The Pemoline Model of Self-Injurious Behavior: An Update.

Neurodevelopmental disorders typically comprise a complex constellation of behavioral symptoms and neurochemical abnormalities. However, many of the symptoms are inconsistently expressed within any one particular patient group or overlap between patient groups. In other words, there is usually heterogeneity of symptoms between diagnostic groups, and there is often partial homogeneity of symptoms across these groups. These include cognitive deficits, emotional lability, and perseverative or aberrant behaviors. Animal models of neurodevelopmental disorders typically reproduce or mimic specific genetic, neurochemical, and/or behavioral sequelae, although they typically fail to replicate the entire spectrum of biological and behavioral characteristics. Indeed, it may be impractical or even impossible to model the entire spectrum of characteristics of a disorder in any single animal model. A focus on one or more specific behavioral characteristics that occur in multiple neurodevelopmental disorders (e.g., self-injury) may be a fruitful strategy. The development of these behaviorally focused models may yield increased understanding of the endogenous and environmental factors that confer vulnerability for aberrant behaviors that commonly occur in these disorders. One such behaviorally focused animal model is the pemoline model of self-injurious behavior.

Safety assessment in pediatric studies.

It typically takes many years before an association of a drug with a rare, serious adverse reaction is established. As related to pediatric drug use, evidence is even more erratic, as most drugs are used off labels. To enhance child safety, there is an urgent need to develop robust and rapid methods to identify such associations in as timely a manner as possible. In this chapter, several novel methods, both clinically based pharmacoepidemiological approaches and laboratory-based methods, are described.

Psychostimulant treatment and the developing cortex in attention deficit hyperactivity disorder.

OBJECTIVE: While there has been considerable concern over possible adverse effects of psychostimulants on brain development, this issue has not been examined in a prospective study. The authors sought to determine prospectively whether psychostimulant treatment for attention deficit hyperactivity disorder (ADHD) was associated with differences in the development of the cerebral cortex during adolescence. METHOD: Change in cortical thickness was estimated from two neuroanatomic MRI scans in 43 youths with ADHD. The mean age at the first scan was 12.5 years, and at the second scan, 16.4 years. Nineteen patients not treated with psychostimulants between the scans were compared with an age-matched group of 24 patients who were treated with psychostimulants. Further comparison was made against a template derived from 620 scans of 294 typically developing youths without ADHD. RESULTS: Adolescents taking psychostimulants differed from those not taking psychostimulants in the rate of change of the cortical thickness in the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region. The group difference was due to more rapid cortical thinning in the group not taking psychostimulants (mean cortical thinning of 0.16 mm/year [SD=0.17], compared with 0.03 mm/year [SD=0.11] in the group taking psychostimulants). Comparison against the typically developing cohort without ADHD showed that cortical thinning in the group not taking psychostimulants was in excess of age-appropriate rates. The treatment groups did not differ in clinical outcome, however. CONCLUSIONS: These findings show no evidence that psychostimulants were associated with slowing of overall growth of the cortical mantle.

A surveillance method for the early identification of idiosyncratic adverse drug reactions.

BACKGROUND: Pemoline is a CNS stimulant that was introduced in 1975 in the US and was used to treat children with attention deficit hyperactivity disorder. Pemoline was withdrawn from the market 30 years later because of fatal hepatotoxicity associated with its use. OBJECTIVE: To create a system that will estimate the potential association between a serious adverse event and a medication early in its marketing cycle. METHOD: All case reports of acute liver failure associated with pemoline and reported to the US FDA from 1975 through 1999 were reviewed. All published articles on pemoline-induced hepatotoxicity were reviewed, and the Naranjo adverse drug reaction probability scale was applied. The incidence rate of idiopathic acute liver failure was estimated from the published literature. The data were analyzed using Fisher's Exact test and relative risks (RR) were calculated. RESULTS: As early as 1978, there was a significant signal indicating that pemoline was associated with acute liver failure, with an RR of 24.08 (95% CI 4.67, 124.10; p < 0.05). With an increased number of cases, the significance of the association had been steadily increased. CONCLUSION: This method enables researchers, clinicians, drug companies and regulators to identify uncommon adverse drug reactions, caused mostly by new medications, earlier than they currently are in the course of marketing and thus quantify serious adverse events.

Methylphenidate use in children and risk of cancer at 18 sites: results of surveillance analyses.

