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PubMed1977

Gilles de la Tourette's syndrome. Familial occurrence and precipitation by methylphenidate therapy.

Gilles de la Tourette's syndrome was independently ascertained in two male cousins once removed. Previous studies have shown familial clustering of individuals with tics, but no consistent pattern of inheritance of Tourette's syndrome has been apparent. The onset and later exacerbation of symptoms in our younger patient were associated with the administration of CNS stimulants given for excessive motor activity. The adverse effects of methylphenidate and dextroamphetamine therapy on Tourette's syndrome supports the hypothesis that this condition results from a relative excess of CNS catecholaminergic activity. Physicians prescribing these agents should inquire about the presence of tics in patients and their families.

Adult↗

PubMed1979

Sedative effects of apomorphine in an animal model of Huntington's disease.

The sedative effectiveness of apomorphine in a newly developed animal model of Huntington's disease was examined. The motor responses of rats with kainic acid lesions of the neostriatum to a sedative dose of apomorphine (50 micrograms/kg) was similar to that observed in intact controls. In contrast, compared to controls, a marked potentiation of the motor stimulant effects of dextroamphetamine was confirmed in the kainic acid-lesioned group. We suggest that the pathological changes underlying the symptoms observed in this animal model and in Huntington's disease do not include abnormalities in presynaptic dopamine receptors in the neostriatum.

Animals↗

PubMed1978

Chronic, multiple tics of Gilles de la Tourette's disease. CSF acid monoamine metabolites after probenecid administration.

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.

Adolescent↗

PubMed1989

Effects of renal clearance on plasma concentrations of homovanillic acid. Methodologic cautions.

Recently, there has been considerable interest in plasma concentrations of homovanillic acid (HVA) in various psychiatric disorders. Homovanillic acid is a weak organic acid, and its excretion probably resembles that of other organic acids (eg, p-aminohippuric acid) that are actively secreted by the kidney. Alterations in renal plasma flow can affect clearance of organic acids, resulting in changes in plasma concentrations. In our study, concentrations of plasma HVA and urinary HVA (from 24-hour urine collections) were measured in 20 prepubescent boys who received 3 weeks of placebo, dextroamphetamine sulfate, and fenfluramine hydrochloride in a randomized, double-blind, counterbalanced study of the treatment of attention-deficit disorder. Plasma HVA concentrations were significantly lower during fenfluramine treatment than during amphetamine treatment. This difference, however, seemed to be caused by alterations in renal clearance of HVA rather than changes in production. Whole-body production of HVA, as indexed by total urinary HVA excretion, was unaffected by the different treatments, while renal clearance of HVA did differ significantly between amphetamine and fenfluramine treatment. It seems that alterations in renal clearance can affect plasma HVA concentrations, which should be taken into account when plasma HVA is studied.

Child↗

PubMed2006

Modeling sensitization to stimulants in humans: an [11C]raclopride/positron emission tomography study in healthy men.

CONTEXT: In animals, repeated exposure to stimulant drugs leads to an enhanced drug-induced psychomotor response and increased dopamine release. This phenomenon, known as sensitization, may confer vulnerability to drug addiction or drug-induced psychosis in humans. A similar phenomenon, referred to as endogenous sensitization, is also believed to play a role in the emergence of positive symptoms in patients with schizophrenia. OBJECTIVE: To determine whether behavioral and neurochemical sensitization occur in healthy individuals after limited exposure to amphetamine in the laboratory. DESIGN: Open-label, 1-year follow-up of repeated amphetamine administration in healthy volunteers. SETTING: Department of Psychiatry, McGill University, and McConnell Brain Imaging Center, Montreal Neurological Institute. PARTICIPANTS: Ten healthy men (mean +/- SD age, 25.8 +/- 1.8 years). INTERVENTION: Three single doses of amphetamine (dextroamphetamine sulfate, 0.3 mg/kg by mouth) were administered on days 1, 3, and 5. MAIN OUTCOME MEASURES: Using positron emission tomography and [11C]raclopride, we measured dopamine release in response to amphetamine on the first exposure (day 1) and 14 days and 1 year after the third exposure. RESULTS: The initial dose of amphetamine caused dopamine release in the ventral striatum (a reduction in [11C]raclopride binding). Consistent with a sensitization-like phenomenon, 14 and 365 days after the third dose of amphetamine there was a greater psychomotor response and increased dopamine release (a greater reduction in [11C]raclopride binding), relative to the initial dose, in the ventral striatum, progressively extending to the dorsal caudate and putamen. A high novelty-seeking personality trait and self-rating assessments indicating impulsivity predicted proneness to sensitization. CONCLUSIONS: Sensitization to stimulants can be achieved in healthy men in the laboratory. This phenomenon is associated with increased dopamine release and persists for at least 1 year.

