抗抑郁剂所致多汗症的研究现状

多汗症是抗抑郁剂的常见不良反应,其发生机制涉及交感神经系统的激活作用,对下丘脑的作用及α肾上腺素受体系统及β肾上腺素受体系统的平衡破坏等多个方面。抗抑郁剂所致多汗症的处理应遵循个体化的原则,可以考虑减少抗抑郁剂的剂量或停药,或更换另一种抗抑郁剂,必要时加用其他药物治疗。     

Ganciclovir hepatotoxicity

A 33-year-old male with acquired immunodeficiency syndrome received ganciclovir for presumed cytomegalovirus retinitis. Although results of baseline liver function tests were abnormal, marked elevations of transaminases and alkaline phosphatase occurred when the drug was first instituted, as well as after rechallenge. These elevated laboratory values declined on each occasion that the drug was withdrawn. As no other toxic or infectious insults could clearly be incriminated in these acute, self-limited episodes of hepatic function abnormalities, ganciclovir was most likely responsible for the toxicity observed in this patient.     

Acetylhydrazine hepatotoxicity

Acetylhydrazine, a human metabolite of isoniazid, causes a dose-dependent centrilobular hepatic necrosis in phenobarbital-pretreated but not control rats. Ballooning degeneration and infiltration by inflammatory cells were confined to the centrilobular area. The portal area however was normal. In conjunction with this necrosis, acetylhydrazine also caused a dose-dependent decline in hepatic cytochrome P-450 in the phenobarbital-pretreated, but not control rats. Isoniazid (0.4 mmol/kg), given concomitantly, reduced the hepatotoxicity of acetylhydrazine. Rifampicin pretreatment did not increase the hepatotoxicity of acetylhydrazine but did cause a dose-dependent decline in hepatic cytochrome P-450.     

Drug-induced hepatotoxicity

The liver is central to the metabolic disposition of virtually all drugs and xenobiotics (foreign substances).^1–3 For the most part, this process is accomplished without injury to the liver itself or to other organs. A few compounds such as acetaminophen, CCl₄ and the toxin responsible for mushroom poisoning are toxic themselves or produce metabolites which cause liver injury in a uniform, dose-dependent fashion.^4–7 However, most agents form a sufficiently toxic byproduct and cause liver injury only quite rarely, under special circumstances. Generation of a toxic metabolite within the hepatocyte may produce direct cell injury with disruption of intracellular function, or may cause indirect injury by immune-mediated membrane damage. Factors promoting the accumulation of toxins include genetic enzyme variants which allow greater formation of the harmful metabolite, induction of an isozyme species which produces more than the usual quantity of the toxin, interference with regular (non-toxic) metabolic pathways by substrate competition for enzyme, or depletion of required detoxifying substrates. The following review will provide clinical examples of some of these well-known metabolic reactions, discuss some new issues in drug-induced hepatotoxicity, such as use of combination agents and complex multiple drug regimens, alternative health strategies (vitamins and herbal remedies) as well as the widespread use of cocaine. The overall message is that, as new compounds are issued, new opportunities for drug-induced hepatotoxicity arise. Until extensive experience with any new compound has evolved, it is best to maintain a healthy paranoia concerning the newer drugs—there are very few totally safe agents.     

Colestipol-induced hepatotoxicity

A 65-year-old man with type IIa dyslipidemia who received flavored colestipol granules 2 scoops/day for 3 months developed asymptomatic hepatotoxicity. Several of his liver enzymes were elevated 10 times the upper limit of normal. One week after discontinuing colestipol, serum transaminases fell dramatically, with some returning to normal limits. Four weeks after colestipol was discontinued, all liver function tests were normal. Rechallenge was not attempted. Other potential causes of hepatocellular injury were evaluated. Bile acid-binding resins commonly are administered to treat type IIa dyslipidemia. Despite extensive use of the resins, significant elevations of transaminase levels are rare. Because the exact mechanism of bile acid resin-induced hepatotoxicity is unknown, high-risk patients may require liver function test monitoring and education on hepatotoxic side effects.     

Amiodarone hepatotoxicity

Potential hepatotoxicity related to amiodarone therapy is often a concern when deciding whether to initiate or continue treatment with this medication. While mostly associated with long-term oral administration of the drug, toxicity has also been reported early during intravenous administration and months after discontinuation of therapy. In the majority of patients, it is discovered incidentally during routine testing of liver biochemistry and rarely do the hepatic effects develop into symptomatic liver injury or failure. Despite the widespread use of amiodarone, prospective clinical studies have been sparse and there has been little consensus among experts in the field regarding optimum monitoring for adverse effects in patients receiving this drug. In order to examine the current state of knowledge surrounding the incidence, pathogenesis and mechanism of liver effects associated with amiodarone, the existing literature was reviewed, with particular emphasis on clinical recommendations for monitoring.     

