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Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 145 records · Page 8Linked to original sources
PubMed1986

Repeated administration of diazepam and triazolam to subjects with histories of drug abuse.

The present study examined the effects of repeated administration of diazepam (DZ) and triazolam (TZ) on psychomotor performance and subject-rated drug liking. Subjects were 11 males (30-41 years) who had documented histories of drug abuse and who resided on a behavioral pharmacology research ward. Six subjects received 80 mg DZ every third day (3 subjects) or every sixth day (3 subjects) for a total of 3-6 dosing occasions and six subjects received TZ (2.0 or 3.0 mg) every second day (4 subjects) or every third day (2 subjects) for a total of 3-5 dosing occasions. The results showed that on the first dose occasion, the two drugs produced generally similar degrees of psychomotor impairment and subject-rated drug liking. Following the first DZ dose, subsequent doses produced less of an effect (i.e. single-dose tolerance). Across at least the first three dose occasions, progressive tolerance development was observed with DZ but no tolerance was observed with TZ. It is hypothesized that pharmacokinetic differences between DZ and TZ may account for the difference in the development of tolerance.

Adult↗
PubMed1986

Diazepam and methadone blood levels following concurrent administration of diazepam and methadone.

Results of a previous study indicated that the opioid effects of methadone were enhanced by the concurrent administration of diazepam in methadone-maintained subjects. To determine whether a pharmacokinetic interaction might account for this methadone-diazepam interaction, the plasma levels of methadone, diazepam and diazepam metabolites were determined in blood samples collected during that study. Five adult male patients on methadone maintenance (50-60 mg/day) were administrated single doses of placebo, diazepam (20 and 40 mg), methadone (100%, 150% and 200% of the maintenance dose), and four diazepam-methadone dose combinations (20 and 40 mg diazepam in combination with 100% and 150% of the maintenance dose). The results showed that the concurrent administration of methadone and diazepam did not significantly change the time-course or areas under the plasma concentration-time curve of methadone, diazepam or N-desmethyl-diazepam compared to the levels following the administration of either drug alone. Thus, plasma drug level analysis does not indicate a pharmacokinetic interaction between diazepam and methadone.

Adult↗
PubMed1986

Relative abuse of diazepam and oxazepam: prescription forgeries and theft/loss reports in Sweden.

Results of previous laboratory studies in humans suggest that the benzodiazepine diazepam has greater abuse liability than the benzodiazepine oxazepam. The validity of these laboratory-based experimental data were examined by analyzing Swedish data on drug abuse. Sales and prescription data showed that use of diazepam was somewhat lower than oxazepam, but of the same general order of magnitude (0.8:1). Prescription data showed that the drugs were prescribed for the same diagnostic indications. After adjustment for differences in use, 'prescription forgeries' and 'mentions in theft and loss reports' were found to be more frequent for diazepam than for oxazepam (2.3:1 and 2.5:1 for forgeries and theft/loss reports, respectively). This effect was consistent for each year examined (1982, 1983, 1984) and occurred when the data were recalculated to exclude Valium, the original and most widely known brand of diazepam. Finally, this pattern with prescription forgeries occurred across different geographical regions in Sweden (1982, 1983).

Cross-Sectional Studies↗
PubMed1986

Human coffee drinking: manipulation of concentration and caffeine dose.

In a residential research ward coffee drinking was studied in 9 volunteer human subjects with histories of heavy coffee drinking. A series of five experiments was undertaken to characterize adlibitum coffee consumption and to investigate the effects of manipulating coffee concentration, caffeine dose per cup, and caffeine preloads prior to coffee drinking. Manipulations were double-blind and scheduled in randomized sequences across days. When cups of coffee were freely available, coffee drinking tended to be rather regularly spaced during the day with intercup intervals becoming progressively longer throughout the day; experimental manipulations showed that this lengthening of intercup intervals was not due to accumulating caffeine levels. Number of cups of coffee consumed was an inverted U-shaped function of both coffee concentration and caffeine dose per cup; however, coffee-concentration and dose-per-cup manipulations did not produce similar effects on other measures of coffee drinking (intercup interval, time to drink a cup, within-day distribution of cups). Caffeine preload produced dose-related decreases in number of cups consumed. As a whole, these experiments provide some limited evidence for both the suppressive and the reinforcing effects of caffeine on coffee consumption. Examination of total daily coffee and caffeine intake across experiments, however, provides no evidence for precise regulation (i.e., titration) of coffee or caffeine intake.

