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.     

司来吉兰联合复合多巴治疗帕金森病的有效性和安全性

目的 探讨司来吉兰联合复合多巴治疗帕金森病的疗效和安全性.方法 将89例帕金森病患者随机分为对照组(45例)和治疗组(44例),对照组患者采用复合多巴等药物治疗,治疗组患者加用司来吉兰治疗,6个月为1个观察周期.于用药前及用药后1、3、6个月采用PD统一评分量表(UPDRS)对两组患者进行疗效评定,并观察其不良反应.结果 治疗组患者治疗1个月时与治疗前相比,除UPDRSⅢ评分降低外(P＜0.01),UPDRSⅠ、Ⅱ、Ⅳ评分变化均无统计学差异(均P＞0.05);治疗3、6个月时与治疗前比较,其UPDRSⅠ～Ⅳ评分均下降(P＜0.01);治疗3、6个月时与治疗1个月时比较,UPDRS Ⅰ、Ⅲ、Ⅳ评分降低均降低(P＜0.01,P＜0.05);治疗6个月时与治疗3个月时相比,其UPDRS Ⅰ～Ⅳ评分均无统计学差异(P＞0.05).治疗3、6个月时,治疗组UPDRSⅠ～Ⅳ评分均明显低于对照组(P＜0.01,P＜0.05).观察期内,两组患者未出现严重不良反应.结论 司来吉兰联用复合多巴可有效改善帕金森病症状,且耐受性好,不良反应少.     

Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease

In an earlier report of our placebo-controlled selegiline trial on de novo parkinsonian patients, we have shown that the need to start additional levodopa therapy is significantly postponed by using selegiline monotherapy. Now we report the two-year interim results of the double-blind continuation of the trial in 44 patients after the introduction of levodopa to the earlier therapy with placebo or selegiline (21 and 23 patients, respectively). The clinical disability was assessed by three rating scales. The daily dose of levodopa needed to maintain an optimal condition had to be increased progressively up to a 52% higher level in the placebo group than in the selegiline group (543 ± 150 and 358 ± 117 mg, respectively, p<0.001). The number of daily doses of levopoda was also statistically significantly higher in the placebo group during the 24 months' observation period (p<0.01). The ratio of levodopa doses that was expected to stay the same contrarily significantly increased suggesting that selegiline would, besides having the levodopa potentiating effect, also have a beneficial influence on the progression of the basic cerebral dopamine deficiency. The combination of selegiline and levodopa was well tolerated, and the adverse event profiles did not differ from each other. In conclusion, early selegiline therapy allows a significant saving in the subsequent levodopa dosage. This saving seems to become even stronger along with the treatment time.     

Deprenyl (selegiline) in combination treatment of Parkinson's disease

ABSTRACT — Long-term treatment of parkinsonian patients with levodopa (plus decarboxylase inhibitor) leads to decreasing levodopa efficacy and increasing side-effects. Then main therapeutic problems are on-off phenomena, end-of-dose akinesia and levodopa-induced dyskinesias. Deprenyl, a selective MAO-B inhibitor, has produced good therapeutic effects in combination either with levodopa alone or with levodopa plus decarboxylase inhibitor in the treatment of end-of-dose akinesia and on-off phenomena.
In an open trial with 48 parkinsonian patients deprenyl was added to previous levodopa plus decarboxylase-inhibitor therapy. Good effects were achieved in respect of mild on-off phenomena and end-of-dose akinesia, minor success in the alleviation of dyskinesia and depression. In four further patients with a post-traumatic parkinsonian syndrome, no improvement of rigidospasticity and vigilance was demonstrable.     

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 the treatment of daily fluctuations in disability of parkinsonian patients with long-term levodopa treatment

Abstract– In order to evaluate in a double-blind manner the therapeutic efficacy of selegiline in the treatment of late-phase Parkinson's disease, 19 patients with end-of-dose type fluctuations were randomized for a double-blind cross-over trial receiving either selegiline 10 mg or placebo. Each period lasted 12 weeks. During a two week prestudy period the dose of levodopa was titrated to optimal levels. The disability was evaluated using the Columbia University Disability Scale (CUDS). The patients kept a daily diary to monitor closely the frequency and severity of their fluctuations and the side-effects of treatment. Their parkinsonian disability and all main symptoms improved significantly during selegiline treatment. The mean duration of action of a levodopa dose was significantly longer and there was significantly less daily end-of-dose and early morning akinesia during selegiline treatment. The side-effects were similar in both treatments. This double-blind study confirms the findings of earlier open studies that selegiline potentiates and prolongs the therapeutic effects of levodopa and thus its use is particularly beneficial in patients with end-of-dose type fluctuations in disability.     

