Selegiline and blood pressure in patients with Parkinson's disease

OBJECTIVES: Parkinson's disease (PD) frequently affects both the extrapyramidal system and the autonomic nervous system (ANS), the latter also being sometimes disturbed by PD medications. Specifically selegiline is known to disturb cardiovascular ANS functions and may cause or enhance orthostatic hypotension. METHODS: In order to study the effect of the withdrawal of selegiline on the regulation of blood pressure (BP) in advanced PD, an orthostatic test was performed in 14 PD patients with wearing-off before the morning levodopa dose and thereafter repetitively at 1-h intervals for up to 4 h. A Unified Parkinson's Disease Rating Scale motor score evaluation was also carried out hourly. The tests were repeated after a 4-week selegiline washout period. RESULTS: Selegiline withdrawal decreased systolic BP significantly during the on-stage in a supine position as well as during the orthostatic test. The initial drop of BP in the orthostatic test was significantly smaller after selegiline withdrawal. The heart rate remained unaffected.     

Differential behavioral syndrome evoked in the rats after multiple doses of SSRI fluoxetine with selective MAO inhibitors rasagiline or selegiline

Summary. This study investigated whether rasagiline and selegiline (MAO-B inhibitors) induce serotonin syndrome in fluoxetine-treated rats. Rats received rasagiline (0.1, 0.5, 2.0 mg/kg), or selegiline (0.8, 4.0, 16.0 mg/kg) (doses reflecting the clinical ratio of 1:8 base) in drinking water for 28 days. During the last 21 days, they received injections of fluoxetine 10 mg/kg (controls received water only, then saline injections; a fluoxetine only group received water only then fluoxetine). Serotonin syndrome was assessed using neurological severity score (NSS), food intake and weight gain. Mean NSS significantly increased, and weight and food consumption significantly decreased in rats receiving fluoxetine alone compared with controls. Selegiline 16 mg/kg but not rasagiline (regardless of dose) exacerbated these effects. We concluded that selegiline’s amphetamine-like metabolites may increase synaptic cathecholamines and possibly serotonin, aggravating fluoxetine’s effect. Rasagiline is devoid of this effect and may therefore be safer for use with serotonergic drugs in parkinsonian patients. Professor S. Cohen and Dr. Z. Speiser are emeritus at Sackler School of Medicine, Tel-Aviv University. Correspondence: Zipora Speiser, Teva, R&D Division, Sapir Industrial Zone, P.O. Box 8077, 42504 Netanya, Israel     

Selegiline in de novo parkinsonian patients: The French selegiline multicenter trial (FSMT)

The French selegiline multicenter trial was conducted in 1990 to test the possibility to improve disability of de novo parkinsonian patients (P. P.) during the first three months of treatment with selegiline (S) (10 mg/day) monotherapy. 93 P. P. were included in this double-blind, randomized, placebo controlled, clinical trial, in which 13 centers participated. Both parallel groups were followed up from inclusion (D0) to D30, D60 and D90. Drug efficacy was judged with Hoehn and Yahr (HY), Hamilton Depression Rating Scale (HDRS), Unified Parkinson's Disease Rating Scale (UPDRS), Schwab and England scores, decision to introduce levodopa and selfassessment. Biological and clinical parameters (cardio- vascular, weight, side-effects reports) were assessed for tolerability. 84 P. P. (38 P, 46 S) were evaluable for efficacy at D90.
When considering the main parameters, S appears superior to placebo: HY scores (p < 0.001), global UPDRS scores (p < 0.001) and UPDRS subscores: mental (p < 0.001), daily living activities (p < 0.01), motor activities (p < 0.01). Depressive scores (HDRS) are significantly improved only at D90 (p=0.005). Levodopa therapy was introduced in 45 % of the cases in S groups versus 18,4 % in P group. Global impression of efficacy was largely in favor of S; failure was noted in half of the cases in P group and only in 1/5th of the cases in S group. Side-effects were rare and minor.
S 10 mg/day monotherapy is statistically superior to placebo in improving de novo P. P. during the first three months treatment. Motor symptoms rapidly improve; mood is only modified after 3 months. S appears to be well tolerated. S may be considered as a good candidate for the initial treatment of P. P.     

The effect of deprenyl (selegiline) on intra-and extraneuronal dopamine oxidation

ABSTRACT — It was found that in that rat striatum DA was oxidized extrasynaptosomally to 11 % by MAO-A and to 3 % by MAO-B. The corresponding intrasynaptosomal oxidations were 84 % and 2 %, respectively. Those figures were virtually unchanged even if the rat brain MAO-B was selectively inhibited to 87 % by deprenyl. In the human brain extrasynaptosomal oxidation was 16 % and 66 %, respectively, by MAO-A and -B. Intrasynaptosomally the corresponding figures were 12 % and 6 %, respectively. Selective inhibition of human caudate MAO-B was calculated to give a total reduction of DA oxidation of 63 %. The differences between man and rat are due to the proportionately greater oxidation of DA by MAO-B in man, which is a consequence of a higher ratio of concentration of MAO-A/-B in the rat.     

Monoamine oxidase inhibitors and their pharmacological significance

ABSTRACT — The role of deprenyl, a selective monoamine oxidase B inhibitor, in the treatment of Parkinson's disease has been evaluated with special reference to the multiple pharmacological actions of the monoamine oxidaseinhibitory group of drugs.     

