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Acute intentional overdoses of disulfiram (app. 30 g) is reported in 15-years-old boy. The neurological disturbances as nystagmus, coma, seizures and than impairment of memory and perception were dominated in the clinical picture. During MRI examination the areas of different signal from corpus callosum were detected which can be referred to focus of demyelinisation. The patient recovered and was discharged from the hospital after 30 days. Neuropsychological examinations have suggested dysfunction of CNS. The control MRI examination 90 days later, did not reveal any pathological changes in the brain.
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One of the events associated with Alzheimer's disease is the dysregulation of α- versus β-cleavage of the amyloid precursor protein (APP). The product of α-cleavage (sAPPα) has neuroprotective properties, while Aβ1-42 peptide, a product of β-cleavage, is neurotoxic. Dimerization of APP has been shown to influence the relative rate of α- and β- cleavage of APP. Thus finding compounds that interfere with dimerization of the APP ectodomain and increase the α-cleavage of APP could lead to the development of new therapies for Alzheimer's disease. Examining the intrinsic fluorescence of a fragment of the ectodomain of APP, which dimerizes through the E2 and Aβ-cognate domains, revealed significant changes in the fluorescence of the fragment upon binding of Aβ oligomers--which bind to dimers of the ectodomain--and Aβ fragments--which destabilize dimers of the ectodomain. This technique was extended to show that RERMS-containing peptides (APP(695) 328-332), disulfiram, and sulfiram also inhibit dimerization of the ectodomain fragment. This activity was confirmed with small angle x-ray scattering. Analysis of the activity of disulfiram and sulfiram in an AlphaLISA assay indicated that both compounds significantly enhance the production of sAPPα by 7W-CHO and B103 neuroblastoma cells. These observations demonstrate that there is a class of compounds that modulates the conformation of the APP ectodomain and influences the ratio of α- to β-cleavage of APP. These compounds provide a rationale for the development of a new class of therapeutics for Alzheimer's disease.
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The CYP inhibitors metyrapone, troleandomycine, disulfiram, sulfaphenazole, quinidine and 1-aminobenzotriazole do not inhibit o-anisidine oxidation catalyzed by HRP. In contrast, ketoconazole, diethyldithiocarbamate, ellipticine, α-naphtoflavone, proadifen SKF525A, piperonylbutoxide, were found to inhibit not only the CYPs, but also the HRP-mediated oxidation of o-anisidine. Interestingly, α-naphtoflavone inhibits oxidation of o-anisidine by HRP with respect to H2O2, but not with respect to o-anisidine. Diethyldithiocarbamate is the most potent peroxidase inhibitor of o-anisidine oxidation with Ki with respect to o-anisidine of 10 μM and Ki with respect to H2O2 of 60 μM, being even the better peroxidase inhibitor than the classical "peroxidase inhibitor" - propyl gallate (Ki with respect to o-anisidine of 60 μM and Ki with respect to H2O2 of 750 μM).
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The oxidation of acrolein by aldehyde dehydrogenase was studied in several subcellular fractions of rat liver by measuring acrolein-dependent production of NADH from NAD+. Mitochondrial and cytosolic fractions each contained two aldehyde dehydrogenase activities with Km values for acrolein of 0.4-0.7 mM and 0.015-0.025 mM. Microsomes demonstrated only a high Km (1.5 mM) activity. The low Km activities of mitochondria and cytosol differed in their sensitivity to inhibition by chloral hydrate and in their response to 1 mM MgCl2 (activation vs. inhibition). The metabolism of acrolein by low Km aldehyde dehydrogenase activities was markedly depressed in mitochondrial or cytosolic fractions from rats pretreated with cyanamide (2 mg/kg for 1 hr) or disulfiram (100 mg/kg for 24 hr). The effect of aldehyde dehydrogenase inhibition on allyl alcohol toxicity was determined by pretreating rats with cyanamide or disulfiram prior to treatment with allyl alcohol. Hepatotoxicity was assessed on the basis of elevated serum alanine aminotransferase and sorbitol dehydrogenase activities and the loss of microsomal cytochrome P-450. Pretreatment with the aldehyde dehydrogenase inhibitors enhanced the hepatotoxicity of allyl alcohol in both male and female rats. The results suggest that acrolein metabolism by rat liver aldehyde dehydrogenase isozymes is important for the inactivation of allyl alcohol-derived acrolein.
