Antiandrogen-associated hepatotoxicity in the management of advanced prostate cancer.
ABSTRACT Antiandrogens available for patients with advanced prostate cancer are reported to cause hepatotoxicity. The aim of this study is to investigate the antiandrogen-associated hepatotoxicity in patients with advanced prostate cancer.
By retrospective charts review, 229 patients (47-89 years old) with advanced prostate cancer treated by total androgen blockade (TAB) with bilateral orchiectomy or LHRH (luteinizing hormone-releasing hormone) analogues plus antiandrogen, or antiandrogen-radiotherapy were enrolled in this study. There were 124 patients taking flutamide 750 mg daily and 105 patients taking cyproterone acetate (CPA) 150 mg daily. Hepatotoxicity defined by the International Consensus Meeting in 1990 and Food and Drug Administration, USA was used to evaluate the hepatotoxicity (including serious hepatotoxicity).
There was a higher occurrence of hepatotoxicity in patients taking flutamide (15.3%) than taking CPA (9.5%) (p = 0.034). The occurrence of serious hepatotoxicity of flutamide and CPA was 4.8% (6/124) and 3.8% (4/105), respectively. The mean latency period of hepatotoxicity for CPA was 4.8 +/- 2.0 months for flutamide and 5.8 +/- 1.9 months for CPA, respectively. The 2 groups made no significant difference of liver enzyme (mean maximal alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) = 284.2 +/- 99.3/300.6 +/- 58.5 U/L versus 341.8 +/- 67.1/301.6 +/- 80.5 U/L). All of the 19 patients (100%) and 9 of 10 patients (90%) with flutamide and CPA-induced hepatotoxicity got self-resolution after discontinuation of the antiandrogens. The average time of self-resolution is 4.5 +/- 3.1 months and 6.3 +/- 4.7 months for flutamide and CPA, respectively. Five patients of flutamide-induced and 2 patients of CPA-induced hepatotoxicity got resolution after changing to other antiandrogen.
Flutamide and CPA appear to cause hepatotoxic effects in some patients. Discontinuation of the antiandrogens seems to be the resolution of hepatotoxicity. A change to other antiandrogen may be the alternative strategy to the antiandrogen-induced hepatotoxicity. The results of this study suggest that all patients received flutamide and CPA should be monitored carefully for signs and symptoms referable to hepatic injury to prevent the development of serious hepatic dysfunction.
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Article: Treatment of acne vulgaris.[show abstract] [hide abstract]
ABSTRACT: Management of acne vulgaris by nondermatologists is increasing. Current understanding of the different presentations of acne allows for individualized treatments and improved outcomes. To review the best evidence available for individualized treatment of acne. Search of MEDLINE, EMBASE, and the Cochrane database to search for all English-language articles on acne treatment from 1966 to 2004. Well-designed randomized controlled trials, meta-analyses, and other systematic reviews are the focus of this article. Acne literature is characterized by a lack of standardization with respect to outcome measures and methods used to grade disease severity. Main outcome measures of 29 randomized double-blind trials that were evaluated included reductions in inflammatory, noninflammatory, and total acne lesion counts. Topical retinoids reduce the number of comedones and inflammatory lesions in the range of 40% to 70%. These agents are the mainstay of therapy in patients with comedones only. Other agents, including topical antimicrobials, oral antibiotics, hormonal therapy (in women), and isotretinoin all yield high response rates. Patients with mild to moderate severity inflammatory acne with papules and pustules should be treated with topical antibiotics combined with retinoids. Oral antibiotics are first-line therapy in patients with moderate to severe inflammatory acne while oral isotretinoin is indicated for severe nodular acne, treatment failures, scarring, frequent relapses, or in cases of severe psychological distress. Long-term topical or oral antibiotic therapy should be avoided when feasible to minimize occurrence of bacterial resistance. Isotretinoin is a powerful teratogen mandating strict precautions for use among women of childbearing age. Acne responses to treatment vary considerably. Frequently more than 1 treatment modality is used concomitantly. Best results are seen when treatments are individualized on the basis of clinical presentation.JAMA The Journal of the American Medical Association 09/2004; 292(6):726-35. · 29.98 Impact Factor
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ABSTRACT: To determine the mechanism by which flutamide administration following trauma-hemorrhage (T-H) decreases cytokine production and hepatic injury under those conditions. Although studies have demonstrated that flutamide administration following T-H improves hepatic and immune functions, the mechanism by which flutamide produces the salutary effects remains unknown. Male Sprague-Dawley rats underwent a 5-cm laparotomy and hemorrhagic shock (40 mm Hg for approximately 90 minutes), followed by resuscitation with 4 times the shed blood volume in the form of Ringer's lactate. Flutamide (25 mg/kg body weight, sc) was administered at the middle of resuscitation and animals were killed 2 hours thereafter. To block estrogen receptor (ER), ER antagonist ICI 182,780 was administrated with flutamide. Hepatic injury, myeloperoxidase activity, nuclear factor-kappaB (NF-kappaB) DNA binding activity and protein expression of intercellular adhesion molecule-1, and cytokine-induced neutrophil chemoattractant (CINC-1 and CINC-3) markedly increased following T-H. Hepatic mRNA and plasma IL-6 levels were also elevated following T-H. The alterations in these parameters induced by T-H were significantly attenuated by flutamide administration. The decreased plasma estradiol levels following T-H were restored to sham levels in the flutamide-treated T-H animals. Coadministration of ICI 182,780 prevented those salutary effects of flutamide administration on pro-inflammatory responses and hepatic injury following T-H. These findings suggest that the reduction in the production of pro-inflammatory mediators and hepatic injury produced by flutamide administration following T-H is likely due to the down-regulation in hepatic NF-kappaB DNA binding activity. Moreover, the salutary effects of flutamide administration appear to be mediated at least in part via ER-related pathway.Annals of Surgery 03/2007; 245(2):297-304. · 6.33 Impact Factor
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ABSTRACT: Although hepatotoxicity is a frequent concern with all medications, chemotherapeutic agents are more often implicated in causing liver damage than most other drug classes. In many instances, these reactions are considered dose related because cytotoxic therapy directed at rapidly growing cancer cells may readily impact hepatocytes even though they are dividing more slowly. Because the stakes (remission of cancer) are high, so are the risks that the oncologist and the patient are willing to assume. The dose of many chemotherapeutic agents is limited by the toxic effects on the lungs, bone marrow, kidneys, and gastrointestinal system, including the liver. An awareness of the toxic potential of each chemotherapeutic agent is necessary before initiation of new oncologic treatments.Clinics in Liver Disease 09/2007; 11(3):641-62, viii. · 2.82 Impact Factor