Caffeine↗
PubMed1986

Discriminative stimulus effects of atypical anxiolytics in baboons and rats.

Baboons and rats were trained to discriminate lorazepam and pentobarbital in a food-maintained two-lever drug vs. no-drug discrimination procedure. Previous research showed that benzodiazepines, but not barbiturates, occasioned drug lever responding in the lorazepam-trained animals. Lorazepam and six nonbenzodiazepines that have been proposed as anxiolytics (CGS 9896, CL 218,872, PK 9084, zopiclone, buspirone and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) were studied in test sessions in which responding on either level produced food. Of the nonbenzodiazepine compounds studied that displace 3H-benzodiazepines in vitro, CL 218,872 and zopiclone occasioned drug lever responding in all animals; PK 9084 did not occasion drug lever responding in any animal; and CGS 9896 did not occasion drug lever responding in lorazepam- or pentobarbital-trained baboons or in lorazepam-trained rats, but did so in the pentobarbital-trained rats. Buspirone, a nonbenzodiazepine anxiolytic with prominent dopaminergic activity, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a gamma-aminobutyric acid agonist, also did not occasion drug lever responding in either baboons or rats, regardless of training drug. Time course studies in baboons with CGS 9896, PK 9084, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and buspirone did not reveal delayed onset of drug stimulus generalization. Some differences in potency as a function of route of administration were found with CL 218,872, zopiclone and buspirone. The discriminative stimulus effects of lorazepam, CL 218,872 and zopiclone were antagonized by the benzodiazepine receptor antagonist Ro 15-1788. It is concluded that the discriminative stimulus properties of these nonbenzodiazepine compounds thus do not co-vary with their antipunishment effects, with their clinical efficacy as anxiolytics or with benzodiazepine receptor binding.

Animals↗
PubMed1986

Comparison of opioid self-injection and disruption of schedule-controlled performance in the baboon.

Eight opioid agonist, mixed agonist/antagonist or antagonist compounds were compared in baboons. In the first experiment, i.v. drug self-injection procedures involved a fixed-ratio schedule with a 3 hr time-out after each injection. Doses of a test drug were substituted for cocaine for 12 or 15 days. Codeine, morphine, butorphanol, nalbuphine and pentazocine all maintained self-injection above vehicle control levels. These compounds differed in their relative potencies, and morphine did not maintain maximal drug self-injection rates. Buprenorphine maintained self-injection in only one of four baboons, and SKF-10,047 and naloxone did not maintain self-injection. In a second experiment, another group of baboons responded on a fixed-ratio 50 schedule of food pellet delivery. Intravenous injections were given 30 min before test sessions that lasted 30 min. All eight drugs produced dose-related decreases in response rates, and the buprenorphine dose-response curve was more shallow and not parallel to the others. Comparison across experiments suggested that the failure of morphine to maintain maximal self-injection rates is due to its relatively high potency in suppressing schedule-controlled performance. The results of this study confirm those of previous studies demonstrating that opioids with morphine-like subjective effects in man are self-administered by laboratory animals.

Animals↗
PubMed1986

Human coffee drinking: reinforcing and physical dependence producing effects of caffeine.

