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Hyporesponsivity of chronic schizophrenic patients to dextroamphetamine.

Among the evidence supporting the dopamine hypothesis of schizophrenia is the finding that both amphetamine and methylphenidate hydrochloride, potent releasers of dopamine, can cause exacerbation of symptoms in the acute schizophrenic patient. The present report describes three experiments in which the effects of amphetamine in chronic schizophrenic patients were studied. In one of the experiments, orally administered, daily doses of 20 mg of dextroamphetamine sulfate given at 8 PM had little or no effect on the sleep duration of the subjects. In the other two experiments, doses up to 40 mg given orally also had little or no effect on the performance of the subjects on a variety of behavioral tests. There was no evidence of an exacerbation of the disease process in any of the subjects. The most consistent amphetamine effect was a dose-related increase in blood pressure. These results indicate that the chronic schizophrenic patient may be hyporesponsive to amphetamine and suggest that if the dopamine hypothesis is correct, then it must be modified to take into account these findings in the chronic patient.

Adult↗

Dextroamphetamine and cortisol in depression. Morning plasma cortisol levels suppressed.

Dextroamphetamine sulfate administered intravenously in the morning to 11 unmedicated depressed patients suppressed previously elevated plasma cortisol levels to normal in 90 minutes, a fall of 33% from baseline. Ten other depressed patients, without amphetamine, maintained high cortisol levels during the same time period. In each of five normal young men, amphetamine identically administered stimulated a rise in cortisol between 15 and 30 minutes after infusion, an acute response absent in ten of the 11 depressed patients; by 90 minutes after amphetamine administration, plasma cortisol had fallen to normal and identical levels in both groups. Since noradrenalin normally inhibits hypothalamic corticotropin releasing factor (and adrenocorticotropic hormone) secretion, a noradrenergic deficit may account for cortisol hypersecretion in depression; amphetamine may transiently "correct" this deficit in depressed patients, thereby reducing their cortisol secretion.

Adult↗

Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men.

The effects of a single oral dose of dextroamphetamine sulfate on motor activity, vigilance, learning, and mood were compared for normal and hyperactive prepubertal boys and normal college-aged men using a double-blind crossover design. Both groups of boys and men showed decreased motor activity increased vigilance, and improvement on a learning task after taking the stimulant drug. The men reported euphoria, while the boys reported only feeling "tired# or "different# after taking the stimulant. It is not clear whether this difference in effect on mood between adults and children is due to differing experience with drugs, ability to report affect, or a true pharmacologic age-related effect. While there were some quantitative differences in drug effects on motor activity and vigilance between these different groups, stimulants appear to act similarly on normal and hyperactive children and adults.

Adolescent↗

Effects of marihuana-dextroamphetamine combination.

Under a double blind, randomized, complete block design, subjects were given either placebo and 10 mg/70 kg dextroamphetamine sulfate (A) orally followed 1 1/2 hr later by a marihuana cigarette (M) prepared to deliver 50 mug/kg delta-9-tetrahydrocannabinol (THC). Statistical analyses suggested that heart rate and blood pressure increased in an additive manner when both drugs were given. Electrocardiogram changes, when present, were nonspecific in character and appeared to be associated with marihuana. In a second study, psychomotor performance was evaluated by a similar design using doses of 10 mg/70 kg of A and M prepared to deliver 25 mug/kg THC. Impairment was related to smoking of M, and no difference could be distinguished between M alone and M-A combination. Subjective evaluation, as measured by the modified Cornell Medical Index (CMI) demonstrated only additive effects for the combination.

Adult↗

Synthesis of dextroamphetamine sulfate and methamphetamine hydrochloride from D-phenylalanine.

Starting from D-phenylalanine, dextroamphetamine sulfate and methamphetamine hydrochloride were synthesized. The reaction sequence proceeds through three intermediates, in which the absolute configuration of the asymmetric carbon atom is changed but the relative configuration remains the same. Either product can be obtained from a common intermediate by altering the reductive conditions employed for the removal of a carbamate protecting group.

Dextroamphetamine↗

Elevated blood pressure in the embryonic chick induced by a teratogenic dose of dextroamphetamine sulfate.

