Oral Disulfiram Research Articles

Effects and Mode of Action of Oleic Acid and Tween 80 on Skin Permeation of Disulfiram.

Oral disulfiram (DSF) has been used clinically for alcohol dependence and recently has been found to have antitumor activity. A transdermal delivery system would be useful for maintaining drug concentration and reducing the frequency of administration of DSF for cancer treatment. Penetrating the stratum corneum (SC) barrier is a challenge to the transdermal delivery of DSF. Therefore, we investigated the promoting effects and mechanism of action of the combination of oleic acid (OA) and Tween 80 on the skin permeation of DSF. Hairless mouse skin was exposed to OA and Tween 80, combined in various ratios (1 : 0, 2 : 1, 1 : 1, 1 : 2, and 0 : 1). A permeation experiment was performed, and total internal reflection IR spectroscopic measurements, differential scanning calorimetry, and synchrotron radiation X-ray diffraction measurements were taken of the SC with each applied formulation. The combination of OA and Tween 80 further enhanced the absorption-promoting effect of DSF, compared with individual application. The peak of the CH2 inverse symmetric stretching vibration near the skin surface temperature was shifted by a high frequency due to the application of OA, and DSF solubility increased in response to Tween 80. We believe that the increased fluidity of the intercellular lipids due to OA and the increased solubility of DSF due to Tween 80 promoted the absorption of DSF. Our study clarifies the detailed mechanism of action of the skin permeation and promoting effect of DSF through the combined use of OA and Tween 80, contributing to the development of a transdermal preparation of DSF.

FORMULATION AND EVALUATION OF IMPLANTABLE DRUG DELIVERY OF DISULFIRAM

Disulfiram is widely prescribed to discourage alcoholics from drinking alcohol. The effectiveness of oral disulfiram as a treatment for alcoholism is severely limited due to its poor bioavailability and poor patient compliance. To minimize the failure of the orally administered drug, efforts have been made to prepare alternative dosage form of subcutaneously implantable disulfiram pellets or tablets. In the present study an attempt has been made to design and evaluate a disulfiram implant using plain drug. The disulfiram implants have been formulated by direct compression and the effect of parameters like pH of site of administration (6.0 and 7.4) and sterilization were studied on in-vitro release of implantable disulfiram pellets. In- vitro release has been studied by vial and rotary flask shaker methods. The release kinetic mechanism from all the formulation was found to be zero order. The in vitro release data of all the formulations was compared with that of marketed disulfiram implant (Esperal). In contrast to other formulation in vitro release from marketed formulation appeared to be independent of hydrodynamics of diffusion (volume of dissolution media and agitation speed). The present study had revealed that, in-vitro drug release from implants is unaffected by pH of site of administration and gamma ray sterilization. Both the methods (Vial Method & Rotating Flask Method) of in vitro dissolution testing are found significantly different for formulations prepared in laboratory but not for marketed formulation, indicating the different mechanism of release of marketed formulation.

A nano-enclatherated-gel-composite for the treatment of alcohol abuse and addiction

Alcoholism is a highly prevalent disease, with successful rehabilitation being poor due to irrepressible cravings that result in relapse. This study developed and analysed an intramuscular injection capable of providing a sustained release of disulfiram over one month. Statistically optimized disulfiram-loaded nanomicelles were prepared and incorporated into a thermosensitive gel resulting in a nano-enclatherated-gel-composite (NEGC). The nanomicelle system demonstrated a drug loading capacity and entrapment efficiency of 33.66% and 50.98%, respectively, with a sustained release of 65% of the administered disulfiram achieved after 28 days through the thermosensitive hydrogel. Additionally, ex vivo release studies have been undertaken using rat muscle tissue with in vivo biodistribution, plasma levels, histopathology and myotoxicity following oral disulfiram administration and intramuscular NEGC administration also assessed in Sprague-Dawley rats. Results obtained in this study have indicated that the designed delivery system has the potential to successfully release disulfiram in a sustained manner for the treatment of alcohol abuse.

Concurrent use of alcohol and cocaine: which is the best drug choice?