In a residential research ward coffee drinking was studied in nine volunteer human subjects with histories of heavy coffee drinking. The presence or absence of caffeine in the coffee was manipulated under double-blind conditions by using caffeinated (C) or decaffeinated (D) coffee. When subjects were switched alternately for 10 or more consecutive days between C and D, the daily number of cups consumed tended to be relatively stable. In a different experiment, preference for C vs. D was assessed. After experimenter-scheduled exposures, subjects were given choices between C and D. When subjects were presumably caffeine tolerant/dependent, C was rated as being better liked than D and was reliably preferred to D in choice tests. When subjects were not caffeine tolerant/dependent, C was not reliably preferred to D, nor were there pronounced differences in ratings of liking. Under these conditions, some subjects preferred D to C, citing adverse symptoms (suggesting caffeine toxicity) as reasons for avoiding C. The effects of caffeine withdrawal were studied by abruptly substituting D for C for 10 or more days. This resulted in an orderly withdrawal syndrome, having an onset latency of 19 hr, peaking on days 1 and 2, and decreasing progressively over the next 5 or 6 days. The withdrawal syndrome, which was detected on subject-rated, staff-rated and objective behavioral measures, was characterized by increased headache, sleepiness and laziness and decreased alertness and activeness. The present study demonstrates the reinforcing effects of caffeine in humans and also documents the severity of the caffeine withdrawal syndrome. It is concluded that caffeine has the cardinal features of a prototypic drug of abuse.

Adult↗
PubMed1985

Effects of repeated RO 15-1788 administration in benzodiazepine-dependent baboons.

Administration of the benzodiazepine antagonist, RO 15-1788, to baboons that were chronically exposed to diazepam or triazolam precipitated withdrawal signs. When RO 15-1788 was administered repeatedly at one or three day intervals, precipitated withdrawal signs were attenuated. However, these baboons remained tolerant to the sedative effects of the high doses of benzodiazepines to which they were continuously exposed. While tolerance to agonist effects of drugs and development of physical dependence are often thought to be functionally interrelated phenomena, the present results suggest that these may be separable properties of the benzodiazepines. The present results clearly indicate that certain actions of benzodiazepine agonists and antagonists can be independently regulated.

Animals↗
PubMed1985

Lorazepam and pentobarbital discrimination: interactions with CGS 8216 and caffeine.

Baboons and rats were trained under a two-lever, food-reinforced drug discrimination procedure. The training drug was either lorazepam (1.0 mg/kg) or pentobarbital (5.6 mg/kg in baboons, 10.0 mg/kg in rats). Under test conditions, a range of training drug doses occasioned 100% drug lever responding. CGS 8216 (3.2-10.0 mg/kg) combined with lorazepam produced a complete shift to the no-drug lever in both species; this shift was surmountable with higher doses of lorazepam. CGS 8216 (32.0 mg/kg) combined with pentobarbital produced a statistically significant decrease in drug-lever responding in rats, and in baboons CGS 8216 initially, but not subsequently, produced a complete shift to the no-drug lever. Caffeine (0.32-10.0 mg/kg) combined with lorazepam inconsistently decreased drug-lever responding across multiple determinations in baboons and significantly decreased drug lever responding in rats. Caffeine combined with pentobarbital also yielded an inconsistent decrease in drug lever responding in baboons but there was no effect in rats. Thus the most reliable and complete antagonism across species was obtained with the CGS 8216/lorazepam combinations.

Animals↗
PubMed1985

Relative abuse liability of triazolam: experimental assessment in animals and humans.

The abuse liability of a drug is a positive, interactive function of the reinforcing and adverse effects of the drug. The relative abuse liability of the hypnotic benzodiazepine, triazolam, has been controversial. This paper reviews animal and human studies bearing on its relative abuse liability, including data on pharmacological profile, reinforcing effects, liking, speed of onset, discriminative stimulus effects, subjective effects, physiological dependence, rebound and early morning insomnia, drug produced anxiety, lethality in overdose, psychomotor impairment, interactions with ethanol, anterograde amnesia, impaired awareness of drug effect, and other psychiatric and behavioral disturbances. It is concluded that the abuse liability of triazolam is less than that of the intermediate duration barbiturates such as pentobarbital. Although there are considerable data indicating similarities of triazolam to other benzodiazepines, there is also substantial speculation among clinical investigators and some limited data suggesting that the abuse liability of triazolam is greater than that of a variety of other benzodiazepines, and virtually no credible data or speculation that it is less. Further research will be necessary to clarify definitively the abuse liability of triazolam relative to other benzodiazepines.