Previous work has demonstrated the cardiovascular teratogenicity of dextroamphetamine sulfate (0.25 mg/egg) in the 4-day (stage 24) chick embryo. Our current studies indicate that embryos treated with this teratogenic dose of d-amphetamine exhibit a mean ventricular blood pressure (MVBP) elevation for 1 hour at 4 hours after treatment. The mean MVBP value 4 hours after d-amphetamine treatment significantly exceeded the mean MVBP value for combined untreated and saline controls by 30%. Furthermore, d-amphetamine significantly decreased heart rate relative to controls by 6-9% at 2, 3, and 5 hours after administration. Elevation of embryonic blood pressure (measured by a water manometer system) during a critical period of aortic arch and ventricular septal morphogenesis is suggested as an etiological factor in the genesis of malformations of these structures.

Animals↗

The effects of dextroamphetamine on kinesthetic figural aftereffects.

The effect of dextroamphetamine, primarily a central stimulant, on kinesthetic figural aftereffects (KFAEs) was examined. The subjects were selected after preliminary testing with the Eysenck Personality Inventory and were classified into three groups: extraverts, ambiverts, and introverts. d-Amphetamine was used at three dose levels and a control group was included for purposes of comparison. The 3 X 4 randomized block design was replicated ten times. KFAEs were measured under two sets of conditions, i.e., before and after the induction experience. The results support the following conclusions: (1) neither personality grouping nor drug treatment during preinduction trials significantly affected KFAE; (2) both types of variables were, however, significantly related to behavior during the postinduction trials; (3) the extraverted subjects showed larger KFAEs than ambiverted and introverted subjects under placebo condition; (4) the extent of KFAE was reduced in extraverted and enhanced in introverted subjects under the influence of the drug; (5) there were significant interactions between the drug treatments and personality variables in effects on KFAE.

Adolescent↗

Dopamine receptor sensitivity after chronic dopamine agonists. Striatal 3H-spiroperidol binding in mice after chronic administration of high doses of apomorphine, N-n-propylnorapomorphine and dextroamphetamine.

Several previous reports have demonstrated that chronic administration of both directly and indirectly acting dopamine agonists produces a supersensitive behavioral response to challenge doses of dopamine agonists when compared to the responses induced by acute administration of these drugs. That is, a given dose of a dopamine agonist will produce a greater response after chronic dopamine agonist treatment than is observed upon acute administration of that dose. A similar behavioral phenomenon resulting from chronic administration of dopamine antagonists has been suggested to be due to an increase in the number of dopamine receptors present in relevant brain areas. The same hypothesis has been put forward for the hypersensitivity induced by chronic dopamine agonist administration. The present study was designed to investigate the effect of chronic administration of high doses of both direct and indirect dopamine agonists on the dopamine receptors labeled by 3H-spiroperidol. Groups of animals (CD-1 mice) were sacrificed 1, 3 and 5 days following the last chronic injection. Striatal tissue from these mice was incubated with 3H-spiroperidol and dopamine receptor binding evaluated. Affinity of the receptors for the ligand was unaltered by treatments. The receptors labeled by 3H-spiroperidol showed no significant differences in number following the chronic administration of high doses of apomorphine (30 mg/kg). The Bmax was significantly decreased at only one time period following chronic administration of dextroamphetamine (4 mg/kg); however, there was a dramatic 30% reduction in the Bmax in striatal tissue from those mice treated with N-n-propylnorapomorphine. These results suggest that the hypersensitive behavioral response in mice following chronic administration of direct and indirect acting dopamine agonists is not due to an increase in the number of dopamine receptors in the striatum which are labeled by 3H-spiroperidol.

Animals↗

Dextroamphetamine-induced changes in regional cerebral blood flow.

Regional cerebral blood flow (CBF), blood pressure, pulse rate, respiratory rate, end-tidal carbon dioxide and mood states were measured before and after IV injections of 15 mg dextroamphetamine sulfate or saline in 22 physically and mentally healthy normal volunteers. Amphetamine administration was associated with significant increases in systolic blood pressure and vigor and decrease in end-tidal carbon dioxide. There were no significant differences between the amphetamine and saline groups on CBF changes. However, there was a non-significant trend towards a post-amphetamine CBF reduction, even after the flow values were corrected for the acute changes in CO2.