IntroductionPatients with comorbid cocaine and alcohol dependence have a worse prognosis with lack of adherence to follow-up and treatment, frequent psychosocial problems, and higher rates of relapse [1]. Concurrent use of both substances produces cocaethylene, which is associated with more toxicity than cocaine alone [2].ObjectivesTo determine the efficacy of disulfiram compared to nalmefene in the treatment of comorbid cocaine and alcohol use.MethodsA quasi-experimental open study was designed on 41 outpatients, with a follow-up of at least 1 year at the Mental Health Unit, aged between 18 and 65 years, diagnosed with cocaine and alcohol dependence (ICD-10). A minimum simultaneous weekly consumption of 2 grams of cocaine and 12 SD (Standard Drink) of alcohol during the month before, described by self-records was established. Treatment with oral disulfiram 250mg/day was assigned to 21 patients, and with oral nalmefene 18mg/day to 20 individuals. Observation period was for 6 months. Urinalysis and alcohol breath test were carried out twice a week. Abstinence was defined by obtaining negative results for at least 4 consecutive weeks. Statistical analysis were performed using SPSS v21.0 (significance p<0.05).Results61.9% of patients treated with disulfiram achieved a minimum of 4 consecutive weeks of abstinence from cocaine and alcohol, compared to 40% in the nalmefene group (χ²=1.188; gl=1; p=0.276). There were no significant differences.ConclusionsDisulfiram or nalmefene monotherapy seems clinically ineffective or insufficient in reducing the combined use of cocaine and alcohol. Further research is needed to assess the effect of both drugs simultaneously.DisclosureNo significant relationships.

Increased Permeability-Glycoprotein Inhibition at the Human Blood–Brain Barrier Can Be Safely Achieved by Performing PET During Peak Plasma Concentrations of Tariquidar

The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar. Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min. Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects.

SY18-2 * EFFICACY OF DISULFIRAM FOR THE TREATMENT OF ALCOHOL DEPENDENCE ASSESSED WITH A MULTI-CENTER RANDOMIZED CONTROLLED TRIAL

Introduction. The efficacy of disulfiram in preventing an alcoholic relapse has been controversial. The aim of our study was to assess the efficacy of supervised disulfiram for the treatment of alcohol dependence with a multi-institutional study in Japan. Methods. 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 four 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 four groups at 26 weeks after discharge was the primary outcome measure. Furthermore, we examined the proportion of abstinence in patients with inactive aldehyde dehydrogenase-2 (ALDH2). Results. There were no significant differences among the four groups in terms of abstinent patients or study drop-outs. Patients with inactive ALDH2 significantly sustained abstinence with the use of disulfiram (P = 0.044). Conclusions. Supervised oral disulfiram use followed by intervention via letters seems to be ineffective for increasing abstinence. We indicated the effectiveness of disulfiram for the maintenance of abstinence in patients with inactive ALDH2.

Efficacy of Disulfiram for the Treatment of Alcohol Dependence Assessed with a Multicenter Randomized Controlled Trial

The efficacy of disulfiram in preventing an alcoholic relapse has been controversial. The aim of our study was to assess the efficacy of supervised disulfiram for the treatment of alcohol dependence with a multi-institutional study in Japan. 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 (200mg 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 26weeks 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). There were no significant differences among the 4 groups in terms of abstinent patients or study dropouts. The ratio of abstinence was not related to the severity of alcohol dependence or the degree of alcohol craving. Patients with inactive ALDH2 significantly sustained abstinence with the use of disulfiram (p=0.044). Supervised oral disulfiram use followed by intervention via letters seems to be ineffective for increasing abstinence. Further studies are necessary to prove the efficacy of disulfiram for the pharmacological treatment of alcohol dependence. We indicated the effectiveness of disulfiram for the maintenance of abstinence in patients with inactive ALDH2.

A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

BackgroundA majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram–ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AimsThis study examined the safety of combining cocaine (30mg i.v.) and ethanol (0.4g/kg i.v.) in disulfiram-treated (0, 250, and 500mg/d, p.o.) cocaine-dependent research volunteers. ResultsThe results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. ConclusionsThough conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤250mg/d) may not be as problematic as some may assume.

Anti-Inflammatory Potency of Oral Disulfiram Compared with Dexamethasone on Endotoxin-Induced Uveitis in Rats

To investigate potency of oral disulfiram (DSF) compared with that of dexamethasone (Dexa), on endotoxin-induced uveitis (EIU) in rats. The oral administration with 750 mg/kg DSF suppressed the number of inflammatory cells, protein concentration, and levels of tumor necrosis factor (TNF)-α, Nitric oxide (NO) and prostaglandin (PG) E2 in the aqueous humor and improved the histiologic status of the ocular tissue at 24 hr after lipopolysaccharide (LPS) injection. The anti-inflammatory potency of DSF oral administration was as strong as that observed with 0.5 mg/kg Dexa in the present study. The results suggest that DSF might pave the way for a novel therapeutic agent for the management of uveitis.