The human placenta contains a considerable amount of 1-pyrroline-5-carboxylate dehydrogenase (23 +/- 6 micrograms/g; n = 12), about 25% of the concentration present in liver. The enzyme is the only form in placenta that oxidizes short- and medium-chain aldehydes, which facilitates its purification from this organ. It can be purified to homogeneity by successive chromatographies on DEAE-cellulose, 5'-AMP-Sepharose and Sephacryl S-300. From 500 g of tissue, about 2.1 units of enzyme can be obtained with a 12% yield. Placental 1-pyrroline-5-carboxylate dehydrogenase is a dimer of Mr-63,000 subunits. It exhibits a pI of 6.80-6.65, and is specific for 1-pyrroline-5-carboxylate, the cyclic form of glutamate gamma-semialdehyde (Km = 0.17 mM, kcat. = 870 min-1), although it also oxidizes short-chain aliphatic aldehydes such as propionaldehyde (Km = 24 mM, kcat. = 500 min-1). These properties are very close to those of the liver enzyme, indicating a strong similarity between the enzyme forms from both organs. The enzyme is highly sensitive to temperature, showing 50% inhibition after incubation for 0.8 min at 45 degrees C or after 23 min at 25 degrees C. It is irreversibly inhibited by disulfiram, and a molar ratio inhibitor: enzyme of 60:1 produced 50% inhibition after incubation for 10 min. A subcellular-distribution study indicates that the enzyme is located in two compartments: the mitochondria, with 60% of the total activity, and the cytosol, with 40% activity. The physiological role of the enzyme in placental amino acid metabolism is discussed.
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The biotransformation of halothane is supposed to be the cause of the rare "halothane-hepatitis". Therefore an inhibition of the metabolism of Halothane is of some interest. We used bromide as a metabolite of Halothane and investigated the bromide level of the serum of patients after halothane anaesthesia by means of x-ray fluorescence spectrometry. The induction of anaesthesia with Thiopental, Methohexital and Etomidate had no influence on the bromide level. Likewise the influence of Enflurane on the metabolism of Halothane was not significant. An effective inhibitor in man is Disulfiram. The authors assume, that further information about the toxicity of Halothane metabolites can be gained through further studies of drugs like Disulfiram.
Ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) were administered orally to young male rats at doses varying from 50 to 500 mg/kg/day and 250 to 1000 mg/kg/day for EGME and EGEE, respectively, for 11 days. At sequential times animals were killed and testicular histology examined. The initial and major site of damage following EGME treatment was restricted to the primary spermatocytes undergoing postzygotene meiotic maturation and division. EGEE produced damage of an identical nature, but a larger dose was required to elicit equivalent severity (500 mg EGEE/kg being approximately equivalent to 100 mg EGME/kg). Additionally, within the spermatocyte population, differential sensitivity was observed depending on the precise stage of meiotic maturation: dividing (stage XIV) and early pachytene (stages I-II) greater than late pachytene (stages VIII-XIII) greater than mid-pachytene (stages III-VII). Equivalent doses of methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) gave injury similar to the corresponding glycol ether. When animals were pretreated with inhibitors of alcohol metabolism followed by a testicular toxic dose of EGME (500 mg/kg), an inhibitor of alcohol dehydrogenase (pyrazole) offered complete protection. Pretreatment with the aldehyde dehydrogenase inhibitors disulfiram or pargyline did not ameliorate the testicular toxicity of EGME. In mixed cultures of Sertoli-germ cells, MAA and not EGME produced effects on spermatocytes analogous to that seen in vivo, at concentrations approximately equivalent to steady-state plasma levels after a single oral dose of EGME (500 mg/kg). It would seem likely that a metabolite (MAA or possibly methoxyacetaldehyde) and not EGME is responsible for the production of testicular damage.
