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This article reviews the literature on alcohol and medication interactions, with a focus on older adults.
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Mushrooms are ubiquitous in nature. They are an important source of nutrition, however, certain varieties contain chemicals that can be highly toxic to humans. Industrially cultivated mushrooms are historically very safe, whereas foraging for mushrooms or accidental ingestion of mushrooms in the environment can result in serious illness and death. The emergency department is the most common site of presentation for patients suffering from acute mushroom poisoning. Although recognition can be facilitated by identification of a characteristic toxidrome, the presenting manifestations can be variable and have considerable overlap with more common and generally benign clinical syndromes. The goal of this two-part article is to review the knowledge base on this subject and provide information that will assist the clinician in the early consideration, diagnosis and treatment of mushroom poisoning. Part I reviewed the epidemiology and demographics of mushroom poisoning, the physical characteristics of the most toxic varieties, the classification of the toxic species, and presented an overview of the cyclopeptide-containing mushroom class. Part II is focused on the presentation of the other classes of toxic mushrooms along with an up-to-date review of the most recently identified poisonous varieties.
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Retinoic acid is synthesized from retinaldehyde by several different dehydrogenases, which are arranged in conserved spatial and developmentally regulated patterns. Here we show for the mouse that a class-1 aldehyde dehydrogenase, characterized by oxidation and disulfiram sensitivity, is found in the brain at high levels only in the basal forebrain. It is present in axons and terminals of a subpopulation of dopaminergic neurons of the mesostriatal and mesolimbic system, forming a retinoic acid-generating projection from the ventral tegmentum to the corpus striatum and the shell of the nucleus accumbens. In the striatum the projection is heaviest to dorsal and rostral regions, declining gradually toward ventral. The enzyme is expressed early in development, shortly after appearance of tyrosine hydroxylase. Other dopaminergic neurons in the brain, as well as the chromaffin cells of the adrenal medulla, do not contain this dehydrogenase. The presence of this enzyme may be a factor in the long-term success of transplants of dopaminergic cells to the corpus striatum in Parkinson disease, and it may play a role in parkinsonism and catatonia due to disulfiram (Antabuse) neurotoxicity.
The study examined the feasibility of screening for hepatotoxicity by an in vitro gene expression analysis using rat primary hepatocytes and Affymetrix Rat Toxicology U34 arrays. Hepatocytes were exposed for 6 or 24 h to eight drugs, with different mechanisms of hepatotoxicity, at one third of the cytotoxic concentration TC50, i.e. acetaminophen, cyclophosphamide, clofibrate, chlorpromazine, lithocholic acid, cisplatin, diclofenac and disulfiram. The types of transcriptional changes observed in this study were generally consistent with previously reported in vivo data, although there were some differences. In hierarchical cluster analysis, drugs formed clusters depending on their mode of toxicity against cells. The number of transcripts affected by the cholestatic hepatotoxicants (lithocholic acid and chlorpromazine) or the drugs that rarely cause of hepatotoxicity (cisplatin, diclofenac and disulfiram) were limited compared with the other drugs (acetaminophen, clobifibrate and cyclophosphamide), where they did not induce transcriptional changes apparently related to toxicity. It is concluded that in vitro gene expression analysis of hepatocytes using microarray is a useful tool for evaluating the toxicological profile of drugs and in screening for the direct toxicity of drugs against hepatocytes.
In experimental animals, diethyldithiocarbamate as well as carbon disulfide exert antihepatotoxic effects in different models of chemically-induced liver injury like carbon tetrachloride, chloroform, bromobenzene, dimethyl nitrosamine, furosemide, D-galactosamine, paracetamol, thioacetamide and trichloroethylene. On the other hand, both dithiocarb and CS2 are strong inhibitors of the microsomal mixed-function oxidase system which is involved in the bioactivation of these hepatotoxic agents. It is concluded that CS2 and CS2-producing agents as dithiocarb and disulfiram may inhibit metabolism of other xenobiotics and, thereby, not only protect against various hepatotoxic compounds that require bioactivation but also affect efficacy and duration of action of many drugs.
The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81-69% (p = 0.007).
Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04).
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Postoperative complications requiring treatment within the first month after surgery. Perioperative immunosuppression measured by delayed type hypersensitivity; myocardial ischaemia and arrhythmias measured by Holter tape recording; episodes of hypoxaemia measured by pulse oximetry. Response to stress during the operation were assessed by heart rate, blood pressure, serum concentration of cortisol, and plasma concentrations of glucose, interleukin 6, and catecholamines.
