Deprenyl (selegiline) combined with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease

ABSTRACT — The purpose of this double-blind placebo controlled study was to estimate how much the levodopa dosage can be reduced, when deprenyl is used, without worsening the disease and to see whether deprenyl can reduce the "off-periods". The trial included 40 patients of both sexes with at least 3 years history of Parkinson's disease who were undergoing stabilized levodopa therapy. The deprenyl dosage was 5 mg daily in the first 4 weeks. The levodopa dosage was reduced until there was demonstrable impairment.
The trial demonstrates that with deprenyl the levodopa dosage can be reduced considerably without prejudicing the therapeutic outcome. Some patients showed improvement, and the "off-periods" were reduced in many cases.     

Selegiline in Parkinson''s disease

Twenty patients with Parkinson's disease were treated with the MAO-B inhibitor selegiline (l-deprenyl) and placebo without levodopa (L-dopa) in a randomized double-blind clinical cross-over study to analyze relative importances of dopamine (DA) synthesis and metabolism. The daily dose of selegiline was gradually increased to a maximum of 30 mg in all patients. The clinical neurological disability (Columbia score) was about 10% less on selegiline (30 mg/day) than on placebo. This difference was neither statistically nor clinically significant. The results are compatible with the possibility that treatment with selegiline without concomitant L-dopa does not significantly increase DA concentration which remains low and is determined mainly by tyrosine hydroxylase activity. At low DA levels the DA re-uptake mechanism recaptures most of the released DA and DA deamination is of minor significance. The pathway of DA oxidation becomes more important only at higher DA concentrations, accomplished by bypassing the rate limiting step of tyrosine hydroxylation using L-dopa.     

TOXICOKINETIC EVALUATION OF A SELEGILINE TRANSDERMAL SYSTEM IN THE DOG

The toxicology and toxicokinetics of a selegiline transdermal system (STS) were evaluated in a 3 month dog study of daily 24 h applications of placebo 4, 8, or 12 STSs in 32 male and 32 female beagle dogs. Each STS delivered approximately 5 mg selegiline over 24 h. No drug-related signs of toxicity were noted in any group with respect to clinical observations, dermal effects, body weight, food consumption, hematology, urinalysis data, or ophthalmoscopic or electrocardiographic examinations. Clinical chemistry data revealed no consistent adverse effects except for an increase in alanine aminotransferase in dogs receiving 8 and 12 STSs. Histological evaluation of tissues revealed the presence of pigment in the Kupffer cells of dogs treated with 8 and 12 STSs. There were no pathology findings suggestive of hemolysis or cholestasis. The no-effect level (NOEL) was 4 STSs (2·9 mg kg⁻¹ d⁻¹). There were no degenerative or life-threatening toxic effects up to 12 STSs (8·5 mg kg⁻¹ d⁻¹). Gender-related differences in steady-state plasma levels were not observed. Steady-state plasma concentrations were similar to maximum plasma concentrations obtained in single-dose studies, suggesting that drug accumulation was not evident. Simulation of systemic exposure following oral administration of 16·8 mg kg⁻¹ d⁻¹ from previous toxicology studies indicated that selegiline exposure following 12 STSs is sixfold greater while N-desmethylselegiline, L-amphetamine, and L-methamphetamine exposure is 0·5, 0·15, and 0·14 times the exposure in the oral study. The threefold difference in NOEL between oral and transdermal studies in the dog (0·8 versus 2·9 mg kg⁻¹ d⁻¹) is probably related to greater L-amphetamine and L-methamphetamine exposure following oral administration. The reduction in metabolite formation, relative exposure of selegiline in the dog at the NOEL compared to oral toxicology studies, and margin of safety provided, given that the expected clinical dose is less than the dosage of oral Eldepryl^™ (0·15 mg kg⁻¹ d⁻¹), documents the safety of the selegiline drug substance and indicates that additional toxicologic findings with the STS may not be expected. © 1997 by John Wiley & Sons, Ltd.     

Pharmacokinetic evaluation of a selegiline pulsatile oral delivery system

Selegiline is a selective, irreversible inhibitor of MAO-B, used in the treatment of Parkinson's disease, either alone or as an adjunct to L-DOPA. The sole recommended dosing regimen is 5 mg given in the morning and at noon with breakfast and lunch. A pulsatile oral dosage form was developed to mimic the conventional tablet release from two oral administrations separated by 4 h, to permit once-daily dosing and increase compliance. The pharmacokinetics of the pulsatile delivery system was studied in six healthy male volunteers. The plasma concentration–time profile from the pulsatile system of selegiline and metabolites is dissimilar to that obtained from the 5 mg bid administration of the conventional tablet and cannot be considered to be bioequivalent. The initial pulse of the delivery system is rapidly absorbed but to a lesser extent than the conventional regimen; the second pulse exhibits absorption which is delayed and prolonged. The decrease in the selegiline concentration may be due to the less absorptive surface of the lower GI tract which is available to the second pulse. Another reason could be the disparity between the in vitro and in vivo release profiles from the second pulse. Compartmental analysis indicates that the ratio of formation–absorption rate constant for the selegiline to N-desmethylselegiline pathway decreases from 1·57±1·04 for the first pulse to 0·61±0·54 for the second pulse of the pulsatile delivery system, suggesting that the upper portion of the GI tract has a greater capacity to convert selegiline to N-desmethylselegiline than the lower GI tract. The lack of in vivo and in vitro correlation is most likely due to site specific absorption/metabolism. Regimen has been previously shown to be a significant factor in estimating the extent of selegiline and metabolite exposure following oral administration. The inequivalence of dosing regimens of the same total daily dose may ultimately be linked to the saturability of gut wall metabolism. This phenomenon may preclude the development of novel delivery systems designed to mimic the recommended dosing regimen of the conventional Eldepryl^™ tablet. © 1997 John Wiley & Sons, Ltd.