype with autoimmune features appears to be a characteristic signature of statin-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Hepatite Autoimune/epidemiologia , Hepatite Autoimune/etiologia , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Espanha/epidemiologia , Adulto Jovem
5.
J Hepatol ; 55(4): 820-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21338638

RESUMO

BACKGROUND & AIMS: Multiple instances of DILI in the same patient with drugs of similar structure or function as well as completely unrelated drugs are not well understood and poorly documented. We have sought evidence of the frequency and characteristics of patients who have experienced two DILI episodes due to different drugs. METHODS: All cases of DILI systematically collected in the Spanish DILI Registry between 1994 and 2009 were retrieved. Data on demographics, clinical, laboratory and pathological findings, and outcome were analyzed. RESULTS: Nine patients (mean age 67 years, four women) out of 742, 1.21%, had evidence of two DILI episodes caused by different drugs. In four cases DILI was associated with structurally related drugs and in an additional two cases the drugs had a common target. In another case, unrelated antibiotics were implicated. In only two cases, the two drugs/herbals were not related in structure or function. All but one patient exhibited hepatocellular damage. The type of damage was consistent in both DILI episodes. Four cases presented as autoimmune hepatitis (AIH) in the second episode. CONCLUSIONS: Multiple episodes of DILI in association with different drugs occur infrequently. In each individual, the type of injury was similar during the two DILI episodes, regardless of the causative drug. Second episodes of DILI are more likely to be associated with features of AIH. It remains uncertain if this is drug-induced unmasking of true AIH or DILI with autoimmune features. These cases illustrate the dilemma faced by clinicians in distinguishing these possibilities.


Assuntos
Anti-Infecciosos/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Hepatite Autoimune/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiarrítmicos/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Antipsicóticos/efeitos adversos , Antirreumáticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Feminino , Hepatite Autoimune/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Espanha/epidemiologia
6.
Rev Esp Enferm Dig ; 100(5): 278-84, 2008 May.
Artigo em Espanhol | MEDLINE | ID: mdl-18662080

RESUMO

INTRODUCTION: reexposure to a causal agent represents a potentially serious event in hepatotoxicity. OBJECTIVES: to assess the characteristics and outcome of cases with positive reexposure. MATERIAL AND METHODS: a retrospective study of cases with evidence of positive reexposure included in Registro Español de Hepatopatías Asociadas a Medicamentos, and an analysis of their relation to demographic and clinical variables, causality, course, and consequences. RESULTS: of a total of 520 cases 31 (6%) met reexposure criteria. Fatal outcomes, needs for admission, and mean recovery time were all higher for hepatocellular-type toxic injury. The most commonly identified drug class was antibiotics. On most occasions (73%) reexposure to the causal compound escaped notice because of: absence of index case diagnosis, lack of information to patients and their physicians, and (12%) development of cross reactions between structurally similar drugs. CONCLUSIONS: accidental reexposure to a drug or a structurally-related compound after an initial hepatotoxicity event is common and may have serious consequences, particularly in hepatocellular-type toxicity. Careful history taking and reflecting diagnostic suspicion in the initial episode s record may reduce the incidence of this iatrogenic event.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Adolescente , Adulto , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos
7.
Rev Esp Enferm Dig ; 100(11): 688-95, 2008 Nov.
Artigo em Espanhol | MEDLINE | ID: mdl-19159172

