Disulfiram-induced hepatitis. Report of four cases and review of the literature

Forns, Xavier; Caballería, Joan; Bruguera, Miquel; Salmerón, Joan Manuel; Vilella, Àngels; Mas, Antoni; Parés, Albert; Rodés, Joan

doi:10.1016/s0168-8278(94)80249-1

Cited by 55 publications

(31 citation statements)

References 23 publications

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“…The main findings on the autonomous nervous system include increased salivation and piloerection; the central nervous system was impaired resulting in tremor, sedation, unconsciousness and tonic convulsion. The observed neurotoxic effects are in accordance with the known toxicity profile described for DTCs [21][22][23][24][25][26]. It is noted that the toxicity of orally applied PDTC might in part be derived from acid-induced decomposition to CS 2 in the stomach.…”

Section: Discussionsupporting

confidence: 85%

“…The major toxicities of DTC compounds are well known, being neurotoxicity and hepatotoxicity [21][22][23][24][25][26]. It is noted that potential toxic effects of a DTC compound dramatically depend upon the nitrogen substituents and oxidation state of a DTC as well as on its route of exposure: The nitrogen substituents and oxidation state influence its rate of decomposition, decomposition products and metabolic pathways.…”

Section: Discussionmentioning

confidence: 99%

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Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Chabicovsky

Prieschl-Grassauer

Seipelt

et al. 2010

Basic Clin Pharma Tox

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Pyrrolidine dithiocarbamate (PDTC) was examined for its potential in the intranasal treatment of human rhinovirus infections. Prior to clinical testing, a comprehensive non-clinical programme was performed to evaluate the general toxicity of PDTC. The animal experiments included investigations in rodents with study durations ranging from single dose to repeated dosing over a period of 28 days. The routes of administration were intranasal, inhalative, oral and intravenous for single-dose toxicity and pharmacokinetic studies, and intranasal for repeated dose studies. Blood and tissue samples were obtained from PDTC-treated rats to analyse pharmacokinetics and tissue distribution. Accumulation of selected metals due to PDTC treatment was examined in liver, brain, nerves and fat tissues.Pyrrolidine dithiocarbamate (PDTC) applied intranasally (up to 121 mg ⁄ kg) or via single inhalation (1.64% PDTC applied for 4 hr) or repeated intranasal dosing up to 28 days (up to 102 mg ⁄ kg ⁄ day) did not result in major systemic toxicities or local intolerance. Pharmacokinetic evaluations indicate a very rapid absorption of PDTC after intranasal application. A high single intravenous or oral dose of PDTC induced neurotoxicity. The neurotoxic effects are in accordance with the toxicity profile described for dithiocarbamates (DTCs) with effects on the autonomous and nervous system. The intravenous LD 50 was defined at 282 mg ⁄ kg in mice and at 306 mg ⁄ kg in rats. The oral LD 50 was calculated at above 1500 mg ⁄ kg for mice and rats. The results from in vitro and in vivo genotoxicity studies do not elucidate a genotoxic potential for PDTC.Concluding from the toxicology data set, PDTC qualifies as a valuable drug candidate for intranasal or inhalative administration.Pyrrolidine dithiocarbamate, a very effective NF-jB inhibitor [1], known to inhibit inflammatory processes [2], is suggested as a key factor in the treatment of human rhinovirus (HRV) infections. Unpublished in vitro data strongly support this hypothesis. Thus, the aim of this project was to describe the toxicity profile of PDTC allowing for clinical use of the potential HRV drug candidate. Pyrrolidine dithiocarbamate is a compound of the class of DTCs. Dithiocarbamates and their disulphides have been used in medicine, industry and agriculture for more than 20 years. The compounds class reported biological effects include ability to influence oxidative stress, apoptosis, enzyme inhibition or modulation of transcription as well as inhibition of inflammatory processes via NF-jB inhibition [1,[3][4][5][6][7][8].Two DTCs, diethyldithiocarbamate and its disulphide disulphiram (Antabuse) are marketed drugs: Diethyldithiocarbamate is used in the treatment of nickel intoxication, Antabuse is marketed for alcohol aversion therapy. The potential clinical use of closely related compounds is currently being explored for various indications including the treatment of ocular inflammations [9,10], infection caused by rhinovirus [11] and coxsackievirus [12], methicillin-resi...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Chabicovsky

Prieschl-Grassauer

Seipelt

et al. 2010

Basic Clin Pharma Tox

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“…3 Although the mechanism of disulfiram-induced hepatotoxicity is not completely understood, 2 hypotheses have been proposed: (1) an allergic or hypersensitivity reaction and (2) the production of toxic metabolites. 6 The latter hypothesis is consistent with the inhibitory effect of both drugs on the CYP450, leading to the accumulation of toxic metabolites derived from disulfiram, such as carbon disulfide, which has been reported to produce toxic hepatitis. Although hepatocellular injury is uncommon in patients receiving clarithromycin, 7 hepatic failure leading to death has been reported occasionally, usually in patients with serious underlying diseases and/or those receiving concomitant drug therapy, 8 as occurred in this case.…”

Section: Commentsupporting

confidence: 59%

Fulminant Hepatitis and Fatal Toxic Epidermal Necrolysis (Lyell Disease) Coincident With Clarithromycin Administration in an Alcoholic Patient Receiving Disulfiram Therapy

Masiá

Gutiérrez²,

Jimeno³

et al. 2002

Arch Intern Med

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Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.

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“…During the use of disulfiram in alcohol aversion therapy treatment over the past several decades, 2 important side effects have been observed: neurotoxicity and hepatotoxicity (9)(10)(11). Although rare, hepatotoxicity is serious and appears to be an idiosyncratic reaction possibly mediated through an immune mechanism (12).…”

Section: Disulfiram (Bis(diethylthiocarbamoyl)disulfide or Antabusementioning

confidence: 99%

Disulfiram Produces a Non-Carbon Disulfide-Dependent Schwannopathy in the Rat

Tonkin¹,

Erve²,

Valentine³

2000

J Neuropathol Exp Neurol

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Abstract. Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS 2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS 2 -mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS 2 , we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS 2 ; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.

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Disulfiram-induced hepatitis. Report of four cases and review of the literature

Cited by 55 publications

References 23 publications

Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Fulminant Hepatitis and Fatal Toxic Epidermal Necrolysis (Lyell Disease) Coincident With Clarithromycin Administration in an Alcoholic Patient Receiving Disulfiram Therapy

Disulfiram Produces a Non-Carbon Disulfide-Dependent Schwannopathy in the Rat

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