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Biomedical subjects

H K Gillespie

Publications and source records attributed to H K Gillespie.

At least 19 recordsLinked to original sources
PubMed1990

The benzodiazepine receptor antagonist, flumazenil does not block clinical effects of delta-9-tetrahydrocannabinol.

Fifteen normal volunteer men were given intravenous doses of 2 mg of delta-9-tetrahydrocannabinol (THC) and 3 were given doses of 0.5 mg. Five, 15 and 30 minutes later, they were given intravenous doses of the benzodiazepine receptor antagonist, flumazenil. Doses of this compound ranged between 0.1 and 3.2 mg for single doses and 0.7 and 6.4 mg for total doses, being increased progressively with each successive subject, until dose-ranging was completed in 10 subjects. After that 5 subjects were given doses of 2 mg of THC on two occasions, followed by either doses of 3.2 or 6.4 mg flumazenil or placebo, administered under blind conditions. Three subjects were treated with 0.5 mg doses of THC followed by 3.2 mg of flumazenil or placebo under similar conditions. Despite doses of the antagonist which would have been adequate to reverse the effects of substantial doses of benzodiazepines, little ameliorative action was observed on the level of intoxication or the degree of conjunctival injection, two quite reliable clinical indicators of THC action. The benzodiazepine receptor does not seem to play any significant role in the psychoactive actions and conjunctival injection produced by THC.

Adult↗
PubMed1989

Terminal elimination plasma half-life of delta 1-tetrahydrocannabinol (delta 1-THC) in heavy users of marijuana.

The terminal elimination half-life of delta 1-tetrahydrocannabinol (delta 1-THC) was investigated in eight men who were heavy users of marijuana. A stable isotope assay, following smoking deuterium-labeled delta 1-THC, was used to determine plasma concentrations. In two additional users plasma levels were followed after administration of unlabeled delta 1-THC. The subjects were asked to smoke a "loading dose" of 56 mg delta 1-THC during two days and then abstain from all marijuana use for 4 weeks. The pharmacokinetic behavior was consistent with a multicompartment model with a mean plasma elimination half-life of delta 1-THC of 4.3 days when concentrations were followed for 10-15 days after smoking. In the two subjects with detectable plasma levels during 4 weeks, half-lives of 9.6 and 12.6 days was obtained.

Dronabinol↗
PubMed1987

Human pharmacology of 1S and 1R enantiomers of delta-3-tetrahydrocannabinol.

Two enantiomers (1S and 1R) of delta-3-tetrahydrocannabinol were assayed in man for psychoactivity. The 1S enantiomer had definite psychic actions, qualitatively similar to those of delta-1-tetrahydrocannabinol, but quantitatively less potent (1:3 to 1:6). Adding the two enantiomers together did not increase the effect, confirming that activity was solely in the one enantiomer and that there was no interaction between them.

Adult↗
PubMed1985

Clinical evaluation of a naltrexone sustained-release preparation.

A clinical evaluation of the naltrexone bead, a biodegradable sustained-release dosage form of 3.0 mg in weight containing 70% naltrexone in a copolymer of lactic and glycolic acids, was carried out in 4 healthy normal males. Subjects were given an intravenous dose of 10 mg naltrexone and approx. 1 week later a 63-mg dose of naltrexone by subcutaneous administration of the beads. Challenge doses of 15 mg morphine were given to each subject during the study for the assessment of narcotic blockade effects of naltrexone. For a 2-4-week period after bead administration, relatively constant plasma levels were maintained at 0.30-0.46 ng/ml for naltrexone and were 0.64-1.07 ng/ml for naltrexol. Urine levels for unchanged and conjugated naltrexone were 79-215 ng/ml and for naltrexol were 315-500 ng/ml. From kinetic analysis, an average of 2.4-2.7% of implanted dose was absorbed each day from the administration of the beads. Opiate effects of morphine challenges were mitigated during the 2-4-week period after administration of naltrexone beads.

Delayed-Action Preparations↗
PubMed1984

Yohimbine and the model anxiety state.