Liquid chromatography-tandem mass spectrometry methodology is described for the determination of S-(N,N-diethylcarbamoyl)glutathione (carbamathione) in human plasma samples. Sample preparation consisted of a straightforward perchloric acid medicated protein precipitation, with the resulting supernatant containing the carbamathione (recovery ~98%). For optimized chromatography/mass spec detection a carbamathione analog, S-(N,N-di-i-propylcarbamoyl)glutathione, was synthesized and used as the internal standard. Carbamathione was found to be stable over the pH 1-8 region over the timeframe necessary for the various operations of the analytical method. Separation was accomplished via reversed-phase gradient elution chromatography with analyte elution and re-equilibration accomplished within 8 min. Calibration was established and validated over the concentration range of 0.5-50 nM, which is adequate to support clinical investigations. Intra- and inter-day accuracy and precision determined and found to be <4% and <10%, respectively. The methodology was utilized to demonstrate the carbamathione plasma-time profile of a human volunteer dosed with disulfiram (250 mg/d). Interestingly, an unknown but apparently related metabolite was observed with each human plasma sample analyzed.
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Although the presence of thyrotropin-releasing hormone (TRH) in the posterior pituitary (PP) was reported more than one decade ago, knowledge on its origin, regulation and functional significance is lacking. In the present study we investigated the regulation of TRH in the rat PP. Analysis by specific RIA, anion and cation exchange chromatography and reverse-phase HPLC showed that all TRH immunoreactivity in the PP is accounted for by authentic TRH. Induction of hyperthyroidism with thyroxine increased levels of TRH in the PP by 20%, whereas in methimazole-treated, hypothyroid rats the content decreased by 25% versus untreated, euthyroid controls. Food deprivation for 3 days increased levels by 35% and refeeding completely normalized TRH content again. Also 14-17 days after castration, TRH in the PP was increased by 25% while testosterone substitution prevented this increase. Castration did not affect proTRH mRNA levels in the hypothalamus. One week after adrenalectomy or daily subcutaneous dexamethasone injections, TRH content in the PP was not affected. Treatment with disulfiram, an inhibitor of the peptidylglycine alpha-amidating monooxygenase (PAM), reduced levels of TRH in the PP by 20%. ProTRH and PAM mRNA levels were not affected in the hypothalamus by this treatment. Since TRH in the PP has been suggested to play a role in prolactin (PRL) release, we determined the content of TRH in the PP during a 6-hour suckling stimulus that increased PRL levels in peripheral blood 30-fold. Whereas TRH in the median eminence increased by 35%, 6 h after the initiation of suckling, TRH levels in the PP remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)
Molinate is a thiocarbamate herbicide used in the rice industry for over 25 years, and regulatory reports have shown that administration of molinate results in reproductive toxicity in male rats. Previous in vitro studies indicate that molinate undergoes oxidative metabolism, forming reactive electrophilic intermediates capable of undergoing nucleophilic addition by protein nucleophiles. On the basis of in vitro studies, carbamylation of an active site serine residue in Hydrolase A has been proposed to be the mechanism responsible for the observed testicular toxicity. The experiments presented here utilize hemoglobin to characterize covalent protein modifications produced in vivo by molinate. Rats were dosed intraperitoneally with molinate as a function of exposure duration. Examination of globin from molinate-treated rats by HPLC demonstrated a new peak in the isolated samples and, when collected and analyzed using MALDI-TOF MS, revealed a 126 Da increase in mass relative to the native beta(3) chain. Digestion of the globin using Glu-C and analysis by MALDI-TOF MS revealed two modified peptide fragments at m/z 2743 and 4985 consistent with a 126 Da increase to peptide fragments [122-146] and [102-146] in the unmodified beta(2) and beta(3) chains of globin. Using selected reaction monitoring LC/MS/MS, S-hexahydro-1H-azepine-1-carbonyl cysteine (HHAC-Cys) was identified in the globin hydrolysates isolated from the molinate-treated rats, but not in the control samples, and the quantity of adduct exhibited a cumulative dose response. These experiments demonstrate the ability of molinate to covalently modify proteins in vivo in a dose dependent manner. For hemoglobin this modification was a carbamylation at Cys-125 similar to the modification produced by disulfiram and N,N-diethyldithiocarbamate. The ability of molinate to covalently modify cysteine residues provides a potential mechanism to account for enzyme inhibition following molinate exposure and suggests that enzymes with cysteine residues in their active site may be inhibited by molinate.
