Isoniazid-Induced Recurrent Pancreatitis

Context Drug induced pancreatitis are rare but potentially serious. Thus, drug withdrawal is warranted. Case report A 79-year-old woman who was treated with antituberculosis therapy for 5 weeks was admitted to our unit for pancreatitis. Usual etiologies of pancreatitis were eliminated. Because of vomiting, antituberculosis therapy was withdrawn and symptoms disappeared. Eight days later, the same treatment was reintroduced and the patient presented recurrent pancreatitis; thus, treatment was withheld again followed by disappearance of clinical and biological abnormalities. Two days later, a treatment without isoniazid was reintroduced and no recurrence of symptoms was observed. Conclusions We have experienced a case of isoniazid induced pancreatitis. This is a rare cause of pancreatitis but potentially fatal thus recognition of drug induced pancreatitis and definitive withdrawal of the drug is required

Novel in vitro and mathematical models for the prediction of chemical toxicity

The focus of much scientific and medical research is directed towards understanding the disease process and defining therapeutic intervention strategies. The scientific basis of drug safety is very complex and currently remains poorly understood, despite the fact that adverse drug reactions (ADRs) are a major health concern and a serious impediment to development of new medicines. Toxicity issues account for ∼21% drug attrition during drug development and safety testing strategies require considerable animal use. Mechanistic relationships between drug plasma levels and molecular/cellular events that culminate in whole organ toxicity underpins development of novel safety assessment strategies. Current in vitro test systems are poorly predictive of toxicity of chemicals entering the systemic circulation, particularly to the liver. Such systems fall short because of (1) the physiological gap between cells currently used and human hepatocytes existing in their native state, (2) the lack of physiological integration with other cells/systems within organs, required to amplify the initial toxicological lesion into overt toxicity, (3) the inability to assess how low level cell damage induced by chemicals may develop into overt organ toxicity in a minority of patients, (4) lack of consideration of systemic effects. Reproduction of centrilobular and periportal hepatocyte phenotypes in in vitro culture is crucial for sensitive detection of cellular stress. Hepatocyte metabolism/phenotype is dependent on cell position along the liver lobule, with corresponding differences in exposure to substrate, oxygen and hormone gradients. Application of bioartificial liver (BAL) technology can encompass in vitro predictive toxicity testing with enhanced sensitivity and improved mechanistic understanding. Combining this technology with mechanistic mathematical models describing intracellular metabolism, fluid-flow, substrate, hormone and nutrient distribution provides the opportunity to design the BAL specifically to mimic the in vivo scenario. Such mathematical models enable theoretical hypothesis testing, will inform the design of in vitro experiments, and will enable both refinement and reduction of in vivo animal trials. In this way, development of novel mathematical modelling tools will help to focus and direct in vitro and in vivo research, and can be used as a framework for other areas of drug safety science

Antibiotic-Associated Hepatitis: Update from 1990

Objective To review the literature on the recent available evidence of antibiotic-associated acute liver injury. Data Sources All published articles from January 1990 to July 1995 were extracted from the monthly updated HEPATOX database. Additional articles were found using MEDLINE, EMBASE, and PASCAL searches. Hepatic injuries associated with antituberculous, antimycotic, antiviral, antiprotozoal, and antiseptic compounds were excluded from this review. Study Selection As the amount of literature was large, only case reports, series, and epidemiologic data were used. Results from clinical trials were reviewed only when no other information was available. Data Extraction Original articles were reviewed to select relevant material. Information regarding the clinical description, histologic features, severity, outcome, and possible risk factors was extracted. Data on incidence were provided by epidemiologic studies or spontaneous reporting to regulatory agencies. Data Synthesis Antibiotic-associated acute liver injury is rare, with an incidence not exceeding 1 case per 10 000 users for most drugs. Among beta-lactams, amoxicillin/clavulanic acid and penicillinase-resistant penicillins are associated with predominant and sometimes protracted cholestasis. The hepatotoxic potential of all available erythromycin salts is confirmed, and recent evidence suggests that roxithromycin could be added to the list of antibiotic-induced liver injury. Among fluoroquinolones, only ciprofloxacin has been associated with serious hepatitis. Trimethoprim/sulfamethoxazole-induced hepatitis is often reported, but trimethoprim alone also appears as a possible cause of acute liver injury. Finally, acute bile duct injuries and ductopenia have been described with several antibiotics. Conclusions The most important recent information is the possibility of protracted liver cholestasis with bile duct injuries induced by several antibiotics, particularly penicillinase-resistant penicillins, and the identification of new potentially hepatotoxic antibiotics, namely, roxithromycin, ciprofloxacin, and trimethoprim. </jats:sec