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The effects of cephem antibiotics and their related compounds on aldehyde dehydrogenase obtained from rat liver mitochondria were studied. A pH of 8.8 and reaction temperature 24 degrees were the conditions for measurement of enzyme activity. The apparent Michaelis constant Km values for NAD, acetaldehyde and propionaldehyde were 3.8 X 10(-5) M, 4.0 X 10(-5) M and 2.5 X 10(-5) M, respectively. Cefamandole, cefoperazone and cefmetazole, having a 1-methyl-5-thiotetrazol group at position 3 of the cephem ring, caused a relatively potent inhibition of aldehyde dehydrogenase. Cefmetazole and cefoperazone also showed a significant inhibition on highly purified yeast aldehyde dehydrogenase; the extent of inhibition on yeast enzyme was almost the same as that on rat mitochondrial aldehyde dehydrogenase. The decrease in enzyme activity effected by 1-methyl-1H-tetrazol-5-thiol (MTT) was greater than those of 1H-tetrazol (TZ), 1H-tetrazol-5-thiol and 1-(2-dimethylaminoethyl)-1H-tetrazol-5-thiol, but was, of course, less than that of disulfiram. Cefamandole, cefmetazole and MTT showed competitive inhibition with NAD, while TZ was uncompetitive inhibitor with respect to both NAD and acetaldehyde. Enzyme inhibition caused by disulfiram, cefmetazole and MTT increased time-dependently and the addition of 2-mercaptoethanol into the medium effectively and completely restored enzyme inhibition. These results suggest that thiol group at position 5 of 1H-tetrazol ring is responsible for the type of inhibition with NAD, and methyl group at position 1 of 1H-tetrazol ring is important to exhibit a potent inhibition on aldehyde dehydrogenase.
Individuals with alcohol use disorders (AUDs) have deficits in cognitive control, but how they change with treatment is unclear. Seven patients with AUD and anxiety from an open-label trial of disulfiram plus lorazepam performed a multisensory Stroop task during fMRI (both pre and post initiation of treatment), and were compared to nine healthy controls (HCs) (n = 16; Albuquerque, NM; years 2009-2012). Evoked BOLD signal and resting state functional connectivity were compared (HC vs. AUD; Scan 1 vs. Scan 2). AUD demonstrated hyperactivity and altered connectivity in the cognitive control network compared to HC, but treatment did not normalize function.
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The levels of high molecular weight (HMW) kininogen and pre-kallikrein in rat plasma were markedly reduced after single injection of bromelain (10 mg/kg, i.v.) and gradually recovered over a 72 hour period. The level of low molecular weight (LMW) kininogen, however, was not changed during this period. Rat pleurisy was induced by intrapleural injection of lambda-carrageenin. The levels of HMW kininogen and prekallikrein, but not of LMW kininogen, in the exudate were markedly decreased, when compared with those in plasma of the same animals. After pretreatment with disulfiram, oral administration of ethanol (2 g/kg) or intravenous injection of acetaldehyde (10 mg/kg) to rats caused significant decrease in the plasma level of LMW kininogen with no significant effect on the plasma HMW kininogen and prekallikrein levels. These results suggest that HMW and LMW kininogens may be consumed separately in vivo and play different roles.
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A low frequency stimulation of the head of the caudate nucleus in freely moving cats leads to an arrest of reactions with an increased muscular tone and tremor. This reaction may serve as an experimental model of one of the expressions of parkinsonism, inasmuch as its accomplishment depends upon the central dopaminergic mechanisms (confirmed on experiments with disulfiram and alpha-methyltyrosine). The similarity is also supplemented by the fact that the arrested reaction is weakened by antiparkinson drugs (d, 1-amphetamine, DOPA, artane) and is increased by neuroeptical preparation (aminazine, haloperidol, reserpine).
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In a single-blinded, randomized placebo-controlled study, we recruited 109 patients diagnosed with alcohol dependence under ICD-10 criteria. The patients were randomly allocated to 4 treatment groups, depending on whether they took disulfiram (200 mg daily) or a placebo or whether they received adjunctive therapy consisting of mailed letters which delineated and emphasized the harmful effect of alcohol and the management of alcohol craving. The proportion of abstinence among the 4 groups at 26 weeks after discharge was the primary outcome measure. The proportion of abstinence was compared with the severity of alcohol dependence and craving. Furthermore, we examined the proportion of abstinence in patients with inactive aldehyde dehydrogenase-2 (ALDH2).