Adult↗

A comparison of the acute effects of dextroamphetamine and fenfluramine in depression.

Fenfluramine (Fen) 40 mg, a selective releaser of serotonin, and dextroamphetamine (Dex) 15 mg were administered in a double-blind crossover design to 16 subjects with major affective disorder, depression. Three hours after administration both drugs significantly improved depression and improved vigor, fatigue, and confusion-bewilderment on the subscales of the Profile of Mood States. Dex was significantly better than Fen only on the vigor and fatigue subscales. Other data from this study suggest that when used acutely Fen can mimic long-term antidepressant effects, whereas the acute effects of Dex are similar to its stimulating effects in normals.

Adult↗

Different pattern of association of beta-endorphin and cortisol responses to dextroamphetamine in postmenopausal women and young men.

A negative correlation between plasma beta-endorphin and cortisol responses to 0.15 mg/kg dextroamphetamine i.v. was found in a group of seven normal postmenopausal women, while the responses of the two hormones were positively correlated in nine normal young men. These results suggest that even though the adrenocorticotropic hormone (ACTH)-cortisol and beta-endorphin are usually regulated by the same mechanism (both ACTH and beta-endorphin are derived from proopiocortin), there are situations in which these systems can be associated in a different pattern. The elucidation of these situations may contribute to the understanding of regulatory mechanisms of the two systems.

Adult↗

Methylphenidate and dextroamphetamine treatments of hyperactivity: are there true nonresponders?

The response to stimulant drugs of 48 boys with attention deficit/hyperactivity disorder was measured following dextroamphetamine, methylphenidate, and placebo in a double-blind crossover study. To distinguish lack of behavioral improvement from adverse drug effects, a day hospital setting and a wide dose range were used. Both drugs were highly and equally efficacious for the group as a whole, and frequently one drug or the other was superior for an individual child, or adverse effects occurred only on one of the stimulants. Only one of the 48 boys (2%) was discharged without the recommendation for continued stimulant drug treatment. "Nonresponse" appears to be extremely rare when both stimulants and a wide range of doses are given.

Analysis of Variance↗

Side effects of dextroamphetamine and methylphenidate in hyperactive children--a brief review.

Four of the most commonly reported side effects of dextroamphetamine ( Dexedrine ) and methylphenidate (Ritalin), viz., anorexia, insomnia, stomach pains, and weight loss, were reviewed, with special attention to growth suppression accompanying weight loss. The available evidence indicates that the effects of insomnia, anorexia, and stomach pains are transient and diminish as treatment continues and as medication is properly managed. There is evidence for growth suppression accomapnying weight loss, and possibly some suppression of stature, but these effects are not long-lasting and, from existing evidence, seem to have little effect on adult height or weight.

Anorexia↗

Parthenolide inhibits the contractile responses of rat stomach fundus to fenfluramine and dextroamphetamine but not serotonin.

The isolated rat stomach fundus preparation, a sensitive bioassay to evaluate serotonin-(5-HT) like activity, was used as a model to study the effects of parthenolide (PAR), a component to Tanacetum parthenium (feverfew), on 5-HT storage, release and stimulation of the 5-HT2B receptor. Cumulative-concentration response curves to 5-HT and the indirect-acting serotonergics fenfluramine (F) and dextroamphetamine (DA) on fundus were obtained in the presence and absence of 1 x 10(-6) to 1 x 10(-5) PAR. 5-HT release elicited by F and DA was indirectly assessed by comparing the contraction elicited by these compounds on tissues from reserpine-treated, L-p-chlorophenylalanine (l-PCPA)-treated and untreated rats. The observed order of agonist potencies on intact fundus was: 5-HT > DA > F and the order of intrinsic activity was: 5-HT > DA > F. PAR did not show agonist effects nor antagonism toward 5-HT on rat fundus at all concentrations used. However, PAR antagonized non-competitively the effects of F and DA. Contractile responses to 5-HT were not significantly different on mucosa-denuded fundus and tissue strips from untreated, l-PCPA- and reserpine-treated rats. PAR appears to inhibit 5-HT release mediated responses by the indirect-acting 5-HT agonists on fundal tissue.

