9 Drug-induced cholestasis

Larrey, Dominique; Erlinger, S

doi:10.1016/0950-3528(88)90010-3

Cited by 49 publications

(25 citation statements)

References 153 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hepatic cholestasis is a common manifestation of druginduced liver injury (Larrey and Erlinger, 1988). Human clinical findings of phenothiazine idiosyncratic hepatic injury generally include elevations of serum markers of cholestasis and modest increases in ALT and AST activities indicative of parenchymal cell damage.…”

Section: Discussionmentioning

confidence: 99%

“…Moderate elevation of ALT and AST is not an uncommon finding in the differential diagnosis of drug-induced jaundice (Zimmerman, 1968;Larrey and Erlinger, 1988), and it occurs in CPZ idiosyncrasy in people (Ishak and Irey, 1972). Indeed, there was an association between increased ALT and AST activities in serum and treatment-related hepatocellular necrosis observed morphologically.…”

Section: Inflammation and Drug Idiosyncrasy 463mentioning

confidence: 99%

See 1 more Smart Citation

Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Buchweitz¹,

Ganey²,

Bursian³

et al. 2002

J Pharmacol Exp Ther

117

View full text Add to dashboard Cite

Idiosyncratic reactions occur in a small fraction (typically Ͻ5%) of the population taking therapeutic drugs. Chlorpromazine (CPZ) is a phenothiazine, antipsychotic drug that has caused several idiosyncratic responses during its therapeutic use. Clinical evidence suggests that conditions associated with inflammation are risk factors for the appearance of these responses. Accordingly, we tested the hypothesis that an inflammatory stimulus, bacterial lipopolysaccharide (LPS), renders animals susceptible to CPZ-induced idiosyncratic reactions seen in humans. Male Sprague-Dawley rats (200 -250 g) were fasted for 24 h. A small dose of LPS (7.4 ϫ 10 6 EU/kg from Escherichia coli) or its vehicle (saline) was administered by tail vein 2 h before an intraperitoneal injection of CPZ (70 mg/kg) or its vehicle (saline). Cholestasis and hepatocellular necrosis were evaluated as increased concentrations of serum bile acids and bilirubin and increased activities of alkaline phosphatase, ␥-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase. With the exception of bile acids, these serum markers were elevated in animals treated with LPS/CPZ. Histopathological lesions in liver sections were consistent with these findings. Elevated serum creatine kinase activity, which is associated with human idiosyncratic responses to phenothiazines, was also found in animals treated with LPS/CPZ, but not with either LPS or CPZ alone. These results raise the possibility that concurrent, modest inflammation may underlie susceptibility of individuals to certain idiosyncratic reactions and may form the basis for an animal model with which to understand and predict drug idiosyncrasy.Drug idiosyncrasy is an untoward biological response to a therapeutic agent occurring in a small percentage of individuals. Idiosyncratic responses appear to occur independently of dose and have an inconsistent temporal relationship to the course of drug administration (Hollister, 1957). Although drug metabolism polymorphisms and drug allergy are widely presumed to underlie idiosyncratic responses, convincing evidence to support these as causes is lacking for the majority of drugs. Reproducing such responses in animals has been met with little success. Inasmuch as drug idiosyncrasy results in human suffering and considerable cost to pharmaceutical companies, animal models that are able to predict such responses in people before a drug is marketed could have great benefit.Among the many drugs that have caused idiosyncratic reactions in people are aliphatic phenothiazines. For example, chlorpromazine (CPZ) (Thorazine, 10-[3-dimethylaminopropyl]-2-chlorphenothiazine) is a tricyclic antidepressant that has been used as a sedative and antiemetic and for the management of psychotic disorders. Two types of adverse reactions result from phenothiazine usage. First, extrapyramidal side effects such as pseudoparkinsonism, dystonic reactions, and akathisia are common, dose-related side effects that likely result from the blockade of dopamine recepto...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Inflammation and Drug Idiosyncrasy 463mentioning

confidence: 99%

Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Buchweitz¹,

Ganey²,

Bursian³

et al. 2002

J Pharmacol Exp Ther

117

View full text Add to dashboard Cite

show abstract

“…Neither CPZ nor LPS when given alone caused changes in plasma markers of tissue injury; by contrast, the LPS/CPZ combination resulted in significant increases in serum activities of each of the enzymes listed above, suggesting a reaction that resembles, at least in part, idiosyncratic responses to antipsychotic drugs in people. In the livers of LPS/CPZ-treated rats, inflammatory infiltrates characterized the lesions as they do in people with idiosyncratic reactions to this class of drugs (Bianchi and Scheuer, 1974;Larrey and Erlinger, 1988;Moradpour et al, 1994).…”

Section: Studies With Drugsmentioning

confidence: 99%

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

121

View full text Add to dashboard Cite

"Drug idiosyncrasy" refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an "idiosyncratic" response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed.

show abstract

“…Outcomes are usually benign with resolution of cholestasis in 1-4 mo following drug withdrawal [2] . However, some patients develop prolonged drug-induced cholestasis, defined as the persistence of jaundice for more than 6 mo or persistently high alkaline phosphatase and gamma-glutamyl transpeptidase for more than 1 year, despite withdrawal of the causative drug, and in the absence of pre-existing liver or biliary tract disease [3] . Patients who develop progressive destruction of the small interlobular bile ducts ("vanishing bile duct syndrome") may ultimately require liver transplantation [4,5] , given the lack of effective treatment.…”

Section: Introductionmentioning

confidence: 99%

Mycophenolate mofetil for drug-induced vanishing bile duct syndrome

Jakab¹,

West²,

Meighan³

et al. 2007

WJG

View full text Add to dashboard Cite

Amoxicillin/clavulanate is associated with liver injury, mostly of a cholestatic pattern. While outcomes are usually benign, progression to cirrhosis and death has been reported. The role of immunosuppressive therapy for patients with a protracted course is unclear. We report the case of an elderly patient who developed prolonged cholestasis secondary to amoxicillin/clavulanate. Vanishing bile duct syndrome was confirmed by sequential liver biopsies. The patient responded to prednisone treatment, but could not be weaned off corticosteroids, even when azathioprine was added. Complete withdrawal of both prednisone and azathioprine was possible by using mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor. Sustained remission has been maintained for more than 3 years with low-dose mycophenolate mofetil.

show abstract

9 Drug-induced cholestasis

Cited by 49 publications

References 153 publications

Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Mycophenolate mofetil for drug-induced vanishing bile duct syndrome

Contact Info

Product

Resources

About