RESUMO

BACKGROUND: toxic liver damage associated with the use of natural remedies is a growing health problem. OBJECTIVES: to analyze the demographics, and clinical and epidemiological characteristics of patients developing liver injury related to these remedies. PATIENTS AND METHODS: all DILI cases associated with the use of herbal remedies (HR) or dietary supplements (DS) submitted to the Spanish Registry were analyzed. Type of liver damage, severity, and outcome were specifically evaluated. RESULTS: thirteen cases out of 521 DILI cases (2%) submitted to the Spanish Liver Toxicity Registry between 1994 and 2006 were related to HR/DS, which ranked as the 10th therapeutic group with a greater number of cases and above pain killers, anxiolytics, and antipsychotic drugs. Nine patients (69%) were female (mean age 45 years). Nine cases (69%) had jaundice at presentation. The predominating type of liver damage was hepatocellular (12; 92%), and 31% of cases exhibited the common features of hypersensitivity. Camellia sinensis (3, 23%) was the main causative herb, followed by Rhamnus purshianus and isoflavones (Fitosoja(R), Biosoja(R)) (2 cases each, 15%). Three cases (23%) were rechallenged with the offending product. CONCLUSIONS: the incidence of hepatic damage related to HR/DS is not so rare, the most common profile of affected patients being a woman with acute hepatocellular hepatitis. Low suspicion regarding the putative role of herbs in hepatotoxicity makes diagnosis more difficult, and probably increases the incidence of inadvertent rechallenge in these patients.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Colestase Intra-Hepática/induzido quimicamente , Fitoterapia/efeitos adversos , Preparações de Plantas/efeitos adversos , Adulto , Idoso , Camellia sinensis/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Colestase Intra-Hepática/epidemiologia , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacologia , Preparações de Plantas/farmacologia , Recidiva , Sistema de Registros/estatística & dados numéricos , Espanha/epidemiologia , Adulto Jovem
8.
Br J Pharmacol ; 150(6): 808-15, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17279092

RESUMO

BACKGROUND AND PURPOSE: The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly by cytochrome (CYP) 450, although other metabolic pathways can contribute. Anecdotal reports suggest a role of CYP 450 polymorphisms in DILI. We aimed to assess in a series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19, known to be involved in the metabolism of several hepatotoxic drugs. EXPERIMENTAL APPROACH: Genotyping of CYP2C9 ((*)2, (*)3) and CYP2C19 ((*)2 and (*)3), was carried out in a total of 28 and 32 patients with a well established diagnosis of DILI. CYP2C9 and CYP2C19 variants were analysed in genomic DNA by means of PCR-FRET and compared with previous findings in other Caucasian populations. KEY RESULTS: CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Fourteen patients (50%) were heterozygous and 1(4%) found to be compound heterozygous for the CYP2C9 allele. Seven (22%) were found to carry one and 1(3%) carried two CYP2C19 mutated alleles. No patients were homozygous for (*)3 allele. The distribution of both CYP2C9 and CYP2C19 allelic variants in DILI patients were similar to those in other Caucasian populations. Patients with variant and those with wild-type alleles did not differ in regard to clinical presentation of DILI, type of injury and outcome. CONCLUSIONS AND IMPLICATIONS: We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Fígado/efeitos dos fármacos , Fígado/lesões , Oxigenases de Função Mista/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Feminino , Frequência do Gene , Variação Genética , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Espanha
9.
Aliment Pharmacol Ther ; 41(1): 116-25, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25394890

RESUMO

BACKGROUND: We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. AIM: To characterise phenotype presentation, outcome and severity of AAS DILI. METHODS: Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. RESULTS: AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001-2009 to 8% in 2010-2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035-1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. CONCLUSIONS: Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.


Assuntos
Anabolizantes/efeitos adversos , Androgênios/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Injúria Renal Aguda/etiologia , Adulto , Idoso , Bilirrubina/sangue , Colestase/complicações , Creatinina/sangue , Humanos , Icterícia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Adulto Jovem
10.
Clin Pharmacokinet ; 10(5): 451-5, 1985.
Artigo em Inglês | MEDLINE | ID: mdl-3930124

RESUMO

The possible development of a displacement interaction involving tolbutamide, in epileptic patients, has been explored by studying the serum protein binding of this drug in vitro in 199 samples of sera from patients treated with antiepileptic agents included in a programme of therapeutic drug monitoring. 82 of the samples were from patients receiving a single drug, 86 from patients treated with 2 drugs, and 31 from patients treated with 3 drugs. The free fraction of tolbutamide was higher in serum from patients treated with antiepileptic drugs than in serum from untreated 'normal' volunteers. The increase was more marked the greater the number of antiepileptic drugs administered. Valproate appeared to be the most powerful displacing agent.


