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Pemoline induced acute choreoathetosis: case report and review of the literature.

BACKGROUND: Pemoline is an oxazolidine derivative that is structurally different from amphetamines and used in the treatment of attention deficit disorder. Pemoline has not been commonly associated in the literature as a cause of acute movement disorders. The following case describes two children acutely poisoned with pemoline who experienced profound choreoathetosis. CASE REPORT: Two, 3-year-old male, identical twin siblings presented to the emergency department after found playing with a an empty bottle of pemoline originally containing 59 tablets. The children had a medical history significant for attention deficit disorder previously treated with methylphenidate without success. This was their first day of pemoline therapy. The choreoathetoid movements began 45 min to 1 h after ingestion. The children gave no history of prior movement disorders and there was no family history of movement disorders. The children received gastrointestinal decontamination and high doses of intravenous benzodiazepines in an attempt to control the choreoathetoid movements. Despite treatment, the children continued to have choreoathetosis for approximately 24 hours. Forty-eight hours after admission, the children appeared to be at their baseline and were discharged home. CONCLUSION: Pemoline associated movement disorder has been rarely reported in the acute toxicology literature. The possibility of choreoathetoid movements should be considered in patients presenting after pemoline overdose.

Athetosis↗

Self-injurious behaviour: a comparison of caffeine and pemoline models in rats.

Self-injurious behaviour (SIB) is a debilitating behaviour disorder that can have life-threatening consequences. It is often exhibited in intellectually handicapped and autistic populations, and it has been modeled with pharmacological manipulations in animals. We have characterized the induction of SIB using high doses of caffeine and pemoline in rats. Caffeine only produced very mild SIB in a small proportion of the rats, when administered repeatedly at very high doses (140-185 mg/kg/day). All the caffeine-treated rats showed profound signs of caffeine-toxicity at these doses, and lower doses did not induce any self-injury. On the other hand, pemoline was effective across a range of doses (100-300 mg/kg/day), including doses that did not produce overt signs of toxicity (100-200 mg/kg/day). The topography of the tissue injury sites (tail vs. paws and ventrum) differed between caffeine and pemoline treatments, and across doses of pemoline. The speed of onset, the incidence, and the severity of SIB occurred in a dose-orderly manner across the pemoline doses, and there was substantial individual variability in the induction of SIB when a moderately high dose (200 mg/kg/day) was used. These individual differences in vulnerability to self-injure are reminiscent of the fact that some humans with specific neurobiological disorders express SIB and some individuals with those same disorders do not. Accordingly, the pemoline model of SIB may be useful to investigate the neurobiological basis of factors that contribute to etiology of SIB.

Adrenocorticotropic Hormone↗

Effect of fluoxetine, pemoline and placebo on heart period and QT variability in normal humans.

OBJECTIVE: To measure the effects of fluoxetine and pemoline on heart period and QT variability. METHODS: Healthy volunteers were randomly assigned treatment with 20 mg daily of fluoxetine (n=7), 56.25 mg of pemoline (n=7) or placebo (n=9). Twenty-four-hour Holter ECGs were obtained before and after approximately 8 weeks of double-blind treatment. RESULTS: There were no significant changes in the fluoxetine group. Pemoline was associated with a significant decrease in the high frequency (HF) power (0.15-0.5 Hz, P=.02) and fractal dimension of RR time series (P=.03). QTvi, a measure of QT interval variability, increased in the pemoline group (P=.05). CONCLUSION: Pemoline, but not fluoxetine, decreases heart period variability (HPV) in the HF power, suggesting a vagolytic effect on cardiac autonomic function. Pemoline is also associated with an increase in QT interval variability, a measure that is sensitive to adrenergic agonists.

Adult↗

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.

Adolescent↗

Hepatotoxicity due to pemoline (Cylert): a report of two cases.

Pemoline (Cylert) is an agent used to treat attention deficit disorders and other behavioral syndromes. There have, however, been three published reports of mild hepatic dysfunction in five patients coincident with pemoline therapy. We report two further cases of probable pemoline hepatotoxicity. One case involved a mild aminotransferase elevation in a 6-year-old who was on pemoline for 5 months. The second case, in an 11-year-old, developed hepatic failure with marked prolongation in prothrombin time nonresponsive to parenteral vitamin K, deep jaundice, and submassive hepatic necrosis. This patient had a long history of pemoline usage. Pharmacokinetics are briefly discussed. A spectrum of hepatic disease due to pemoline is considered and the importance of obtaining aminotransferase values before, during initiation, and throughout treatment is stressed.

Attention Deficit Disorder with Hyperactivity↗

Pemoline therapy resulting in liver transplantation.

