OVERVIEW

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Benzbromarone	3562-84-3	C17-H12-Br2-O3
Amiodarone	1951-25-3	C25-H29-12-N-O3
Benzarone	1477-19-6	C17-H14-O3
Dronedarone	141626-36-0	C31-H45-CIN2-O5-S

ANNOTATED BIBLIOGRAPHY

References updated: 05 September 2017

• Grosser T, Smyth E, FitzGerald GA. Pharmacology of gout. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 994-1004.

  (Textbook of pharmacology and therapeutics).
• Babany G, Larrey D, Pessayre D, Degott C, Rueff B, Benhamou JP. Chronic active hepatitis caused by benzarone. J Hepatol 1987; 5: 332-5. [PubMed: 3429840]

  (61 year old woman developed jaundice after more than a year of benzarone therapy [bilirubin 4.4 mg/dL, ALT 38 times ULN, Alk P 1.5 times ULN], with recovery on stopping, but patient started medication again on her own twice, each time redeveloping jaundice; liver biopsy showed bridging fibrosis and chronic hepatitis; eventually recovered completely; SMA 1:500 but ANA negative).
• Nakad A, Azzouzi K, Gerbaux A, Delcourt A, Sempoux C, Tamo F, Rahier J, Geubel AP. [Hepatitis due to benzarone: a second case] Gastroenterol Clin Biol 1990; 14: 782-4. [PubMed: 2262129]

  (70 year old woman developed jaundice 1 month after starting benzarone [a benzofurane used for peripheral vascular disease and available in France since 1964] with bilirubin 6 mg/dL, ALT 400 U/L, Alk P 415 U/L; positive rechallenge after another month of therapy with bilirubin rising to 7.1 mg/dL, ALT 1015 U/L, Alk P 392 U/L, slow recovery).
• Sepulchre D, De Plaen JL, Geubel AP. [Drug-induced hepatitis due to benzarone (Fragivix): apropos of a clinical case report] Acta Gastroenterol Belg 1990; 53: 499-503. [PubMed: 2130580]

  (46 year old woman developed fatigue and jaundice one month after starting benzarone [bilirubin 11.3 mg/dL, ALT 1340 U/L, Alk P 400 U/L], resolution in several months; recurrence 14 days after restarting [bilirubin 16 mg/dL, ALT 1012 U/L, Alk P 157 U/L and hyperglobulinemia], resolving within 2 months of stopping).
• van der Klauw MM, Houtman PM, Stricker BH, Spoelstra P. Hepatic injury caused by benzbromarone. J Hepatol 1994; 20: 376-9. [PubMed: 8014449]

  (68 year old woman developed malaise and jaundice 3 months after switching from allopurinol to benzbromarone [bilirubin 4.9 mg/dL, ALT 793 U/L, Alk P 217 U/L], full recovery and positive rechallenge 6 weeks after restarting therapy).
• Gehenot M, Horsmans Y, Rahier J, Geubel AP. Subfulminant hepatitis requiring liver transplantation after benzarone administration. J Hepatol 1994; 20: 842. [PubMed: 7930488]

  (62 year old woman developed jaundice and fatigue 10 weeks after starting benzarone therapy for venous insufficiency [bilirubin 2.1 rising to 8.0 mg/dL, ALT 160 rising to 3792 U/L], with subsequent hepatic failure and death, autopsy showing confluent necrosis).
• Hautekeete ML, Henrion J, Naegels S, deNeve A, Alder M, Deprez C, Devis G, Kloppel G. Severe hepatotoxicity related to benzarone: a report of three cases with two fatalities. Liver 1995; 15: 25-9. [PubMed: 7776854]

  (2 women and 1 man, ages 35, 67 and 68 years, developed jaundice 1.5-5 months after starting benzarone for peripheral vascular disease [bilirubin 4.6-29 mg/dL, ALT 819-1810 U/L, Alk P 164-282 U/L]; 1 died, 1 transplanted, 1 developed cirrhosis).
• Wagayama H, Shiraki K, Sugimoto K, et al. Fatal fulminant hepatic failure associated with benzbromarone. J Hepatol 2000; 32: 874. [PubMed: 10845680]

  (62 year old man developed jaundice 5 months after starting benzbromarone with bilirubin rising to 31.2 mg/dL, AST 1369 U/L, progressing to hepatic failure and death; lymphocyte stimulation test negative).
• Suzuki T, Suzuki T, Kimura M, Shinoda M, Fujita T, Miyake N, Yamamoto S, Tashiro K. A case of fulminant hepatitis, possibly caused by benzbromarone. Nippon Shokakibyo Gakkai Zasshi 1001; 98: 421-5. [PubMed: 11400273]

  (58 year old man developed jaundice after 7 months of benzbromarone therapy [bilirubin 7.9 mg/dL, ALT 1168, Alk P 792 U/L], progressing to hepatic failure, lymphocyte stimulation test negative).
• Arai M, Yokosuka O, Fujiwara K, Kojima H, Kanda T, Hirasawa H, Saisho H. Fulminant hepatic failure associated with benzbromarone treatment: a case report. J Gastroenterol Hepatol 2002; 17: 625-6. [PubMed: 12084041]

  (53 year old woman developed jaundice 2 months after starting benzbromarone for hyperuricemia [bilirubin 23.3 mg/dL, ALT 1140 U/L and Alk P 123 U/L], with progressive downhill course despite stopping the medication; living donor liver transplantation done and explant showed massive necrosis).
• Kaufmann P, Trk M, Hnni A, Roberts P, Gasser R, Krhenbhl S. Mechanisms of benzarone and benzbromarone-induced hepatic toxicity. Hepatology 2005; 41: 925-35. [PubMed: 15799034]

  (In vitro studies showing effects of benzarone and benzbromarone on hepatic mitochondrial function, inhibiting beta-oxidation and uncoupling oxidative phosphorylation, causing hepatocellular apoptosis).
• Lee MH, Graham GG, Williams KM, Day RO. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf 2008; 31: 643-65. [PubMed: 18636784]

  (Benzbromarone was introduced in 1970s and available in ~20 countries, never in the US, withdrawn by sponsor in 2003 because of hepatotoxicity; among 11 published cases, 9 were fatal; estimated rate of hepatotoxicity 1:17,000; authors argue for its use in refractory gout).
• Haring B, Kudlich T, Rauthe S, Melcher R, Geier A. Benzbromarone: a double-edged sword that cuts the liver? Eur J Gastroenterol Hepatol 2013; 25: 119-21. [PubMed: 23196726]

  (77 year old woman developed jaundice 4 months after starting benzbromarone [bilirubin 9.5 mg/dL, ALT 1771 U/L, Alk P 194 U/L, ANA positive], with progressive hepatic failure and death 53 days after presentation).
• Kumagai J, Kanda T, Yasui S, Haga Y, Sasaki R, Nakamura M, Wu S, et al. Autoimmune hepatitis following drug-induced liver injury in an elderly patient. Clin J Gastroenterol 2016; 9: 156-9. [PubMed: 27170297]

  (77 year old Japanese man developed liver test abnormalities 8 months after starting benzbromarone for gout [bilirubin not given, ALT 353 U/L, Alk P 433 U/L] which worsened over the next several months while continuing therapy [bilirubin 4.3 mg/dL, albumin 2.2 g/dL], eventually developing weakness, ascites, elevated IgG [2636 mg/dL] and ANA [titer not given], with slow recovery on stopping benzbromarone and starting ursodiol and prednisone).