Assuntos
Anticonvulsivantes/efeitos adversos , Proteínas Sanguíneas/metabolismo , Tolbutamida/sangue , Adolescente , Adulto , Anticonvulsivantes/sangue , Ligação Competitiva , Criança , Clonazepam/farmacologia , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenobarbital/farmacologia , Fenitoína/farmacologia , Ligação Proteica , Ácido Valproico/farmacologia
11.
Thromb Res ; 81(3): 367-81, 1996 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-8928094

RESUMO

Cyclosporin A (CsA), a potent immunosuppressor used in organ transplants and autoimmune diseases, is associated with adverse effects in the kidney, liver, and nervous system. This drug was recently shown to stimulate platelet aggregation, to increase thromboxane synthesis, and to decrease vascular prostacyclin synthesis. In experimental cholestasis, thrombocyte function is altered. The present study was designed to assess the effects of CsA on platelet function in extrahepatic biliary obstruction (EBO) in rats. Cyclosporin or its excipient (Cremaphore El, polyethoxylated castor oil) did not modify collagen-induced platelet aggregation. In animals with EBO, platelet aggregation decreased by 50%. The administration of CsA (5 or 10 mg/kg) or Cremaphore El increased aggregation by 163%, 253% and 123% respectively. Thromboxane production increased by 119% after Cremaphore El was administered, but was not significantly modified by CsA. Cholestasis increased thromboxane synthesis by 48.4%, whereas CsA showed a direct dose-dependent effect, and excipient had no significant effect. Excipient inhibited the vascular synthesis of 6-keto-PFG1 alpha by 67.2%, as did 5 mg/kg (56.8%) and 10 mg/kg CsA (27.6%). EBO led to a nonsignificant increase in the vascular synthesis of 6-keto-PFG1 alpha. Cremaphore EI inhibited prostacyclin synthesis by 79%; inhibition by CsA was dose-dependent (31% at 5 mg/kg, 60% at 10 mg/kg). Our findings show that cholestasis enhances the effects of CsA on platelet aggregation and thromboxane/prostacyclin balance. These results may reflect the vascular effects of CsA, which in turn may be enhanced by cholestasis.


Assuntos
Colestase Extra-Hepática/sangue , Ciclosporina/farmacologia , Epoprostenol/biossíntese , Imunossupressores/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tromboxanos/biossíntese , Animais , Óleo de Rícino/análogos & derivados , Óleo de Rícino/farmacologia , Colestase Extra-Hepática/cirurgia , Modelos Animais de Doenças , Rim/metabolismo , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar
12.
Int J Clin Pharmacol Ther ; 35(1): 19-23, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9021437

RESUMO

AIM: The question regarding the minimal effective oral dose of fenoterol remains unanswered. The present study was undertaken to compare the therapeutic effects of sustained release theophylline and a conventional low dose oral fenoterol in patients with asthma. PATIENTS AND METHODS: A double-blind, double-dummy, randomized, 2-phase, cross-over comparison between sustained-release theophylline (SR-T) and oral fenoterol 2.5 mg 3 times daily in 21 patients with stable bronchial asthma (mean age 51 years) was conducted. Each drug was administered for a 2-week period. All patients qualified with a > or = 15% reversibility in forced expiratory volume in 1 second (FEV1) following 200 micrograms of inhaled salbutamol. Spirometric tests and body plethysmography were done at baseline and at the end of each treatment period. Blood was drawn for routine laboratory analysis and serum theophylline concentration. During each treatment period the patient kept a diary of symptoms and the concurrent use of inhaled salbutamol was recorded. RESULTS: During SR-T administration trough serum concentrations were 12.9 (1.5) mg/l mean (+/- SEM). SR-theophylline produced greater maximal changes in all parameters measured: FEV1, forced vital capacity, and specific airway resistance from the pretreatment and fenoterol phase, while fenoterol caused significant changes in none of the test variables. Patients showed an overall preference for SR-T over fenoterol (p < 0.05). CONCLUSIONS: Thus, 2.5 mg of fenoterol at 8-hour intervals did not prove to be an effective alternative to sustained release theophylline for management of patients with asthma. An appropriate dosing schedule for fenoterol needs to be redefined.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Fenoterol/administração & dosagem , Teofilina/administração & dosagem , Administração por Inalação , Administração Oral , Adulto , Albuterol/administração & dosagem , Asma/fisiopatologia , Estudos Cross-Over , Preparações de Ação Retardada , Método Duplo-Cego , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade
13.
Int J Clin Pharmacol Ther ; 32(10): 567-9, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7834165

