Drug interactions with psychostimulants

The psychostimulants methylphenidate, dextroamphetamine, and pemoline are among the most common medications used in child and adolescent psychiatry. Often, these agents are used in combination with other medications. This review summarizes reported drug interactions and assesses both causality and clinical significance. A computerized search was undertaken using MEDLINE (1966 to 1998) to obtain all pertinent reports of adverse events associated with the coadministration of psychostimulants and other drugs. A total of 38 reports involving 25 different drugs from various classes were systematically evaluated along with research studies conducted to specifically assess drug interactions. Methylphenidate appeared to be involved primarily in pharmacokinetic interactions suggestive of cytochrome P450 inhibition while dextroamphetamine and pemoline were more often involved in apparent pharmacodynamic interactions. The published data support the safe use of psychostimulants with most classes of medications with few absolute contraindications.     

Behavioral electrophysiology of psychostimulants.

The motor-activating effects of amphetamine and other psychostimulants such as cocaine depend on an increase in dopamine (DA) transmission in the striatum, a key component of the basal ganglia and the forebrain motive circuit. This review focuses on research aimed at using electrophysiological techniques--including extracellular unit recording and iontophoresis--in alert, fully functioning animals to understand how these drugs alter striatal neuronal processing under behaviorally relevant conditions. The data indicate that DA works in conjunction with glutamate (GLU), an excitatory amino acid, to enhance the signal-to-noise ratio of afferent information. This DA-GLU interaction appears to play a critical role in the amphetamine-induced activation of striatal neurons. The pattern of striatal activation, moreover, changes as the behavioral response changes from unfocused locomotion to highly focused, stereotyped behavior, but interestingly, the striatal response pattern is not reflected in substantia nigra reticulata, a primary target of striatal efferents. Although cocaine also activates striatal neurons during behavior, the underlying mechanisms appear to be complicated by factors unique to this drug and deserve further evaluation. Collectively, these findings provide unique insight into the neuronal processes by which the striatum participates in psychostimulant-induced motor behavior.     

Pharmacokinetics of benzodiazepines and psychostimulants in children

The pharmacokinetics of benzodiazepines and psychostimulants are reviewed and an overview of the kinetic principles relevant to the utilization of these drugs in infancy and childhood is provided. Newborns and premature infants can metabolize and eliminate diazepam, although the parent drug has a longer half-life and decreased rate of biotransformation to its primary metabolites than in older children and adults. The newborn's capacity to carry on metabolic processes involved in the biotransformation of diazepam, including hydroxylation, demethylation, and glucuronide conjugation, is also limited before 5 months of age; after this time hepatic enzymes develop to adult capacity. Kinetic studies of psychostimulants in childhood indicate that methylphenidate is metabolized in the child as it is in the adult. The drug appears to be rapidly metabolized to ritalinic acid and the half-life seems to be relatively short. Volumes of distribution appear to be relatively large, suggesting extensive distribution of the drug to body tissues. Neither diazepam nor methylphenidate is without the potential for toxicity, which increases with dosage. The authors conclude that advancements in the technical capacity for obtaining and analyzing microsamples of blood as well as the use of noninvasive urinary studies will make future research in children possible.     

Age-specific behavioral responses to psychostimulants in mice

This study investigated the influence of age on the behavioral responses elicited by psychostimulants in male CD-1 mice. Behavioral activity including locomotion and stereotypy was measured following acute or repeated administration of cocaine, methylphenidate, amphetamine or saline to postweanling (24 days old), periadolescent (33 days old) and adult (60 days old) mice. Postweanling mice exhibited less total and ambulatory activity than periadolescent mice following a single acute injection of cocaine (20 or 30 and 30 mg/kg, respectively). Further, postweanling mice showed less total activity than both periadolescent and adult mice at a dose of 10 mg/kg methylphenidate. Less stereotypy was also seen in postweanling mice when compared to adolescent mice after 30 mg/kg amphetamine. Seven daily injections of cocaine resulted in a heightened behavioral response on day 7 as compared to day 1, indicative of behavioral sensitization in adult and periadolescent, but not postweanling mice. Repeated methylphenidate resulted in increased total activity in adult, but not periadolescent or postweanling mice. None of the animals were sensitized to the behavioral activating effects of amphetamine. The magnitude of behavioral response and the development of sensitization were dependent upon the age of the animal and the agent tested.     