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The disposition of chlordiazepoxide, diazepam, oxazepam and lorazepam was studied before and after disulfiram administration to normal subjects and alcoholic patients. Similar studies to determine the effect of ethanol administration on diazepam and oxazepam disposition were also performed. After disulfiram, decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05; diazepam, 41% p < 0.05) and their active metabolites were observed. Oxazepam and lorazepam have no important active metabolites and the effect of disulfiram on their net disposition was minimal. In normal subjects ethanol (> 800 mg/l maintained for 8 h) increased the AUC free diazepam (26.6 +/- 17.3% mean +/- SD, p < 0.05) and decreased the AUC for N-desmethyldiazepam (50.5 +/- 11.7%, p < 0.05) indicating inhibition of diazepam N-desmethylation. In contrast, there was no significant change in the disposition of oxazepam in four healthy subjects after a single oral dose of ethanol. Thus, disulfiram and ethanol appear not to inhibit the metabolic disposition of oxazepam or lorazepam, benzodiazepine derivatives principally biotransformed by glucuronidation. On pharmacokinetic grounds oxazepam and lorazepam may be the drugs of choice if benzodiazepine therapy is required in chronic alcoholics.
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The interaction between the alcohol assumption and industrial chemicals may be toxicokinetic or toxicodynamic. Alcohol can interfere in the processes of biotransformation of xenobiotics and modify the doses and the effect indicators used for the biological monitoring, causing wrong interpretations of the results. The metabolism of ethanol can be altered by the exposures to toxic industrial materials, creating some clinical pictures of alcohol intolerance, like an "antabuse syndrome" or an "degreaser flush syndrome". Professional exposure to carbon sulfide or to dimethylformamides, trichloroethylene as well as to nitroglycerin and nitroglycole ethylenic can produce similar syndromes. Interactions are reported between alcohol and solvents: on toxicokinetic bases for methanol, isopropanol, glycol ether, trichloroethylene, methyl ethyl ketone and toluene; and on toxicodynamic bases for CNS. Also between alcohol and metals there can occur toxicokinetic interactions, like in the case of lead and mercury. Alcohol can also interfere with the biological monitoring of solvents, producing an over-estimation of the exposure.
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In this largest cost study to date of alcohol pharmacotherapy, patients who received medication had lower healthcare utilization and total costs than patients who did not. XR-NTX showed an advantage over oral medications in treatment persistence and healthcare utilization, at comparable or lower total cost.
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An ex vivo model was established which allows the testing of drugs on lens epithelial cell ablation. Drug treatment reduced the number of viable cells on the specimens drastically, ranging between 0.44 ± 0.53% (6.0 ± 7.3 cells/mm²) for disulfiram, 0.27 ± 0.50% (3.7 ± 6.9 cells/mm²) for methotrexate and 0.07 ± 0.19% (0.1 ± 0.27 cells/mm²) for actinomycin D. Rabbit eyes treated with a mixture of methotrexate/actinomycin D showed no posterior capsule opacification at 4 months and a low opacification 6 months postoperatively. Without drug treatment low opacification starts 6 weeks postoperatively.
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Alcohol dependence is a widespread, chronic disorder with enormous health consequences. Psychological and behavioral therapies have been the mainstay of treatment and are demonstrated to be effective, but they do not lead to reduced drinking or abstinence in all patients. Advances in neurobiology have led to the identification of drug targets and the development of novel drugs to treat alcohol dependence, and many patients will benefit from the addition of pharmacotherapy to their treatment regimen. Pharmacologic treatment options for use in conjunction with psychotherapy include the aversion-based therapy disulfiram, the opioid receptor antagonist naltrexone, and acamprosate, which is thought to act by normalizing the glutamate and gamma-aminobutyric acid neurotransmitter systems. The effectiveness of pharmacotherapies depends on adherence, which is often poor in alcohol-dependent patients. Recently, a monthly, extended-release formulation of naltrexone has been approved for alcohol dependence, which promises to minimize nonadherence, a problematic factor in the management of alcohol dependence.
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Hepatitis serologies and baseline transaminase levels were obtained for 57 male alcoholics starting treatment with disulfiram. Sequential liver function test results were obtained for up to 12 weeks while subjects took disulfiram.