Animals↗

Dextroamphetamine or methylphenidate as adjuvants to opioid analgesia for adolescents with cancer.

The doses of opioid analgesics required to control pain in patients with cancer may result in somnolence and reduced interaction with family members. Psychostimulants such as dextroamphetamine (DA, Dexedrine) or methylphenidate (MP, Ritalin) have been used in adults to counteract the sedation of opioid analgesia. We retrospectively reviewed our experience using these agents at Children's Hospital. Eleven patients (age 12-20 years) received DA or MP, and decreased somnolence or improved interaction was noted in five patients. Adverse effects potentially related to DA or MP were noted in two patients, none of which resulted in discontinuance of the stimulant. Further prospective, controlled studies are needed to assess the safety and efficacy of DA and MP in counteracting the sedation of opioid analgesia in children and adolescents.

Adjuvants, Pharmaceutic↗

Dextroamphetamine modulates the response of the human amygdala.

Amphetamine, a potent monoaminergic agonist, has pronounced effects on emotional behavior in humans, including the generation of fear and anxiety. Recent animal studies have demonstrated the importance of monoamines, especially dopamine, in modulating the response of the amygdala, a key brain region involved in the perception of fearful and threatening stimuli, and the generation of appropriate physiological and behavioral responses. We have explored the possibility that the anxiogenic effect of amphetamine in humans reflects the drug's influence on the activity of the amygdala. In a double-blind placebo controlled study, fMRI revealed that dextroamphetamine potentiated the response of the amygdala during the perceptual processing of angry and fearful facial expressions. Our results provide the first evidence of a specific neural substrate for the anxiogenic effects of amphetamine and are consistent with animal models of dopaminergic activation of the amygdala.

Adult↗

The effects of hyperbaric air in combination with ethyl alcohol and dextroamphetamine on serial choice-reaction time.

The effects of ethyl alcohol (1.5 ml/kg body weight) and dextroamphetamine (15 mg) on nitrogen narcosis were investigated in two experiments using a 2-, 3- and 4-choice serial reaction time (RT) task with accuracy held constant. Narcosis was induced with air at 6.4 atmospheres absolute (ATA) and a heliox mixture was used as a control. Heliox at 6.4 ATA did not affect RT. Alcohol alone and air at 6.4 ATA increased the intercept of the Hick-Hyman function whereas amphetamine alone decreased it. The increased intercept with air at 6.4 ATA was exacerbated additively by alcohol and ameliorated antagonistically by amphetamine. The slope of the Hick-Hyman function was unaffected. Frequency distributions were shifted as a whole and their shapes were unaltered. It is concluded that these data are consistent with the slowed processing model which proposes that the effects of narcosis on performance are due to a decrease in arousal in conjunction with secondary changes in task strategy.

Adult↗

A possible clonidine-trazodone-dextroamphetamine interaction in a 12-year-old boy.

A 12-year-old boy on a dextroamphetamine-clonidine-trazodone treatment regimen had a recurrence of insomnia, and his bedtime trazodone dose was doubled from 50 mg to 100 mg. Within 45 mins after taking the first 100-mg trazodone dose on an empty stomach, the patient had a syncopal episode associated with hypotension, bradycardia, and sedation. The drug reaction could have resulted from either trazodone or clonidine, but it is more likely to have resulted from a pharmacodynamic clonidine-trazodone interaction, presumably aggravated by rapid absorption (on an empty stomach) of a recently increased dose of trazodone. It is conceivable but less likely that the psychostimulant was a clinically significant factor. However, a drug interaction between clonidine and D-amphetamine does not need to be postulated to explain this child's syncopal reaction. The authors advise that (1) if trazodone and clonidine are used concurrently, the doses of both agents should be changed slowly, (2) blood pressure and pulse should be carefully monitored at baseline and then periodically during treatment, and (3) administration of trazodone on an empty stomach, and especially dose increases on an empty stomach, should be avoided. Physicians should remain aware that trazodone has the potential to produce hypotension and sedation, especially when combined with other agents (such as clonidine) that might produce the same adverse effects.

Antihypertensive Agents↗