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Biomedical subjects

H de Wit

Publications and source records attributed to H de Wit.

106 records · Page 6Linked to original sources
PubMed1987

Prevention by thioethers of the hepatotoxicity and covalent binding to macromolecules of N-hydroxy-2-acetylaminofluorene and its sulfate ester in rat liver in vivo and in vitro.

In order to find potentially effective compounds that could prevent the covalent binding of the carcinogen N-hydroxy-2-acetylaminofluorene (N-OH-AAF) to rat liver macromolecules in vivo, the prevention of the covalent binding to RNA of the sulfate ester of the carcinogen N-OH-AAF by a series of thioethers was investigated in vitro. The most effective thioethers, which inhibited the covalent binding by 70% or more, were studied for their protection against acute hepatotoxicity of N-OH-AAF in the rat in vivo. Three of these thioethers, thiazolidine, methyl 4-(methylthio)benzoate, and 2-(methylthio)benzimidazole significantly decreased the hepatoxicity of N-OH-AAF, by 45, 71 and 83%, respectively. The effects of these thioethers on the covalent binding of N-OH-AAF to cellular macromolecules in vivo were also studied. Methyl 4-(methylthio)benzoate and 2-(methylthio)benzimidazole decreased the adduct formation of N-OH-AAF to DNA by 54 and 44%, respectively, but had no effect on protein adduct formation. Only 2-(methylthio)benzimidazole caused a slight decrease (23%) in the AAF-- protein adduct formation. 2-Acetylaminofluorene (AAF) and methyl 4-(methyl-sulfinyl)benzoate were the main products in the incubation of methyl 4-(methylthio)benzoate with AAF-N-sulfate in vitro. This suggests that the thioether attacks the nitrenium ion which is formed by spontaneous breakdown of AAF-N-sulfate; the formation of a sulfonium--AAF conjugate is postulated which decomposes into AAF and a sulfinyl compound.

2-Acetylaminofluorene↗
PubMed1987

Individual differences in behavioral and subjective responses to alcohol.

The reinforcing properties and subjective effects of alcohol were assessed in 29 normal volunteers using a seven-session choice procedure. On the first four sessions, subjects sampled an alcohol (0.5 g/kg) and a placebo beverage twice each. On three subsequent choice sessions, subjects chose the drink they preferred. The number of times they chose alcohol was the measure of its reinforcing properties. On all sessions subjects completed mood questionnaires before and several times after consuming the beverage. Other dependent measures during the experiment included a cognitive performance task, drug liking and identification questionnaires, and breathalyzer alcohol determinations. Demographic and personality data also were obtained. Approximately one-third of the subjects chose the alcohol-containing beverage on all three choice sessions, one-third alternated in their choices of alcohol and placebo, and one-third consistently chose the placebo. When the subjective effects of alcohol (determined during sampling sessions) were compared across the three choice groups, qualitative differences in response to alcohol were observed. For example, alcohol increased elation and vigor scores in the consistent choosers of alcohol, whereas it decreased scores on these measures in the consistent placebo choosers. Consistent alcohol choosers did not differ from placebo choosers in gender or age but they reported more marijuana use and slightly more alcohol use outside the laboratory. They also scored higher on certain measures of arousal and depression, on the Sensation Seeking Scale and on the Psychopathic State Inventory. The results are discussed in terms of individual differences in vulnerability to excessive use of alcohol.

Adult↗
PubMed1986

Lack of preference for diazepam in anxious volunteers.

Using a choice procedure, these experiments tested whether diazepam is more highly preferred by anxious subjects than by normal control subjects. Subjects first sampled and then chose between two capsules containing diazepam (5 or 10 mg) and placebo, or amphetamine (5 mg) and placebo. The number of times each drug was chosen over placebo and the subjective effects of the drugs were measured. Anxious subjects did not differ from controls in their drug choices. Most subjects chose diazepam less often than placebo, especially at the higher dose, whereas they chose amphetamine more often than placebo. The subjective drug effects (including anxiety reduction after diazepam) were similar for anxious and nonanxious subjects, despite predrug differences in anxiety. The results suggest that individuals with high anxiety are not at greater risk for dependence on antianxiety drugs.

