The phenothiazine-derived antipsychotic drugs, such as chlorpromazine and thioridazine, are bactericidal against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, but produce undesirable side effects at clinically relevant doses. We have previously modified four novel phenothiazines and maintained their antimycobacterial activity. This study evaluated the pharmacological and toxicity profiles of these novel non-neuroleptic phenothiazines, PTZ3, PTZ4, PTZ31 and PTZ32, for their metabolic stability, kinetic solubility and potential cytotoxic effects in vitro. To further support the safet use of these drug candidates, the in vivo pharmacological and toxicity profiles were assessed in C57BL/6 mice via single or repeated oral gavage. In acute toxicity studies, all four modified phenothiazines showed favourable safety in mice. When treated daily with 100 mg/kg of PTZ3 and PTZ4 for 2 weeks, mice displayed no signs of toxicity. Alternatively, treatment with PTZ31 resulted in 20% mortality with no toxicity evident in biochemical or histological analysis, while exposure to PTZ32 resulted in a 45% survival with increased serum concentrations of uric acid and alkaline phosphatase. The combined non-neuroleptic and antimycobacterial effects of the novel phenothiazines PTZ3, PTZ4, PTZ31 and PTZ32 demonstrated favourable pharmacological and toxicity profiles in this study, highlight the potential of these compounds as suitable anti-tuberculosis drug candidates.

The liver is the organ by which the majority of substances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first-pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.

Systematic assessment of the prevalence and pattern of liver function test (LFT) abnormalities associated with regular antipsychotics in adult humans and consideration of management of such abnormalities.

Systematic search identifying cohort, cross-sectional or case studies/series, reporting LFT abnormalities in patients receiving regular antipsychotics. EMBASE, PsychINFO, and MEDLINE were searched for studies in English from record onset.

Abstracts were independently screened for eligibility by 2 researchers. Ineligible studies included those that did not report LFT reference ranges, those that studied fewer than 10 patients on a given antipsychotic, and those studying children.

Key variables in group studies were extracted. Case studies/series were examined for patient outcome.

Ten group studies and 91 case studies/series were eligible, although quality was poor. All groups receiving regular antipsychotics had a prevalence of LFT abnormalities greater than chance. The median percentage of patients with any abnormal LFT on any antipsychotic was 32%, with a range of 5% to 78%. The median percentage of patients with clinically significant elevations was 4%, with a range of 0% to 15%. Transaminases were most commonly elevated. Abnormalities were generally asymptomatic, arose within 6 weeks, and were either stably persistent or resolved with continued treatment. Case reports suggested that antipsychotics can be associated with severe hepatitis, fatal in a small minority of cases. Chlorpromazine is most commonly associated with acute liver injury.

The LFT abnormalities in patients receiving regular antipsychotics are common but generally mild and transient. Very rarely, a severe or fatal hepatic injury can emerge.

Drug-induced liver injury (DILI) is an important differential diagnosis in many patients in clinical hepatology. DILI is the leading cause of acute liver failure and is an important safety issue when new drugs are developed.

To provide a review of the recent data on DILI with particular focus on the most common and relevant issues seen in clinical practice.

A Medline search was undertaken to identify relevant literature using search terms including 'drug-induced liver injury' and 'hepatotoxicity'.

The true incidence of DILI remains unknown but incidence up to 14 cases per 100 000 inhabitants and year has been reported. Antibiotics, analgesics and NSAIDs are the most common drugs causing liver injury. Idiosyncratic DILI has been shown to have a dose-dependent component and drugs without significant hepatic metabolism rarely cause DILI. Chronic elevation in liver enzymes can develop after DILI but this is rarely associated with clinical morbidity or mortality.

Drug-induced liver injury remains a diagnostic challenge. Multicentre studies and international collaborative work with well-characterized patients will increase our understanding of liver injury associated with drugs. New therapies for acute liver failure resulting from drugs are needed.

A 78-year-old woman with liver damage resembling chronic active hepatitis and occuring during long-term nitrofurantoin treatment is described. On admission to hospital she displayed jaundice, ascites and high serum levels of GOT, GPT, bilirubin and gamma-globulin as well as high titres of ANF and antibodies against smooth muscle cells. After withdrawal of nitrofurantoin the clinical and laboratory picture normalized without corticosteroid treatment, suggesting that the liver reaction was drug-induced.

Two patients with osteomyelitis who developed reversible cholestatic jaundice during treatment with oxacillin derivatives are described. The clinical course as well as the biochemical pattern and the investigation of liver biopsy specimens enabled us to establish the diagnoses of drug-induced canalicular and hepatocanalicular cholestasis.

