Hepatotoxicity of commonly used drugs: nonsteroidal anti-inflammatory drugs,antihypertensives, antidiabetic agents,anticonvulsants, lipid-lowering agents,psychotropic drugs

Hepatotoxic adverse drug reactions have contributed to the decline of many promising therapies, even among mainstream medication classes (bromfenac and troglitazone are recent examples). The spectrum of nonsteroidal anti-inflammatory drug-related liver toxicity continues to expand, with reports in children, interactive toxicity in persons with hepatitis C, and recognition of the toxicity of both the preferential and selective cyclooxygenase-2 inhibitors. Of the antihypertensive agents, methyldopa is now rarely prescribed and adverse effects are reported infrequently, whereas cases of liver injury associated with the angiotensin receptor and converting enzyme inhibitors are increasingly reported. Of the antidiabetic agents, acarbose, gliclazide, metformin, and human insulin have been implicated in causing liver injury. To date, the newer thiazolidinediones do not appear to share the hepatotoxic potential of troglitazone, although a few reports of acute hepatitis have accrued. Although liver injury has been associated with the "statins," the frequency of such toxicity is lower than that of the background population and the value of biochemical monitoring remains unproved. Newer concepts in anticonvulsant hepatotoxicity have been the recognition of the reactive metabolite syndrome, delineation of the risk factors for valproic acid toxicity, the potential role of carnitine in preventing valproic acid hepatotoxicity, and the toxicity of second-line antiepileptic drugs. Liver injury associated with newer psychotropic agents, particularly the selective serotonin reuptake inhibitors, is also discussed. The focus of the review is the hepatotoxicity of commonly used drugs with particular reference to recent and novel reports of toxicity. Well-known causes of liver injury such as chlorpromazine, phenytoin, and methyldopa are not discussed.     

AIDS, drugs and history

This paper analyses the relationship of history to two current and inter-related policy issues, AIDS and drugs. AIDS, in particular in its early years, was a disease surrounded by history; and historians and others actively brought the ‘lesson of history’ into the public debates. Cholera and the Black Death provided historical examples of reactions to past epidemic disease; and the record of voluntarism in Britain in the area of sexually transmitted diseases was used to justify a non-punitive response to AIDS. As the perception of AIDS has changed from epidemic to chronic disease, as reactions to the disease have become ‘normalized’, so the type of historical input has also altered. The lesson of history' approach has appeared less relevant, or has changed focus to encompass chronic—TB, multiple sclerosis—rather than epidemic disease. The concept of AIDS itself as an historic event, of the ‘contemporary history’ of AIDS has also come to the fore. The paper contrasts the relationship of AIDS and history with the ahistorical reaction to the particular impact of AIDS on drug policy. The policy reaction to illicit drugs has been historically conscious, in particular in the 1960's. But little of this historical perspective filtered into the reaction to AIDS on drug policy. Drugs, unlike AIDS, was not an open policy arena. The paper argues that overall drug policy objectives were already clear and it suited no policy interest to call on the historical record. The achievement of established policy objectives was better achieved by an emphasis on the newness of development, a response to potentially epidemic and unusual circumstances.     

Antimicrobial drugs, microorganisms, and phagocytes

The literature on the interaction between antimicrobial drugs, microorganisms, and phagocytes is reviewed. Critical assessment of the methods used in various studies is indispensable in the interpretation of results. The available data seldom permit firm conclusions, but a number of interactions can be postulated. Chemotaxis is influenced by beta-lactam antibiotics, which induce an increased release of chemoattractants from bacteria; inhibitors of protein synthesis (erythromycin, tetracyclines) reduce the release of chemoattractants. Rifampin and tetracyclines inhibit chemotactic activity of granulocytes. Phagocytosis is diminished by tetracyclines and bacitracin. Intracellular killing is impaired by trimethoprim and sulfamethoxazole. Antimicrobial drugs that inhibit protein synthesis alter the surface of bacteria, changing the opsonic requirements for phagocytosis. Antimicrobial agents that act on the cell wall or disrupt the organization of the outer membrane of gram-negative bacteria increase bacterial vulnerability to the lethal action of granulocytes. Cellular enzymes of granulocytes act synergistically with a variety of drugs. Synergism between monocytes and penicillins has also been shown. The degree of penetration of an antimicrobial drug into phagocytic cells is not correlated with the intracellular activity of the drug. Polymyxin B, colistin, rifampin, vancomycin, clindamycin, and quinolones kill bacteria phagocytosed by granulocytes. Penicillins, rifampin, and chloramphenicol show microbicidal activity against bacteria ingested by monocytes or macrophages.     

Cardiovascular remodeling,apoptosis, and drugs

Apoptosis, a form of programmed cell death, mediates the controlled deletion of so-called “unwanted” cells. This review deals with the key features of this cell death program, showing that apoptosis is regulated by factors extrinsic and intrinsic to the dying cell.The elucidation of the possible interactions between these factors may be of major interest in preventing the progression to cardiovascular remodeling in patients with hypertensive disease. New pathways of research are emerging for drugs, such as β-blockers, ACE inhibitors, the calcium-antagonists, and the receptor antagonist of angiotensin II, all of which have beneficial effects on cardiovascular remodeling. This may be due to the direct effect of these drugs on the cell proliferation/apoptosis balance.     

Functional MRI, drugs, and poststroke recovery

Stroke is the first cause of disability in industrialized countries. Thus, understanding the mechanisms of poststroke recovery appears to be crucial in improving motor performance and reducing disability in stroke patients. Strategies through which brain restores lost functions after ischemic lesions are numerous. The mechanisms underlying poststroke recovery, known as cerebral plasticity, are so far hypothetical. However, functional magnetic resonance imaging (fMRI) studies recently have provided new insights in to stroke recovery. This article sketches out the mechanisms that are thought to underly recovery and focuses on fMRI experimental studies that have investigated the influence of a number of drugs on functional recovery. Functional MRI is a valuable tool in understanding functional recovery and may help to disclose new therapeutical approaches.     

Thrombosis, immunology and drugs]

Diagnosis of thrombopenia due to heparin in sometimes false. We present a case with venous thrombosis in whom the suspicion of thrombopenia induced by heparin finally proved to be a quinidine induced lupus. Related to this observation we emphasise the importance of immunological investigation in patient with venous thrombosis.