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PubMed2001

Aberrant behavioral effects of a dopamine D1 receptor antagonist and agonist in monkeys: evidence of uncharted dopamine D1 receptor actions.

BACKGROUND: Basic research indicates a role for dopamine (DA) D1 antagonism in the treatment of schizophrenia. Clinical trials have not confirmed any role. Besides the defining second messenger (adenylyl cyclase [AC]), DA D1 receptors are linked to other effectors (e.g., phospholipase C [PLC]). Differing actions of DA D1 antagonists upon differing effectors could explain conflicting results between the lab/clinic. METHODS: In a monkey model in which behavioral effects of DA D1 antagonists/agonists have been well characterized we examined: 1) SKF 83959, biochemically, a DA D1 antagonist, behaviorally a DA D1 agonist, and 2) SKF 83822, biochemically, a DA D1 agonist, which, unlike all previously tested DA D1 agonists, does not also stimulate PLC. SKF 83959 and SKF 83822 were given alone and combined with DA D1 and D2 agonists, antagonists, and dextroamphetamine (AMP). RESULTS: SKF 83959 acted as a DA D1 agonist (induced oral dyskinesia given alone, counteracted DA D1 antagonist [NNC 756], induced dystonia, and did not inhibit AMP induced behaviors). SKF 83822, unlike previously studied DA D1 agonists, did not induce dyskinesia, but resulted in a state of extreme arousal and locomotor activation without stereotypy, effectively counteracted by NNC 756, but not by SKF 83959 nor raclopride (DA D2 antagonist). CONCLUSIONS: It is hypothesized that: 1) dyskinesia is linked to PLC stimulation; 2) DA D1 agonism can play a role in the induction of psychosis, via a mechanism linked neither to AC nor PLC, and 3) DA D1 antagonists differ in antipsychotic potential, possibly via this unidentified mechanism.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1985

Testicular cancer in homosexual men with cellular immune deficiency: report of 2 cases.

Embryonal cell carcinoma of the testis was seen in 2 homosexuals with peripheral lymphadenopathy of the head and neck, and abnormal cellular immunity measured by reduced T helper cells and increased T suppressor cells. One patient had no history of venereal disease but had taken marijuana, nitrites and methyl-dextroamphetamines regularly. The other patient had a history of syphilis, gonorrhea, hepatitis and venereal warts but rarely used inhalant recreational drugs. Both patients had smoked cigarettes. Neither patient had any known risk factors that predisposed to testicular cancer. Biopsy of a supraclavicular lymph node in 1 patient showed histological features of reactive follicular hyperplasia similar to those described previously in the acquired immune deficiency syndrome. These cases of testicular cancer increase the spectrum of rare cancers developing in young male homosexuals with acquired cellular immune abnormalities.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Pharmacotherapies for attention-deficit/hyperactivity disorder: expected-cost analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood neurobehavioral disorder characterized by inattention, hyperactivity, and impulsivity. Prevalence estimates in elementary school children generally range from 3% to 8%. ADHD is frequently treated with psychostimulant medications, which have been shown to improve both cognitive and behavioral outcomes for most children. OBJECTIVE: The goal of this study was to estimate the total expected costs for the treatment and management of school-age children with ADHD using 6 commonly prescribed pharmacotherapies: methylphenidate immediate-release/extended-release (MPH IR/ER), methylphenidate immediate-release (MPH IR), Metadate CD (branded MPH IR/ER), Concerta (branded MPH ER), Ritalin (branded MPH IR), and Adderall (a combination of dextroamphetamine and amphetamine salts). METHODS: A literature review and clinical assessment using a 27-question survey instrument were used to capture information on the clinical characteristics of ADHD, including common treatment regimens, clinical management of patients, pathways of care, and components of care. A meta-analysis provided response rates for 3 commonly used pharmacotherapies: Metadate CD, MPH IR, and Adderall. Information from the clinical assessment and the meta-analysis were used to populate a decision-analytic model to compute total expected cost for each comparator. RESULTS: The average total annual expected cost per patient was $1,487 for Metadate CD, $1,631 for Concerta. $1,792 for MPH IR/ER, $1,845 for MPH IR, $2,080 for Ritalin, and $2,232 for Adderall. CONCLUSIONS: Metadate CD had the lowest total expected cost and Adderall had the highest total expected cost among the ADHD pharmacotherapies evaluated. The differences were attributable to differences in drug-acquisition costs and the need for in-school dosing of twice-daily and thrice-daily medications.

Amphetamines↗
PubMed2002

Methylphenidate elevates resting dopamine which lowers the impulse-triggered release of dopamine: a hypothesis.

