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Biomedical subjects

A S Ward

Publications and source records attributed to A S Ward.

At least 19 recordsLinked to original sources
PubMed1999

Abstinence symptoms following oral THC administration to humans.

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral delta9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915-1700 hours), and in the evening engaged in private or social recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1-3, 8-11, and 16-19. Active THC was administered on days 4-7 (20 mg qid) and on days 12-15 (30 mg qid). Both active doses of THC increased ratings of "High," "Good Drug Effect," and "Willingness to Take Dose Again" compared to baseline (days 1-3). THC also increased food intake by 35-45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of "Anxious," "Depressed," and "Irritable," decreased the reported quantity and quality of sleep, and decreased food intake by 20-30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use.

Administration, Oral↗
PubMed1999

Abstinence symptoms following smoked marijuana in humans.

Symptoms of withdrawal after oral delta9-tetrahydrocannabinol (THC) administration have been reported, yet little is known about the development of dependence on smoked marijuana in humans. In a 21-day residential study, marijuana smokers (n = 12) worked on five psychomotor tasks during the day (0915-1700 hours), and in the evening engaged in recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day. Food and beverages were available ad libitum from 0830 to 2330 hours. Marijuana cigarettes (0.0, 1.8, 3.1% THC) were smoked at 1000, 1400, 1800, and 2200 hours. Placebo marijuana was administered on days 1-4 . One of the active marijuana doses was administered on days 5-8, followed by 4 days of placebo marijuana (days 9-12). The other concentration of active marijuana cigarettes was administered on days 13-16, followed by 4 days of placebo marijuana (days 17-20); the order in which the high and low THC-concentration marijuana cigarettes were administered was counter-balanced between groups. Both active doses of marijuana increased ratings of "High," and "Good Drug Effect," and increased food intake, while decreasing verbal interaction compared to the placebo baseline (days 1-4). Abstinence from active marijuana increased ratings such as "Anxious," "Irritable," and "Stomach pain," and significantly decreased food intake compared to baseline. This empirical demonstration of withdrawal from smoked marijuana may suggest that daily marijuana use may be maintained, at least in part, by the alleviation of abstinence symptoms.

Adult↗
PubMed1999

Effect of a selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in humans.

RATIONALE: Data in laboratory animals suggest that D1 receptor agonists may have potential utility for the treatment of cocaine abuse. OBJECTIVE: The effects of ABT-431, a selective agonist at the dopamine D1 receptor, on the reinforcing, cardiovascular and subjective effects of cocaine were investigated in humans. METHOD: Nine experienced cocaine smokers (8M, 1F), participated in nine self-administration sessions while residing on an inpatient research unit: three doses of ABT-431 (0, 2, 4 mg i.v.) were each given in combination with three doses of smoked cocaine (0, 12, 50 mg). ABT-431 was intravenously administered over a 1-h period immediately prior to cocaine self-administration sessions. A six-trial choice procedure (cocaine versus $5 merchandise vouchers) was utilized, with sessions consisting of: (a) one sample trial, where participants received the cocaine dose available that day, and (b) five choice trials, where participants chose between the available cocaine dose and one merchandise voucher. RESULTS: ABT-431 did not affect the number of times participants chose to smoke each dose of cocaine, but produced significant dose-dependent decreases in the subjective effects of cocaine, including ratings of "High," "Stimulated," dose liking, estimates of dose value, "Quality," and "Potency." Furthermore, there was a trend for ABT-431 (4 mg) to decrease cocaine craving. ABT-431 also increased heart rate, while decreasing systolic and diastolic pressure at each dose of cocaine. CONCLUSIONS: These data suggest that D1 agonists may have potential utility for the treatment of cocaine abuse.

Administration, Inhalation↗
PubMed1999

Fluoxetine-maintained obese humans: effect on food intake and body weight.

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.

Adult↗
PubMed1998

Effects of methysergide and loratadine on food intake, mood, and performance of humans living in a residential laboratory.

The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate (p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including "Vomiting," "Stomach Pain," and "Miserable." These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).

Adult↗
PubMed1998

Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.

Administration, Inhalation↗
PubMed1998

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

Adult↗
PubMed1997

Binge cocaine self-administration in humans: intravenous cocaine.

Cocaine is frequently used in intermittent cycles of repeated dosing, or "binges." This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of "I want cocaine" decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of "binge" cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use.

Adult↗
PubMed1997

Effects of d-amphetamine on task performance and social behavior of humans in a residential laboratory.

Six healthy adult male volunteers lived for 11 days in a residential laboratory. Acute effects of d-amphetamine (0, 5, or 10 mg/70 kg) on performance of tasks, social interaction, and self-reports of drug effects were measured. Each day, participants engaged in a 6.5-hr work period and a 6.5-hr recreation period. Beverages containing d-amphetamine or placebo were consumed daily before the work period and before the recreation period. d-Amphetamine increased response rate without affecting accuracy on some tasks. d-Amphetamine increased the proportion of time spent engaging in verbal interaction during the first but not the second week of study. No changes in self-reported drug effects were observed. Thus, d-amphetamine improved performance in the absence of stimulant-like subjective effects. This differentiation between performance and subjective effects confirms the importance of determining the effects of drugs on a range of behaviors.