Adult↗
PubMed1986

Individual differences in the reinforcing and subjective effects of amphetamine and diazepam.

This study explored the relation between the reinforcing properties of different drugs and their subjective effects. Preference for a drug (amphetamine or diazepam) over placebo was measured in a choice procedure, and mood changes after drug administration were monitored by self-report questionnaires. Individual differences in behavioral drug preferences were then examined for their relationships to subjective drug responses as well as other subject variables. In Part I, the subjective effects of amphetamine were compared in those subjects who consistently preferred (i.e. chose) amphetamine over placebo, and those who preferred placebo over amphetamine. The two subject groups showed markedly different subjective responses to the stimulant drug: the choosers reported increased positive mood and euphoria, whereas the non-choosers reported only increased anxiety and depression. In Part II, the subjective effects of diazepam in consistent choosers of diazepam were compared to the subjective effects in consistent non-choosers of the drug. The non-choosers showed appreciable subjective effects, which were predominantly sedative in quality. In contrast to the results with amphetamine, the choosers showed negligible subjective drug effects. These results underline the importance of considering more than one response measure when attempting to characterize the reinforcing effects of drugs.

Adult↗
PubMed1985

Drug preference in normal volunteers: effects of age and time of day.

These experiments assessed the influence of two variables, age of subjects and time of drug administration, on the reinforcing properties of amphetamine and of diazepam in normal volunteers. Three groups of subjects were tested: i) a group of 40-55-year-old subjects (AGE group; N = 11) who were tested in the morning, ii) a group of 21-35-year-old subjects (CTL group; N = 12) who were also tested in the morning, and iii) a group of 21-35-year-olds who were tested in the late afternoon (AFT group; N = 13). All subjects participated in three separate experiments comparing one drug (5 mg d,l-amphetamine, 5 mg diazepam or 10 mg diazepam) to placebo. Each experiment consisted of nine sessions: On the first four sessions subjects sampled two color-coded capsules on alternate sessions and on the following five sessions they chose and ingested the capsule they preferred. Subjective effects of the drugs were monitored using the Profile of Mood States (POMS) and a shortened version of the Addiction Research Center Inventory (ARCI). Subjects in all three groups chose 5 mg diazepam as often as placebo but preferred placebo to 10 mg diazepam. In contrast, they chose amphetamine either as often as or more often than placebo. The subjective effects of diazepam (i.e. sedation) were similar across all three groups, but after amphetamine the AGE group showed greater stimulant effects. In addition, the AFT group showed fewer positive mood effects after amphetamine than the CTL group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Reaction of 2-acetylaminofluorene-N-sulfate with RNA and glutathione: evidence for the generation of two reactive intermediates with different reactivities towards RNA and glutathione.

The sulfate ester of N-hydroxy-2-acetylaminofluorene (AAF-N-sulfate) is one of the reactive intermediates of this carcinogen. This ester breaks down spontaneously to a very reactive nitrenium ion, which reacts with nucleophilic groups in protein, DNA, RNA and glutathione (GSH). Reactions involving the nitrenium ion with several nucleophiles under various conditions were studied. The adduct formation to RNA was much higher in Tris-HCI buffer than in phosphate buffer (at pH 7.4), while adduct formation to deoxy-guanosine monomers was the same in both buffers. The presence of 150 mM KCI had the same decreasing effect in both cases. Ionic strength effects may be involved in these phenomena. GSH decreased RNA adduct formation by 20-45%, while other thiols were much more effective. On the other hand, RNA did not decrease the formation of GSH conjugates from AAF-N-sulfate. The decrease in RNA adduct formation by thiols corresponded with an increase in the formation of 2-acetylaminofluorene (AAF) from AAF-N-sulfate, while no N-hydroxy-AAF was formed. These results suggest that two independent reactive intermediates are formed from AAF-N-sulfate, with different reactivities towards RNA and glutathione. Possibly these intermediates are the 'hard' triplet state nitrenium ion and the 'soft' singlet state nitrenium ion. Cysteine, cysteamine and penicillamine were most effective in the inhibition of RNA adduct formation; the extent of inhibition correlated with the extent of AAF formation. The mechanisms involved are discussed.