Advances in the delivery of treatments for Parkinson’s disease

Innovative drug delivery in Parkinson’s disease (PD) has the potential to reduce or avoid many side effects of current treatment, such as wearing-off type fluctuations, dyskinesia, on-off phenomena or bouts of motor freezing. The traditional orally administered formulations of l-dihydroxyphenylalanine combined with a peripheral aromatic acid decarboxylase inhibitor remain the mainstay of treatments for PD. However, such combination therapies have been further formulated to extend their duration of action by including a catechol-O-methyltransferase inhibitor. Preventing the breakdown of dopamine has also been achieved by monoamine oxidase-B inhibition; this approach now having been formulated for sublingual use (Zelapar^®, Valeant Pharmaceuticals). An alternative approach bypasses the oral route of administration and instead relies on continuous duodenal infusion (Duodopa^®, Solvay, NeoPharma AB) for better therapeutic effect. The clinical use of dopamine agonists as antiparkinsonian drugs now incorporates a variety of delivery techniques. For example, apomorphine, which relies on parenteral administration for maximum bioavailability, may be delivered via rectal, intranasal, sublingual and subcutaneous (e.g., Apokyn^®, Mylan Bertek) routes. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches. Finally, the authors examine more experimental delivery techniques, including the delivery of genes via viral vectors or liposomes, intracranial transplant of a variety of cells and of l-dihydroxyphenylalanine by prodrug-dispensing liposomes or pulmonary delivery (AIR^®, Alkermes). The advent and application of these varied technologies will help encourage patient-specific means of treatment for PD.     

SELEDO: a 5-y-ear long-term trial on the effect of selegiline in early parkinsonian patients treated with levodopa

The SELEDO (from selegiline plus levodopa) study was carried out as a randomized, prospective, placebo-controlled, double- blind, multicenter long-term, 5-year trial to evaluate the possible advantages of combining selegiline and levodopa in the early treatment of Parkinson's disease. One-hundred-and-sixteen patients were randomized either to selegiline or placebo. Before starting the study medication, the levodopa dose was titrated to the individual requirements of each patient. The primary study end point (time when levodopa had to be increased by >50% of the titrated dose) was reached in 23 of 59 patients in the selegiline group and 26 of 48 patients in the placebo group. At the end of the 5 years' treatment period the rates derived from a life-table analysis were 50.4% in the selegiline group and 74.1% in the placebo group (P = 0.027, log-rank test). The median time to reach the primary end point was 4.9 years in the selegiline group and 2.6 years in the placebo group. In patients treated with selegiline, the mean levodopa dose changed only slightly over the 5 years of treatment compared to the initially titrated dose, but rose markedly in the placebo group, where the dose of levodopa had to be adjusted earlier than in the selegiline group. At the same time, the lower levodopa dosage in the selegiline group was accompanied by at least equal therapeutic efficacy (which is necessary for an unambiguous interpretation). Subgroup analyses showed greater benefit for selegiline treated) patients in the earlier stages. Long-term side effects appeared later in the selegiline group, although the difference was not significant. The early combination of selegiline and levodopa proved to be clearly superior to levodopa monotherapy.     

SELEGILINE IN THE TREATMENT OF BEHAVIOURAL DISTURBANCE IN ALZHEIMER'S DISEASE

Objective. The purpose of this study was to examine the behavioural and cognitive effects of selegiline in a group of moderately behaviourally disturbed AD patients. Design. This was a 14-week randomized double-blind placebo-controlled study of selegiline (10 mg) and placebo. Setting. An outpatient clinic in an urban-based tertiary referral centre in the USA. Patients. Twenty-five outpatients meeting NINCDS criteria for probable Alzheimer's disease with associated behavioural disturbance. Measures. The Brief Psychiatric Rating Scale (BPRS), the Dementia Mood Assessment Scale (DMAS) and the Alzheimer Disease Assessment Scale (Cognitive) (ADAS-COG). Results. In the primary analysis, improvement on the BPRS and DMAS scores with selegeline treatment did not reach statistical significance. A secondary analysis using a parallel design showed a significant benefit of drug treatment on BPRS scores with a trend towards improvement on the DMAS. Among the 10 subjects who could be tested, there was a significant improvement in cognitive function on the ADAS-COG with selegiline compared to placebo. Conclusions. Short-term selegiline treatment produced an improvement in behaviour and had a significant effect on cognition in a subset of testable patients. © 1997 by John Wiley & Sons, Ltd.     

The pharmacology of selegiline ((−)deprenyl). New aspects

Abstract– Male rats were treated from the end of their 2nd year of life either with saline (1 ml/kg, s.c.) (n=66) or with deprenyl (0,25 mg/kg, s.c.) (n=66) three times a week until death. Whereas none of the two-year-old saline-treated rats displayed full scale sexual activity, this appeared in 64 out of 66 rats on deprenyl. The longest living rat in the saline-treated group lived 164 weeks. The average lifespan of the group was 147.05±0.56 weeks. The shortest living animal in the (−)deprenyl-treated group lived 171 weeks and the longest living rat died during the 226th week of its life. The average lifespan was 191.91±2.31 weeks. This is the first instance that a well-aimed medication prolonged lifespan of members of a species beyond their maximum age of death (182 weeks in the rat). A close relation between sexual activity and lifespan was detected.
Male rats (n=94) selected from an 8-month old population as sexually inactive ones were found to be miserable learners. This group was treated either with saline (1 ml/kg, s.c.) (n=46) or with (−)deprenyl (0.25 mg/kg, s.c.) (n=48) three times a week for 36 weeks. Their performance in the shuttle box during 5 consecutive days was tested before and after treatment. The total number of conditioned avoidance responses (CAR) which remained unchanged in the saline-treated group (6.53±1.41 before and 5.98±1.15 after treatment) increased from 5.57±0.65 to 20.73±1.39 (p<0.001) in the (−)deprenyl-treated group of rats. (−)Deprenyl-treatment (0.25-2 mg/kg, s.c., daily for 21 days) increased superoxide dismutase (SOD) activity in the striatum of CFY rats, whereas clorgyline-treatment (0.1–1 mg/kg) inhibited it.