OBJECTIVE: To describe a case of pemoline-induced liver failure resulting in liver transplantation. CASE SUMMARY: A 9-year-old white boy, diagnosed with attention deficit/hyperactivity disorder (ADHD) and treated with pemoline, developed signs and symptoms of liver failure. Pemoline therapy was discontinued, but the patient's liver function continued to decline. Ultimately, a liver transplantation was required. DISCUSSION: Pemoline, an agent used in ADHD treatment, has been associated with hepatotoxicity with the majority of cases occurring in pediatric patients. To our knowledge, this is the second reported case of pemoline-induced liver failure resulting in liver transplantation. The mechanism of action remains unclear, with several hypotheses being postulated including hypersensitivity reactions, dose-related phenomena, and autoimmune-mediated reactions. CONCLUSIONS: With increasing evidence linking pemoline to liver failure, this agent should not be considered first-line therapy for ADHD. Prior to initiating therapy, baseline liver function tests should be obtained and closely monitored, and parents and patients should be educated on the signs and symptoms of liver toxicity.

Attention Deficit Disorder with Hyperactivity↗

Pemoline pharmacokinetics and long term therapy in children with attention deficit disorder and hyperactivity.

The pharmacokinetic behaviour of pemoline was studied in 28 children, aged 5 to 12 years, diagnosed as having the attention deficit disorder with hyperactivity. The mean elimination half-life of pemoline in these children was approximately 7 hours, which is considerably shorter than the half-life of 11 to 13 hours previously reported in adults. The tendency of the half-life to increase with age may be explained by the statistically significant decrease in total body clearance with age. The increasing half-life of pemoline with age should be considered during long term drug therapy. In this study no tolerance to the beneficial effects of pemoline was observed over 6 months. The apparent therapeutic serum concentration range for these children was attained after doses of 37.5 to 131.25 mg pemoline daily. Since the optimum serum concentration shows wide variation, the dosing regimen must be determined individually. Routine monitoring of the pemoline serum concentrations is not useful because of this apparent variation in optimum serum concentration and because of the linear relationship between dose and concentration.

Aging↗

Intensive and sustained air operations: potential use of the stimulant, pemoline.

BACKGROUND: Intensive and sustained military operations involve long periods of overnight work and the occasional use of a stimulant to maintain performance may be beneficial. In this context a dose response study was carried out to investigate the effects of pemoline, a dopamimetic agent, on overnight work and to assess potential residual effects on subsequent sleep. METHODS: Six healthy volunteers participated in a placebo-controlled, double-blind, cross-over trial involving a 12-h period of work during which subjective alertness and performance on a range of tasks were assessed at 1.5 h intervals following ingestion at 2000 hours of pemoline (10, 20, 30 and 40 mg) and, on two occasions, placebo. The work period was preceded by a 6-h sleep period with temazepam 20 mg, and followed by a 4-h recovery sleep with no medication. All sleep periods were recorded electroencephalographically. RESULTS: There was no difference between sleep periods preceding the work period. Subjective alertness and performance on all tasks deteriorated significantly during the work period, with the earliest impairments in performance observed at 0200 hours. Pemoline increased subjective alertness and performance on all but two tasks, compared with placebo. The onset of activity was seen 4.5 h after drug ingestion and alerting effects of 30 and 40 mg pemoline persisted beyond the work period, disturbing morning recovery sleep. Doses of 10 and 20 mg pemoline had no effect on recovery sleep. CONCLUSION: The present studies indicate that a 20 mg dose of pemoline may be suitable for maintaining nocturnal performance without having adverse effects on recovery sleep.

Adult↗

The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis.

BACKGROUND: Amantadine hydrochloride and pemoline, both frequently used to treat the fatigue of multiple sclerosis (MS), may also improve attention and other cognitive functions in MS. To our knowledge, these agents have never been compared in a placebo-controlled trial of patients with MS. OBJECTIVE: To evaluate the effects of amantadine and pemoline on cognitive functioning in MS. METHODS: A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine, pemoline, or placebo using a parallel group design. They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning. Primary outcome measures were tests of attention (Digit Span, Trail Making Test, and Symbol Digit Modalities Test), verbal memory (Selective Reminding Test), nonverbal memory (Benton Visual Retention Test), and motor speed (Finger Tapping Test). RESULTS: Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment. All three treatment groups improved on tests of attention (P < .003), verbal memory (P < .001), and motor speed (P < .002). There were no significant differences between amantadine, pemoline, and placebo. CONCLUSIONS: Cognitive functioning in MS is independent of fatigue. Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo.

Adolescent↗

Repeated pemoline produces self-injurious behavior in adult and weanling rats.