How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? In summary, the hypothesis for the anti-hyperactivity effects of the stimulants is as follows: during normal nerve activity, extracellular dopamine levels transiently rise 60-fold. At low therapeutic doses (0.2-0.5 mg/kg) to treat attention-deficit hyperactivity disorder, stimulant drugs such as methylphenidate and dextroamphetamine reduce locomotion in both humans and animals. The drugs raise resting extracellular levels of dopamine several-fold, but reduce the extent to which dopamine is released with nerve impulses, compared to the impulse-associated release in the absence of the drug. This relatively reduced amplitude of impulse-associated dopamine would result in less activation of post-synaptic dopamine receptors which drive psychomotor activity. At higher doses, stimulants produce generalized stimulation of the nervous system, as a result of the very high concentrations of extracellular dopamine at rest, and the markedly increased release of dopamine with nerve impulses. These high levels of resting and pulsatile dopamine cause widespread stimulation of post-synaptic dopamine receptors, overcoming any concomitant presynaptic inhibition of dopamine release.

Central Nervous System Stimulants↗
PubMed1996

Use of stimulants in the medically ill.

This article discusses the use of psychostimulants, such as dextroamphetamine, methylphenidate, and pemoline, in a variety of illnesses, including depression in the medically ill, cancer, HIV, and AIDS. The chemistry and pharmacology, side effects, drug interactions, dosing, and abuse potential also are reviewed.

Central Nervous System Stimulants↗
PubMed1996

Postherpetic neuralgia and its treatment: a retrospective survey of 191 patients.

One hundred and ninety-one patients with postherpetic neuralgia (PHN) in whom treatment was begun 3 or more months after acute herpes zoster (HZ) were retrospectively considered. Relieved (> or = 75% fall in visual analogue score for worst pain within last 24 hr) and unrelieved groups were subdivided into those who had and those who had not received antiviral treatment for their acute shingles. More than 90% of all patients experienced allodynia with a clinically evident sensory deficit for temperature and/or pinprick sensation. The probability of relief is worst in patients with PHN of the isolated ophthalmic nerve and of the brachial plexus, and best when involving the jaw, neck, and trunk. The presence (90%) or absence of allodynia has no predictive significance; but the small number of patients without allodynia or sensory deficit (all of whom had had antiviral treatment for their acute shingles) all improved. The probability of pain relief was found to correlate very strongly with the brevity of the interval between rash onset and commencement of treatment with an adrenergically active antidepressant. Further, time to relief in patients treated with an antidepressant starting at the same interval after HZ is significantly shorter in patients who received acyclovir for their original HZ. With the possible exception of dextroamphetamine added to the antidepressant, other treatments (particularly analgesics, anticonvulsants, and sympathetic blockade) were found to be without value in most cases. Thirty percent of patients who recover from PHN and have had their original shingles treated with acyclovir subsequently suffer from severe itching. It is recommended that elderly patients be given low-dose antidepressant on diagnosis of shingles, and asked to report back in 6 weeks. If they are pain-free at this interval, low-dose antidepressant should be continued for another month or so and then stopped. If, however, pain is present at 6 weeks, the dose of antidepressant should be increased and the patient reviewed every 2 months.

Aged↗
PubMed1999

Chronic dopamine D1, dopamine D2 and combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys: antiamphetamine effects and extrapyramidal side effects.

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Amphetamine↗
PubMed1999

PET measures of amphetamine-induced dopamine release in ventral versus dorsal striatum.

Regional differences in dextroamphetamine (AMPH)-induced dopamine (DA) release in the baboon striatum were assessed using positron emission tomographic (PET) measures of [11C]raclopride specific binding to DA D2/D3 receptors acquired before and after AMPH administration. The magnitude of the reduction in [11C]raclopride binding, following AMPH administration, was two-fold greater in the anteroventral striatum (comprised of ventral caudate, anteroventral putamen, and nucleus accumbens) than the dorsal striatum (dorsal caudate). A simulation study demonstrated that any potential biases due to resolution (partial volume) and alignment effects were significantly smaller than the magnitude of the observed results. These regional differences in the sensitivity of AMPH are compatible with microdialysis evidence in rats indicating that the magnitude of DA release in response to AMPH concentrations in the range tested is greater in ventral than dorsal striatal regions. Post hoc tests involving measures in other striatal regions showed that the baseline DA D2/D3 binding was highest and the correlation between AMPH dose and change in [11C]raclopride binding most significant in the putamen.

Amphetamine↗
PubMed2002

Attention deficit disorder in adults.