Adult↗
PubMed1997

The effects of a monetary alternative on marijuana self-administration.

The availability of alternative reinforcers can reduce drug self-administration. This 21-day residential study investigated the effect of monetary alternatives on marijuana self-administration. Three female and four male participants performed computer tasks (baseline) in the morning before smoking a sample marijuana cigarette (0.0, 1.8, or 3.9% delta 9-tetrahydrocannabinol (THC) and receiving the sample alternative ($5.00 voucher). In the afternoon, participants had five opportunities to choose either the marijuana cigarette sampled earlier or a voucher for $5.00. Participants were required to meet a criterion level of task performance to obtain each choice. The monetary performance criterion varied from day to day (80, 100, or 120% of baseline); the marijuana performance criterion remained constant at 100% of baseline. Choices were delivered in the evening, after task completion. Marijuana choice varied as a function of THC concentration and criterion to earn money. Active marijuana was always chosen more often than placebo, and active and placebo marijuana were chosen over money when the criterion to earn money was high. Task performance improved when criteria were imposed, even after participants had smoked the sample marijuana cigarette. Subjective ratings of drug effects increased with increasing THC concentration, but did not predict choice. The availability of a monetary alternative was effective in shifting choice to self-administer marijuana, and marijuana choice was sensitive to contingency manipulations. The results further indicate that contingency manipulations may override the performance-impairing effects of marijuana observed in other studies.

Adult↗
PubMed1997

Binge cocaine self-administration by humans: smoked cocaine.

Tolerance develops to the cardiovascular and subjective effects of intravenous cocaine during single self-administration sessions, but diminishes within 3 h after the session ends. To examine whether a similar pattern of tolerance occurs to smoked cocaine, seven adult 'crack' cocaine users completed a protocol investigating changes in behavior during the repeated self-administration of smoked cocaine. During sessions, participants could self-administer up to 6 doses of smoked cocaine (50 mg per dose), one every 14 min. Both two- and three-day binge conditions were tested. During the two-day binge, a 2.5 h cocaine self-administration session began at 1200 h and again at 1600 h on two consecutive days, while during the three-day binge, self-administration sessions occurred at 1200 h and 1600 h on three consecutive days. The first one or two cocaine doses in each session increased cardiovascular and subjective effects ratings; subsequent cocaine inhalations during the session did not increase these measures further, suggesting the development of acute tolerance to these effects. Ratings of 'I want cocaine' decreased slightly across three days of repeated smoked cocaine self-administration, while anxiety scores increased slightly across three days, suggesting that some effects of smoked cocaine may persist beyond a binge.

Adult↗
PubMed1997

Factors influencing marijuana self-administration by humans.

The self-administration of marijuana cigarettes varying in tetrahydrocannabinol (THC) content was measured by having participants choose between marijuana and an alternative reinforcer, i.e., snack food. Twelve marijuana users (eight men, four women), in groups of four, participated in a 16-day residential study. Each day, participants had the opportunity to choose repeatedly between a marijuana cigarette and a snack. The THC concentration of the cigarette changed each day (0.0, 2.2 or 3.9% delta 9-THC w/w), as did the number of snack items (one or two); each THC concentration was compared to each snack condition twice. Days were divided into a work period (09.15-16.45 h), comprising performance and subjective-effects tasks, and a recreation period (17.15-23.30 h). Each day at 10.00 h, participants "sampled" a marijuana cigarette containing the delta 9-THC concentration available that day, and selected the number of snack items available that day. Six "choice" trials occurred from 14.00-19.00 h, when participants responded under a modified progressive ratio schedule for either marijuana or snacks. At 18.15 h, participants could participate in a 10-min math task, in which each correct answer earned $1.00. Cigarettes containing 2.2 or 3.9% delta 9-THC were self-administered more often than placebo. The only other factor influencing marijuana choice was the opportunity to earn additional money, with participants choosing not to smoke immediately before the math task. By the end of the study, active marijuana had smaller effects on ratings of "high", "stimulated," and "good drug effect." These data demonstrate that: (a) delta 9-THC is an essential reinforcing component of marijuana; (b) marijuana use may be manipulated by monetary contingencies; and (c) tolerance may develop more readily to marijuana's subjective effects than its reinforcing effects.

Adult↗
PubMed1996

Variations in cocaine self-administration by inbred rat strains under a progressive-ratio schedule.

