Attentional and motivational effects of psychoactive drugs.
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Biomedical subjects
Publications and source records attributed to M Bird.
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3,4-Methylenedioxymethamphetamine (MDMA) is a psychoactive phenylisopropylamine which is structurally similar to both amphetamine-related sympathomimetics and the hallucinogen, mescaline. MDMA produces pleasurable effects which include euphoria, and recent reports continue to demonstrate its widespread recreational use. The aim of the present study was to assess the effects of racemic MDMA on the threshold for rewarding intracranial self-stimulation, an animal model used to assess a drug's abuse liability in man. Rewarding electrical stimulation was delivered via electrodes stereotaxically implanted in the medial forebrain bundle-lateral hypothalamic area of the rat brain. Thresholds were determined by means of a rate-independent psychophysical method. MDMA produced a dose-related lowering of the reward threshold in all four animals tested. Given that increased sensitivity for rewarding brain stimulation, measured as a lowering of the reward threshold, is an animal model of drug-induced euphoria these results suggest a similar mode of action for its reinforcing effects as other abused substances.
Methaqualone is considered a sedative hypnotic drug with a pattern of pharmacological effects similar to those of barbiturates such as pentobarbital. It does have chemical similarities to the barbiturates but was, in fact, synthesized as part of an Indian program looking for antimalarial drugs (Brown and Goenechea, 1973). Methaqualone was selected for the focus of this study five years ago, because of its popularity as a euphoriant among casual recreational drug users in the Boston area. Methaqualone, instead of a barbiturate hypnotic, was therefore used to test our proposed methodology for the assessment of the abuse liability of sedative drugs. As one reviews the history of the clinical use and illicit abuse of methaqualone, it appears particularly unfortunate that a study of this sort was neither completed nor available to our Food and Drug Administration (FDA) and Drug Enforcement Agency (DEA) in 1965. It was at this time that the drug was approved for prescription use and placed in Schedule V, a schedule which essentially places no restrictions on the clinical use of a prescription drug (Falco, 1976). This paper will both review the development of methaqualone and present an experimental methodology for assessing its abuse liability under seminaturalistic conditions.
Subjective effects of two benzodiazepines--alprazolam and lorazepam--were compared with two drugs of known abuse potential--diazepam and methaqualone--and placebo. This double-blind, crossover trial tested 30 casual recreational sedative users in a seminaturalistic setting. Methaqualone was more euphoriant and less sedative than the benzodiazepines. Diazepam and lorazepam were more euphoriant than placebo; alprazolam's euphoriant effect did not differ from these treatments. On other measures of abuse liability the benzodiazepines rated similarly, diazepam rating highest.
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Weight data taken from a 6-week randomized double-blind study comparing amitriptyline, trazodone and placebo were analyzed to determine differential weight changes between the two drugs. In 272 depressed outpatients doses were increased over a period of 4 days to reach a maximum level of 200 mg amitriptyline or 400 mg trazodone. After grouping the subjects according to initial weights (ideal, overweight, 20% above, and underweight, 20% below) mean changes were determined for each treatment. The results indicate that amitriptyline, which differed from placebo and trazodone, produced significantly higher weight gains in the ideal and overweight groups. Trazodone on the other hand produced a slight weight loss in the overweight group. Due to a low number of patients in the underweight group, the results were not significantly statistically. The antidepressant effects of both trazodone and amitriptyline were the same and no correlations between Hamilton scores and weight change were found.
A two-compartment model was developed to analyze the temporal changes in plasma triacylglycerol (TG)-specific radioactivity after injection of [2-3H]glycerol into rats. The analysis, which yielded fractional rate constants of TG secretion, was tested in rats fed diets either adequate or deficient in essential fatty acids (EFA) and containing either glucose, fructose or sucrose as the dietary carbohydrate. The method of analysis appeared valid, first, because of a close agreement between experimental and computer-fitted TG-specific radioactivity curves, and second, because the fractional rate constants obtained were quite similar to fractional rate constants determined previously by the Triton WR-1339 technique in rats maintained on identical diets. The results show that EFA deficiency increased the fractional rate constant of TG secretion 1.7-, 1.8- and 3.3-fold and the rate of TG secretion 1.8-, 1.6- and 1.4-fold when the dietary carbohydrate was glucose, sucrose and fructose, respectively, in comparison with control rats fed diets supplying these same carbohydrates but adequate in EFA. In the latter groups, the rates of plasma TG secretion were in the range of 0.14-0.17 mg/min per 100 g body weight, and the rate of secretion in the fructose-fed rats was only 20% higher than in the glucose-fed rats.