Rationale for current therapies in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder that affects an estimated 1 million people in the US and tens of millions worldwide. Medication therapy has made significant advances and improvements especially over the last 10 years. A number of new treatments and new strategies have emerged and the quality of life for the average sufferer has improved. This review will describe the rationale and strategies for current medical therapies in PD, with special emphasis on the use of antipsychotic agents. Levodopa remains the most efficacious medication for the management of PD. Long-term use of levodopa, however, is associated with the development of motor fluctuations including dyskinesia. Trials with dopamine agonists have demonstrated a delay in the onset of dyskinesia with the use of this therapy. There is also active, ongoing investigation to determine whether a neuroprotective effect may be present with agonist therapy. Anticholinergics have been successfully used to treat tremor as well as sialorrhoea and urinary urgency. Catechol-O-methyltransferase inhibitors increase 'on time', decrease 'off time,' and improve motor scores. Continuous stimulation of dopamine receptors may decrease the fluctations observed with pulsatile delivery of anti-Parkinsonian medications, but this will require more study. Monoamine oxidase-B inhibitors, specifically selegiline, may provide symptomatic improvement; the question as to whether a neuroprotective benefit is present remains unanswered. Amantadine has demonstrated both symptomatic benefit and dyskinesia benefit in some patients. Selective dopamine blockers such as clozaril and quetiapine, have been shown to be effective in the treatment of psychosis. This class of medications is particularly useful as an adjunctive to levodopa and dopamine agonists. Doses of dopaminergic drugs can be escalated to treat Parkinsonian symptoms, whereas selective dopamine blockers can be added to block psychosis. Old management strategies required a reduction in dopaminergic therapy and therefore worsened Parkinsonian symptoms. Even though there have been great advances in the medical options for symptomatic management of PD, there are still many unmet needs for this patient population.     

Advanced findings on the molecular mechanisms for behavioral sensitization to psychostimulants

Repeated administration of psychostimulants like methamphetamine and cocaine induce behavioral sensitization, which is recognized as an animal model for dependence and psychoses. Many previous studies have proved two major cascades play a crucial roles for molecular mechanisms underling sensitization. The first one is activation of D1 dopamine receptors by robust increase of dopamine release, followed by activation of adenylyl cyclase, increase of cyclic AMP, activation of protein kinase A (PKA) and phosphorylation of proteins by PKA. The second one is activation of NMDA receptor by enhanced release of glutamine, followed by increased intracellular Ca2+ concentration, formation of Ca2+/calmodulin complex, and phosphorylation of several proteins such as calcineurin, CaM-K II and nitric oxide synthase. Recent advanced findings on sensitization mechanisms were reviewed from three different aspects: 1) Studies using knockout mice offered quite amazing findings that D1DA-receptor-lacking mice or dopamine-transporter-lacking mice can develop sensitization and dependence, which were not consistent with the previously established hypotheses based on behavioral pharmacology. In addition, those data showed the important roles of vesicular monoamine transporter 2, 5HT1B receptors and delta FosB. 2) Research on neural-plasticity-related sensitization revealed the involvement of several molecules such as tissue plasminogen activator, arc (activity-regulated, cytoskeleton-associated), synaptophysin and stathmin. Increased expression of these genes may participate in the rearrangement of neural networks with synaptogenesis and expansion of dendrites 3) Trials to discover novel-genes-involved sensitization phenomenon using differential display or subtraction cloning found some candidate genes, mrt-1, NAC-1 and CART. Although in these areas are still in progress, accumulating findings will elucidate the details of the molecular mechanism of behavioral sensitization and dependence.     

Rationale for targeting interleukin-17 in the lungs

An increasing body of evidence suggests that an exaggerated accumulation of activated neutrophils in the airways can cause decline of the clinical state in several lung diseases, including acute, severe asthma. In spite of this, an effective pharmacotherapy against this type of exaggerated neutrophil activity has yet to be developed. This review presents the scientific rationale for targeting the T-cell cytokine interleukin (IL)-17 in inflammatory lung diseases, to normalize neutrophil activity. Evidence leads to the conclusion that the production and release of IL-17 orchestrates neutrophil activity in the lungs. Hypothetically, local blockade of IL-17 may prove effective to normalize exaggerated neutrophil activity in lung diseases.     