Self-injurious behavior (SIB) is a serious problem among the mentally handicapped and is often accompanied by other repetitive or stereotyped behaviors. Acute administration of high doses of amphetamine or pemoline to rats produces transient SIB which is accompanied by severe deterioration of the behavioral repertoire. Repeated subcutaneous (SC) administration of pemoline to rats produces a high incidence of SIB without the dramatic behavioral changes produced by high doses of oral pemoline. Repeated pemoline increased locomotions and rears and produced intermittent stereotyped sniffing and licking/biting. However, the animals were still able to eat, drink, sleep and groom. Hotplate tests provided no evidence for analgesia. Because SIB is often associated with human developmental disorders, the effects of repeated SC administration of pemoline to weanling rats was also investigated. SC injections every 12 hours produced a high rate of SIB in weanling rats.

Animals↗

Gas chromatographic determination of pemoline in biological fluids using electron capture detection.

A simple and sensitive gas chromatographic (GC) method for the determination of pemoline in biological fluids, utilizing electron capture detection is described. Plasma samples with a pemoline analog added as internal standard were deproteinized with sulfosalicylic acid, and the supernatants were heated at 80 degrees. The pemoline-dione formed was extracted with benzene, and the extract was analyzed on a gas chromatograph equipped with a tritium foil electron capture detector. Poly A-103 (3%) on Gas-Chrom Q (100-120 mesh) packed in a 3-ft. silanized glass column was used as the stationary phase, with nitrogen serving as carrier gass. Under the same GC conditions, benzene extracts of pemoline-dione from acid-hydrolyzed urine samples were analyzed. Us-ng 1 ml of plasma or urine, the lower limit for the assay was about 0.1 microgram/ml. The method is accurate and reproducible, with a relative standard deviation with +/-4%. Mandelic acid (a metabolite of pemoline) does not interfere with the assay.

Animals↗

Cortical damage enhances pemoline-induced self-injurious behavior in prepubertal rats.

Self-injurious behavior (SIB) is a devastating characteristic of several developmental disorders including a number of mental retardation syndromes. The functional neuroanatomy and neuropharmacology of SIB is not well understood. Self-biting behavior (SBB) can be induced in rats by a high dose, systemic injection of pemoline (250 mg/kg, SC). This animal model allows for the investigation of anatomical and pharmacological aspects of SIB. Cortical pathology is a common occurrence in human disorders with SIB, and may be a fundamental pathological factor in producing the behavior. The present experiment was designed to investigate the effects of cortical damage on pemoline-induced SBB in prepubertal rats. Bilateral cortical aspirations were performed in 3-5-week-old rats. One week postsurgery, a pemoline challenge was administered. Behavioral comparisons were completed between the lesion group and an anesthetized-only control group. Results indicated that cortical damage significantly enhanced pemoline-induced SBB, along with some of the other pemoline-induced stereotypical behaviors. These results support the hypothesis that cortical damage influences the expression of stimulant-induced self-injury, and potential mechanisms for this influence are suggested.

Animals↗

Determination of pemoline in plasma, urine and tissues by reversed-phase high-performance liquid chromatography.

A simple and selective high-performance liquid chromatographic method with ultraviolet detection at 215 nm for the determination for pemoline in rat plasma, urine and tissues is described. Pemoline in the samples was extracted with methylene chloride at pH 10 and the organic phase was evaporated after adding 5-methyl-5-phenylhydantoin used as an internal standard. Pemoline and the internal standard were separated on a Kaseisorb LC C8-60-5 reversed-phase column. The limits of determination of pemoline in 0.1-0.2 ml of plasma, urine and tissue homogenates were 2, 100 and 20 ng, respectively. The method should be useful for studies of the pharmacokinetics and distribution of pemoline in small animals.

Animals↗

Gas/liquid chromatographic analysis of pemoline in biological fluids using electron capture detection.

An analytical gas/liquid chromatographic (GLC) protocol is described for the quantitation of pemoline in biological fluids of the horse. Plasma samples containing known quantities of pemoline and its analog as an internal standard (IS) were deproteinized with 5-sulfosalicylic acid, heated at 80 degree C, and centrifuged. 5-Phenyl-2,4-oxazolidinedione, the hydrolytic product of pemoline in acid medium, was extracted with dichloromethane (DCM). The organic layer was in turn re-extracted with 1% NaHCO3. The aqueous layer was acidified with HCI, and re-extracted with DCM, which was evaporated to dryness. The resulting residue was methylated with ethereal diazomethane. The methylated dione was dissolved in benzene, and analyzed with a gas/liquid chromatograph equipped with a tritiated scandium foil (Sc3H) electron capture detector (ECD). Urine samples to which pemoline was added were hydrolyzed with hydrochloric acid and carried through the analytical procedure in a manner similar to the plasma, except that the urine was further washed with lead acetate solution prior to the sodium bicarbonate extraction. The lower limits of detection were found to be 0.05 microgram/ml for plasma and 0.1 microgram/ml for urine when 1.0 ml of sample was used. This procedure can be used for pemoline detection control in international sporting events.

