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Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-beta-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D(1) receptor agonist; BP 897 is a D(3) receptor partial agonist.A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a "cocaine vaccine" found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.
Activation of macrophages leads to the secretion of cytokines and enzymes that shape the inflammatory response and increase metabolic processes. This, in turn, results in increased production of reactive oxygen species. The role of Cu/Zn superoxide dismutase (SOD-1), an important enzyme in cellular oxygen metabolism, was examined in activated peritoneal elicited macrophages (PEM) and in several inflammatory processes in vivo. LPS and TNF-alpha induced SOD-1 in PEM. SOD-1 induction by LPS was mainly via extracellular signal-regulated kinase-1 activation. Transgenic mice overexpressing SOD-1 demonstrated a significant increase in the release of TNF-alpha and of the metalloproteinases MMP-2 and MMP-9 from PEM. Disulfiram (DSF), an inhibitor of SOD-1, strongly inhibited the release of TNF-alpha, vascular endothelial growth factor, and MMP-2 and MMP-9 from cultured activated PEM. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. In vivo, transgenic mice overexpressing SOD-1 demonstrated a 4-fold increase in serum TNF-alpha levels and 2-fold stronger delayed-type hypersensitivity reaction as compared with control nontransgenic mice. Conversely, oral administration of DSF lowered TNF-alpha serum level by 4-fold, lowered the delayed-type hypersensitivity response in a dose-dependent manner, and significantly inhibited adjuvant arthritis in Lewis rats. The data suggest an important role for SOD-1 in inflammation, establish DSF as a potential inhibitor of inflammation, and raise the possibility that regulation of SOD-1 activity may be important in the treatment of immune-dependent pathologies.
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Within the limitations of a pretreatment animal model, the combination of cimetidine and disulfiram significantly mitigates the effects of pennyroyal toxicity and does so more effectively than either agent alone. These data suggest that R-(+)-pulegone metabolism through CYP1A2 appears to be more important in the development of a hepatotoxic metabolite than does metabolism via CYP2E1.
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N-Hydroxy-2-acetylaminofluorene reductase was purified from rabbit liver cytosol by fractionation with ammonium sulfate, and chromatography with DEAE-cellulose, Sephadex G-200 and hydroxylapatite. The purified enzyme was homogeneous by the criterion of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The molecular weight of the enzyme was estimated to be 34,000 by the electrophoresis and by gel filtration on Sephadex G-200. The enzyme required cysteine, glutathione, dithiothreitol, 2-mercaptoethanol, NADPH or NADH as an electron donor. The enzyme activity was inhibited by p-chloromercuribenzoic acid, N-ethylmaleimide, cupric sulfate or disulfiram, but little by oxygen.
We have described a patient in whom EEG abnormalities, a seizure disorder, and Capgras syndrome developed two weeks after she started taking disulfiram. That disulfiram has been shown to inhibit dopamine beta-hydroxylase in vitro suggests an etiologic role for dopaminergic pathways in at least some cases of Capgras syndrome. Our experience with this patient suggests that convulsions and psychosis may occur as a side effect of standard dosages of disulfiram in patients with no previous history of psychosis or brain disease. Furthermore, the symptoms may resolve spontaneously without the long-term use of antipsychotic or anticonvulsant medication.
Patients present to psychiatrists with substantial drinking problems either masquerading as mental illness or occurring simultaneously with it. This article reviews the clinical disturbances seen in alcoholism, the process of recovery from alcoholism, and how the various components of alcoholism treatment work. An approach to history-taking and assessment is followed by discussion of the decision whether to treat a person in an alcoholism treatment facility, a psychiatric hospital, or both.