2-Acetylaminofluorene↗
PubMed1984

Reinforcing properties of lorazepam in normal volunteers.

These experiments were designed to test the positive reinforcing property of a benzodiazepine in normal volunteer subjects. A choice procedure was used to measure preference for lorazepam, a benzodiazepine with a relatively short plasma half-life, over placebo. In separate experiments, subjects were given a choice between three doses of lorazepam (0.5, 1.0 and 2.0 mg, p.o.) and placebo, and in a fourth experiment subjects were given a choice between lorazepam (1.0 mg) and a therapeutically equipotent dose of diazepam (5 mg). Subjective effects of the drugs were monitored using an experimental version of the Profile of Mood States and a shortened version of the Addiction Research Center Inventory. Subjects showed no preference for 0.5 mg lorazepam over placebo (49% drug choice) or for 1.0 mg lorazepam over diazepam (46% lorazepam choice). However, subjects preferred placebo to both 1.0 and 2.0 mg lorazepam (32% and 16% drug choice for 1.0 and 2.0 mg, respectively). Subjective effects were consistent with the drug's known sedative and anxiolytic properties. Relative to diazepam, lorazepam had a longer duration of effect than might be expected from its plasma half-life. Differences in the pharmacokinetic properties of the two drugs account for the results. The results showed that lorazepam is not an effective positive reinforcer in these subjects, suggesting that it also does not have high dependence potential in this population.

Adult↗
PubMed1984

Lack of preference for flurazepam in normal volunteers.

The reinforcing efficacy of flurazepam (15 and 30 mg) in humans was assessed using an experimental choice procedure. Twelve healthy volunteers were tested in two 3-week choice experiments, in which each dose of the drug was compared to placebo. Subjective effects of the drug (and placebo) were monitored using the Profile of Mood States and a 49-item version of the Addiction Research Center Inventory. The lower dose of flurazepam was chosen equally as often as placebo and produced no significant subjective effects. The higher dose (30 mg) was chosen significantly less often than chance, and produced typical tranquilizer-like effects (e.g., sedation). These results are consistent with previous results using other benzodiazepines such as diazepam and lorazepam, and suggest that the reinforcing efficacy of these drugs in normal volunteers is low.

Adult↗
PubMed1984

The dependence potential of benzodiazepines.

A series of studies has been carried out using a choice procedure to investigate the reinforcing properties of benzodiazepines in adult volunteer subjects. Amphetamine and other drugs with undisputed dependence potential are clearly preferred by the majority of subjects using this procedure. However, diazepam has not been found to be an effective reinforcer across a range of doses, using various subject populations and under different experimental conditions. In the present study, lorazepam, a benzodiazepine with a shorter half-life than diazepam, was tested. Twelve normal volunteer subjects were tested in 4 separate experiments in which three doses of lorazepam (0.5, 1.0 and 2.0 mg) were each compared to placebo, and in a separate experiment, 1.0 mg lorazepam was compared to 5.0 mg diazepam. Subjects showed no preference between 0.5 mg lorazepam and placebo or between 1.0 mg lorazepam and 5.0 mg diazepam, but at the 1.0 and 2.0 mg doses of lorazepam they showed a clear preference for placebo. Subjective effects of the drugs were also monitored, and showed changes consistent with the anxiolytic and sedative effects of the drugs. The duration of the effects of lorazepam was unexpectedly long (as long as 6 hours), so the question whether a shorter-acting benzodiazepine would be a more effective reinforcer in this situation remains unanswered.

Adult↗
PubMed1983

Drug reinstatement of heroin-reinforced responding in the rat.