ADHD/ADD, once thought to occur only in children, is now recognized as continuing into adulthood in many people. In order to be labeled as such, signs and symptoms must start before age 7 and are primarily characterized by inattention, distractibility, and impulsiveness. Although the exact mechanism is unknown, a number of associated neurochemical and structural abnormalities have been observed. This disorder can negatively affect the educational, social, and occupational lives of those who suffer from its symptoms. It interferes with the ability to establish and maintain close relationships. Pharmacotherapy remains the primary mode of treatment. Stimulants such as dextroamphetamine and methylphenidate are the main drugs utilized; they are available in immediate and longer duration versions. Bupropion is another important medicinal option, and there are a variety of other miscellaneous medications to consider, including modafinil, venlafaxine, tricyclic antidepressants, and guanfacine. Psychotherapy is shown to help control impulsiveness, form more satisfactory relationships, rear children more effectively, and improve organizational and problem-solving skills.

Adult↗
PubMed1999

Neuropsychiatric aspects of carbon monoxide poisoning: a review and single case report suggesting a role for amphetamines.

Sublethal exposure to carbon monoxide (CO) can result in severe neurologic and psychiatric complications. Once in the body, CO can wreak havoc on virtually every organ system, with the brain being the most vulnerable to the damaging effects. Neuropathological injury is frequently widespread, and while white matter injury is most common, both gray and white matter injury occurs. Consequently, no neurologic or psychiatric syndrome is pathognomonic for CO poisoning. There are currently no effective treatments for the delayed neuropsychiatric sequelae of CO poisoning, and medical management focuses on correcting immediate symptoms through the use of oxygen, hyperbaric oxygen therapy, and supportive measures. Preliminary data suggest, however, that dopaminergic agents may be useful for the treatment of some of the delayed sequelae of CO neurotoxicity. To our knowledge, ours is the first case report in which dextroamphetamine (DAMP), a potent dopaminergic agent, has been used for treating the neuropsychiatric symptoms of CO poisoning. Our data demonstrate that it is effective in shortening cognitive and motor recovery time, that psychostimulant actions occur slightly sooner than locomotor effects, and that theraputic benefit is most dramatic within the first ten days of use. Therefore, DAMP appears to be a pharmacological agent that can be combined with supportive interventions to reverse, attenuate, or symptomatically improve the delayed sequelae that occur in these patients.

Amphetamines↗
PubMed2000

Functional deficits in basal ganglia of children with attention-deficit/hyperactivity disorder shown with functional magnetic resonance imaging relaxometry.

Attention-deficit/hyperactivity disorder is a highly heritable and prevalent neuropsychiatric disorder estimated to affect 6% of school-age children. Its clinical hallmarks are inattention, hyperactivity and impulsivity, which often respond substantially to treatment with methylphenidate or dextroamphetamine. Etiological theories suggest a deficit in corticostriatal circuits, particularly those components modulated by dopamine. We developed a new functional magnetic resonance imaging procedure (T2 relaxometry) to indirectly assess blood volume in the striatum (caudate and putamen) of boys 6-12 years of age in steady-state conditions. Boys with attention-deficit/hyperactivity disorder had higher T2 relaxation time measures in the putamen bilaterally than healthy control subjects. Relaxation times strongly correlated with the child's capacity to sit still and his accuracy in accomplishing a computerized attention task. Daily treatment with methylphenidate significantly changed the T2 relaxation times in the putamen of children with attention-deficit/hyperactivity disorder, although the magnitude and direction of the effect was strongly dependent on the child's unmedicated activity state. There was a similar but nonsignificant trend in the right caudate. T2 relaxation time measures in thalamus did not differ significantly between groups, and were not affected by methylphenidate. Attention-deficit/hyperactivity disorder symptoms may be closely tied to functional abnormalities in the putamen, which is mainly involved in the regulation of motor behavior.

Attention Deficit Disorder with Hyperactivity↗
PubMed2000

Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder.

The gene for the synaptic vesicle docking fusion protein, synaptosomal-associated protein of 25 kDa (SNAP-25), has been implicated in the etiology of attention-deficit hyperactivity disorder (ADHD) based on the mouse mutant strain coloboma. This neutron-irradiation induced mouse strain is hemizygous for the deletion of the SNAP-25 gene and displays spontaneous hyperactivity that is responsive to dextroamphetamine. Because of these characteristics, this strain has been suggested to be a mouse model for ADHD. We identified using single stranded conformational polymorphism analysis (SSCP) four DNA sequence variants in the 3' untranslated region of the human SNAP-25 gene. We searched for polymorphisms in the 3' untranslated region because the intron/exon structure of this gene has not yet been determined. We tested for linkage of this gene and ADHD using two of the identified polymorphisms that change a restriction enzyme recognition site. We examined the transmission of the alleles of each of these polymorphisms and the haplotypes of both polymorphisms using the transmission disequilibrium test in a sample of 97 small nuclear families consisting of a proband with ADHD, their parents, and affected siblings. We observed biased transmission of the haplotypes of the alleles of these two polymorphisms. Our findings are suggestive of a role of this gene in ADHD.