Administration, Oral↗

PubMedDate not supplied

A controlled trial of stimulant medication in children with the fragile X syndrome.

Attentional deficits and hyperactivity frequently are major problems for fra(X) boys. This study evaluated the effectiveness of 2 stimulant medications, methylphenidate and dextroamphetamine compared to placebo in 15 children (13 males, 2 females) with the fra(X) syndrome. A double-blind crossover design was used with outcome measures which included parent and teacher behavior checklists, a controlled observation period, continuous performance tasks and an actometer measure of movement. When the children were treated with methylphenidate only, improvement was seen in socialization skills and attention span according to teacher checklists. Ten children were clinically considered responders and treatment was continued after the study was completed.

Attention Deficit Disorder with Hyperactivity↗

PubMed1982

Maturation and d-amphetamine-induced changes in web building.

Webs of Araneus diadematus Cl. were obtained under drugged (dextroamphetamine) and control conditions at three age-periods in the development of the spider from juvenility to sexual maturity. Although certain features of construction are affected in all periods and some exhibit differential effects with age, it was not possible to separate the latter from changes in body mass between periods.

Age Factors↗

PubMed1991

Drug effects on orthostatic intolerance induced by bedrest.

Effective and practical preventive procedures for postflight orthostatic intolerance are highly desirable. The current practice of attempts to expand plasma volume by ingestion of salt and fluids before reentry has proven benefits. This study evaluated alternative options using fludrocortisone (F) to expand plasma volume (PV), dextroamphetamine (Dex) to enhance norepinephrine (NE) release and atropine (A) to reduce the effects of vagal stimulation. Seven subjects with proven post-bedrest orthostatic intolerance returned for a 7-day 6 degrees head-down bedrest study. F (0.2 mg) was given at 8:00 AM and 8:00 PM the day before and 8:00 AM the day the subjects got out of bed (2 hours before standing). PV was measured before and 1 hour after the last dose of F. D (5 mg) and A (0.8 mg) were then taken orally 1 hour before the stand test. F expanded PV by 16% and caused sodium retention. Four of the 7 subjects stood for 1 hour post-bedrest and HR, plasma NE and PRA responses to standing were greatly enhanced and sustained. Although there was a narrowing of pulse pressure, the ability to overcome orthostatic intolerance with these countermeasures was largely due to vasoconstriction and sustained high heart rate. The existing literature on pharmacologic countermeasures for post-flight and post-bedrest orthostatic hypotension is reviewed, and the results are discussed in that context.

Adult↗

PubMed1977

Sex differences in drug evaluations.

Twenty normal, nonobese subjects (10 males and 10 female) were administered a battery of seven psychomotor tests as well as affect checklists and physiological measurements on 6 alternate days. Subjects performed the entire battery predrug and at 45,90, and 135 min postdrug. Fenfluramine, dextroamphetamine, two combined doses of the drugs, and a placebo were given in a double-blind, repeated measures design. Findings revealed significant sex-based differences in initial performance on five of the seven psychomotor tasks and in two physiological measures, with males performing at higher levels than females. Additionally, sex differences in postdrug changes were found in three psychomotor and two physiological measures, with females evidencing greater change scores than males.

Adult↗

PubMed2001

What is a "low dose" of d-amphetamine for inducing behavioral effects in laboratory rats?

BACKGROUND: Because of the amphetamines' abuse potential and capability of exacerbating or inducing mood and psychotic disturbances, investigations of the behavioral effects of amphetamines commonly involve non-human animals, with the laboratory rat being by far the most common species used. Although investigators of the behavioral effects of amphetamine in rats sometimes refer to doses used as being "low", "moderate", "high", etc., it is not clear in what sense these terms apply. OBJECTIVES: To develop an operational definition of a low dose of amphetamine in rats, we reviewed studies that assessed the behavioral effects of dextroamphetamine (d-AMP) in rats in which some subset of doses, administered SC, IM or IP, was described as being "low". We then used the results of these studies to establish what the lowest effective dose ranges were across a variety of behavioral domains and compared these doses and their effects with those obtained with normal, healthy adult humans. RESULTS: While the range of the lowest doses used in the studies with rats was quite broad (0.025-2.0 mg/kg), the median lowest effective doses observed (in the studies using doses of 0.125 mg/kg or less) were between 0.125 and 0.165 mg/kg across the behavioral domains of consummatory behavior, unconditioned or spontaneous behavior, learned behavior, and drug discriminative control. This range of doses was also found to be comparable to the lowest behaviorally effective doses of d-AMP (SC or PO) in normal human adults, which suggests that the sensitivity to the behavioral effects of amphetamine in these two species is fairly comparable. CONCLUSIONS: Because of their ability to alter a wide variety of behaviors in rats, we conclude that low doses of d-AMP are in the 0.1-0.4 mg/kg range. Doses within this range typically: 1) constitute the ED50 in most drug discrimination/generalization procedures; 2) increase a variety of consummatory behaviors; 3) increase a variety of unconditioned or spontaneous motor activities; 4) increase low rate schedule-controlled behavior while exerting variable effects on high rate schedule controlled behavior; and 5) improve performance on some choice tasks, particularly those requiring sustained attention. Our analyses also indicate that, with respect to behavior, investigators do not always agree on what constitutes a low dose of amphetamine in rats and that doses assumed to be low for this species often are relatively high.