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20-Hydroxyleukotriene B4 was converted by rat liver homogenates in the presence of NAD+ to a more polar product on reverse-phase high-performance liquid chromatography. The product was identified as 20-carboxyleukotriene B4 by straight-phase high performance liquid chromatography, ultraviolet spectrophotometry and gas chromatography-mass spectrometry. The oxidative activity of the homogenates was located in the cytosol with an optimal pH of 8.0. The activity was dependent on NAD+, and NADP+ could not substitute for NAD+. 1 mol of 20-carboxyleukotriene B4 was formed with the reduction of 2 mol of NAD+. The reaction was inhibited by pyrazole and 4-methylpyrazole, inhibitors of alcohol dehydrogenase, and by various alcohols, such as ethanol, 12-hydroxylaurate, and 20-hydroxyprostaglandin E1. Disulfiram, an inhibitor of aldehyde dehydrogenase, also inhibited the activity. These results suggest that two discrete steps catalyzed by different enzymes, alcohol dehydrogenase and aldehyde dehydrogenase, are involved in the oxidation of 20-hydroxyleukotriene B4 in rat liver cytosol. The enzyme system seems to be different from that of human neutrophils.
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Exposure of isolated rat hepatocytes to allyl alcohol (AA), diethyl maleate (DEM) and bromoisovalerylurea (BIU) induced lipid peroxidation, depletion of free protein thiols to about 50% of the control value and cell death. Vitamin E completely prevented lipid peroxidation, protein thiol depletion and cell death. A low concentration (0.1 mM) of the lipophylic disulfide, disulfiram (DSF), also prevented the induction of lipid peroxidation by the hepatotoxins; however, in the presence of DSF, protein thiol depletion and cell death occurred more rapidly. Incubation of cells with a high concentration (10 mM) of DSF alone led to 100% depletion of protein thiols and cell death, which could not be prevented by vitamin E. The level of free protein thiols in cells, decreased to 50% by exposure to AA, DEM and BIU, could be reversed to 75% of the initial level by dithiothreitol (DTT) treatment, indicating that the protein thiols were partially modified into disulfides and partially into other, stable thiol adducts. The 100% depletion of protein thiols by DSF was completely reversed by DTT treatment. The involvement of lipid peroxidation in protein thiol depletion was studied by measuring the effect of a lipid peroxidation product, 4-hydroxynonenal (4-HNE), on protein thiols in a cell free liver fraction. 4-HNE did not induce lipid peroxidation in this system, but protein thiols were depleted to 30% of the initial value, irrespective of the presence of vitamin E. DTT treatment could reverse this for only 25%. Similar, DSF-induced protein thiol depletion could be reversed completely by DTT. We conclude that (at least) two types of protein thiol modifications can occur after exposure of hepatocytes to toxic compounds: one due to interaction of endogeneously generated lipid peroxidation products with protein thiols, which is not reversible by the action of DTT, and one due to a disulfide interchange between disulfides like DSF and protein thiols, which can be reversed by the action of DTT.
Two groups of male Wistar rats weighing about 140 (WI) and 200 g (WII) and a group of Sprague-Dawley (S.D.) rats (140 g) received oral disulfiram 220-580 mg/kg (DSF) daily for one or three weeks. Isolated ilea of both control and treated rats showed similar responses to acetylcholine, but the responses to 5-hydroxytryptamine (5-HT) were decreased after one and three weeks' treatment in the WI and SD rats. Pretreatment with reserpine intensified this effect in treated WI rats. A distinct decrease in the histochemical reactivity for the acetylcholinesterase and the non-specific cholinesterase was observed in the nerve plexuses of the gut wall indicating a DSF-induced nerve damage. Autonomic (cholinergic) nerves seemed thus to be affected by DSF. The two rats strains studied did not differ in their responses to 5-HT.
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We suggested that disulfiram, by removing NA-mediated inhibitory control on noradrenergic terminals, causes an unrestrained cocaine-induced DA release from those terminals in the mPF cortex. In the accumbens and caudate nuclei, "allogenic" DA concentration might be clouded by DA originated from dopaminergic terminals. The possible role of "allogenic" DA in disulfiram ability to prevent stress-induced reinstatement of cocaine seeking is discussed.