Rationale for including metabolites in chemical toxicity bioassay

Toxicity and biodegradability are major factors affecting the fate and behavior of an organic contaminant in the environment. In this report, 2,4-dinitrotoluene (DNT), an important industrial chemical, was used as a model toxicant to demonstrate that toxicity and biodegradability are intimately related in determining a chemical's effect and impact on the total ecosystem. DNT was found to be aerobically stable, but could undergo anaerobic biotransformation with the formation of three metabolites. One of the metabolites, namely 2-nitroso-4-nitrotoluene, was extremely toxic to the six test bacterial isolates, while the other two aminonitro metabolites and the parent compound DNT were much less toxic or nontoxic to the bacterial cultures. It is suggested that the incorporation of some known metabolites into short-term bioassay procedures could increase the reliability of these tests in the impact assessment of toxic chemicals on the environment. In addition, the difference between toxicity data generated from short-term bioassay procedures and those from long-term toxicological studies was also delineated from a biochemical viewpoint.     

Lisdexamfetamine dimesylate for childhood ADHD

Stimulants are extremely effective and safe and have been the mainstay for the pharmacological treatment of attention deficit hyperactivity disorder (ADHD) for many years. However, there have been some concerns regarding their abuse, especially by teenagers and young adults. Lisdexamfetamine was recently approved for the treatment of ADHD in 6-12-year-olds and provides a novel approach to the treatment of ADHD. Lisdexamfetamine is a prodrug comprised of dextroamphetamine covalently attached to an essential amino acid, L-lysine. Following oral administration, the amide linkage between the two molecules is enzymatically hydrolyzed in the gastrointestinal tract, thus releasing active dextroamphetamine, which mediates the therapeutic effect in a fashion similar to other stimulants. The parent drug does not bind to sites responsible for the reuptake of norepinephrine and dopamine in vitro. Lisdexamfetamine does not produce high dextroamphetamine levels when injected or snorted, and thus may have lower abuse potential compared to conventional stimulants. Lisdexamfetamine appears to have efficacy and tolerability comparable to other extended-release stimulant formulations used to treat ADHD, but reduced potential for abuse-related liking effects. Compared to equivalent amounts of immediate-release dextroamphetamine.     

Long-lasting behavioral sensitization to psychostimulants following p-chloroamphetamine-induced neurotoxicity in mice

Amphetamine analogs such as p-chloroamphetamine (PCA) cause serotonergic and dopaminergic neurotoxicity. The behavioral consequences and the responsiveness to psychostimulants following the neurotoxic insult are unclear. The present study was undertaken to investigate the outcome of neurotoxic and non-neurotoxic PCA pre-treatments on the sensitivity of Swiss Webster mice to the psychomotor stimulating effects of PCA, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine. PCA (15 mg/kg x 2; i.p.) caused 37-70% depletion of dopaminergic and serotonergic markers in mouse brain. Saline and PCA (15 mg/kg x 2) mice were challenged on days 5, 12, 40 and 74 with one of the following drugs: PCA (5 mg/kg), MDMA (10 mg/kg) and cocaine (20 mg/kg). The PCA pre-exposed mice showed marked locomotor sensitization from days 5-74 to all three drugs tested. The time course of the sensitized response coincided with the time course of the neurotoxic insult as determined by reduced densities of striatal dopamine transporter and frontal cortex serotonin transporter binding sites. A single injection of PCA (5 mg/kg) caused neither neurotoxicity nor sensitization to the locomotor stimulating effects of PCA, MDMA and cocaine. Repeated administration of a low non-neurotoxic dose of PCA (5 mg/kg/day; 6 days) caused a transient locomotor sensitization to PCA that dissipated after one month. Results of the present study suggest that PCA-induced serotonergic and dopaminergic neurotoxicity coincides with long-lasting locomotor sensitization to psychostimulants. These findings may be relevant to the psychopathology of amphetamines-induced neurotoxicity.     