Chronic evolution after drug-induced liver injury (DILI) has been reported. How often this leads to liver-related morbidity and mortality is unexplored.

Patients who survived DILI and concomitant jaundice reported to the Swedish Adverse Drug Reaction Advisory Committee (1970-2004) were linked to the Swedish Hospital Discharge and Cause of Death Registries.

Among the 712 survivors, 27 could not be retrieved but 685 patients could be linked to the registries, 392 females (57.2%) and 293 males (42.8%) median age 58 (41-74), a mean follow-up of 10 years. A total of 23/685 (3.4%) patients had been hospitalized for liver disease and 5 had liver-related mortality. Eight patients developed cirrhosis (7 decompensated, 5 died), 5 had "cryptogenic" cirrhosis in which DILI might have played a role in this development. Duration of therapy before DILI was longer in patients with liver-related morbidity/mortality (135+/-31 days vs. 53+/-3; p<0.0001). Autoimmune hepatitis developed in 5/23 (22%), all of female gender after a mean of 5.8 years.

Development of clinically important liver disease after severe DILI associated with jaundice is rare after acute DILI. However decompensated "cryptogenic" cirrhosis developed in some patients with fatal outcome in which DILI might have played a role in this development.

To evaluate the long-term prognosis of patients diagnosed with drug-induced liver injury, and the nature of the liver injury.

Patients with a diagnosis of drug-induced liver injury between 1994 and 2005 were identified in a university hospital clinic. Patients surviving drug-induced liver injury-associated liver failure were excluded.

Seventy-seven cases were identified and those who were alive (69) were invited to attend follow-up. Of those patients who had died, none had died of liver disease. Of those patients who had survived, 59 were reviewed in the clinic. Patients had a median follow-up of 48 months. Before the diagnosis of drug-induced liver injury, nine had a chronic liver disease, four with autoimmune hepatitis, two with non-alcoholic liver disease, one each with non-alcoholic fatty liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. There was no evidence of progression of their liver disease during follow-up. Among 50 patients without a known liver disease prior to the drug-induced liver injury, 10 had abnormal liver tests. Diagnostic work-up revealed alternative cause of liver disease in all except three patients (6%), who had asymptomatic abnormal liver tests (but normal bilirubin in all).

Chronic abnormalities in liver tests, not explained by an identified liver disease, are very rare in patients previously diagnosed with drug-induced liver injury. This group of patients did not seem to have a clinically significant liver injury at long-term follow-up.

NSAIDs are one of most frequently prescribed agents in clinical practice. Whereas hepatotoxicity is a rare complication of most NSAIDs (typically 1 to 10 per 100,000 persons exposed), the high level of usage means that these drugs cause liver disease. Because of their divergent chemical structures, the mechanisms and clinicopathological manifestations of hepatotoxicity vary widely. The reactive metabolite syndrome, in which serious rash, eosinophilia, and other forms of tissue injury are common, may be incited by several NSAIDs, including newer agents. Women, people aged more than 50 years, and for some drugs, the type of arthritis, may be risk factors for drug-induced liver injury. The spectrum of NSAID-drug related hepatotoxicity continues to expand, with reports of interactive toxicity in adults with hepatitis C and recognition of rare cases of liver disease associated with non-selective, selective, and preferential COX-2 inhibitors. Better outcomes require people taking NSAIDs to be aware of possible drug reactions involving the liver, and prescribers should be vigilant for early symptoms of hepatotoxicity so that incriminated agents are discontinued promptly.

We describe a 33-yr-old pregnant woman in whom a primary biliary cirrhosis-like syndrome developed after 2 wk of chlorpromazine therapy. The clinical course was characterized by severe jaundice lasting 22 mo, intense pruritus, fever, steatorrhea, high alkaline phosphatase levels and hypercholesterolemia. Jaundice resolved with initiation of ursodeoxycholic acid therapy, but subclinical cholestasis and low-level inflammatory activity persisted and ultimately evolved into biliary cirrhosis. The pathological substrate of this severe and prolonged cholestatic reaction was found to be the vanishing bile duct syndrome with a marked transient pseudoxanthomatosis.

