sulindac and Liver-Diseases

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the management of rheumatological disorders, and as analgesics and antipyretics. Hepatotoxicity is an uncommon, but potentially lethal complication, which usually occurs within 12 weeks of starting therapy. It can occur with all NSAIDs, but appears to be more common with diclofenac and particularly sulindac. Female patients aged >50 years, with autoimmune disease, and those on other potentially hepatotoxic drugs, appear to be particularly susceptible. Liver function test abnormalities generally settle within 4-6 weeks of stopping the causative drug. However, some patients may develop acute liver failure and successful orthotopic liver transplantation may be undertaken in such patients. Recent in vitro animal studies have shown that the mechanism of diclofenac toxicity relates both to impairment of ATP synthesis by mitochondria, and to production of active metabolites, particularly n,5-dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial permeability transition (MPT) has also been shown to be important in diclofenac-induced liver injury, resulting in generation of reactive oxygen species, mitochondrial swelling and oxidation of NADP and protein thiols. Physicians and hepatologists must be vigilant to the hepatotoxic potential of any NSAID, as increased awareness, surveillance and reporting of these events will lead to a better understanding of the risk factors and the pathophysiology of NSAID-related hepatotoxicity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chemical and Drug Induced Liver Injury; Diclofenac; Disease Susceptibility; Drug Hypersensitivity; Female; Humans; Liver Diseases; Liver Failure, Acute; Middle Aged; Mitochondria, Liver; Risk Factors; Sulindac

The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use both prescription and over-the-counter-makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.

Topics: Acetaminophen; Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Diclofenac; Humans; Liver Diseases; Risk Factors; Salicylates; Sulindac

The nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used medications worldwide for the treatment of a variety of common chronic and acute inflammatory conditions. The association between NSAIDs and liver disease is poorly documented, the exceptions being sulindac and, to a lesser degree, diclofenac. The incidence of liver disease is very low and is relatively unimportant compared with the risk of peptic ulcer disease and gastrointestinal bleeding. Reports of hepatic injury range from insignificant and transient liver enzyme elevation to severe and fulminant hepatitis.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Chemical and Drug Induced Liver Injury; Cohort Studies; Diclofenac; Humans; Incidence; Indomethacin; Liver; Liver Diseases; Naproxen; Oxaprozin; Phenylbutazone; Propionates; Risk Factors; Sulindac

Several non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with liver damage. The aim of this study was to compare proportions of hepatic adverse drug reaction reports associated with NSAIDs in France and Spain. Information from the Spanish and French pharmacovigilance databases were used from 1982 to 2001. To assess the risk of liver injury, the case/non-case methodology was applied, 'cases' being reports of liver damage and 'non-cases' or controls, all other reports. Exposure was considered as the presence of at least one NSAID. Liver injury risk was estimated for each drug in the two databases by calculation of reporting odds ratio in cases and non-cases, with its 95% confidence interval. Out of 62 456 reports from the Spanish database, 2114 (3.38%) were identified as liver injuries, whereas there were 27 372 liver injuries out of 200 046 (13.68%) in the French database. In Spain, there was a significant association between liver injuries and droxicam, sulindac, and nimesulide. The risk was also slightly above 1 for aceclofenac. In France, the risk was very high with clometacin, followed by sulindac, and was slightly above 1 for naproxen, diclofenac, piroxicam, and tenoxicam. This study shows that some NSAIDs are associated with reports of hepatic injuries when compared with other drugs, and most of those have been withdrawn from the market for this reason. However, the frequency of drug-related hepatic injuries reported differed in the French and Spanish databases, and some drugs did not show the same risk level in the two countries. These discrepancies could be explained in part not only by reporting rates, but also by difference in drug use patterns and/or by genetic or environmental factors.

Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Utilization; France; Genetic Predisposition to Disease; Humans; Incidence; Liver; Liver Diseases; Odds Ratio; Pyridines; Risk Assessment; Spain; Sulfonamides; Sulindac

Sulindac (Clinoril), an anti-inflammatory drug increasingly used in Australia for the treatment of rheumatological conditions, is unpredictably associated with a cholestatic hepatitis. We present three cases of sulindac hepatitis. The first case exemplifies acute sulindac hepatitis, the second, continuously exposed to sulindac for 18 months, had chronic sulindac hepatotoxicity, and in the third case, the long-term histological outcome after cessation of sulindac is described. The clinical, biochemical, and histopathological characteristics are those of a cholestatic hepatitis which resolves on withdrawal of the drug. We report marked anisonucleosis with cytoplasmic invaginations into the nucleus and binuclearity of hepatocytes as additional histological features of sulindac hepatitis. There is no evidence that sulindac hepatitis progresses to irreversible structural liver damage, although nuclear changes may persist for up to two months after cessation of the drug. The clinical and biochemical features of all reported cases of sulindac hepatitis are summarised.