Antidepressant-induced undesirable weight gain: prevention with rimonabant without interference with behavioral effectiveness

Antidepressant pharmacotherapy has dramatically improved the quality of life for many patients. However, prolonged use may induce weight gain, resulting in enhanced risk for treatment noncompliance. Cannabinoid CB(1) receptor antagonists decrease food intake and body weight, but may also affect mood. We investigated in female Sabra mice first, whether acute treatment with the cannabinoid receptor antagonist rimonabant (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, SR141716, 5 mg/kg) interfered with the tricyclic antidepressant desipramine (15 mg/kg) or the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) in the Porsolt forced swimming test. Second, whether chronic treatment (3 months) with desipramine (5 mg/kg) enhanced weight gain and whether cotreatment with rimonabant (2 mg/kg), prevented the excessive weight gain, while retaining antidepressant effectiveness. Motor activity and anxiety-like behavior were also investigated. The acute studies indicated that rimonabant did not influence 'antidepressant' activity of desipramine or fluoxetine. In the chronic studies, desipramine enhanced weight gain, despite the observation that the injection procedure reduced weight gain. The enhanced weight gain continued at least 35 days after treatment ended. Rimonabant reduced weight gain to which no tolerance developed and which persisted at least 30 days beyond treatment. Mice cotreated with rimonabant and desipramine had body weights closer to controls or to those receiving rimonabant alone than to those treated with desipramine alone. The antidepressant effects of desipramine were maintained throughout treatment; this was not altered by the chronic rimonabant treatment at any time, although rimonabant together with desipramine transiently enhanced anxiety-like behavior. These observations suggest that combined treatment with antidepressants and cannabinoid CB(1) receptor antagonist to prevent undesirable weight gain, should be further investigated.     

Thalidomide-induced severe hepatotoxicity

Thalidomide is a relatively safe and efficacious form of therapy in the treatment of advanced, refractory multiple myeloma. Hepatotoxicity is listed as an extremely rare adverse effect associated with its use. We describe a 76-year-old woman with multiple myeloma who was treated with dexamethasone and thalidomide. By week 6 of therapy, she had developed acute increases in her aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to more than 50 times the upper limit of normal. Her liver function test results had been within the normal ranges before and immediately after the start of therapy, and the patient had no known history of underlying liver disease. A liver biopsy specimen demonstrated evidence of acute injury with chronic changes of underlying steatosis and bridging fibrosis due to previously undiagnosed nonalcoholic steatohepatitis. Immediately after discontinuing thalidomide, her liver function test results began trending downward. Seven days later, her AST and ALT levels had improved to 86 and 165 U/L, respectively. This case and a limited number of other reports demonstrate severe hepatotoxicity as a rare but potentially serious adverse effect of thalidomide therapy. With the expanding use of thalidomide as a therapeutic agent, clinicians must recognize severe hepatotoxicity as a potential complication. Whether patients with preexisting liver disease are at increased risk when receiving thalidomide remains to be seen.     

Suspected carbamazepine-induced hepatotoxicity

Carbamazepine is a potent anticonvulsant agent with proven efficacy in the treatment of partial and tonic-clonic seizures. An epileptic child treated with therapeutic dosages of carbamazepine developed severe hepatitis and hepatic insufficiency. She had a positive response to withdrawal of the drug and administration of corticosteroids. The Roussel UCLAF method for estimating causality of the adverse event was applied for an acute hepatocellular problem, with a final score of 8. This method has advantages over other tools because it involves many clinical factors that give additional guides to clinicians in patients with liver injury, but it must be adapted for adverse events in the pediatric population.     

Acetaminophen-induced hepatotoxicity.

The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1beta is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.     

Idiosyncratic drug hepatotoxicity

The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.     

Aspirin hepatotoxicity.

A case of aspirin hepatotoxicity in a 46-year-old male with rheumatoid arthritis is discussed, and this adverse reaction is reviewed. The patient was started on 900 mg aspirin four times daily; five days later the dose was increased to 1200 mg four times daily. After six days' therapy of 4.8 g aspirin daily, the serum salicylate level rose to 25 mg/100 ml and liver enzymes became elevated. Aspirin was discontinued and ibuprofen, 600 mg four times daily, begun. Eight days after cessation of aspirin therapy, the patient's liver enzyme values returned to normal. Previous case reports and studies of aspirin-induced hepatotoxicity are reviewed. It is concluded that aspirin-induced hepatotoxicity occurs much more frequently in patients with rheumatoid arthritis and other connective tissue disorders than previously recognized.     

Molindone and hepatotoxicity

An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.     

Bicalutamide-associated fulminant hepatotoxicity

Abstract Bicalutamide is a nonsteroidal antiandrogen used extensively during the start of androgen deprivation therapy with a luteinizing hormone-releasing hormone agonist to reduce occurrence of the symptoms of tumor flare in patients with metastatic prostate carcinoma. The most common adverse effects of bicalutamide are induced by its pharmacologic property of competitive androgen receptor blockade and include gynecomastia, hot flashes, fatigue, and decreased libido. Although not as common, increases in liver function test results are also seen with bicalutamide therapy. These elevations are typically transient, and patients remain asymptomatic. We describe a 59-year-old man with metastatic prostate carcinoma treated with bicalutamide as part of androgen deprivation therapy before starting chemotherapy. At baseline, his liver function test results and serum creatinine concentration were within normal limits, and an abdominal computed tomographic scan did not demonstrate liver metastasis. After 4 days of bicalutamide therapy, the patient came to the emergency department with complaints of abdominal pain, distension, and tenderness. His liver function tests were abnormal, and bicalutamide was discontinued. After 2 days of increasing liver function tests and symptoms of hepatotoxicity, the patient developed tachycardia and hypotension that was resistant to fluid resuscitation. Multiorgan damage was manifested by an alanine aminotransferase level greater than 40 times the upper limit of normal, serum creatinine concentration of 4.2 mg/dl, and troponin I level of 18 ng/ml. The patient died 8 days after bicalutamide therapy was begun secondary to multiorgan failure, most likely as a result of fulminant hepatotoxicity. The Naranjo adverse drug reaction probability scale showed a probable (score of 5) causal relationship between bicalutamide and fulminant hepatotoxicity. Fulminant hepatotoxicity is a rare but potentially fatal adverse effect of bicalutamide. Liver function tests should be monitored before and during bicalutamide therapy, even for patients who have previously completed a course of this therapy with no signs or symptoms of toxicity.