Amnesia↗
PubMed1985

Effects of graded smoke inhalation on subsequent cigarette smoking behavior.

Five smokers smoked a cigarette ad libitum one minute after inhaling either 0, 2, 4, 8 or 12 puffs of tobacco smoke according to a standardized smoking regimen. Heart rate and expired air carbon monoxide levels increased in a linear manner with increasing number of pretreatment puffs. Subjects took fewer puffs on, and spent less time smoking, and puffing on, the cigarette as the number of pretreatment puffs increased. The duration of individual puffs decreased with successive puffs as the cigarette was smoked, but was not affected by the puff pretreatments. Intervals between successive puffs (interpuff intervals) generally increased over the first half, and leveled off or decreased over the second half of the cigarette. Interpuff intervals occurring early in the cigarette tended to increase after the 12-puff pretreatment. The results are consistent with the suggestion that the observed increase in interpuff interval as a cigarette is smoked is the result of a satiation process.

Adolescent↗
PubMed1985

Effects of cigarette rod length on puff volume and carbon monoxide delivery in cigarette smokers.

As part of a continuing series of studies to investigate the variables controlling various topographical aspects of cigarette smoking, the present study examined the extent to which cigarette rod length influenced smoking. Cigarette smoking was examined under conditions in which subjects smoked cigarettes they could not see. Both puff volume and puff duration varied as a direct function of rod length, although they were not highly correlated. Peak flow rate was not affected by rod length. Other results suggest that visual stimulus control and satiation did not affect puff volume. Comparison of puffing whole cigarettes versus short cigarette rods suggests that puff volume, but not puff duration, may be decreased in response to increased pharmacological delivery as a result of particulate build-up during smoking of a whole cigarette. Carbon monoxide (CO) exposure was substantially greater after puffing full length cigarette rods than after short cigarette rods. Comparison of these human CO data with CO delivery from syringe-simulated puffing of full length and short cigarette rods indicates that knowledge of puff volume and duration during human smoking is insufficient for accurately predicting biological (CO) exposure.

Adult↗
PubMed1985

Comparison of triazolam and pentobarbital: performance impairment, subjective effects and abuse liability.

On a residential research ward, the acute effects of placebo, 0.5 to 3.0 mg of triazolam (TZ) and 100 to 600 mg of pentobarbital (PTB) were examined using a within-subject, double-blind design in male volunteers with documented histories of drug abuse. Drug effects were examined through the use of subject ratings including measures of drug liking and estimates of street value, staff ratings, objective psychomotor/cognitive performance measures, subject estimates of performance, immediate and delayed recognition memory tasks and subject ratings of nighttime sleep quality. Staff ratings and objective performance measures showed that TZ and PTB produced comparable dose-related impairment; TZ had a more rapid onset and a shorter duration of action than PTB. With these measures, TZ was 159 to 274 times more potent than PTB. With subject-rated measures of drug effect, sleepiness and drunkenness, in contrast, TZ produced smaller effects than PTB or was only 135 to 163 times more potent than PTB. Similarly, with subject ratings of drug liking and estimated street value, TZ produced smaller effects than PTB and was only 91 to 122 times more potent than PTB. Other results showed that TZ produced greater amnestic effects than PTB and subjects under the influence of TZ more consistently underestimated the degree of their impairment. Overall, these results suggest that TZ has a lower liability for abuse (likelihood) than PTB, but a greater liability of abuse (hazard) with regard to performance impairment on certain kinds of tasks.

Adult↗
PubMed1984

Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure.