PURPOSE: A recent report linked methylphenidate (MPH) use in children to cytologic abnormalities in plasma lymphocytes, a possible cancer biomarker. The purpose of this study was to investigate the association of MPH use and childhood cancer risk. METHODS: Using automated pharmacy databases and the SEER-affiliated cancer registry of the Kaiser Permanente Medical Care Program (KPMCP), we compared cancer rates at 18 sites among 35,400 MPH users who received it before age 20 to rates among KPMCP membership (age, sex, and calendar year standardized). Medical records of MPH exposed cancer cases were reviewed to identify the presence of established risk factors. RESULTS: There were 23 cancers among MPH users, versus 20.4 expected (standardized morbidity ratio, SMR = 1.13, 95% confidence interval (0.72, 1.70)). Given the small number of cancers, site-specific SMR estimates were imprecise. Only one SMR was statistically significant at the p < 0.05 level, which given the number of comparisons is consistent with the absence of a true association at any site. MPH use was associated with increased risk of lymphocytic leukemia (SMR = 2.64 (1.14, 5.20)), based on eight observed cases). The medical records of these exposed cases did not reveal any lymphocytic leukemia risk factors (prior cancer, radiotherapy or chemotherapy, or Down syndrome). CONCLUSIONS: Our results are consistent with no moderate or strong association between MPH use and cancer risk in children, although our ability to examine dose and duration of use or risk at specific sites was limited by small numbers. Further study of MPH use and lymphocytic leukemia risk is needed to determine whether our results are due to chance alone.

Eficacia del bupropión en el tratamiento de la dependencia de pemolina / Efficacy of bupropion in the treatment of pemoline dependence

Presentamos el caso de una mujer que solicita evaluación psiquiátrica por llevar 6 meses consumiendo pemolina en unas dosis de entre 100 y 150 mg/día, encontrándose con dificultades para abandonar el consumo de dicha sustancia. La instauración de 300 mg/día de bupropión resuelve la dependencia que tenía la enferma. Proponemos el uso de antidepresivos como el bupropión para el tratamiento de conductas adictivas sobre estimulantes del sistema nervioso central

We present the case of a woman who requested psychiatric evaluation because she had been taking pemoline for six months at a dose between 100-150 mg/day, and was finding it difficult to discontinue taking this substance. Initiation of 300 mg/day of bupropion solved the patient's dependence problem. We propose using antidepressants such as bupropion for the treatment of addictive behaviors due to central nervous system stimulants

Effectiveness of risk management plans: a case study of pemoline using pharmacy claims data.

PURPOSE: To assess the effectiveness of a pharmaceutical risk management plan using pemoline as a case study and pharmacy claims as the data source. METHODS: Prescription claims from a continuously enrolled US population (September 1, 2000-September 30, 2002) from Caremark, a pharmacy benefit manager, were evaluated for patients with one or more pemoline claims. Patients were categorized using pemoline as second-line or first-line therapy depending on presence or absence of other central nervous system (CNS) stimulants prescriptions 90 days prior to the first pemoline claim. Logistic regression was performed to compare second-line and first-line usage with regard to patient age, gender and prescribing physician specialty and region of practice. RESULTS: Of 1,279,296 prescription claims for CNS stimulants, 17,256 (1.3%) were for pemoline. Nine hundred thirteen patients received pemoline and had 90 days or more prior enrollment. Overall, 10% of patients receiving pemoline received it as second-line therapy (95%CI: 8-12%). After adjusting for age, gender, specialty, and region, the odds of receiving pemoline as second-line therapy were significantly greater in pediatrics relative to adults (OR = 2.82, 95%CI: 1.58-5.03), and among those whose prescribers were psychiatrists versus primary care physicians (OR = 2.48, 95%CI: 1.37-4.50). Children treated by a psychiatrist had the greatest likelihood for use as second-line therapy (36%, 95%CI: 19-56%). CONCLUSIONS: Among patients who received pemoline, concordance with second-line therapy recommendations was low, even among the primary target audience of children. These results in a large geographically diverse patient population are consistent with an earlier regional study.

A rare case of dependence on pemoline.

This is the first case to report about a patient dependent on the dopaminergic CNS-stimulant pemoline. Throughout the treatment of adult attention-deficit hyperactivity disorder (ADHD) with pemoline mental (e.g. craving, loss of control) and physical symptoms (e.g. tolerance, withdrawal symptoms) appeared that fulfill the DSM-IV or ICD-10 criteria for dependence on psychostimulants. However, the dependence was regarded not to be induced by pemoline itself because the patient was prone to irregular and reinforced intake of amphetamines since her adolescence. Therefore, this case confirms the experience that in the treatment of ADHD the high risk to develop a dependence on psychostimulants is combined with a history of stimulant abuse.

Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the effects of medications used in the treatment of adults with attention-deficit/hyperactivity disorder (ADHD) on blood pressure and pulse. METHOD: Subjects were those with DSM-III-R-/DSM-IV-diagnosed ADHD enrolled in placebo-controlled studies of 5 different medications for ADHD. Cardiovascular data from these studies of both stimulants (methylphenidate, amphetamine compounds, pemoline) and nonstimulants (bupropion, desipramine) were reanalyzed for baseline-to-endpoint active-treatment or placebo effects on blood pressure and heart rate. RESULTS: There were 125 subjects with a mean +/- SD age of 39 +/- 9 years. In general, active drug treatment for ADHD compared to baseline was associated with several statistically significant changes in systolic blood pressure (bupropion: +5.9 mm Hg, p < .05 by paired t test; amphetamine: +5.4 mm Hg, p < .05), diastolic blood pressure (desipramine: +7.1 mm Hg, p < .05), and heart rate (bupropion: +6.9 mm Hg, p < .05; amphetamine: +7.3 mm Hg, p < .05; methylphenidate: +4.5 mm Hg, p < .05). New-onset cases of systolic or diastolic hypertension (blood pressure > or = 140/90) were recorded in 8% (7/89) of placebo-treated subjects and 10% (9/89) of subjects receiving active medication, regardless of the class (stimulant, nonstimulant). CONCLUSION: Both stimulant and nonstimulant catecholaminergic medications used in adults with ADHD are associated with minor, but statistically significant, changes in heart rate and blood pressure that were often observed in those receiving placebo. Given the minor pressor and chronotropic effect of these medications, adults with ADHD should have their blood pressure and heart rate checked at baseline and periodically during treatment.

Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ.

OBJECTIVE: The aim of this study was to examine the safety and efficacy of risperidone, with or without concomitant psychostimulant use, in the treatment of children with conduct disorder (CD) or other disruptive behavior disorders [oppositional defiant disorder (ODD), disruptive behavior disorder-not otherwise specified (DBD-NOS)], and comorbid attention-deficit hyperactivity disorder (ADHD). METHODS: Data from two 6-week placebo-controlled trials assessing risperidone therapy in children with subaverage IQs and CD, ODD, DBD-NOS were combined, and patients with comorbid ADHD were selected for this post hoc analysis. Patients were grouped according to randomized drug therapy (risperidone or placebo), and then subgrouped according to their use of a concomitant psychostimulant. Safety outcomes included adverse events and weight change, while efficacy outcomes included changes in scores on disruptive behavior and hyperactivity-based subscales of two behavior-rating instruments (Nisonger Child Behavior Rating Form and the Aberrant Behavior Checklist). RESULTS: The analysis included 155 of 208 originally tested children divided into four sub-groups (35-43 patients each). There was no significant difference in the frequency of adverse events in patients who received risperidone alone and those who received risperidone plus a stimulant. The most common adverse events in risperidone-treated patients were somnolence, headache, dyspepsia, rhinitis, and vomiting. Within each randomized treatment group, actual weight gain was comparable, regardless of concomitant stimulant use. Risperidone-treated patients had clinically and statistically significant reductions in both disruptive behavior and hyperactivity subscale scores, compared to placebo, regardless of concomitant stimulant use. The addition of risperidone to a psychostimulant resulted in significantly better control of hyperactivity (p < 0.001) than was achieved with stimulant treatment alone, without causing an increase in adverse events. CONCLUSION: Risperidone was a safe and effective treatment, with or without a combined psychostimulant, for both disruptive behavior disorders and comorbid ADHD in children.

Inappropriate pemoline therapy leading to acute liver failure and liver transplantation.

A 36-year-old female, presenting with jaundice, developed acute liver failure requiring orthotopic liver transplantation. On admission, none of the known causative factors for acute hepatitis, including use of drugs, were found to be present. Several days after hospitalization, the patient admitted taking therapy prescribed by a "non-traditional" physician, that she had been using for several years due to overweight and which had recently been modified with the introduction of pemoline. A considerable body of evidence exists in the medical literature showing that pemoline, which is a central nervous system stimulant, has variable hepatotoxic effects, ranging from a mild transient increase of serum transaminases to liver failure, including some lethal cases.

