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Both human and animal studies relating to the combined effects of alcohol and benzodiazepine (BZD) are reviewed. Although the combination of alcohol and BZD is sometimes associated with drug-induced deaths, drug overdoses and traffic accidents or fatalities, epidemiological information is lacking on the true extent of the combined abuse and on the patterns and prevalence of use of these two drugs. Since BZD are widely used for the short- and long-term treatment of alcoholics, these patients are deemed more at risk of developing BZD or alcohol/BZD dependence than the general population. There is a dire need for large-scale controlled studies concerning the efficacy of BZD in the long-term treatment of alcoholics. Compared to men, women are at a higher risk as far as the potential for BZD addiction is concerned, since they tend to use BZD more often. Epidemiologic studies on the patterns of use of BZD, alcohol or alcohol/BZD in pregnant women are called for. Animal models are also needed to ascertain whether prenatal exposure to both alcohol and BZD can impart long-lasting behavioral changes in the progeny. It is possible that BZD can exacerbate the damaging prenatal effects of alcohol.
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Hypotensive action of a new dopamine beta-hydroxylase (DBH) inhibitor, 5-(4'-chlorobutyl)picolinic acid (FD-008) was investigated in dogs and rats. FD-008, which is one of the most potent inhibitors among fusaric acid derivatives, decreased blood pressure in spontaneously hypertensive rats relatively parallel to DBH inhibition in vitro. The effect of FD-008 on blood pressure was stronger in hypertensive rats than in normotensive rats. No cumulative effect was observed in rats by repeated administration, On the other hand, repeated administration was required to lower blood pressure in normotensive dogs. The acute effect of FD-008 on blood pressure of anesthetized dogs was somewhat different from that of its mother compound, fusaric acid.
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Given the poor prognosis of glioblastoma, we have been investigating treatments adjunctive to the current standard of resection, irradiation and temozolomide. Our focus has been on exploring already-marketed medicines that have evidence of inhibiting growth factors previously identified as active and important in glioblastoma. In this short note we describe how previous research has demonstrated that the common angiotensin-converting enzyme (ACE) inhibitor captopril used to treat hypertension and for renal protection inhibits 72-kDa matrix metalloproteinase-2 and 92-kDa matrix metalloproteinase-9, which a separate body of research shows are used by glioblastoma cells to grow and invade. We review these bodies of data and combine them to conclude that captopril may slow glioblastoma progression. Two other drugs, the aldehyde dehydrogenase inhibitor disulfiram used to treat alcoholism and the anti-HIV protease inhibitor nelfinavir also have a database supporting their incidental inhibition of matrix metalloproteinases. Given the importance of matrix metalloproteinases in helping glioblastomas grow and invade, we suggest that this trio-captopril, disulfiram, and nelfinavir-be tested for antiglioblastoma activity.
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Relapse was defined as any alcohol consumption between discharge from the hospital and 3-month follow-up.
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Acute, oral administration of 7.0 mg/kg calcium carbimide (calcium cyanamide) to rats, 2 h before sacrifice, produced complete inhibition of hepatic, low-Km (less than 1 microM acetaldehyde) mitochondrial and cytosolic aldehyde dehydrogenase enzymes and significantly inhibited high-Km (approximately 1 mM acetaldehyde) mitochondrial, cytosolic, and microsomal aldehyde dehydrogenase isozymes. Calcium carbimide had no effect on several other hepatic enzyme activities including mitochondrial glutamate dehydrogenase and monoamine oxidase, cytosolic alcohol dehydrogenase, microsomal NADPH-cytochrome c reductase, benzo[a]pyrene hydroxylase and aminopyrine N-demethylase activities, and microsomal cytochrome P-450 content. It is concluded that calcium carbimide is a more specific inhibitor of hepatic aldehyde dehydrogenase enzymes than disulfiram.
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Human erythrocyte aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 188.8.131.52) was purified to apparent homogeneity. The native enzyme has a molecular weight of about 210,000 as determined by gel filtration, and SDS-polyacrylamide gel electrophoresis of this enzyme yields a single protein and with a molecular weight of 51,500, suggesting that the native enzyme may be a tetramer. The enzyme has a relatively low Km for NAD (15 microM) and a high sensitivity to disulfiram. Disulfiram inhibits the enzyme activity rapidly and this inhibition is apparently of a non-competitive nature. In kinetic characteristic and sensitivity to disulfiram, erythrocyte aldehyde dehydrogenase closely resembles the cytosolic aldehyde dehydrogenase found in the liver of various species of mammalians.