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Acetaldehyde is the first and principal metabolite of ethanol administered systemically. To its rise in blood, after administration of disulfiram, is ascribed the aversive reaction that should discourage alcoholics from drinking. In the present study, we sought to determine the effect of acetaldehyde on the electrophysiological properties of dopamine (DA)-containing neurons in the ventro tegmental area (VTA) of rats in vivo. Intravenous (i.v.) administration of acetaldehyde (5-40 mg/kg) readily and dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. Ethanol (250-1000 mg/kg/i.v.) administration produced similar increments in electrophysiological parameters. In addition, a second group of rats was pretreated with the alcohol-dehydrogenase inhibitor 4-methyl-pyrazole (90 mg/kg) intraperitoneally (i.p.), and ethanol and acetaldehyde were administered i.v. at the same doses, 48 h later. In this group, ethanol effects were drastically reduced and the firing rate, spikes/burst, and burst firing were not significantly altered. In contrast, acetaldehyde fully retained its capacity to stimulate electrophysiological indices. The results indicate that acetaldehyde produces electrophysiological actions on VTA neurons in vivo, similar to those produced by ethanol, and significantly participate in ethanol-induced increment in DA neuronal activity. These results also suggest that acetaldehyde, by increasing DA neuronal activity in the VTA, may significantly contribute to the centrally mediated positive motivational properties of ethanol, which would oppose the well-known peripherally originating aversive properties.
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The oral administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of TNF-α, NO, and PGE2 in the aqueous humor and improved the histiologic status of the ocular tissue. The expression of activated NF-κB-positive cells in the ICB was significantly inhibited by oral administrated with DSF 3 hr after the LPS injection. The LPS-induced increased expressions of iNOS and COX-2 proteins in the ICB were also inhibited by oral DSF 24 hr after LPS injection.
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We have reported previously that diethyldithio-carbamate (DDC) and pyrrolidine dithiocarbamate (PDTC) induce apoptosis in rat thymocytes. Apoptosis was shown to be dependent upon the transport of external Cu ions into the cells and was accompanied by the oxidation of intracellular glutathione, indicating the inducement of pro-oxidative conditions (C. S. I. Nobel, M. Kimland, B. Lind, S. Orrenius, and A. F. G. Slater, J. Biol. Chem. 270, 26202-26208, 1995). In the present investigation we have examined the chemical reactions underlying these effects. Evidence is presented to suggest that dithiocarbamates undergo oxidation by CuII ions, resulting in formation of the corresponding thiuram disulfides, which are then reduced by glutathione, thereby generating the parent dithiocarbamate and oxidized glutathione (glutathione disulfide). Although DDC and PDTC were found to partially stabilize CuI ions, limited redox cycling of the metal ion was evident. Redox cycling did not, however, result in the release of reactive oxygen species, which are believed to be scavenged in situ by the dithiocarbamate. DDC and PDTC were, in fact, shown to prevent copper-dependent hydroxyl radical formation and DNA fragmentation in model reaction systems. The thiuram disulfide disulfiram (DSF) was found to induce glutathione oxidation, DNA fragmentation, and cell killing more potently than its parent dithiocarbamate, DDC. Of particular importance was the finding that, compared with DDC, the actions of DSF were less prone to inhibition by the removal of external copper ions with a chelating agent. This observation is consistent with our proposed mechanism of dithiocarbamate toxicity, which involves their copper-catalyzed conversion to cytotoxic thiuram disulfides.
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The use of a number of antibiotics which contain an N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of hypoprothrombinemia. The suggested role of NMTT as an inhibitor of the liver microsomal vitamin K-dependent carboxylase has been investigated. In standard incubations, NMTT had no effect on carboxylation when vitamin KH2 was a substrate but was a weak inhibitor when [vitamin K + NADH] was a substrate. Microsomal vitamin K reductases, however, were not inhibited by NMTT. Preincubation of the incubation mixture with NADH and NMTT resulted in inhibition of carboxylase activity when either vitamin KH2 or [vitamin K + NADH] was the substrate. A fraction of the microsomal membrane which was not readily solubilized by dilute detergent protected the enzyme from this inhibition. The data suggest that NMTT is metabolized to an active inhibitor or is able to covalently inactivate the enzyme in the presence of NMTT. The vitamin K responsiveness of the clinically observed hypoprothrombinemia suggests that it is not related to this in vitro inhibition of the vitamin K-dependent carboxylase.