RESUMO

Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin. We therefore studied the sensitivity of EMIT Convenience Pack Digoxin immunoassay to interference by DLIS in patients with liver failure. Serum digoxin was measured in cirrhotic patients with moderate to severe liver failure (Child-Pugh B or C grade), patients with mild liver disease (chronic hepatitis) and matched control patients without liver disease. Excluded were patients taking or who had ever received any cardiac glycoside in the past. Blood samples were obtained by venipuncture and assayed in duplicate. Twenty-two out of 30 cirrhotic patients (73%) showed false-positive results, vs. one of 6 patients (16.7%) with mild liver disease, and 1 of 10 (10%) controls. The serum DLIS level was negatively correlated with prothrombin activity (r = -0.55, p < 0.00011). Digoxin levels must be interpreted carefully in patients with moderate to severe liver failure.


Assuntos
Digoxina/sangue , Hepatite/sangue , Cirrose Hepática/sangue , Doença Crônica , Técnica de Imunoensaio Enzimático de Multiplicação , Reações Falso-Positivas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos
14.
Int J Clin Pharmacol Ther ; 40(1): 2-8, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11841050

RESUMO

BACKGROUND: The role of silymarin in the treatment of liver cirrhosis is controversial. AIM: Clinical outcome,biochemical profile and the antiperoxidative effects of silymarin MZ-80 during 6 months treatment were investigated in patients with alcoholic liver cirrhosis. METHODS: Sixty consecutive patients with alcoholic liver cirrhosis were randomized to receive either silymarin MZ-80 (S) (150 mg t.i.d. per day) or placebo (P) for periods of 6 months. Erythrocyte total glutathione (GSH) content, platelet malondialdehyde (MDA) and serum amino-terminal propeptide of procollagen Type III (PIIINP) were determined at baseline and at the end of treatment. RESULTS: Forty-nine patients completed the study (24 S and 25 P). The 2 groups were well-matched for demographic as well as baseline clinical and laboratory parameters. Silymarin increased total GSH at 6 months (4.5 +/- 3.4 to 5.8 +/- 4.0 micromol/g Hb) whereas, in the placebo group, GSH remained unchanged (4.1 +/- 3.9 to 4.4 +/- 4.1 micromol/gHb) (p < 0.001), and platelet-derived non-induced MDA decreased by 33% (p < 0.015). A parallel decrease in PIIINP values was seen with silymarin (1.82 1.03 to 1.36 +/- 0.5 U/ml, p < 0.033) but not with placebo (1.31 +/- 0.4 to 1.27 +/- 0.6 U/ml). There were no concurrent changes on laboratory indices of the pathology. CONCLUSIONS: Silymarin is well-tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in patients with alcoholic liver cirrhosis. Despite these effects no changes in routine liver tests were observed during the course of therapy.


Assuntos
Cirrose Hepática Alcoólica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Silimarina/farmacologia , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Método Duplo-Cego , Feminino , Humanos , Cirrose Hepática Alcoólica/complicações , Cirrose Hepática Alcoólica/tratamento farmacológico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Silimarina/uso terapêutico
15.
Int J Clin Pharmacol Res ; 7(1): 33-7, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3583486

RESUMO

The present study was carried out to evaluate the changes in digitoxin kinetics during ampicillin administration. Subjects were informed of the nature of the study and the treatment was applied to those who gave their written consent. Six healthy volunteers received a single oral dose of 1.0 mg of digitoxin. Three days later, they were given orally ampicillin trihydrate, 500 mg four times daily, for five consecutive days. Blood samples were taken at 24, 36, 48, 60, 72, 96, 120, 144, 168 and 192 hours after digitoxin. Compliance with ampicillin regimen was verified by fluorimetric measurement of serum ampicillin. Concentrations of serum digitoxin were determined by radioimmunoassay. The mean digitoxin elimination half-life changed from 162.8 +/- 12.9 h before to 181.3 +/- 10.1 h (mean +/- s.e. mean) after ampicillin. These differences were not significant. No consistent evidence of a kinetic interaction between digitoxin and the broad-spectrum antibiotic ampicillin was found.