Animals↗

PubMed1999

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects.

RATIONALE: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy ["therapeutic index" (TI)] has fit well with clinical results. OBJECTIVES: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D1 antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT2 serotonergic/DA D1 and D2 antagonist) and DOD 647 (DA D1 and D2 antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine's neuropharmacology. METHODS: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. RESULTS: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2-4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3-5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses.

Amphetamine↗

PubMed2000

Psychostimulants in supportive care.

Psychostimulant medications have been used clinically and investigated in psychiatric populations, the medically ill, cancer patients and healthy people. This article discusses the pharmacology of dextroamphetamine, methylphenidate, pemoline (and other psychostimulants such as caffeine and ephedrine), their use in general medicine and cancer care, side effects, and abuse potential. Therapeutic use in children is addressed only insofar as it illustrates facets of their use in adults.

Adult↗

PubMed1979

The effect of psychotomimetics on therapist--patient matching of speech "rhythms".

This study examined the effects of lysergic acid (LSD) and dextroamphetamine (DA) on therapist--patient matching of speech rhythms (mean phrase period) in psychotherapy. LSD, DA, and placebo (PL) were administered repeatedly over a 1 1/2-year period to seven patients in a randomized double-blind design. The second, fourth, and sixth encounters with LSD, DA, and PL were analyzed. These therapy dialogues were processed by an on--off detector of speech which computed probabilities of vocalizing when already talking (T), when listening (L), and when pausing (P) for therapist and patient, respectively. The mean phrase period for the therapist and the patient was calculated from the vocalization probabilities (T, P). The results show that both LSD and DA significantly enhance therapist-patient matching of mean phrase period in the earliest (second) session, an effect that disappears for both drugs, but later for DA (sixth session) than for LSD (fourth session). At no time was this effect observed in PL sessions, nor was the matching a simple function of a therapist--patient convergence of the components (T, P) of the mean phrase period.

Adult↗

PubMed1982

Differential interaction between stressors and chronic amphetamine or phencyclidine upon operant behavior in the rat.

Three types of stress were examined for their effects upon fixed-ratio 15 (FR-15) operant behavior in Sprague-Dawley rats before and after chronic dextroamphetamine to determine if cumulated drug could interact with stress to produce a state of behavioral toxicity. Six daily s.c. injections of saline were given to rats following 30 min behavioral sessions. Thirty minutes of exposure to a cold environment (7 degrees C) or to electric footshock (2mA for 0.5 sec, 1 shock/min) had no significant effect upon FR-15 behaviour beginning 15 min afterward. Five daily s.c. injections of 2.5 mg dextroamphetamine/kg after behavioral sessions suppressed behavior during the following days an average of 12%. Rats were again stressed twenty-two hours after the sixth injection. Footshock further suppressed behavior to 26% of the unstressed, chronic amphetamine-treated control group. Cold exposure failed to suppress behavior significantly below control levels. A similar experiment employing cold water exposure (15 degrees C for 2 min) as the stressor showed that, although, this stressor suppressed FR-15 behavior to 53% of the previous day's rates and reduced body temperature 2.1 degree C, chronic amphetamine failed to interact with the cold water stress to suppress behavior further. In a third experiment, 4.5 mg phencyclidine/kg, s.c., given after 30-min FR-15 sessions for six days, failed to interact with the footshock stress to cause behavioral suppression different from control treatment. While stress can interact with chronic treatment with lipophilic drugs, the quality of the stress, and the physical and pharmacologic properties of the drug are important determinants of the outcome upon conditioned behavior.

Animals↗

PubMed1990

Conditioned aversion after delay place conditioning with amphetamine.

Male, Sprague-Dawley rats received subcutaneous injections of either dextroamphetamine sulfate (AMP; 3.0 mg/kg) or vehicle [VEH (phosphate buffer); 1 ml/kg] immediately before (standard conditioning) or after (delay conditioning) conditioning sessions in a place-conditioning paradigm. AMP was paired for 4 conditioning sessions with one compartment of a three-compartment place-conditioning apparatus; VEH was paired for 4 conditioning sessions with another compartment. Animals were then tested for place preference or aversion by determining the proportion of time spent in each compartment during a 15-minute test session. Standard conditioning with AMP produced a place preference while delay conditioning produced a place aversion. Similar findings had earlier been reported from studies involving conditioned place-preferences and aversions with nicotine. These studies demonstrated that the time of drug administration can be as strong a determinant of place-conditioning effects as the drug itself.