We confirmed by HPLC-mass spectrometry that MeDDC sulfine was the major product of MeDDC formed by human liver microsomes and by FMO3. Recombinant FMO3 was an efficient catalyst for the formation of MeDDC sulfine (5.3+/-0.2 nmol/min/mg, mean+/-SEM, n = 6). Inhibition studies showed MeDDC was metabolized primarily by CYP450 in human liver microsomes at pH 7.4, with a 10% contribution from FMO (total microsomal activity 3.1+/-0.2, n = 17). In the course of this work, methyl p-tolyl sulfide (MTS), sulfoxidation of which is used by some investigators as a specific probe for FMO activity, was found to be a substrate for both FMO and CYP450 in human liver microsomes.
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The authors describe a case of the catatonia syndrome associated with disulfiram therapy. Although useful in the management of chronic alcoholism, disulfiram is being increasingly associated with a wide spectrum of side effects and untoward medical sequelae, which now include catatonia. The authors note that catatonia is a clinical syndrome associated with multiple medical conditions as well as psychiatric disorders.
Noradrenergic system ablation was attained by intracerebroventricular (i.c.v.) administration of the neurotoxin anti-DBH-saporin (aDBH-sap). DA, noradrenaline (NA), and DOPAC were assessed by HPLC after ex vivo tissue extraction or in vivo microdialysis. Control and denervated rats were subjected to microdialysis in the mPFC and caudate nucleus to evaluate the effect of nepicastat-cocaine combination on extracellular DA levels and their regulation by α2-adrenoceptors.
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Although disulfiram used as a pharmacological agent in the treatment of alcoholism is reported to act on both peripheral and central nervous systems with several adverse effects, the neurotoxic property of the drug has not been properly elucidated. We observed that the chronic administration of the drug to rats significantly inhibited synaptosomal (Na+,K+)-ATPase and basal Mg(2+)-ATPase activities. Further, the uptake of gamma-aminobutyric acid and L-glutamate which rely on the energy provided by this system was depleted following chronic drug administration. Similar findings were observed when the isolated synaptosomes were treated with the drug in an in vitro system. Further, treatment of synaptosomes with ouabain, a known inhibitor of (Na+, K+)-ATPase resulted in significant depletion of 3H-GABA and L-[3H]glutamate uptake into synaptosomes indicating the importance of the enzyme in the uptake mechanism. However, diethyldithiocarbamate, a major metabolite of disulfiram did not elicit any change in either the enzyme activity or the uptake of these neurotransmitters. On the basis of these evidences, we suggest that the chronic disulfiram administration attenuated the neurotransmitter uptake mechanism and resulted in higher extracellular concentration of glutamate that could lead to glutamate-induced neurotoxicity.
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Low molecular weight thiols (LMWTs) like N-acetyl cysteine, D-penicillamine, captopril, Disulfiram and Amifostine, etc. have been used as chemo-preventive agents. Recent studies have reported cell growth inhibition and cytotoxicity in several different types of cancer cells following treatment with several LMWTs. Cytotoxic and cytostatic effects of LMWTs may involve interaction of the thiol group with cellular lipids, proteins, intermediates or enzymes. Some of the mechanisms that have been proposed include a p53 mediated apoptosis, thiyl radical induced DNA damage, membrane damage through lipid peroxidation, anti-angiogenic effects induced by inhibition of matrix metalloproteinase enzymes and angiostatin generation. LMWTs are strong chelators of transition metals like copper, nickel, zinc, iron and cobalt and may cause metal co-factor depletion resulting in cytotoxicity. Oxidation of thiol group can also generate cytotoxic reactive oxygen species (ROS).
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Antioxidants and several other compounds, some of which are known to inhibit carcinogenicity, have been screened for their effectiveness as inhibitors of benzo[a]pyrene (BP) mutagenicity towards Salmonella typhimurium strain TA98 in the Ames test. A total of 32 compounds were tested. In the assay, metabolic activation of BP (8.2 nmoles/plate) was mediated by the S9 fraction from beta-naphthoflavone-induced rat livers. Among compounds which are known to inhibit carcinogenicity, retinol, phenothiazine, disulfiram, phenethylisothiocyanate and phenylisothiocyanate were the most effective inhibitors of BP mutagenicity, being effective at equimolar concentrations. Several other compounds showed inhibition at higher concentrations of antioxidant and the remainder showed little or no inhibition. Dose-response curves have been obtained for the 17 most active compounds. No general pattern of inhibition is obvious from our studies, inhibitors are not drawn ;from any single class of compounds, nor does a particular compound necessarily appear to inhibit more than one mutagen.