Assuntos
Ampicilina/efeitos adversos , Digitoxina/urina , Adulto , Ampicilina/sangue , Digoxina/sangue , Interações Medicamentosas , Feminino , Meia-Vida , Humanos , Cinética , Masculino
16.
Int J Clin Pharmacol Res ; 7(2): 135-40, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-3294618

RESUMO

A study was conducted to evaluate the effects of a single oral dose of digitoxin on the circulatory function and the renin-angiotensin-aldosterone system. Seven doses of digitoxin and 6 of a placebo were given at random to 13 healthy volunteers, all of whom remained at rest, without smoking, throughout the study. Blood samples were taken initially after 1 h at rest, and at 1, 2 and 24 h after receiving the dose. Concentrations of serum digitoxin, aldosterone, angiotensin II (A II) as well as plasma renin activity (PRA) were determined by radioimmunoassay (RIA). In all subjects the blood pressure did not change throughout the study. Digitoxin decreased the heart rate significantly during the first and second hours, while in the placebo group the heart rate remained unchanged during the same period. The placebo had no detectable effect on PRA, A II and aldosterone. Digitoxin decreased PRA and A II levels, reaching its maximum effect 2 h after the administration. There was no correlation between the serum digitoxin concentration and PRA, A II or the aldosterone values. Digitoxin reached its maximum effect upon these parameters faster than what is generally accepted.


Assuntos
Digitoxina/farmacologia , Hemodinâmica/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Adulto , Aldosterona/sangue , Angiotensina II/sangue , Pressão Sanguínea/efeitos dos fármacos , Digitoxina/sangue , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Distribuição Aleatória , Renina/sangue
17.
Hum Exp Toxicol ; 12(2): 141-6, 1993 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8096712

RESUMO

Hyperlipidaemia commonly develops in both transplant recipients and experimental animals receiving cyclosporin A (CsA). However, the threshold of CsA induced-changes on lipoproteins and the role of parenteral vehicle (cremophor) has not been defined. Male Wistar rats were classified into five groups of six animals each and received CsA in cremophor vehicle at doses of 5, 10 or 20 mg kg-1 d-1, s.c., vehicle alone or saline for 7 d. Blood was obtained 24 h after the last dose and plasma was analysed. Plasma very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein subfractions (HDL-2, HDL-3) were isolated by sequential ultracentrifugation and their content of cholesterol, triglyceride and phospholipid was determined. Whole blood and trough plasma CsA levels were measured by monoclonal radioimmunoassay. Plasma lipids did not differ significantly among the five groups. At a dose of 20 mg kg-1 d-1 of CsA VLDL cholesterol rose significantly (P < 0.05). Administration of either CsA or cremophor vehicle increased HDL-2 phospholipids (P < 0.05) and decreased HDL-3 cholesterol. There was not a linear relationship between whole blood and plasma CsA levels and increasing CsA doses. Short-term treatment with low doses of CsA have little influence on lipid profile in the rat. Changes on lipoprotein composition can be attributed mainly to cremophor vehicle, conceivably due to its ethanol content.