Non-contingent, 'priming' IV drug injections led to reinstatement of heroin-reinforced responding after a period of extinction. Rats implanted with IV catheters were trained to self-administer heroin (100 micrograms/kg/infusion diacetylmorphine HCl) and were given test sessions consisting of a period of self-administration followed by extinction conditions. 'Priming' infusions of heroin and other drugs were presented during extinction and lever pressing following the injection was observed. Priming injections of 50, 100 and 200 micrograms/kg heroin effectively restored responding after a period of extinction. Morphine and, to a lesser extent, amphetamine and apomorphine also reinstated heroin-reinforced responding whereas cocaine and clonidine did not. These results may help our understanding of 'relapse of drug-taking' behavior.

Animals↗
PubMed1981

Reinstatement of cocaine-reinforced responding in the rat.

Non-contingent "priming" drug injections and conditioned stimuli associated with drug injections led to reinstatement of responding after a period of extinction. Rats implanted with intravenous catheters were trained to self-administer cocaine 1 mg/kg/injection), and then given daily test sessions consisting of a period of self-administration followed by extinction conditions. Test drug injections or conditioned stimuli were presented during extinction and the latency to the first response and the total number of responses following the treatment were measured. Cocaine injections of 0.5, 1.0, and 2.0 mg/kg restored responding during extinction, regardless of the duration of the extinction period (between 10 min and 180 min) since drug self-administration. Amphetamine, apomorphine, and morphine but not ethanol, heroin, or methohexital reinstated previously cocaine-reinforced responding. Amphetamine, cocaine, and morphine did not increase responding in animals trained to bar press only for food reinforcement, suggesting that the reinstatement effect is specific to drug-reinforced responses. The statement effect is specific to drug-reinforced responses. The final experiment showed that a tone that had been paired with drug infusions acquired a statistically significant tendency to facilitate responding when tested during extinction but this effect disappeared after the first test presentation of the tone.

Animals↗
PubMedDate not supplied

Antiemetic efficacy of smoked marijuana: subjective and behavioral effects on nausea induced by syrup of ipecac.

Although the public debate about the legalization of marijuana has continued for as long as 25 years, few controlled studies have been conducted to assess its potential medical benefits. The present study examined the antiemetic effect of smoked marijuana cigarettes (8.4 and 16.9 mg Delta(9)-tetrahydrocannabinol [THC]) compared to a highly potent antiemetic drug, ondansetron (8 mg) in 13 healthy volunteers. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of "queasiness" and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces feelings of nausea and also reduces emesis in this model. However, its effects are very modest relative to ondansetron, and the psychoactive effects of marijuana are likely to limit its clinical usefulness in the general population.

Adolescent↗
PubMedDate not supplied

Effects of d-amphetamine in grouped versus isolated humans.

This study was designed to determine whether the subjective, behavioral or physiological effects of a stimulant drug in humans depend on whether subjects are tested under isolated or social conditions. Forty-two subjects were randomly assigned to either the Social (SOC) or Isolated (ISO) condition. SOC subjects participated in 4 h laboratory sessions in groups of 3 or 4, whereas ISO subjects participated in the sessions alone. All subjects participated in three sessions, during which they received capsules containing d-amphetamine (10 or 20 mg) or placebo, in mixed order under double blind conditions. Subjective, physiological and behavioral measures were obtained at regular intervals, d-amphetamine produced dose-related, prototypic stimulant effects on many measures, including self-reported mood states, behavioral indices and physiological measures. Most of these effects were unaffected by the setting in which subjects were tested (SOC vs ISO). However, body temperature was overall higher in the SOC group, and there was a trend for d-amphetamine to produce greater hyperthermic effects in the SOC group. In addition, 10 mg d-amphetamine increased heart rate in the SOC group but not in the ISO group. The results suggest that, like in laboratory animals, some of the effects of stimulants in humans are greater under aggregated conditions. However, unlike in the animal studies, this observed enhancement of the drug's effects under aggregated conditions was limited to physiological measures and did not apply to other subjective or behavioral measures.

Adult↗