Ten subjects were treated with 30 and 60 mg oral doses of yohimbine hydrochloride or placebo under controlled clinical conditions to determine if such doses would create a "model anxiety state." Some evidence of anxiety was found on various rating scales, especially after the 60 mg dose. However, maximum anxiety produced by this dose of the drug exceeded that which occurred during placebo testing in only 5 of the 10 subjects. The 60 mg dose produced substantial increases in systolic blood pressure and less increase in diastolic blood pressure and pulse rate. It was concluded that yohimbine does not produce a very good model of anxiety.

Adult↗
PubMed1983

Theophylline antagonizes diazepam-induced psychomotor impairment.

Eight healthy men received an oral dose of 0.25 mg/kg diazepam followed 40 min later by an intravenous infusion of 100 ml physiological sodium chloride solution, with or without 4.4 mg/kg theophylline. Psychomotor function was assessed after each blood sampling up to 5 h post-infusion. Thirty min after diazepam psychomotor performance measured by Card Sorting test and Digit Symbol Substitution test was impaired and subjects felt sleepy and could think less clearly (two factors of the Clyde Mood Scale). Theophylline antagonized the diazepam-induced impairment statistically significantly for up to 5 h and subjects felt less tense and less apprehensive (State Anxiety Inventory). Since pharmacokinetic parameters of diazepam seemed not to be different after theophylline, interaction at receptor level can be assumed.

Administration, Oral↗
PubMed1983

Plasma concentrations of delta-9-tetrahydrocannabinol and impaired motor function.

Fifty-nine volunteer subjects were allowed to smoke marijuana cigarettes until a satisfactory level of 'high' was obtained. They then had blood samples taken 5, 30, 90 and 150 min following smoking after which they were tested with the roadside sobriety test. Attempts to correlate passing or failing on three coordination tests with plasma concentrations of delta-9-tetrahydrocannabinol (THC) showed that if concentrations measured at 5 min were ignored, failures were almost inevitably associated with plasma concentrations of THC above 25-30 ng/ml. Overall, 94% of subjects failed to pass the test 90 min after smoking and 60% after 150 min, despite the fact that by then plasma concentrations were rather low. It would seem that establishing a clear relation between THC plasma concentrations and clinical impairment will be much more difficult than it has been for alcohol.

Adult↗
PubMed1983

Hemolyzed blood and serum levels of delta 9-THC: effects on the performance of roadside sobriety tests.

A pilot study was conducted to ascertain the range of induced hemolyzed blood/serum delta 9-tetrahydrocannabinol (delta 9-THC) concentrations in 58 human subjects. Subjects were tested within 5 min of smoking a delta 9-THC cigarette and then at half-hour intervals to 150 min. The subjects initially demonstrated a broad range of delta 9-THC hemolyzed blood levels, which settled within an hour to levels comparable to those measured in California drivers who had been stopped for impaired driving, arrested, and tested for delta 9-THC. Serum levels, when correlated with performance or roadside sobriety tests, demonstrated a broad range (5 to 183 ng/mL) of delta 9-THC levels and an "adaptation" effect in the subjects' perception of their own impairment. Although this preliminary study was not a double-blind placebo experiment, the overall performance of human subjects demonstrated the "adaptation" effect, which may be a significant factor in making judgments while performing such complex tasks as driving. Also, the effects of the drug extended beyond the period of elevated delta 9-THC blood levels, perhaps because of THC metabolites that may contribute to impairment or the persistence of THC in the central nervous system. This pilot study will lay the groundwork for a program designed to determine the epidemiology and behavior correlates of marijuana use in motorists.

Adult↗
PubMed1982

Single dose kinetics of deuterium labelled delta 1-tetrahydrocannabinol in heavy and light cannabis users.