Impact of psychostimulants on vesicular monoamine transporter function

The vesicular monoamine transporter-2 (VMAT-2) facilitates the sequestration of catecholamines and serotonin into synaptic vesicles, and is therefore an essential regulator of monoaminergic neuronal function. VMAT-2 proteins may also play a role in neuroprotection, since these transporters have the capacity to sequester neurotoxins within vesicles. Recent studies have demonstrated that psychostimulants, particularly dopamine "releasers" and "reuptake inhibitors", differentially alter VMAT-2 function. As described in this review, these studies not only provide insight into the pharmacological actions of stimulants, but also mechanisms underlying neurodegenerative disorders, including Parkinson's disease.     

Activity density in the open field: a measure for differentiating the effect of psychostimulants

Traditional open-field activity measures do not provide a sharp behavioral differentiation across psychomotor stimulants such as d-amphetamine (AMPH) and cocaine (COC) in the mouse. We used Software for the Exploration of Exploration (SEE) to investigate and develop a novel behavioral endpoint to characterize the "structure" of AMPH- and COC-induced locomotor behavior in two inbred strains of mouse, C57BL/6 (B6) and DBA/2 (D2). We suggest a measure we term "activity density" as a means to differentiate the behavioral effects of COC and AMPH. Activity density is defined as the activity divided by the range over which it took place. It characterizes the restriction of behavioral repertoire that does not result merely from inactivity. In both the B6 and D2 mice, AMPH increased activity density in a dose-dependent fashion by restricting the range of activity compared with COC doses producing the same level of activity. While AMPH restricted the range in both genotypes, characterizing the geographical region in which the restriction took place further differentiated the genotypes. The newly developed activity density measure thus provides a more general measure than stereotypy of the path, and can differentiate the effects of AMPH and COC both within and across genotypes.     

Rationale for once-daily therapy in asthma: compliance issues

Compliance in asthma is known to be poor. Once-daily treatment provides an additional therapeutic option for the clinician whose treatment aims include maximising treatment satisfaction and compliance. Once-daily treatment is preferred by some but not all patients and may lead to greater compliance in patients who are concerned about the effect of corticosteroids on their health. When switching to once-daily treatment, patients should be given a choice as to the time of treatment to minimise the impact of forgetting a dose.     

Stimulant Medication for ADHD in Opioid Maintenance Treatment

Objective: The use of central stimulant medication in adults with attention deficit hyperactivity disorder (ADHD) who receive opioid maintenance treatment remains controversial and empirical evidence is limited. Because of the abuse potential of stimulant drugs, Norway has restrictions on prescribing central stimulants to individuals who have substance use disorders or who are on opioid maintenance treatment. In this naturalistic study, we describe experiences from a program through which central stimulant medication was administered to patients with ADHD receiving opioid maintenance treatment. Methods: This report is based on a program evaluation of a combined treatment project designed to provide stimulant medication to patients with adult ADHD who were receiving opioid maintenance treatment. As part of the clinical treatment, patients were monitored closely for any medical issues or adverse medication reactions and provided regular urine samples for analysis and information regarding demographics, treatment goals, legal involvement, diagnoses, substance abuse, and ADHD symptoms. Monitoring occurred at baseline, at 2 months (after patients being stabilized on the central stimulant), and again at 3, 6 and 24 months. Results: Among 42 patients initially offered the combined treatment, 24 were actually eligible, 20 started the combined treatment, and 10 stayed in the program. We were not able to identify a single major cause of treatment dropout. Patients reported significantly fewer symptoms of ADHD at the 6- to 8-week point, regardless of whether the data were analyzed using an intent-to-treat (all participants) or per-protocol (only those with complete data at all points) method. Even though self-assessed ADHD scores dropped significantly during treatment, the scores still remained fairly high, suggesting persistent functional impairment. Neither severe complications nor increase in substance abuse were observed during treatment with central stimulants. Conclusions: These findings show some promise with regard to the safety and utility of central stimulant medications for patients with ADHD who are receiving opioid maintenance treatment. Our study has methodological limitations, and systematic, well-designed clinical investigations are needed to increase the knowledge base.