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Higher blood acetaldehyde concentration following disulfiram pretreatment significantly attenuated acute hepatic inflammation in the ethanol-loaded, LPS-challenged rat (18 +/- 2.9 vs 30 +/- 3.7 polymorphonuclear cells/portal area; P = 0.01). After LPS challenge, ALDH inhibitor pretreatment attenuated Kupffer cell release of TNF-Alpha in the presence of disulfiram at 5063 +/- 151 pg/ml and cyanamide at 4390 +/- 934 pg/ml, versus no inhibitor, 5869 +/- 265 pg/ml ( P < 0.01), but not in the absence of ethanol. Acetaldehyde significantly suppressed Kupffer cell TNF-Alpha release ( P < 0.05), but acetate treatment did not.
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1. Cytoplasmic aldehyde dehydrogenase was shown to be free of contamination by the mitochondrial enzyme by isoelectric focusing. 2. Both enzymes showed multiple banding in activity stains. The cytoplasmic enzyme gave two very close bands pI = 5.22 +/- 0.03 whereas the mitochondrial enzyme showed seven bands, a pair at pI = 5.22 and five further bands of pI 5.48 +/- 0.09, 5.56 +/- 0.07, 5.65 +/- 0.06, 5.70 +/- 0.03 and 5.76 +/- 0.02. Possible origins of the isoenzymes are discussed. 3. Disulfiram in a fourfold excess reduced the activity of the cytoplasmic enzyme to 9% of the initial value. The residual activity represents the activity of the disulfiram-modified enzyme and is not due to mitochondrial contamination. This casts doubt on the role of an essential thiol group. 4. The mitochondrial enzyme shows a low amplitude (22%) burst in the production of 4-nitrophenoxide ion during the hydrolysis of 4-nitrophenyl acetate at pH 7.6. The burst rate constant was 7.3 +/- 1 s-1 and the steady-state rate constant was 0.2 s-1, values similar to those previously reported for the cytoplasmic enzyme. 5. The mitochondrial enzyme shows a burst in the release of protons during the oxidation of propionaldehyde at pH 7.6. The burst rate constant was 6 s-1 and the amplitude was equal to half the formal enzyme concentration. The significance of these results for the steady-state mechanism is discussed.
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Previous studies indicate that disulfiram (DS), an anti-alcoholism drug, is cytotoxic to cancer cell lines and reverses anticancer drug resistance. Cancer stem cells (CSCs) are the major cause of chemoresistance leading to the failure of cancer chemotherapy. This study intended to examine the effect of DS on breast cancer stem cells (BCSCs).
A 46-year-old patient, treated with disulfiram for the past 4 years for chronic alcoholism, presented with progressive bilateral, painless, severe visual loss, related to optic neuropathy. An extensive work-up did not disclose any other possible cause than a toxic optic neuropathy caused by disulfiram. Discontinuation of disulfiram resulted in rapid, complete visual recovery.
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Human corneal aldehyde dehydrogenase (designated ALDH3) was purified to homogeneity and characterised with respect to substrate specificity and inhibition by thiol reagents. The enzyme was present as a major soluble protein (5% of the total soluble protein) and was found to efficiently catalyse the oxidation of medium chain peroxidic aldehydes which may be found in the cornea. These findings are consistent with the proposal that ALDH3 plays a dual role in the absorption of UVR and in the oxidation of peroxidic aldehydes in the mammalian cornea. Disulfiram did not inhibit this enzyme under the conditions used in this study, however p-hydroxymercuribenzoate rapidly inactivated the enzyme. Analysis of the proteins of the cornea and surrounding tissue indicated that in both the cow and the human, changes in the nature and quantity of soluble proteins occurred. Phenotype variants of the ALDH3 were apparent in a small Australian population.