Thiocarbamates are chemicals widely used as pesticides. Occupational exposure is associated with acute intoxication. Populations can be exposed through food and water. Moreover, certain thiocarbamates are used clinically. The widespread use of thiocarbamates raises many issues regarding their toxicological and pharmacological impact.
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The thresholds for pentylenetetrazol and lidocaine-induced clonic convulsions were significantly influenced by manipulation of brain biogenic amines. Pretreatment with inhibitors of monoamine synthesis, alpha-methyl-p-tyrosine and p-chlorophenylalanine, caused significant decreases in brain monoamine contents and pentylenetetrazol seizure threshold, while the threshold for lidocaine-induced convulsions was significantly increased by either treatment. Moreover, the inhibitor of dopamine-beta-hydroxylase, disulfiram, caused significant decrease in brain noradrenaline (NA) and significant increase in brain dopamine (DA) contents. The threshold for pentylenetetrazol-induced convulsions was decreased by treatment with disulfiram, while that of lidocaine was increased by the same treatment. Furthermore, treatment with L-dihydroxyphenylalanine (L-DOPA) caused significant increase in brain DA contents, while 5-hydroxytryptophan (5-HTP) treatment caused significant increase in brain 5-hydroxytryptamine (5-HT) contents, but the thresholds for lidocaine and pentylenetetrazol-induced convulsions were not influenced by either treatment. These results may suggest that the brain monoaminergic systems, different from their ability to inhibit control of pentylenetetrazol seizures, act to potentiate lidocaine-induced convulsions.
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Although disulfiram has been used in the treatment of alcoholism due to the unpleasant sensations its concomitant ingestion with ethanol provokes, some patients reported stimulant effects after its ingestion. This issue has not been addressed in studies with animals. In mice, the stimulant effect of ethanol has been associated with increased locomotor activity and behavioural sensitization. This study sought to analyze the influence of disulfiram on the development of behavioural sensitization to the stimulant effect of ethanol.
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This paper has examined the possibilities of applying significant pharmacologic help to a variety of psychiatric problems that may accompany narcotic addiction. It has been shown that many of the patients do have such difficulties, with affective disorders being most common. As far as the various psychotropic drugs are concerned, neuroleptics for schizophrenia and lithium for manic disorders are generally agreed upon. A more extensive trial of lithium in a variety of situations seems indicated. Minor tranquilizers for anxiety and MAO-inhibitors for depression are both seen as problematic in this population--the former because of the possibility of abuse, the latter because of the danger of drug interaction associated with the addict's careless lifestyle. Tricyclic antidepressants may clearly have a role in treating major depression in opiate addicts on or off methadone, but the lability of the syndrome over time with frequent spontaneous remission argues against their routine use until it is clear that depression has persisted 3-6 months into methadone. Disulfiram appears to be a useful adjunct for drug abusers with serious alcohol problems. Psychotropic agents are most helpful to opiate addicts when used to treat coexisting psychopathology. While there is no clear evidence that such agents will reduce or affect the addiction itself, they may help keep patients available for rehabilitation efforts. Failure to intervene may make treatment dropout and recidivism more likely. Given the relative frequency of potentially treatable psychiatric disorders in these patients and the consequences of undiagnosed and untreated conditions, it is important for clinicians to maintain a high index of suspicion for concomitant psychiatric illness and for programs to have a mechanism for routinely diagnosing either all patients or, at a minimum, all patients not doing well. If programs used a standard instrument such as the SADS, it would be possible to compare various programs on this factor; in addition, it would provide a rich source of data for outcome studies.
The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not yet been established. Multiple-dosage absorption pharmacokinetics of lopinavir/ritonavir 400/100mg twice daily (the mean peak [C(max)] and trough [C(trough)] plasma concentrations at steady-state and the 12-hour area under the plasma concentration-time curve [AUC(12)] of either drug) were stable in antiretroviral therapy-naive and single PI-experienced adult patients receiving therapy over a 24-week evaluation period. The C(trough) values of lopinavir, achieved with lopinavir/ritonavir 400/100mg twice daily, were median 84-fold higher than the protein binding-adjusted 50% effective concentration (EC(50)) of lopinavir against wild-type HIV-1 in antiretroviral therapy-naive HIV-1-infected patients in a phase II study. Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content. At steady state, lopinavir is approximately 98-99% plasma protein bound and the percentage of its unbound (i.e. pharmacologically active) fraction is dependent on total drug plasma concentration. Both lopinavir and ritonavir penetrate poorly into the human genital tracts and the cerebrospinal fluid. Both agents undergo extensive and rapid first-pass metabolism by hepatic cytochrome P450 (CYP) 3A4 isoenzyme. However, ritonavir also potently inhibits this enzyme and acts as a pharmacokinetic enhancer of lopinavir. The elimination half-life and apparent oral clearance of lopinavir average approximately 4-6 hours and approximately 6-7 L/h, respectively, with lopinavir/ritonavir 400/100mg twice daily administration. Less than 3% and 20% of the lopinavir dose is excreted unchanged in the urine and faeces, respectively. Limited data show similar pharmacokinetics of lopinavir in children as in adults.