This study investigated the influence of genetics on extent of cocaine taking in rats that were self-administering cocaine under a progressive-ratio schedule. Fischer 344, ACI and Brown Norway rats were subjects because previous genetic studies on dopamine receptor loci have indicated that these are genetically divergent strains. All subjects were assessed for acquisition and stability of cocaine self-administration under a progressive ratio schedule. Subsequently, a dose-effect curve for cocaine self-administration was determined for each strain. Fischer 344 rats maintained a higher average breaking point than did the ACI or Brown Norway strains. In addition, dopamine receptor antagonists differentially reduced the ability of cocaine to serve as a reinforcer across the three strains. The D1-selective dopamine receptor antagonist, SCH 23390, and the D2/D3-selective dopamine receptor antagonist, eticlopride were significantly more effective in reducing the self-administration of cocaine in Brown Norway rats than for the other two strains. The results of this study demonstrate that genetic differences may play an important role in determining responding under progressive-ratio schedules for cocaine, possibly due to differences in the reinforcing efficacy of cocaine.

Animals↗
PubMed1995

Arteriovenous fistulae complicating orthopaedic procedures.

Arterial injuries in general and arteriovenous fistulae in particular are uncommon complications of orthopaedic procedures. We report the case of a 75 year old patient who suffered an arteriovenous fistula following bone graft insertion for an un-united tibial fracture. Aetiology diagnosis and management of these potentially serious injuries are reviewed.

Aged↗
PubMed1994

Peripheral thrombolysis with tissue plasminogen activator. Results of two treatment regimens.

OBJECTIVE: The purpose of this study was to document the response to tissue plasminogen activator given as either a low-dose intra-arterial infusion or a bolus infusion in patients with peripheral arterial or bypass graft occlusion. DESIGN: Fifty thrombolytic procedures were carried out in 45 patients with a recent occlusion of a peripheral artery (41) or bypass graft (nine). A continuous infusion of 1.0 mg/h of tissue plasminogen activator was used in 27 patients (group A), while 23 patients were given a 20-mg bolus followed by an infusion of 1.0 mg/h (group B). Patients in the two groups were followed up for 12.1 +/- 9.3 months and 11.1 +/- 9.1 months, respectively. RESULTS: In group A, the angiographic lysis rate was 74% and clinical success rate was 67%. In group B, the comparable rates were 70% and 48%. Lysis was quicker when a bolus infusion was used, the mean lysis time being 14.4 +/- 7.9 hours compared with 26.7 +/- 9.4 hours following infusion alone (P = .0005). There was one instance of major hemorrhage in group A and eight in group B (P = .0022), including two patients with cerebral hemorrhage, one of whom died. CONCLUSION: Low-dose tissue plasminogen activator infusion is safe and reasonably effective, although a long treatment time is required. A bolus infusion regimen speeds lysis but is attended by a high incidence of serious hemorrhage.

Aged↗
PubMed1994

Thrombolysis with tissue-plasminogen activator: results with a high-dose transthrombus technique.

PURPOSE: Low-dose intraarterial tissue plasminogen activator (t-PA) is effective in peripheral thrombolysis but treatment time is prolonged. The aim of this study was to determine whether a transthrombus bolus of t-PA before low-dose infusion shortens lysis time. METHODS: Twenty-three patients with peripheral arterial or bypass graft occlusion were treated with an initial bolus of 20 mg t-PA followed by a continuous infusion of 1 mg/hr. RESULTS: Angiographic lysis was achieved in 16 patients (70%) with a mean time to complete lysis of 14.4 +/- 7.9 hours. Two patients had reocclusion on days 1 and 3, respectively. There were three deaths within the first week of treatment, one from cerebral hemorrhage and two from myocardial infarction. A clinically successful outcome was achieved in 11 patients (48%). Those patients with patency at 1 week maintained this response at a mean follow-up of 11.7 +/- 9.1 months. Thrombolysis was unsuccessful in seven instances. In three of these cases the infusion had to be discontinued prematurely because of serious hemorrhage. Of the seven unsuccessful cases, three patients subsequently underwent a femorodistal bypass, two were left with tolerable ischemic symptoms, and two required a major amputation. There were eight major bleeding complications (35%), four at or adjacent to the catheter entry site and four at a distance, including two cases of cerebral hemorrhage, one of which was fatal. CONCLUSIONS: Transthrombus bolus delivery of tissue plasminogen activator followed by a low-dose infusion shortens lysis time, but this technique appears to be associated with an increased risk of serious hemorrhage.

Adult↗
PubMed1994

Distant haemorrhagic effects in intra-arterial tissue plasminogen activator--the effect of a bolus dose.

Details are reported of four patients who developed serious distant haemorrhagic complications while undergoing peripheral arterial thrombolysis with intra-arterial tissue plasminogen activator (t-PA). The thrombolytic regime comprised a 20 mg bolus of t-PA followed by a continuous infusion of 1 mg/hr. Four additional cases of haemorrhage at the catheter entry site were also encountered in a group of 23 patients exposed to the bolus-infusion t-PA regimen. The high haemorrhage rate (31%) is a significant disadvantage of this thrombolytic protocol.

Aged↗