Topics: Adult; Aged; Alkaline Phosphatase; Chemical and Drug Induced Liver Injury; Female; Humans; Indenes; Liver Diseases; Male; Middle Aged; Sulindac

Sulindac sulfoxide is a prodrug which must be converted to a reduced active metabolite, sulindac sulfide, in order to inhibit arachidonate cyclooxygenase. Oral administration of sulindac sulfoxide does not yield substantial amounts of sulindac sulfide in the urine. To determine whether sulindac sulfide inhibits renal prostaglandin (PG) synthesis, the active form of the drug, sulindac sulfide (5 mg/kg i.v.), was administered to four sham-ligated dogs and four dogs with liver disease induced by chronic (6 weeks) common bile duct ligation (CBDL). In both the sham and CBDL animals the sulindac sulfide caused a 60 to 90% reduction in PGE2, PGF2 alpha and 6-keto-PGF1 alpha excretion rates. In the same animals, subsequent treatment with another cyclooxygenase inhibitor, naproxen (10 mg/kg i.v.), did not result in any further decrease in PGE2 or PGF2 alpha excretion but did decrease 6-keto-PGF1 alpha excretion. In the CBDL animals, sulindac sulfide treatment decreased renal blood flow, glomerular filtration rate and urine volume and resulted in the urinary excretion of large amounts of the sulindac sulfide. Similar changes in PG excretion and renal function were observed in CBDL animals treated solely with naproxen (10 mg/kg i.v.) or with ibuprofen (20 mg/kg i.v.). In four normal and three CBDL animals, we determined that i.v. administration of the prodrug, sulindac sulfoxide (5-15 mg/kg), resulted in plasma levels of 2-5 micrograms/ml of the active drug, sulindac sulfide, only in the CBDL animals. In subsequent experiments, we gave sulindac sulfoxide, 5 mg/kg i.v., to five CBDL dogs and three CBDL miniature swine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bile Ducts; Cyclooxygenase Inhibitors; Dogs; Female; Glomerular Filtration Rate; Ibuprofen; Indenes; Kidney; Ligation; Liver Diseases; Naproxen; Prostaglandins; Sulindac; Swine; Swine, Miniature

Renal cortical prostaglandin synthesis, particularly by arterioles and glomeruli, is important to preserve renal blood flow (RBF) and glomerular filtration rate (GFR). Glomeruli and arterioles synthesize not only the vasodilatory prostaglandins PGE2 and PGI2, but also the vasoconstrictor, thromboxane A2. The primary renal cortical actions of these prostaglandins are renal vasodilatation and maintenance of GFR (PGE2 and PGI2) or renal vasoconstriction and reduction of GFR (thromboxane A2). Vasodilatory renal prostaglandins are relatively unimportant under normal circumstances but play a modulatory role after ischemia or in the presence of increased concentrations of vasoconstrictor substances such as angiotensin II (ANG II), vasopressin or norepinephrine. ANG II and vasopressin stimulate the synthesis of PGE2 in rat glomerular epithelial and mesangial cells maintained in cell culture. These stimulatory actions of constrictor peptides are dependent upon calcium entry into the cells since removal of extracellular calcium or co-incubation with verapamil or nifedipine block the prostaglandin stimulatory capacity of ANG II or vasopressin. In vivo indomethacin potentiates the actions of ANG II on the kidney, particularly the reduction of RBF and GFR. Isolated rat glomeruli contract in response to ANG II and this contractile effect, which reflects reduction in glomerular filtration surface area, can be potentiated by cyclooxygenase blockade. Conversely, arachidonic acid reduces the glomerular contractile effect of ANG II. The importance of renal prostaglandins in support of RBF and GFR has been studied in dogs after chronic bile duct ligation (CBDL). CBDL dogs have significant increase in renal PGE2 and PGI2 which maintain RBF and GFR since cyclo-oxygenase inhibition resulted in a 50% decrease in both RBF and GFR. Indomethacin, ibuprofen, naproxen, and sulindac sulfide had comparable effects. The pro-drug, sulindac sulfoxide, was tested in normal volunteers and found to spare renal prostaglandin synthesis whereas indomethacin reduced renal synthesis of PGE2 and PGF2 alpha by more than 50%. In vitro, sulindac sulfide is a potent inhibitor of renal prostaglandin synthesis by kidney cells in culture. It is, therefore, concluded that renal prostaglandins play an important vasoregulatory role. Furthermore, sulindac sulfoxide may spare renal cyclo-oxygenase and thereby preserve renal function.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Female; Humans; Kidney; Kidney Function Tests; Kidney Glomerulus; Liver Diseases; Prostaglandins; Rats; Sulindac