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The onset, duration, and offset of pemoline action to improve cognitive performance is examined intensively in 25 prepubescent males suffering from attention-deficit disorder with hyperactivity (ADDH). The purpose was to characterize the pharmacodynamics of pemoline in ADDH patients through correlation of plasma pemoline concentration with psychometric measures of memory search efficiency and paired-associates learning, with the physiological effect of pemoline on dopaminergic transmission concurrently measured by analysis of plasma prolactin response. The effect of pemoline on neuroprocessing is apparent within the first 2 hours after administration with an inverse relationship between plasma pemoline and prolactin concentration present at hour one only (r = 0.84; p = 0.005). Pemoline therapy for 3 weeks does not significantly affect area under the curve for pemoline or prolactin nor did the effect on memory search efficiency decrease, suggesting no apparent tolerance.
Plasma pemoline levels were measured in 6- to 12-year-old, severely hyperactive males coincident with onset of abnormal involuntary movements. Acute exposure to pemoline (2 mg/kg orally) was associated with choreoathetoid movements of face, limbs, and trunk in five of 20 subjects in an acute study of pemoline pharmacokinetics. Also reported is a series of four chronically treated patients who developed choreiform movements and dyskinesias after variable periods of exposure from 3 weeks to 3 months with pemoline (1.5-2.0 mg/kg/day). Abnormal movements following acute or chronic exposure to pemoline cleared after pemoline discontinuation. Pemoline pharmacokinetics does not seem to be a primary determinant in the development of abnormal involuntary movements after chronic exposure. Total amount of pemoline absorbed may play a role in the development of choreoathetoid movements following acute exposure.
Methylphenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.
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.
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.
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.
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.
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.
A simple gas chromatographic assay of the psychostimulant pemoline in human urine has been developed. Instead of extraction of the drug from urine, it is hydrolysed to 5-phenyl-2,4-oxazolidinedione with 1 N hydrochloric acid. After the extraction, this compound is methylated with diazomethane and determined by gas-liquid chromatography using a nitrogen-selective detector and a solid injection system. The method has been applied in preliminary human pharmacokinetic studies, by measuring the urinary excretion rate of pemoline following oral administration. At present, the screening procedures for doping control do not involve the detection of pemoline, but the method described can easily be incorporated in such procedures.
The clinical and psychological effects of pemoline were compared with placebo in a double-blind study of 20 depressed patients. Target symptoms were disturbances of concentration and memory, tension, depression, fatigue, decreased libido, anorexia and insomnia. The two groups were matched for their clinical picture, age, sex, and duration of illness. During the three-week study period the pemoline group received 50 mg daily. Significant differences in some clinical symptoms were found between the groups, but not in the performance of psychological tests, administered before and after the three-week study period. These differences proved the effectiveness of pemoline in combating symptoms of disturbances in concentration, memory, tension, depression and fatigue.
Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability. Few options for treatment are available. We conducted a double-blind, placebo-controlled, crossover trial for each of two 4-week treatment periods. Forty-six eligible patients entered and five dropped out due to concurrent exacerbations. Nineteen patients (46.3%) experienced excellent or good relief of fatigue with pemoline, and eight patients (19.5%) with placebo (p = 0.06, Fisher's exact test). One-fourth of patients did not tolerate the drug well, and 7% had to discontinue pemoline during the study due to side effects. The most common side effects were anorexia, irritability, and insomnia. Pemoline may be an effective short-term treatment for fatigue associated with MS, but its adverse effects are not well tolerated by many patients.
A specific GLC method for the determination of microgram quantities of the central stimulant pemoline in biological fluids is described. Extraction problems due to the low solubility of pemoline are avoided by acid hydrolysis of the drug to 5-phenyl-2,4-oxazolidinedione, which then can be easily isolated by two-phase extraction with dichloromethane, ether, or chloroform. Amide-imide tautomerism enables a cleanup of the extract. Quantitative determination at the microgram level is done on a methylated fraction of the dichloromethane extract by GLC using a suitable internal standard. For supporting evidence of the GLC method's specificity, the compound is also identified by examining an aliquot of the final dichloromethane extract by TLC.
Extractive alkylation was used to determine intact pemoline in serum and urine. Pemoline was extracted into methylene chloride as an ion-pair with tetrapentylammonium hydroxide under alkaline conditions. Evaporation of the solvent at 70 degrees in the presence of methyl iodide yielded the N,N-dimethylpemoline derivative. GLC analysis was performed on a 5% FFAP column with nitrogen-specific detection. Sensitivity was 0.05 microgram/ml with 1 ml of urine of serum. Calibration curves were linear to at least 4 microgram/ml with serum and 15 microgram/ml with urine. Precision was excellent with a pooled relative standard deviation of +/- 7.5% for serum samples in a 0.1-4 microgram/ml range.
Pemoline, the constituent of Tradon, is able to slow down the decrease of the mitotic index caused by 0.1% caffeine in roots of Vicia faba, and mitotic aberrations are reduced. With 0.005% colchicine and 3 x 10(-4) g/ml pemoline, no metaphase-accumulation can be observed, and anaphase-disorder is delayed.
A description is given of a gas-liquid chromatographic (GLC) method for the detection and determination of pemoline in biological samples. On treatment with hydrochloric acid, pemoline is converted into 5-phenyl-2,4-dioxooxazolidine, an acidic compound, which can be easily extracted with dichloromethane and determined by GLC. A combined GLC-mass spectrometric method is described.
A simple gas chromatographic assay of the psycho-stimulant pemoline in human urine, plasma and saliva has been developed. Instead of direct extraction of the drug from urine, plasma and saliva, it is hydrolyzed to 5-phenyl-2,4-oxazolidine-dione with 1 N hydrochloric acid. After extraction this compound is methylated with diazomethane and determined by gas-liquid chromatography using a capillary SCOT column with a mixed stationary phase, a solid injection system and a nitrogen-selective detector. 5-Phenyl-2,4-oxazolidinedione, which was also found to be a metabolite of pemoline, could be determined quantitatively in human urine.
Decreased longitudinal growth was observed in 24 hyperkinetic children receiving pemoline therapy. Mean height velocity was 3.67 +/- 0.25 cm/year during therapy but 5.35 +/- 0.42 cm/year after treatment had been discontinued (P less than 0.01). There appeared to be an inverse relationship between growth velocity and drug dosage. All patients receiving less than the median dose of 3.72 mg/kg grew 4 cm/year or more, while seven of 12 patients receiving more than this dose grew at a slower rate. Body weight, basal and stimulated growth hormone values, and plasma somatomedin concentrations were not significantly altered by pemoline treatment, suggesting that this drug may have a direct effect on cartilage metabolism.