The abuse potential of buspirone, a new dopaminergic antianxiety drug, was evaluated by assessing its subjective effects in standard (10 mg) and high (40 mg) doses. These were compared with methaqualone (300 mg), diazepam (20 mg and 10 mg), and placebo in 24 casual recreational sedative users. Addiction Research Center Inventory scales measuring euphoria, sedation, dysphoria, and abuse liability were used as dependent measures. Groups of subjects received all treatments in randomized order in six weekly 4-hour sessions. Compared to placebo, methaqualone caused elevated scores on euphoria, physical sedation, and abuse liability scales compared to placebo, while 40 mg buspirone caused increased physical sedation, increased physical and mental dysphoria, and lower abuse liability scores. Overall, buspirone at 40 mg appeared unlikely to be reinforcing to recreational illicit drug users; the 10 mg dose was not discriminable from placebo or 10 mg diazepam. Diazepam at 20 mg showed some euphoriant effect compared to placebo.
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Urine dialysate from rats treated orally with 25 mg/Kg 3H-labeled niridazole was fractionated by DEAE-Sepharose column chromatography and was found to contain three radioactive metabolites and no parent compound. When human niridazole urine dialysate (NUD) was fractionated under identical conditions, fractions corresponding to the three rat NUD metabolites were found to inhibit the human one-way MLR. No inhibition was obtained with fractionated control urine dialysate. It was concluded that nonimmunosuppressive niridazole is metabolized by rats and man to produce three active compounds with the ability to suppress the in vitro response to alloantigens.
A new silastic and teflon cannula has been developed for temporary hemodialysis access. It is introduced through the subclavian vein by the Seldinger technique. The cannula which is quick and easy to insert, can be used repeatedly for weeks or months without limiting the patient's mobility and without the need for repeated vessel punctures. Complications are few and largely preventable. Since introduction of the subclavian hemodialysis cannula at the Toronto Western Hospital in September 1977 no patient with end-stage renal failure has required insertion of a silastic-teflon shunt or temporary peritoneal dialysis, nor has hemodialysis had to be postponed because of lack of an arteriovenous fistula.
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Niridazole, an antischistosomal agent, was given to renal transplant recipients in addition to azathioprine and prednisolone, as there is experimental evidence that this combination of drugs is highly immunosuppressive. Sera obtained from kidney-graft recipients during the first two weeks after transplantation were examined for their ability to inhibit the one-way mixed lymphocyte reaction (MLR). Sera from seven patients receiving azathioprine, prednisolone, and niridazole (triple-drug treatment), five patients receiving azathioprine and prednisolone, and two other patients treated with niridazole alone for schistosomiasis produced MLR inhibition by comparison with pretreatment (control) sera.A mean of 78% inhibition was observed with sera taken after one day's treatment with the three-drug combination, whereas this level of in-vitro immunosuppression occurred only after eight days of treatment with azathioprine and prednisolone. Niridazole alone produced an effect similar to azathioprine and prednisolone. Concentrated dialysate of urine from a patient receiving triple-drug treatment not only inhibited the MLR but also significantly prolonged the survival of heterotopic heart allografts in rats, whereas dialysate from the same patient after niridazole had been stopped gave less MLR inhibition and failed to prolong heart allograft survival.Since niridazole thus increased the in-vitro and in-vivo immunosuppressive action of azathioprine and prednisolone, we suggest that this triple-drug combination might be useful for preventing early acute kidney graft rejection.
The immunosuppressive properties of niridazole, an antihelminthic drug, have been investigated in rats. When given orally in a dose of 50 mg/kg, it extended the median survival of cardiac allografts from 7 to 20 days. The immunosuppressive effect was not increased by giving either azathioprine or prednisolone concurrently but when all three drugs were combined, immunosuppression was profound and only two of eight grafts were rejected. Drug combinations incorporating niridazole at a lower dosage or for a shorter period were less effective, and azathioprine and prednisolone on their own or used together prolonged graft survival only marginally in this model. It is concluded that niridazole is a powerful immunosuppressive drug in this species and a synergistic effect can be obtained by using it in combination with azathioprine and prednisolone.