Assuntos
Ciclosporina/toxicidade , Lipoproteínas/sangue , Animais , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Ciclosporina/administração & dosagem , Ciclosporina/sangue , Enzimas/sangue , Injeções Subcutâneas , Testes de Função Hepática , Masculino , Veículos Farmacêuticos , Ratos , Ratos Wistar
18.
Rev Esp Enferm Dig ; 93(7): 423-32, 2001 Jul.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-11685939

RESUMO

OBJECTIVE: To evaluate the characteristics of flutamide induced hepatotoxicity. MATERIAL AND METHODS: In this retrospective study we have analyzed all cases of flutamide hepatotoxicity submitted to the Andalucian Registry of drug-induced liver disease. Data were collected using a structured reporting form. Causality assessment was performed using two clinical scales: the standard CIOMS scale and the recently developed María and Victorino scale. RESULTS: Nine of 185 patients (4.9%) were identified. In 8 male patients, mean age 75 years (range 65-83), flutamide was indicated for palliative therapy of disseminated prostatic carcinoma, and in one young female (14 years) was given for the treatment of facial hirsutism. The mean duration of the flutamide therapy was 151 days (range 4-443). All patients presented with overt liver injury, the most frequent features being asthenia, anorexia, weight loss, nausea, vomiting and jaundice. No patient showed hypersensitivity features. In two patients (22%) the hepatic damage evolved to fulminant liver failure, one of them undergoing a liver transplantation and the other subsequently died. An additional patient died of a non-hepatic related cause when his liver function was improving. Causality assessment by the two clinical scales did not exclude any case, but the two patients who died where classified as unlikely by the María and Victorino scale. CONCLUSIONS: Flutamide can induce severe acute hepatitis, probably due to an idiosyncratic metabolic mechanism. Liver tests monitoring should probably be mandatory during the first months of flutamide therapy and the drug withdrawn if transaminases began to increase.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Flutamida/efeitos adversos , Fígado/efeitos dos fármacos , Adolescente , Idoso , Idoso de 80 Anos ou mais , Feminino , Hirsutismo/tratamento farmacológico , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Estudos Retrospectivos
19.
Gastroenterol Hepatol ; 20(7): 353-6, 1997.
Artigo em Espanhol | MEDLINE | ID: mdl-9377233

RESUMO

The case of a 39-year-old female with mild renal failure and asymptomatic hyperuricemia who developed generalized exanthema, fever and eosinophilia followed by progressive jaundice and worsening of renal function 19 days after the initiation of treatment with alopurinol (300 mg/day) is reported. Liver biopsy showed a combination of mixed inflammatory infiltrate with abundant eosinophils and periportal necrosis and bridging, together with cholestasis and moderate steatosis. A review of the literature is made providing detailed analysis of other cases with preexisting renal failure and the role of renal dysfunction as a risk factor is discussed.


Assuntos
Alopurinol/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Supressores da Gota/efeitos adversos , Insuficiência Renal/induzido quimicamente , Ácido Úrico/sangue , Doença Aguda , Adulto , Biópsia por Agulha , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Feminino , Humanos , Fígado/patologia , Insuficiência Renal/diagnóstico , Fatores de Risco
20.
Gastroenterol Hepatol ; 25(10): 589-93, 2002 Dec.
Artigo em Espanhol | MEDLINE | ID: mdl-12459120

RESUMO

OBJECTIVES: Analysis of all cases of tetrabamate (Atrium)-induced hepatotoxicity reported in the Andalusian Registry of drug-induced liver disorders and comparison with cases reported in the literature. MATERIAL AND METHOD: Information was gathered in a structured protocol. The causal role of tetrabamate was estimated in each case using the diagnostic scale of the Council for International Organizations of Medical Sciences (CIOMS). RESULTS: Of 327 cases of hepatotoxicity, 7 (2%) were due to tetrabamate. The mean age was 57 years (4 men). In 57% of the cases, the presenting symptom was tremor. The latency period was between 15 and 730 days. Liver damage was mainly cytolytic without signs of hypersensitivity. In all cases outcome was favorable with complete recovery between 60 and 120 days. The CIOMS diagnostic scale rated a causal role of tetrabamate as highly probable in six cases and as probable in one. CONCLUSION: Tetrabamate can induce hepatotoxicity, probably due to an idiosyncratic metabolic mechanism. Because of this finding and the existence of more appropriate therapeutic alternatives, tetrabamate should not be used in the treatment of alcohol withdrawal.


Assuntos
Barbitúricos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fenobarbital/efeitos adversos , Adulto , Idoso , Combinação de Medicamentos , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade
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