Baboons were exposed to diazepam via continuous injection at doses of 0.125-20.0 mg/kg per day intragastrically (i.g.) for 7 days or to 20 mg/kg per day, i.g. for 1 h or 1 to 35 days. After diazepam administration, Ro 15-1788, a benzodiazepine antagonist was given (5.0 mg/kg i.m.) and precipitated benzodiazepine withdrawal was evaluated by scoring individual signs. The severity of the withdrawal, as indicated by the number of the different signs as well as by frequency of individual signs, increased as the dose and duration of diazepam exposure were increased. Consistent elevations in diazepam withdrawal signs were evident after a dose as low as 0.25 mg/kg per day for 7 days and after administration of 20 mg/kg per day for as short as 3-7 days. Data also suggested that history of previous benzodiazepine exposure sensitized animals to subsequent development of physical dependence. Overall, this study suggests that benzodiazepines produce meaningful functional changes in the central nervous system after exposure to relatively low doses and after relatively short durations of exposure.

Animals↗
PubMed1984

Effects of ethanol on cigarette smoking by volunteers without histories of alcoholism.

The effects of ethanol on cigarette smoking were assessed in volunteer research subjects who had histories of light to moderate social drinking. Five subjects participated individually in daily 90-min sessions that were conducted in rooms equipped to permit automatic monitoring of cigarette smoking behavior. Each subject was tested at four dose levels of ethanol and placebo, which were given orally on a double-blind basis, 30 min prior to sessions. Dose order was according to a random block sequence in which each dose was given in each of five blocks of five sessions. Data from five alcoholic subjects who were similarly tested at only one ethanol dose level were used for comparison. For the nonalcoholic group, ethanol doses that produced reliable changes in group scores on various psychometric instruments produced no significant change in smoking behavior. There were differences among the nonalcoholic subjects, however, in that smoking was significantly decreased by ethanol in two subjects, was increased by ethanol in two subjects, and was unchanged in the fifth subject. For the alcoholic group, ethanol produced reliable changes in psychometric measures and significant increases in cigarette smoking. Within- and between-group analyses of results suggest that the effect of ethanol on cigarette smoking may be related to prior history of alcoholic beverage consumption.

Adolescent↗
PubMed1984

Relative abuse liability of diazepam and oxazepam: behavioral and subjective dose effects.

The effects of diazepam (10-160 mg) and oxazepam (30-480 mg) were studied in volunteers with histories of drug abuse. Oral doses were administered every third day under double-blind and counterbalanced conditions. Dose-effects with area under the time-action curve data (AUC) showed diazepam to be 2.6-5.7-times more potent than oxazepam on various psychomotor, cognitive, staff-rated, and subjective measures. Comparison of relative potencies showed diazepam to be relatively more potent in producing 'liking' than in producing psychomotor and cognitive effects. Diazepam produced greater peak effects than oxazepam on a number of staff- and subject-rated measures, including liking. Onset of effect was more rapid and time to maximal effect was shorter (1-2 h versus 4-12 h) with diazepam than oxazepam, while time to offset of effect was similar for the two drugs. Diazepam was categorized as producing barbiturate-like subjective effects (38.3%) more frequently than was oxazepam (13.8%), while oxazepam was identified as placebo more often than diazepam. Repeated administration of 160 mg diazepam and 480 mg oxazepam showed that AUC liking was greater for diazepam than oxazepam and that tolerance to psychomotor and cognitive effects occurred with oxazepam but not diazepam. This study suggests that diazepam may have a higher abuse liability than oxazepam.

Adult↗
PubMed1984

Phencyclidine-analogue self-injection by the baboon.

Self-injection of phencyclidine HCI (PCP) and four of its analogues was examined in baboons. IV injections of drug were dependent upon completion of 160 lever presses (a 160-response fixed-ratio schedule). A 3-h time-out period followed each injection, permitting a maximum of eight injections per day. Self-injection performance was first established with cocaine and, once stable, test doses of each drug were substituted for 15 days. All five compounds maintained maximal self-injection performance, differing only in their relative potencies. The order of potency was approximately PCP greater than NMPCA = TCPY greater than NNBPCA greater than ketamine. Analysis of the distribution of injections throughout the day indicate that lower doses (and vehicle) were injected mainly during the daylight hours (i.e., 9 AM-6 PM), but as the dose was increased the injections became more uniformly distributed. Only the highest doses of these compounds affected food intake, though the degree of suppression was modest. No differences between these compounds with respect to their abuse potential could be found.

Animals↗