Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation

Tonkin, Elizabeth G.; Valentine, Holly L.; Zimmerman, Lisa J.; Valentine, William M.

doi:10.1016/s0041-008x(03)00093-0

Cited by 24 publications

(26 citation statements)

References 24 publications

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“…Oral administration of the acid labile N,N-diethyldithiocarbamate (DEDC) may result in the production of biologically significant amounts of carbon disulphide (CS 2 ) potentially resulting in CS 2 -mediated protein cross-linking [25]. In contrast, parenteral administration of DEDC or oral administration of the more acid-stable dimer of DEDC, disulphiram, is characterized by the generation of S-(diethylaminocarbonyl) cysteine adducts in the absence of CS 2 -mediated protein cross-linking [26,28]. Additionally, a single alkyl substituent on nitrogen gives enhanced acid stability and provides for the generation of an alkyl isothiocyanate capable of acylating nucleophilic sites within biological systems [29].…”

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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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: 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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“…The results demonstrated that although molinate produced comparable levels of cysteine modification to those observed in disulfiram-induced neuropathy and was accompanied by ALDH and esterase inhibition, no differences relative to controls were observed regarding morphology in the peripheral nervous system. These findings together with a report that parenteral administration of N,N-diethyldithiocarbamate but not its S-methyl-N,N-diethyldithiocarbamate metabolite produced identical lesions to disulfiram, despite a 2-fold greater level of adducts produced by S-methyl-N,N-diethyldithiocarbamate, argue against a role for cysteine modification in disulfirammediated neuropathy (29). Alternatively, it appears that neurotoxicity is mediated through the dithiocarbamate metabolite of disulfiram, and because a similar metabolite is not produced through metabolism of thiocarbamates, it seems unlikely that thiocarbamates can produce the segmental demyelination observed for dithiocarbamate compounds.…”

Section: Discussionmentioning

confidence: 83%

Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat

Zimmerman

Valentine

2004

Chem. Res. Toxicol.

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Thiocarbamates are a major class of herbicides used extensively in the agricultural industry. It has been shown that thiocarbamates can form reactive sulfoxide and sulfone intermediates, which may be involved in the toxicity of thiocarbamates through covalent modification of cysteine and serine active sites of enzymes. Molinate has been shown to generate an S-hexahydro-1H-azepine-1-carbonyl adduct on the Cys-125 residue of the beta2- and beta3-chains of rat globin analogous to that reported for disulfiram and to inhibit aldehyde dehydrogenase and nonspecific esterase activity. The present study examined whether other thiocarbamate herbicides produce similar covalent protein modifications and enzyme inhibition to that reported for molinate and whether S-(N,N-dialkylaminocarbonyl)cysteine adduct levels are correlated to enzyme inhibition or the structure of thiocarbamate herbicides. Additionally, the potential of molinate to act as a peripheral demyelinating agent similar to disulfiram was evaluated. To address these aims, rats were exposed ip to molinate, vernolate, ethiolate, EPTC, or butylate for 5 days after which hemogloblin was isolated and analyzed for protein adducts using HPLC and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. In addition, brain, liver, and testes mitochondrial and microsomal fractions were assayed for nonspecific esterase, low Km ALDH, or total ALDH activities, and S-(N,N-dialkylaminocarbonyl)cysteine adducts were measured by LC/MS/MS. For the neurotoxicity assessments, rats were administered molinate parenterally for subchronic periods and morphological evaluations performed on peripheral nerves. All of the thiocarbamates except butylate produced S-(N,N-dialkylaminocarbonyl)cysteine adducts on globin and the quantity of adducts detected decreased with increasing size of the nitrogen substituents. In contrast, a clear relationship between cysteine modification in mitochondrial and microsomal samples to nitrogen substituents was not evident, and although molinate produced relatively high levels of adducts and esterase inhibition and butylate low levels of adducts and esterase inhibition for most samples, in general, the level of S-(N,N-dialkylaminocarbonyl)cysteine adducts did not appear to be related to enzyme inhibition. Molinate did not produce segmental demyelination in peripheral nerve, suggesting that molinate and possibly other thiocarbamates do not share the neurotoxic potential of dithiocarbamates.

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“…However, some studies in animals have not demonstrated neurotoxic CS 2 levels after direct oral intake of disulfiram which instead resulted in ME-DEDC pathway activation, Schwann cell damage and primary demyelination of peripheral nerves (4,23,24). Therefore, a DEDC-mediated demyelinating pathogenic mechanism was also supposed.…”

Section: Filosto Et Almentioning

confidence: 99%

“…Disulfiram (tetraethylthiuram disulphide) is a dithiocarbamoyl drug used in the treatment of alcoholism that irreversibly inhibits acetaldehyde oxidation by competing with nicotinamide adenine dinucleotide (NAD) for binding sites on liver aldehyde dehydrogenases (3,4). Increased acetaldehyde levels are thought to produce the unpleasant side effects associated with acetaldehyde syndrome (3).…”

Section: Introductionmentioning

confidence: 99%

“…Disulfiram may induce a peripheral neuropathy characterized by distal sensory impairment with loss of coordination, painful paresthesias and distal weakness with foot drop (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The severity of the neuropathy is directly related to dose and duration of exposure (3,(5)(6)(7)(11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Disulfiram neuropathy: Two cases of distal axonopathy

Filosto

Tentorio

Broglio

et al. 2008

Clinical Toxicology

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Background. Disulfiram may cause a peripheral neuropathy that is considered dose-and duration-of-exposure-related. Axonal degeneration has been described as a pathological hallmark of disulfiram toxicity, but experiments have reported a primary toxic effect of the molecule on Schwann cells and myelin. Case Reports. Case 1: At the end of two months of treatment with disulfiram 250 mg/day, a 31-year-old woman complained of weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and the legs below the knees; bilateral walking steppage, reduction in foot strength, absence of ankle jerk and knee tendon reflexes, and tactile stocking pin-pick and vibratory sensory impairment in the lower limbs below the knee. Disulfiram was discontinued and she recovered partially over three months. Case 2: After one month of treatment with disulfiram 1600 mg/day, a 27-year-old man reported walking impairment, distal lower limb weakness and paresthesias. He had unsteady gait with bilateral steppage and foot drop, absence of ankle jerks and overall sensation impairment below the knee. Disulfiram was discontinued and nine months later there was almost complete recovery of motor deficits, only minor motor weakness in distal leg muscles, and no dysesthesia, sensation deficits or areflexia. In both of them clinical and neurophysiological patterns were indicative of a distal axonopathy. Discussion. The mechanisms by which disulfiram cause injury in human nerves are unclear, though may involve carbon disulfide. The discrepancy between experimental and clinical observations is still unexplained. Conclusion. We report two cases of disulfiram axonal toxicity and the partial response following discontinuation of the drug.

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Parenteral N,N-diethyldithiocarbamate produces segmental demyelination in the rat that is not dependent on cysteine carbamylation

Cited by 24 publications

References 24 publications

Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Pre‐Clinical Safety Evaluation of Pyrrolidine Dithiocarbamate

Characterization of S-(N,N-Dialkylaminocarbonyl)cysteine Adducts and Enzyme Inhibition Produced by Thiocarbamate Herbicides in the Rat

Disulfiram neuropathy: Two cases of distal axonopathy

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