Animals↗

PubMed1990

Delayed effects of amphetamine or phencyclidine: interaction of food deprivation, stress and dose.

Tritium-labelled phencyclidine (PCP) hydrochloride (12 mg/kg) was injected SC for six consecutive days into two groups of eight male rats maintained at 85% of their initial free-feeding weights. Eight days after the last injection, electric footshock raised fat levels of PCP 28% over nonshocked controls, and lowered blood levels 18%, but did not alter brain levels of the drug significantly. Thus, application of an acute stressor does result in redistribution of tissue stores of phencyclidine as predicted in the literature; however, the direction of the redistributions was to fat, rather than to brain. To explore the relation of a long-term stressor (one that eliminates adipose tissue as a sink for mobilized PCP), exploratory behavior was evaluated in male rats during six days of food deprivation commencing after six daily injections of PCP HCl (2 or 4 mg/kg, SC). Exploratory behavior of the 4 mg/kg dose group was abruptly altered, compared to saline controls, at six days of food deprivation, when the rats' body weights were about 70% of initial weights and when body fat would be severely reduced or depleted. To assess replicability and generalizability of this phenomenon, PCP HCl (4 or 8 mg/kg, SC) or dextroamphetamine sulfate (3.2 or 6.4 mg/kg, SC) was injected into male rats for six days and food deprivation followed afterward for nine consecutive days, or until similar body weight reductions as in the first experiment were achieved. Again, exploratory behavior was altered in comparison to saline controls in phencyclidine-treated rats (at the 4 mg/kg dose level) when rats reached about 70% of initial weights.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMedDate not supplied

Relative efficacy of the proposed Space Shuttle antimotion sickness medications.

Space motion sickness has been estimated as affecting between 1/3 and 1/2 of all space flight participants. NASA has at the moment proposed a combination of promethazine and ephedrine (P/E) and one of scopolamine and dextroamphetamine (S/D), both given orally, as well as a transdermally applied scopolamine (TAS), as preventive and ameliorative measures. The reported double-blind study, tests the early phase actions and efficacy of the transdermal scopolamine (Transderm (TM)-V of ALZA Corporation) and compares these in detail to the oral medications. Motion sickness resistance was tested by standardized head movements while accelerating at 0.2 degree/sec2 to a maximum rotation of 240 degrees/sec, with an intermediate plateau of 10 min at 180 degrees/sec. To permit weighting motion sickness protection against other system influences, cardiovascular, psychological (subjective and objective), and visual parameter changes were documented for the three therapeutic modes. The relative impact of the various modalities on operational and experimental components of space missions is discussed. A comparison to intramuscularly administered promethazine (a backup therapeutic mode suggested for Space Shuttle use) is also included.

Administration, Cutaneous↗

PubMed1993

Comparison of treatment strategies for Space Motion Sickness.

Treatment strategies for Space Motion Sickness (SMS) were compared using the results of postflight oral debriefings. Standardized questionnaires were administered to all crewmembers immediately following Space Shuttle flights by NASA flight surgeons. Cases of SMS were graded as mild, moderate, or severe based on published criteria, and medication effectiveness was judged based on subjective reports of symptom relief. Since October 1989, medication effectiveness is reported inflight through Private Medical Conferences with the crew. A symptom matrix was analyzed for 19 crewmembers treated with oral combination of scopolamine and dextroamphetamine (scopdex) and 15 crewmembers treated with promethazine delivered by intramuscular i.m. or suppository routes. Scopdex has been given preflight as prophylaxis for SMS, but analysis showed delayed symptom presentation in 9 crewmembers or failed to prevent symptoms in 7. Only 3 crewmembers who took scopdex had no symptoms inflight. Fourteen out of 15 crewmembers treated with i.m. promethazine and 6 of 8 treated with promethazine suppositories after symptom development had immediate (within 1-2 h) symptom relief and required no additional medication. There were no cases of delayed symptom presentation in the crewmembers treated with promethazine. This response is in contrast to untreated crewmembers who typically have slow symptom resolution over 72-96 h. We conclude that promethazine is an effective treatment of SMS symptoms inflight. NASA policy currently recommends treating crewmembers with SMS after symptom development, and no longer recommends prophylaxis with scopdex due to delayed symptom development and apparent variable absorption of oral medications during early flight days.

Aerospace Medicine↗