Inhibitory Effects of Oral Disulfiram on Endotoxin-Induced Uveitis in Rats

Purpose: Disulfiram (DSF) exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the effect of oral DSF on endotoxin-induced uveitis (EIU) in rats.Methods: We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-α (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in the anterior chamber. Some eyes were enucleated for histologic examination and immunohistochemical analysis. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour before the LPS injection, either 250, 500, or 750 mg/kg DSF was administered orally. Twenty-four hours later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-α, NO, and PGE2 were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis in the iris ciliary body (ICB) cells was perfomed to determine the expression of activated nuclear factor kappa B (NF-κB), inducible-nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).Results: 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.Conclusions: The present results indicate that oral DSF suppresses the inflammation in EIU by inhibiting the NF-κB-dependent pathway and the subsequent production of pro-inflammatory mediators.

Disulfiram and low nickel diet in the management of hand eczema: A clinical study

Hand eczema due to nickel sensitivity is a challenging task for the dermatologist. The average human diet provides sufficient amount of nickel, which acts as a provocating factor in nickel-sensitive individuals. When such patients are treated with steroid or other immunosuppressives, only short-term remission is obtained. This is because unless the dietary intake of nickel is minimized and the existing amount of nickel in the body of the sensitized individual is depleted, long-term remission is unlikely. To evaluate the efficacy of oral disulfiram, a nickel-chelating agent and low nickel diet (LND) in reducing the clinical symptoms and preventing frequent relapse of hand eczema in nickel-sensitive individuals. A total of 21 patients with chronic vesicular hand eczema with nickel sensitivity were taken for this study. Patients were randomly divided into two groups: (a) Study group consisting of 11 patients (8 females and 3 males). They were prescribed disulfiram orally for a period of 4 weeks; they started LND 2 weeks prior to initiation of disulfiram therapy and continued till the end of follow-up period. (b) Control (placebo) group consisting of 10 patients (7 females and 3 males). They were allowed to continue with normal diet. Each of them received lactose tablet daily as placebo for 4 weeks. It was a comparative study and participants were not aware if they belonged to study group or control group (single blind trial). Hand eczema healed completely in 10 (90.9%) out of 11 patients treated with disulfiram and LND during the treatment period in the study group, compared with 1 out 10 patients in control (placebo) group (non significant). Mild relapse was noted in 5 patients in between 2-12 weeks of follow-up period. Low nickel diet and short course of oral disulfiram therapy can be considered a good option for the control of chronic hand eczema in nickel-sensitive individuals.

The efficacy of disulfiram: a review of outcome studies

Twenty-four studies of outcome following oral disulfiram and 14 following implanted disulfiram were identified for review from MEDLINE and PsycINFO databases and by manual searching for the period 1967-95. The methodological rigour of these studies was generally poor, albeit not as poor as that of earlier studies (not reviewed here). An overall assessment of the results of research in this field is hampered by the diversity of both the methods used and the subject populations studied. However, it is clear that support for the general use of oral disulfiram is equivocal, mostly being found in the form of reduced quantity of alcohol consumed and a reduced number of drinking days. Evidence for an effect in increasing the proportion of patients who achieve abstinence is surprisingly lacking. Where it is prescribed, disulfiram use should be supervised and it should be employed as one part of a comprehensive treatment programme. There is no good evidence in favour of implanting disulfiram tablets, but the possibility of a depot injection is intriguing.

The efficacy of disulfiram: a review of outcome studies

Twenty-four studies of outcome following oral disulfiram and 14 following implanted disulfiram were identified for review from MEDLINE and PsycINFO databases and by manual searching for the period 1967–95. The methodological rigour of these studies teas generally poor, albeit not as poor as that of earlier studies (not reviewed here). An overall assessment of the results of research in this field is hampered by the diversify of both the methods used and the subject populations studied. However, it is dear that support for the general use of oral disulfiram is equivocal, mostly being found in the form of reduced quantity of alcohol consumed and a reduced number of drinking days. Evidence for an effect in increasing the proportion of patients who achieve abstinence is surprisingly lacking. Where it is prescribed, disulfiram use should be supervised and it should be employed as one pan of a comprehensive treatment programme. There is no good evidence in favour of implanting disulfiram tablets, but the possibility of a depot injection is intriguing.

Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis

SummaryBackground Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.Methods 20 elective surgical patients received either disulfiram (500 mg orally, n=10) or nothing (controls, n=10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1·0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.Findings Total halothane dose, measured by cumulative end-tidal (3·8 SE 0·1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12 900 (SE 1700) and 2010 (440) μmol, respectively (p<0·001) while that of bromide was 1720 (290) and 160 (70) μmol (p<0·001).Interpretation The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.

Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the elimination half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/- 9.9 versus 38.7 +/- 10.3 micrograms/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazone, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1-activated toxins.

A Randomized Phase II Study of Cisplatin Alone Versus Cisplatin Plus Disulfiram

Preclinical evidence has suggested that disulfiram (DS) and related compounds can decrease the toxicity and enhance the therapeutic index of cisplatin (CP). To study this further, we have performed a prospective randomized study wherein 53 patients with CP-sensitive malignancies were assigned to therapy with CP 100 mg/m2 alone (group I) or CP 100 mg/m2 and oral DS 2,000 mg/m2 (group II). Both groups were comparable with regard to sex distribution, age, performance status, prior chemotherapy, and radiotherapy. Twenty-three patients were not evaluable for response (3 refused follow-up, 18 had less than two courses, one had an early death, and one had excessive toxicity during the first cycle of treatment). Of the 30 evaluable patients (16 in group I, 14 in group II), only one in group II achieved a complete response. There was no statistically significant difference in response rate, time to progression, or median survival between the two groups. Fifty-two patients (98.1%) were evaluable for toxicity. Significant differences in toxicities were observed between the two groups: patients in group I encountered lower [Eastern Cooperative Oncology Group (ECOG) 0-1)] grades of nausea, vomiting, and ototoxicity, and patients in group II experienced higher grades (ECOG 2-3) of toxicity in general. In addition, there was no difference in nephrotoxicity between the two groups, as measured by the change in serum creatine or 24-h urine creatinine clearance over the first course of treatment. We conclude that, contrary to previously published reports, DS does not afford significant nephroprotection against CP and, in fact, enhances gastrointestinal and ototoxicities.

Phase I study of the combination of disulfiram with cisplatin.

In light of preclinical evidence that disulfiram and related compounds decrease the toxicity and increase the therapeutic index of cisplatin, 12 patients were treated with a combination of cisplatin and oral disulfiram to determine the maximum tolerated dose of disulfiram that could be combined with cisplatin 100 mg/m2, and to determine the dose-limiting toxicity of disulfiram in this combination. Reversible confusion was the dose-limiting toxicity at a disulfiram dose of 3,000 mg/m2 administered 1 h before the end of a 2-h cisplatin infusion. A randomized study of cisplatin with or without disulfiram 2,000 mg/m2 p.o. is currently being conducted to determine the effect of disulfiram on cisplatin toxicity and pharmacology.

Cisplatin chronotherapy and disulfiram rescue reduce toxicity without interfering with anticancer activity: animal findings and preliminary clinical experiences.

Cisplatin-induced mortality and nephrotoxicity are each predictably worse when the drug is given at certain points within the circadian schedule. Oral disulfiram protects rats from toxic effects at some circadian stages but not others. This manuever does not diminish the anticancer activity of cisplatin in these rats. Human beings given 2 g of oral disulfiram and high doses of cisplatin at the circadian stage associated with least cisplatin nephrotoxicity (prospectively determined potassium excretion acrophase) suffer little or no kidney damage. Disulfiram administration apparently does not interfere with the antineoplastic activity of cisplatin in humans. This is the first demonstration of the feasibility of assignment of treatment time according to a measure of the patient's 'internal clock' as assessed by pretreatment marker rhythmometry. It also establishes the feasibility of giving disulfiram to human beings.

Neurotoxic effects of disulfiram on autonomic nervous system in rat.

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.

The use of disulfiram implantation in alcoholism.

The unpleasant reaction to alcohol experienced by patients taking disulfiram was reported twenty-four years ago (Hald and Jacobsen, 1948; Martensen-Larsen, 1948). For as long as patients continue to take oral disulfiram they may be too afraid to drink. Unfortunately in practice they often discontinue the therapy, and drink with impunity a few days later. Thus a long-acting preparation of disulfiram would be desirable.