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Six studies that randomized patients to drugs versus placebo and also made complaint/noncompliant determinations were reviewed to document the main effects of compliance on health outcome. While the studies varied in terms of demonstrating a main effect of drugs, in five of six cases a main statistical effect of compliance was observed. Possible mechanisms for this effect are briefly noted.
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Evidence from decades of research suggests psychological effects as principal mode of action of supervised disulfiram. Future randomized controlled trials are needed that investigate psychological actions and long-term outcomes of this alcohol deterrent.
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Adverse drug-drug interactions can occur between active and/or inactive ingredients in different formulations. The occurrence of a disulfiram reaction that developed postpartum following a 7-day course of metronidazole is presented. The case is presented, followed by a discussion of the mechanism of action and treatment. Recommendations for prevention of adverse drug effects are reviewed.
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Breath samples were taken from two groups of alcohol-dependent patients, one group on a daily disulfiram regimen and one group receiving no disulfiram. The breath samples were analysed for the combined concentration of carbon disulphide and acetone produced from the metabolism of disulfiram. From these data, two reference ranges were prepared and used for sensitivity and specificity assessments.
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Recent and proposed decreases in federal funding in support of publicly funded detoxification facilities and increased costs of inpatient detoxification will predictably lead to family physicians being faced with the problem of alcohol detoxification for many of their patients. Outpatient detoxification is possible in the majority of cases provided that good initial screening is accomplished and strong supportive resources exist. The ambulatory route is frequently not considered when examining mechanisms for the withdrawal of individuals from alcohol. The literature and experience indicate that, except in a small number of cases which can be adequately screened during the admission process, outpatient withdrawal can be an effective mechanism. Outpatient withdrawal must be considered not only by family physicians operating in the absence of alcohol support programs but also by alcohol treatment programs as a cost-effective alternative to many of the more expensive means of detoxifying alcoholic patients.
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The alcohol deterrent drug disulfiram plays a minor role in the treatment of alcohol dependency in Germany. The study looks at the efficacy, tolerability and feasibility of a disulfiram outpatient treatment program in a German psychiatric hospital.
Sixteen habitual drunken offenders agreed to take disulfiram in liquid form under supervision as a condition of a probation order. They knew that failure to take medication, as with failure to observe any other condition of probation, could result in their being returned to court. Three defaulted but only two of the remainder committed further offences. Nine were entirely successful. At the end of the study the average period of abstinence for the whole group was 30 weeks compared with six weeks during the previous two years. Nine risked drinking alcohol but none suffered any serious consequences or side effects. This technique may be a judicially acceptable and more hopeful alternative to prison for these offenders.
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Seventeen detoxified alcoholics were randomly assigned to a waiting list group or an inpatient treatment group. The waiting list group members were informed that they had to wait some time until there was a vacant place. By their discharge from the Detoxification Unit they were told to complete a self-report form every day with regards to drinking, working, sleeping home and use of disulfiram orally. Two weeks later they had an outpatient appointment in which the self-reports were collected and reviewed. This was repeated once for everybody so that they all had to wait 4 weeks. By discharge from further inpatient treatment, the inpatient treatment group was instructed to record the same four behaviors daily as the waiting list group did, and they, too, got an outpatient appointment with a 2 week interval. No significant differences between the groups were observed in the three main variables of drinking, working and sleeping home, but the waiting list group used significantly more disulfiram than the inpatient treatment group.
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A reversible toxic liver damage was observed in a non-alcoholic woman treated with disulfiram. The causative relationship was proven by challenge.
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Influence of 5-hydroxytryptophan (5HTP) and disulfiram on a reaction of emotional resonance (RER) was studied in two groups of female rats: I--with good and II--with poor elaboration of RER and, correspondingly, with the minimal and the maximal time of stay in the dark compartment. One week after 5HTP injection good elaboration of RER in animals of the I group was substituted for poor. In the II group of animals RER was unchanged. Injection of disulfiram increased the stay in the dark compartment in the I group and decreased it in the II group. At the same time dopamine content in the midbrain and medulla increased. The results confirm the hypothesis on participation of monoamines and their different contribution in RER realization in different groups of animals.
Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.