Acute, drug-induced hepatocellular cholestasis (either pure or cholestatic hepatitis) is a common manifestation of drug-induced hepatic injury. The drugs most frequently responsible are hormonal steroids and psychopharmacological agents (in particular phenothiazines and some antidepressants). Cholestasis usually subsides without sequelae in less than six months. Acute, drug-induced ductular cholestasis is uncommon and can resemble biliary tract obstruction. Complete recovery occurs promptly after the withdrawal of the causative drug in most cases. The pathogenetic mechanism may be immunoallergic. Prolonged ductular or ductal cholestasis can follow drug-induced acute hepatitis despite prompt withdrawal of the offending drug. This syndrome, observed mainly with chlorpromazine and uncommonly with twenty other drugs, is characterized by the progressive disappearance of small bile ducts and by manifestations mimicking primary biliary cirrhosis. However, its prognosis appears to be better than that of primary biliary cirrhosis, the condition being reversible in the majority of cases or even subsiding completely. The mechanism is still unknown, but several features suggest some form of autoimmunity. Extrahepatic cholestasis related to sclerosing cholangitis is a frequent and long-term complication of intra-arterial infusion of floxuridine in patients treated for hepatic metastases from colorectal carcinoma. Although it may be reversible, floxuridine-induced sclerosing cholangitis has a poor prognosis and can lead to death in a few patients. The mechanism is probably related to the vascular supply of the common hepatic duct and its relationship to the perfusion territory of floxuridine.

Generic and chemical names of drugs and the possible adverse effects of these drugs on the human liver are tabulated. Most drugs compiled in these tables have been approved by the Federal Drug Administration. They are currently available in the United States, and they are listed in the 1983 Physicians' Desk Reference. Some important investigational drugs are listed also. The tables include: (1) generic names of drugs that have caused a characteristic morphologic change, such as granulomatous hepatitis; (2) morphologic diagnoses that have been documented after administration of each drug; and (3) references that can be matched to each drug and to its effects on the liver.

A compilation of drugs and the histopathological changes that can occur in the liver is presented. The purpose of this review is to provide the reader with a comprehensive and reliable source of information on various drugs that have been documented by liver biopsy to cause hepatocellular damage. The morphologic terms used in the tables have been chosen based on past publications dealing with this subject. This review is intended as a concise guide to aid in the identification of drug-induced liver diseases.

Geneic and chemical names of drugs and the possible adverse effects of these drugs on the human liver were tabulated. All drugs compiled in these tables have been approved by the Federal Drug Administration. They are currently available in the United States, and they are listed in the 1979 Physicians' Desk Reference. The tables include: (1) names of drugs that have caused a characteristic morphologic change, such as cholestatic lobular hepatitis; (2) morphologic diagnoses that have been documented after administration of each drug; and (3) references that can be matched to each drug and to its effects on the liver.

A number of chronic hepatic lesions can result from adverse reactions to medicinal agents. Such lesions include a form of chronic active hepatitis; hepatic steatosis, phoepholipidosis and granulomatosis; several vascular lesions; two types of noncirrhotic portal hypertension; several types of cirrhosis and several neoplasms.

The large number of chemical agents administered for therapeutic or diagnostic purposes can produce various types of hepatic injury by several mechanism. Acute injury may be cytotoxic, cholestatic or mixed. Cytotoxic injury may consist of necrosis or steatosis. Cholestatic injury may be cholangiolitic (hepatocanalicular) or bland (canalicular). Chronic hepatic lesions caused by medicinal agents include chronic active hepatitis, steatosis, cirrhosis, fibrosis, hepatoportal sclerosis (non-cirrhotic portal hypertension), hepatic vein thrombosis, peliosis hepatis, adenoma, carcinoma, and angiosarcoma. There is a useful relationship between the type of hepatic injury and the chemical setting in which the drugs are employed. Some agents produce the liver damage because they are intrinsic (true, predictable) hepatotoxins. Other (non-predictable "hepatotoxins"), produce hepatic injury only in the rare and unusually susceptible individual (idiosyncratic injury). Hepatotoxic agents can be recognised by their dose-dependent and experimental reproducibility, properties which are not shared by agents which produce hepatic injury only in idiosyncratic hosts. Intrinsic hepatotoxins may be categorised as direct or indirect. Direct hepatotoxins injure the hepatocyte by direct physiochemical alteration and as a consequence produce metabolic defects. Indirect hepatotoxins selectively block metabolic pathways and, by producing a precise biochemical lesion, lead to structural changes. They may lead to hepatic steatosis or necrosis (cytotoxic indirect hepatotoxins) or block bile flow (cholestatic indirect hepatotoxins). Direct hepatotoxins are rarely encountered as drugs. Overdoses of some drugs and antineoplastic agents appear to be indirect cytotoxic hepatotoxins, and the C-17 alkylated anabolic and contraceptive steroids are indirect, cholestatic hepatotoxins. Idiosyncracy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberration of the host permitting the production of hepatotoxic metabolites.