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In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.
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The decision to use disulfiram to assure sobriety for high risk groups, e.g. criminal offenders is discussed.
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Disulfiram is the commonly prescribed drug for the treatment of alcohol dependence. It's major metabolite (diethyldithiocarbamate) is an inhibitor of dopamine-betahydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine resulting in psychosis. We recommend that disulfiram should be used at the lowest effective dose, possibly 250 mg daily and caution should be taken while prescribing disulfiram for patients with personal and familial antecedents of psychosis.
Study medication, either disulfiram or placebo, was placed directly in the methadone to ensure compliance for 12 weeks.
Drugs stimulating catecholaminergic transmission (dopa, apomorphine, amphetamine, and their combination with disulfiram) weakened the epileptogenic properties of the caudate nucleus in freely moving rats. Under the influence of these drugs the cortical electroencephalographic response to single stimulation of the nucleus was shortened in animals receiving subconbulsant doses of leptazol and the intensity of the spike-wave rhythm bound with repeated caudate stimuli was reduced. Conversely, inhibitors of catecholaminergic transmission (chlorpromazine, haloperidol, alpha-methyltyrosine, and disulfiram) potentiated the epileptogenic effects of the caudate nucleus.
To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders.
The putative antimutagenic/anticarcinogenic organosulfur compound, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (AC-DDTC), has been demonstrated to inhibit the metabolic activation and the genotoxicity of N-nitrosodiethylamine. We have investigated the chemopreventive activity of AC-DDTC against benzo[a]pyrene (B[a]P) in the Salmonella typhimurium bacterial mutation assay, in the chromosome aberration assay using Chinese hamster lung fibroblast (CHL), and in the mouse micronucleus assay in bone marrow cells. In the bacterial mutation assay, AC-DDTC produced a concentration dependent decrease in the number of mutant colonies induced by B[a]P. The chromosome damaging responses of B[a]P in CHL cells were abolished by the treatment of AC-DDTC, approximately to the level of the control. In the in vivo mouse bone marrow micronucleus test, pretreatment of AC-DDTC 1 h prior to B[a]P reduced the frequency of micronucleated polychromatic erythrocytes. The inhibitory effects were statistically significant and dose-dependent. Our results demonstrate that AC-DDTC, one of the mixed disulfide model compounds of disulfiram, prevents the mutagenic effects of B[a]P.
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This work presents evidence that compounds that inactivate retroviruses by targeting the zinc finger motif in their nucleocapsid proteins are also effective against RSV. AT-2-inactivated RSV vaccine is not strongly immunogenic in the absence of adjuvants. In the adjuvanted form, however, vaccine induces immunopathologic response. The mere preservation of surface antigens of RSV, therefore may not be sufficient to produce a highly-efficacious inactivated virus vaccine that does not lead to an atypical disease.
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The comorbidity of substance use disorders (SUDs) in bipolar disorder is among the highest in psychiatric disorders. Evidence-based controlled psychosocial or pharmacological interventions trials, which may guide treatment decisions, have not been systematically reviewed.
The authors report a case of symmetric multiple lipomatosis in a young woman with chronic liver disease caused by previous alcohol abuse whose onset occurred three years after the suspension of the toxic agent. The introduction includes a review of the latest literature, focusing in particular on the most probable etiopathogenetic causes, the most common clinical presentations and therapeutics choices. After a description of this particular case, the authors discuss the unusual presentation of the syndrome caused by the rapid onset of lipid accumulation a long time after the suspension of alcohol abuse.