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Alcohol abusers have suppressed cellular immune function. The aim of the study was to investigate the time of sobriety required to normalize immune function. Delayed hypersensitivity was investigated during disulfiram controlled abstinence in ten heavy alcoholics and in seven moderate drinkers without liver diseases. For comparison a control group of eight previous drinkers was tested. The skin test responses were modest initially with a median area of response of 12 mm2 (range 0-31) in the heavy alcoholics and 3 mm2 (0-15) in the moderate drinkers. It improved significantly in both groups after two weeks of sobriety. The responses stabilized after 8 weeks at 74 mm2 (54-102) in the heavy alcoholics and after 9 weeks at 63 mm2 (42-76) in the moderate drinking group. The control group had skin test responses of 70 mm2 (46-87), not different from the responses of the alcohol groups after two months of abstinence. The results suggest that while 2 weeks of abstinence from alcohol will improve the depressed cellular immunity, 2 months of sobriety is necessary to normalize it.
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The influence of a 28-week treatment with disulfiram (DSF), D-penicillamine (PA), and nitrosodiethylamine (NDEA), as well as with a combination of DSF or PA with NDEA on the concentrations of eight essential trace elements in the whole liver tissue of rats was measured by means of neutron activation analysis. While NDEA treatment lowered the Zn content of the liver, DSF alone or in combination with NDEA enhanced the Zn and Se concentration by 50%-80%. Co, Cu, and Cd levels were increased by factors of 10, 60, and 110, respectively. The Mo concentration was decreased by 50% after DSF administration. PA reduced Cu, Co, and Zn in the liver. PA/NDEA treatment also lowered Cu, Co, and Zn content, but there was no strengthening effect of PA on the decrease in Zn observed with NDEA. The change of trace element concentrations, especially of Cu, is discussed with regard to the observed tumor induction in the liver, which tended to be increased by a combined NDEA/PA administration compared with NDEA treatment alone, whereas a protective action of DSF against NDEA induced liver tumors could not be established.
The use of combination chemotherapy is the accepted standard for most human malignancies but little attention has been paid to drug interactions. A combination of drugs may be synergistic, additive, or antagonistic in cytotoxic activity. This study evaluated combinations of agents with docetaxel, one of the most active agents in human breast cancer, using a median effects model to look at synergy or antagonism in vitro as a potential predictor of clinical outcome. Three human breast cancer cell lines, MCF7/wt, MCF7/adr (multiply drug resistant), and BT474 were grown to confluence, plated into 96 well dishes, and incubated with combinations of drugs for 72h. Cytotoxic effect was measured by the MTT assay. Median effect analysis was used to calculate the combination index (CI) with values less than 1 indicating synergism, 1 additive effects, and greater than 1 antagonism. Potentially useful combinations for clinical study which were identified included docetaxel with vinorelbine, docetaxel with dexrazoxane, docetaxel with cis-retinoic acid, docetaxel with disulfiram and either doxorubicin or epirubicin, and docetaxel with dexrazoxane and epirubicin.
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The identification of genes inducing resistance to anticancer chemotherapeutic agents and their introduction into hematopoietic cells represents a promising approach to overcome bone marrow toxicity, the limiting factor for most high-dose chemotherapy regimens. Because resistance to cyclophosphamide has been correlated with increased levels of expression of the aldehyde-dehydrogenase (ALDH1) gene in tumor cell lines in vitro, we tested whether ALDH1 overexpression could directly induce cyclophosphamide resistance. We have cloned a full-length human ALDH1 cDNA and used retroviral vectors to transduce it into human (U937) and murine (L1210) hematopoietic cell lines that were then tested for resistance to maphosphamide, an active analogue of cyclophosphamide. Overexpression of the ALDH1 gene resulted in a significant increases in cyclophosphamide resistance in transduced L1210 and U937 cells (50% inhibition concentration [IC50], approximately 13 mumol/L). The resistant phenotype was specifically caused by ALDH1 overexpression as shown by its reversion by disulfiram, a specific ALDH1 inhibitor. ALDH1 transduction into peripheral blood human hematopoietic progenitor cells also led to significant increases (4- to 10-fold; IC50, approximately 3 to 4 mumol/L) in cyclophosphamide resistance in an in vitro colony-forming assay. These findings indicate that ALDH1 overexpression is sufficient to induce cyclophosphamide resistance in vitro and provide a basis for testing the efficacy of ALDH1 gene transduction to protect bone marrow cells from high-dose cyclophosphamide in vivo.