Animals↗

An open trial of pemoline in drug-dependent delinquents with attention-deficit hyperactivity disorder.

OBJECTIVE: Adolescents with conduct disorder and substance use disorders have high rates of comorbid attention-deficit hyperactivity disorder (ADHD); ADHD may contribute to the severity and persistence of substance use disorders and antisocial behaviors. Treatment of ADHD may help patients utilize substance and other behaviorally focused treatment. Yet little is known about the response of ADHD symptoms to psychopharmacological intervention in substance-dependent delinquents. METHOD: Pilot data are presented for 13 male adolescents with conduct disorder, substance use disorders, and ADHD, in a residential substance use treatment program. Patients were treated with pemoline. Scores from the Conners Hyperactivity Index and continuous performance tasks were obtained at baseline and after about 1 month of treatment with pemoline. Physical activity measurements were also assessed at baseline and 1 month. Postmedication assessments were obtained after at least 1 week at maximal dosage (1.2 to 3.3 mg/kg). RESULTS: Mean Conners Hyperactivity Index scores declined 13.9% (p < or = .002) and mean motility declined 7% (p < or = .04) with pemoline treatment. Continuous performance task scores did not change. CONCLUSIONS: Preliminary data indicate that pemoline may be a useful treatment for ADHD in substance-dependent delinquents; the authors propose a controlled trial of pemoline in such youths.

Adolescent↗

A study of compliance with FDA recommendations for pemoline (Cylert).

OBJECTIVE: To assess compliance with product labeling recommendations to use pemoline as second-line therapy for attention-deficit/hyperactivity disorder (ADHD) and to obtain baseline and biweekly liver enzyme tests. METHOD: Retrospective cohort study using administrative claims data to identify first-line therapies and liver enzyme tests among pemoline users between January 1, 1998, and March 31, 2000. Prescriptions for first-line therapy were searched for 90 days prior to the first pemoline claim. Liver enzyme testing (baseline and follow-up) was compared between two groups (the prerecommendation cohort October 1,1998, to March 31, 1999, and the postrecommendation cohort October 1,1999, to March 31,2000). RESULTS: 1,308 patients received at least one pemoline prescription during the study period; 76% of patients < or = 20 years were male. ADHD was the claims-identified indication for 688 patients (52%). Despite the labeling recommendation for use as second-line therapy, only 237 ADHD patients (34%) received a first-line therapy prior to pemoline. Only 12% and 11% of the pre- and post-cohort patients, respectively, received baseline liver enzyme tests; 9% in the pre- and 12% in the post-cohort received at least one liver enzyme follow-up test. CONCLUSIONS: Compliance with product labeling was low for both recommendations. Understanding the reasons for this finding could help improve risk management strategies.

Attention Deficit Disorder with Hyperactivity↗

The effects of pemoline on nuclear fusion, karyokinesis, and cytokinesis in caffeine treated cells.

The effect of 0.2% caffeine combined with 5-phenyl-2-imino-4 oxazolidone (pemoline, Tradon), in different ways, on mitosis in lateral roots of Vicia faba L. has been studied by means of aerated hydrocultivation. The results show that prolonged treatment with 10(-6) g/ml or 3 x 10(-4) g/ml (=saturated solution) pemoline to a certain degree compensates the negative influences of caffeine on mitotic index during and after the caffeine treatment. Depending on the duration of treatment 10(-6) g/ml pemoline are able to increase rates of nuclear fusions, bimitoses and 4n-mitoses, while 3 x 10(-4) g/ml have the opposite effects. The number of irregular cytokineses is increased by 10(-6) g/ml, whereas no abnormal cell walls are formed during treatment with 3 x 10(-4) g/ml pemoline. The conclusion is that pemoline has the same sites of action as caffeine, partly antagonistically, partly synergistically.

Caffeine↗

Pemoline-induced choreoathetosis and rhabdomyolysis.

Pemoline is an indirectly acting sympathomimetic with actions similar to amphetamine and methylphenidate. While choreoathetosis is a well-recognised complication of acute or chronic amphetamine abuse, only 3 previous case reports have implicated pemoline in such a movement disorder. We report a 49-year-old man who developed severe choreoathetosis with rhabdomyolysis after markedly increasing his intake of pemoline. Abnormal movements responded to diazepam and completely resolved over 48 hours. He made a complete recovery with supportive care. This is only the second case of pemoline-induced choreoathetosis in an adult reported in the English literature, and the first case of rhabdomyolysis and myoglobinuria complicating choreoathetosis.

Alcoholism↗