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A transient release of protons with an amplitude corresponding to one proton per active site has been observed for the oxidation of propionaldehyde, acetaldehyde, and benzaldehyde by sheep liver cytoplasmic aldehyde dehydrogenase at pH 7.6 with phenol red as indicator. At saturating substrate levels, the rate constants for the proton burst are in each case the same, and for acetaldehyde and propionaldehyde show the same dependence on the concentrations of the substrates, as the rate constants for the transient production of NADH reported previously [MacGibbon, A.K.H., Blackwell, L.F., & Buckley, P.D. (1977) Biochem. J. 167, 469-477]. Although, with propionaldehyde as a substrate, a full proton burst is also observed at pH 6.0, no proton burst is observed at pH 9.0. For 4-nitrobenzaldehyde, there is no burst in NADH production, but a burst in proton release is observed, showing that proton release precedes hydride transfer. No protons were released during the binding of the substrate analogues acetone and chloral hydrate nor on reaction of the enzyme with the inhibitor tetraethylthiuram disulfide (disulfiram). A model is proposed in which the rate-limiting step in the pre-steady-state phase of the reaction is a conformational change which occurs after the binding of aldehydes to the enzyme. As a result of the conformational change, the environment of a functional group on the enzyme, which initially has a pKa of about 8.5, is perturbed to give a final pKa value for the group of less than 5. Computer simulations were used to show that the model accurately reproduces all of the experimental data. The lack of observation of a second transient proton release, as required by the overall stoichiometry, argues that its release occurs in a slow step prior to NADH dissociation.
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We performed search of MEDLINE for case reports on drug-induced liver injury associated with: amoxicillin/clavulanic acid, carbamazepine, diclofenac, disulfiram, erythromycin, flucloxacillin, halothane, isoniazid, phenytoin, sulindac and trimethoprim/sulfametoxazol.
Substance use disorders are a leading cause of morbidity and mortality in the United States. Medications for the treatment of substance use disorders are effective yet underutilized. This article reviews recent literature examining medications used for the treatment of alcohol and opioid use disorders. The neurobehavioral rationale for medication treatment and the most common ways medications work in the treatment of substance use disorders are discussed. Finally, the medications and the evidence behind their effectiveness are briefly reviewed. Physicians and other prescribing clinicians should take an active role in facilitating remission and recovery from substance use disorders by prescribing these effective medications with brief medical management counseling.
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Disulfiram is a cocaine addiction pharmacotherapy that inhibits dopamine β-hydroxylase (DβH) and reduces norepinephrine production. We examined whether a functional variant of the ADRA1A gene (Cys to Arg at codon 347 in exon 2, Cys347Arg) may enhance treatment response through decreased stimulation of this α1A-adrenoceptor, since antagonists of this receptor show promise in reducing cocaine use. Sixty-nine cocaine and opioid co-dependent (DSM-IV) subjects were stabilized on methadone for two weeks and subsequently randomized into disulfiram (250 mg/day, N=32) and placebo groups (N=37) for 10 weeks. We genotyped the ADRA1A gene polymorphism (rs1048101) and evaluated its role for increasing cocaine free urines in those subjects treated with disulfiram using repeated measures analysis of variance, corrected for population structure. The 47 patients who carried at least one T allele of rs1048101 (TT or TC genotype) reduced their cocaine positive urines from 84% to 56% on disulfiram (p=0.0001), while the 22 patients with the major allele CC genotype showed no disulfiram effect. This study indicates that a patient's ADRA1A genotype could be used to identify a subset of individuals for which disulfiram and, perhaps, other α1-adrenoceptor blockers may be an effective pharmacotherapy for cocaine dependence.
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Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N-acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose.
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Randomized, placebo-controlled, double-masked (for medication condition), factorial (2 x 2) trial with 4 treatment conditions: disulfiram plus CBT, disulfiram plus IPT, placebo plus CBT, and placebo plus IPT.
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(13) C magnetic resonance spectroscopy measurements of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation allow real-time assessment of ALDH2 activity in liver in vivo.
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The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non-small cell lung cancer. The results from this small study seem encouraging enough for assessment in larger trials. Disulfiram is an inexpensive and safe drug; if its addition to chemotherapy could be shown to prolong survival, an effective regimen could be established and used widely, even in resource-poor countries.
High concentrations of aldehydes slow the inactivation of cytoplasmic aldehyde dehydrogenase by disulfiram and also slow the reaction of the enzyme with 2,2'-dithiodipyridine. It is concluded that a low-affinity aldehyde-binding site is probably the site at which thiol-group modifiers react with aldehyde dehydrogenase, as well as being the active site for hydrolysis of 4-nitrophenyl acetate.