Ethanol in the presence of disulfiram (N,N,N',N'-tetraethylthiuram disulfide, an inhibitor of aldehyde dehydrogenase) inhibited liver beta-alanine-oxoglutarate aminotransferase (beta-AlaAT I) activity yet activated tyrosine aminotransferase (TAT) in weanling rats in vivo. The effect on beta-AlaAT I was followed by the inhibitory expression of beta-AlaAT I mRNA. The beta-AlaAT I activity was reduced with a pseudo-first-order profile with time, and the half-life was calculated to be 12.3 +/- 0.83 h with the rate constant (Kd) of 0.056 +/- 0.004 h-1. The synthesis of beta-AlaAT I in rat liver was estimated to be 1.56 x 10(-10) mol/g of wet tissue per hour at a steady state. A combination of ethanol and disulfiram also reduced beta-alanine-pyruvate aminotransferase (beta-AlaAT II) activity to 60% of the control after 24 h.
The effect of ethyl alcohol and disulfiram (Antabuse) on the secretion and the irrigation of an isolated and denervated gastric pouch has been studied in the dog. In these conditions, disulfiram increased the differential acidity; the association of ethanol with disulfiram impaired the proteolytic activity of the secretion and induced a hyperirrigation of the gastric mucosa more definite than with ethanol alone. Effects on ethanol absorption from stomach are discussed.
Older adults who drink alcohol and who take medications are at risk for a variety of adverse consequences depending on the amount of alcohol and the type of medications consumed. It is important for clinicians to know how much alcohol their older patients are drinking to be able to effectively assess their risks and to counsel them about the safe use of alcohol and medications. Similarly, it is important for older adults to understand the potential risks of their combined alcohol and medication use to avoid the myriad of problems possible with unsafe use of these substances..
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In an attempt to characterize a possible drug interaction between methadone and disulfiram, 500 mg/day insulfiram was administered orally for seven days to seven subjects on methadone maintenance. Plasma methadone concentrations and urinary excretion of methadone and its pyrrolidine and pyrrolidone metabolites were measured and subjective symptoms of opiate intoxication and abstinence were noted before, during, and after disulfiram administration. Mean trough plasma methadone concentrations and terminal half-lives were lowest and shortest during disulfiram treatment, although this finding was not statistically significant. The ratio of urinary methadone to its pyrrolidine metabolite decreased during disulfiram treatment in all subjects. There is no evidence to support our original hypothesis that disulfiram might inhibit methadone metabolism. In contrast, urinary excretion of the major pyrrolidine metabolite increased relative to excretion of methadone. This suggests enhanced N-demethylation during disulfiram treatment. Disulfiram had no effect on opiate intoxication or abstinence symptoms. Disulfiram may alter methadone disposition, but in this study it was shown that in doses used for management of alcoholism there was no significant interaction between disulfiram and methadone.
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We studied the effect of prior narcotic addiction on response to treatment of alcoholism. Patients in the Elmhurst Alcoholism Treatment Program are offered medical care, counseling, disulfiram, and close affiliation with Alcoholics Anonymous. We compared 85 alcoholics who had a history of narcotic use with a control group of 85 alcoholics matched for age, sex, and race who had never used narcotics. Among controls, 30 (35%) became abstinent from alcohol for at least half the time that they were known to us. Of the former narcotic users, only 8 (9%) became abstinent for at least half the time they were known to us. Former narcotic users did poorly in alcoholism treatment, whether or not they had ever been treated with methadone maintenance. Alcohol use, often heavy, began before heroin use in at least half the narcotic group. We conclude that a history of narcotic use reduces markedly the chance of success in conventional alcoholism treatment, and that alcoholism and narcotic addiction develop independently.
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Nowadays there exists consent in the matter that Disulfiram should only be adminsitered as part of a comprehensive therapy program, this means in the context of an intake under medical supervision. This paper is supposed to help estimate the value of disulfiram in recent addiction medicine.