Deuterium labelled delta 1-tetrahydrocannabinol was administered intravenously (5.0 mg) and by smoking (10.0 mg) to five heavy and four light marihuana users. All subjects smoked an estimated amount of 8.6-9.9 mg delta 1-tetrahydrocannabinol. The plasma levels of delta 1-tetrahydrocannabinol were followed for 48 hours and in two subjects fof 72 hours after administration. The systemic availability after inhalation calculated from the area under curve values was in the range of 27 +/- 10% for the heavy users and 14 +/- 1% for the light users. There was little difference between the groups with regard to the amount of smoked delta 1-tetrahydrocannabinol or plasma levels and area under curve values obtained after i.v. administration. Thus, it seems likely that the statistically significant difference in systemic availability of smoked delta 1-tetrahydrocannabinol was due to a more efficient smoking by the heavy users. It is also indicated that heavy users prefer slightly higher delta 1-tetrahydrocannabinol plasma levels than light users. Based on the area under curve values after i.v. administration, a plasma clearance of 760-1190 ml min-1 was calculated. The elimination half-life of delta 1-tetrahydrocannabinol is more than 20 hours. The present results do not suggest that tolerance or sensitivity to delta 1-tetrahydrocannabinol in heavy users is readily achieved.

Adolescent↗
PubMed1981

Aversive effects of naltrexone in subjects not dependent on opiates.

Naltrexone was given to ten opiate-free volunteer subjects following the same dosage schedule used for initiating treatment of opiate-dependent persons. During the three-week initiation period, three subjects dropped from the study owing to aversive effects of the drug. The remaining seven subjects reported similar unpleasant but tolerable effects. A separate group of ten volunteer subjects was given single doses of 50 or 100 mg of naltrexone or a naltrexone placebo on three separate occasions using blind controls. These subjects also reported aversive effects. The principal symptoms reported were loss of energy, gastrointestinal disturbances and mental depression. It is possible that these aversive reactions of naltrexone have limited acceptance of the drug as a treatment for opiate-dependent persons.

Adult↗
PubMed1980

Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking.

Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.

Administration, Oral↗
PubMed1978

Propranolol in experimentally induced stress.

The beta-adrenergic receptor-blocking drug, d,l-propranolol, was compared with placebo for relief of experimentally induced anxiety. Subjects were chosen on the basis of having high levels of trait anxiety. Stress was induced experimentally by two performance tests. Single 40-mg doses of propranolol significantly slowed the heart rate, suggesting a satisfactory pharmacologic effect of the drug. The treatment was not superior to placebo, however, on any other measure. The experimental model used had clearly demonstrated an antianxiety effect of single 5-mg doses of diazepam. Propranolol at the dose used had little effect on psychic anxiety as determined by this model.

Adolescent↗
PubMed1978

A model for evaluation of antianxiety drugs with the use of experimentally induced stress: Comparison of nabilone and diazepam.

Volunteer subjects were used to compare a potential antianxiety drug (nabilone, 2-mg single doses) with a standard drug (diazepam, 5-mg single doses). A double-masked design with placebo control was used. Volunteer subjects were selected on the basis of high levels of train anxiety and were tested by two anxiety-inducing procedures--the mirror drawing test and the Stroop color-word test. Anxiety induced by the experimental procedure was alleviated by diazepam and, to a lesser extent, by nabilone. Since doses of the two drugs may not have been equivalent, or the time courses identical, conclusions about their relative efficacy must be guarded. The experimental model is unusual in that antianxiety drugs can be tested in volunteer subjects for true antianxiety effects rather than for side effects, such as cognitive or motor impairment, sleepiness, or other signs of central nervous system depression.

Adolescent↗
PubMed1975

Action of delta-9-tetrahydrocannabinol. An approach to the active metabolite hypothesis.

The active metabolite hypothesis, that delta-9-tetrahydrocannabinol (THC) must be converted to its 11-hydroxy metabolite before it becomes active, was tested in a study of subjects chosen as rapid and slow hydroxylators of drugs on the basis of antipyrine and phenylbutazone plasma disappearance rates. Although the sample of subjects showed the customary wide variations in effects experienced after an intravenously administered dose of THC, it was impossible to correlate either the speed of onset, total intensity, or duration of these effects with speed of hydroxylation of drugs. Although 11-hydroxy-THC has unquestioned activity indistinguishable from THC itself, it need not necessarily be solely responsible for the pharmacologic activity of THC.

Adolescent↗
PubMed1970

Marihuana and temporal disintegration.

High oral doses of marihuana extract, calibrated for content of 1 (-)-Delta(1)-tetrahydrocannabinol, significantly impaired the serial coordination of cognitive operations during a task that required sequential adjustments in reaching a goal. This disintegration of sequential thought is related to impaired immediate memory.

Adult↗