Adolescent↗
PubMed2005

The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.

The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD.

Animals↗
PubMed1993

Effects of extracts of Tetraselmis suecica and Isochrysis galbana on the central nervous system.

In the course of our continuing pharmacological studies of marine microalgae, we look now at Tetraselmis suecica Stewart (Prasinophyceae) and Isochrysis galbana Demart (Haptophyceae), assessing the effects which aqueous extracts of these algae exert upon the central nervous system. To this end, we have tested for effects upon the following: spontaneous motor activity, body temperature, motor coordination, dextroamphetamine-induced hypermotility, exploratory conduct, muscle relaxation, catalepsy, conditioned avoidance response, oxotremorine-induced cholinergic syndrome, and pentylenetetrazole-induced convulsions. Our results show that aqueous extracts of both microalgae display action profiles which prove difficult to categorize by standard pharmacological criteria.

Animals↗
PubMed1995

Psychostimulants apparently reverse sexual dysfunction secondary to selective serotonin re-uptake inhibitors.

Sexual dysfunction secondary to selective serotonin re-uptake inhibitors (SSRIs) is an almost universal, yet pooly understood phenomenon. Not uncommonly, this unpleasant side effect leads to noncompliance. Since SSRIs have been so successful clinically, it is time to find a safe and effective treatment for this side effect. This paper reports on five cases in which low dosages of the psychostimulants, dextroamphetamine and methylphenidate, administered on a p.r.n. basis, reversed the sexually inhibiting side effects of the SSRIs fluxetine, setraline, and paroxetine in patients with and without attention deficit hyperactivity disorder. In addition, the women experienced enhanced levels of arousal, orgasmic sensation and excitement during the resolution phase (afterglow) of the sexual response cycle on psychostimulants, and the men noted firmer erections.

Adult↗
PubMed1996

Amphetamine in recovery from brain injury.

A chart review of dextroamphetamine treatment in 27 traumatic brain injury patients during rehabilitation therapy suggests that amphetamine treatment enhanced the recovery and functional status of 15 patients.

Adolescent↗
PubMed1996

Pemoline therapy in college students with attention deficit hyperactivity disorder: a retrospective study.

Pemoline, a dopamine agonist, is effective in children with attention deficit hyperactivity disorder (ADHD), but its efficacy in adults is unknown. The authors studied the efficacy and safety of pemoline, using retrospective chart review of treated students with ADHD over a 2-year period. Forty students met diagnostic and treatment criteria; pemoline was associated with much improved or very much improved Clinical Global Impression symptoms scores in 70% of the students during a treatment period of 14 or more days. Severity of illness scores dropped from 4.11 to 3.01 between baseline and subsequent evaluation. Nine evaluable patients had adverse events, most commonly headaches, insomnia, and decreased appetite. Five additional students, who failed to meet the treatment-duration criterion, terminated because of severe initial insomnia. The authors concluded that pemoline is effective and safe in students with ADHD and has a lower abuse potential than methylphenidate and dextroamphetamine, the other two widely used, structurally dissimilar compounds, but controlled studies may be necessary before any final conclusions are reached.

Adolescent↗
PubMed1999

A Treatment Algorithm for Attention Deficit Hyperactivity Disorder in Cocaine-Dependent Adults: A One-Year Private Practice Study with Long-Acting Stimulants, Fluoxetine, and Bupropion.

A subgroup of adults in private treatment for cocaine dependence in remission reported a therapeutic effect from cocaine during the initial phases of cocaine addiction and, also, met DSM-IV criteria for ADHD. We report evidence that study subjects probably medicated their ADHD symptoms with cocaine and describe a 1-year treatment algorithm featuring long-acting stimulants that was effective in the management of their ADHD and cocaine dependence. Nineteen stable patients in full remission from all substance dependence were entered into an open label, prospective, treatment trial for ADHD. The treatment schedule consisted of the progressive introduction-and discontinuation of ineffective medication-of each of several medications in the following order: fluoxetine, bupropion, pemoline, sustained-release methylphenidate, dextroamphetamine spansules, and methamphetamine gradumets. Treatment of ADHD was successful. Several treatment regimens, especially those including long-acting stimulants, alone or in combination with other agents, were highly effective. All but 1 of the 19 subjects had a fully effective response for at least 1 full year. Mean UTAH scale scores were 7.4 before any medications were administered and 1.6 at the end of the study. Treatment proved successful in suppressing ADHD symptoms, with minimal cocaine slips or side effects.

Journal Article↗