Pemoline hepatotoxicity and postmarketing surveillance.

OBJECTIVE: To review the numerous reports of hepatotoxic adverse drug reactions (ADRs) ascribed to pemoline that were sent to the U.S. Food and Drug Administration (FDA) between 1975 and 1996 and to describe the medical community's lack of awareness of these reports. METHOD: All ADR reports from 1975 through 1996 wherein pemoline was the suspect agent were obtained from the FDA MedWatch Internet site, and some details of nine pemoline-related deaths in youths were obtained directly from the FDA. The published literature on this subject was fully reviewed. RESULTS: (1) In premarketing clinical trials with pemoline in the early 1970s, hepatic abnormalities were noted in enzyme levels (1%-3% of youths receiving maintenance treatment), during rechallenges (6 of 6), and in biopsies (2 of 2). (2) Between 1975 and 1989, 12 cases of jaundice and 6 deaths in youths ascribed to pemoline hepatotoxicity were reported to the FDA. (3) The first medical literature report of a serious ADR ascribed to pemoline was in a 1989 letter to the editor. (4) Physicians generally only became aware of serious pemoline hepatotoxicity in December 1996. (5) Pemoline use increased until 1997. CONCLUSION: Limitations in postmarketing surveillance and public reporting in the United States, particularly in the 1980s, largely accounted for delays in an appropriate response to pemoline hepatotoxicity.

Emergence of tics in children with attention deficit hyperactivity disorder treated with stimulant medications.

The emergence of tics in children treated with stimulant medication for attention deficit hyperactivity disorder (ADHD) was investigated. A retrospective chart review of the medical records of 555 subjects was performed to examine the emergence of tics in relation to treatment with a stimulant medication, dosage, duration of treatment, and age of subjects. A total of 7.8% of the subjects treated with stimulants developed tics: 8.3% of subjects treated with methylphenidate, 6.3% with dextroamphetamine, and 7.7% with pemoline. The subjects who developed tics were significantly younger than those who did not. Subjects treated with higher doses of stimulant medication were not more likely to develop tics. While the emergence of tics was common, these subjects may have developed tics irrespective of stimulant medication. Controversy remains as to the long-term risk of tics in relation to stimulant medication and to appropriate practice should tics emerge during the course of stimulant medication treatment.

Pemoline treatment of adolescents with attention deficit hyperactivity disorder: a short-term controlled trial.

BACKGROUND: Despite the increased recognition of attention deficit hyperactivity disorder (ADHD) in adolescents, few controlled studies have assessed treatments for this age group. Adolescent issues, such as embarrassment at receiving medication at school and experimentation with abusable substances, have accelerated efforts to find effective, well-tolerated treatments beyond traditional stimulants. Pemoline has been found effective for treating both children and adults with ADHD but has not been evaluated in adolescents with ADHD. METHODS: Twenty-one adolescents (mean age 14 years old) diagnosed with ADHD by structured and clinical interviews participated in a 10-week, double-blind crossover design study of pemoline. Dosing was optimized with robust doses up to 3 mg/kg/day in one to two doses. Clinical evaluations of ADHD, depression, anxiety, and oppositional defiant disorder (ODD) symptoms were assessed weekly. RESULTS: Adolescents with ADHD exhibited a marked response to pemoline treatment relative to placebo on the ADHD rating scale (p = 0.001), with an average reduction of 3.02 points per week of treatment. Sixty percent of adolescents responded to pemoline, compared to 11% treated with placebo. This response was independent of gender or lifetime psychiatric comorbidity. Pemoline was well tolerated, with patients averaging 2.88 mg/kg/day in two doses per day, with a mean dose at end of follow-up of 181.1 mg (SD 45.6, range 112.5-262.5 mg). Side effects were mild, and no adverse hepatic events occurred. CONCLUSIONS: These findings resemble those reported in children and adults with ADHD. This trial suggests pemoline is well tolerated and effective in adolescents and may be a particularly useful ADHD treatment for adolescents.

Severe hypotension in a patient receiving pemoline during general anesthesia.

IMPLICATIONS: This case reports hypotension under general anesthesia in a patient taking pemoline. Vigilance for unexpected hypotension is important in patients who are treated with psychostimulants. If hypotension occurs, vasopressors that act directly on adrenergic receptors should be used.

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.