左旋多巴对C17．2神经干细胞的毒性作用及司来吉兰的神经保护作用

目的　 探讨左旋多巴对C17.2神经干细胞的毒性作用和司来吉兰对其的拮抗作用。 方法　 采用MTT法检测不同剂量左旋多巴对C17.2神经干细胞的毒性作用 ,用Brdu标记检测左旋多巴对细胞增殖的影响 ,用透射电镜、Annexin V染色荧光显微镜和流式细胞仪检测细胞凋亡 ,用WesternBlot检测Caspase3及其活性片段 ;相同条件下同时检测司来吉兰的保护作用。结果　 MTT显示左旋多巴可使C17.2神经干细胞活性降低 ,与剂量相关 (P <0 .0 5 ) ,Brdu标记显示 2 0 0 μmol/L左旋多巴可使细胞增殖活力下降 ,与时间相关 (P <0 .0 5 ) ,作用 12及 2 4h后的透射电镜、Annexin V染色荧光显微镜和流式细胞仪可检测到凋亡细胞 ,WesternBlot显示Caspase 3表达量增加 ,并逐渐被切割成活性片段。司来吉兰能部分保护细胞免受左旋多巴的影响 (P <0 .0 5 ) ,并能部分抑制左旋多巴引起的细胞凋亡 (P <0 .0 5 )。 结论　 大剂量左旋多巴对C17.2神经干细胞具有毒性作用 ,呈剂量和时间依赖性。毒性剂量的左旋多巴可通过抑制DNA合成影响细胞增殖 ,并通过活化Caspases 3促进细胞凋亡 ,司来吉兰可部分拮抗上述作用。     

Clinical evaluation of deprenyl (selegiline) in the treatment of Parkinson's disease

ABSTRACT — The experiences of a seven-year study on deprenyl in the treatment of Parkinson's disease are summarized. It was found that the main advantage of deprenyl was that it permitted the reduction of die dose of levodopa in optimally treated patients. In the initial stage of Parkinson's disease deprenyl is only partially sufficient as monotherapy. Deprenyl can administered successfully for correcting the "wearing off" effect.     

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 cognition and emotion in parkinsonian patients undergoing long-term levodopa treatment

ABSTRACT — The effects of deprenyl on memory, other cognitive functions, vigilance and emotional processes were investigated in seven parkinsonian patients undergoing long-term levodopa treatment. The patients were selected on the basis of their cognitive impairment, observed during a follow-up study of 8–10 years. Four of the patients had progressive dementia and three did not. After deprenyl treatment lasting 4 weeks, there were two patterns of responses. Patients with slow progressive dementia failed to respond to treatment, whereas patients without progressive impairment tended to show improvement in memory and motor speed; the former group also showed more emotional changes than the latter. Typical responses in all patients treated with deprenyl were: increased arousal, paradoxical spells of tiredness, deterioration in vigilance and in set shifting, but improvement of parkinsonian disability. These preliminary findings indicate that there is a dissociation between pure motor responses and cognitive as well as other behavioural responses to deprenyl. It is probable that although enhanced availability of dopamine by MAO-B inhibition partly explains the present neuropsychological findings, also other brain mechanisms are involved.     

Combination of selegiline and controlled release levodopa in the treatment of fluctuations of clinical disability in parkinsonian patients

Abstract– Thirteen parkinsonians with a long duration of the disease and long-term dopa therapy, seven of them showing severe on-off oscillations and 6 an "end—of—dose impairment", were treated with a controlled release (HBS) preparation of L-DOPA/benserazide for more than 3 years.
Thereafter, selegiline was added in a progressively increasing dosage up to a maximum of 10 mg/day during 4 months, with the aim of a) further improving the long-term results and b) reducing the doses of the new formula of L-DOPA.
A significant decrease of early morning parkinsonism and reduction of motor disability throughout the day were observed; "wearing-off'cases showed better results compared with those presenting "on-off'oscillations. A mean reduction of 20% in the doses of levodopa was achieved. Likewise, a mild reduction of dyskinesias and a mild-moderate enhancement of dystonias were recorded. Only one patient did not tolerate selegiline and two others received lower doses due to side-effects.
Selegiline was capable of enhancing the antiparkinsonian effect of the new formula of L-DOPA, while allowing a reduction of the doses administered. It must also be emphasized that such improvement was achieved in complicated patients, most of whom showed some deterioration of response in the late stages of long-term sustained release levodopa treatment.     

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.     

Lisuride plus selegiline in the treatment of early Parkinson''s disease

We treated 20 early Parkinson's disease subjects with the dopamine agonist lisuride in combination with the MAO-B inhibitor selegiline (L-deprenyl). We started with lisuride alone for one month, then we added selegiline versus placebo to lisuride in double-blind conditions for 3 months; finally all patients received lisuride and selegiline for another 3 months. Lisuride alone (1.43 +/- 0.10 mg) significantly improved PD. When selegiline (10 mg/day) was added in the double-blind phase the mean lisuride dosage could be reduced by 22.8% without deterioration of the clinical effects, and the same occurred in the former placebo group when selegiline was added. The combination of both drugs was well tolerated. These data are of interest for the interpretation of the effects of selegiline.     

Deprenyl (selegiline) in the treatment of Parkinson''s disease

ABSTRACT — The effects of deprenyl were investigated in 45 parkinsonian patients suffering from fluctuations in disability under long-term levodopa treatment. During a 1 to 3 month period of treatment, 5–10 mg of deprenyl caused a significant reduction in response fluctuations in 26 out of 45 patients (58 %). This improvement was only moderate (58 %) or minimal (42 %). Of 11 parkinsonian patients taking deprenyl with levodopa and benserazide for up to 4 years, 6 patients (55 %) showed moderate and 5 patients (45 %) minimal improvement initially. The improvement in response fluctuations was maintained during the follow-up period, although there was a clear decline in the degree of improvement. The addition of deprenyl to levodopa treatment also caused a further improvement in parkinsonian disability, which, however, decreased during the treatment period. Deprenyl appears to be a useful adjuvant to levodopa in patients with daily fluctuations in disability.     

盐酸司来吉兰治疗早期帕金森病的疗效观察

目的 观察司来吉兰治疗早期帕金森病（PD）的疗效和安全性。方法 采用随机空白对照法,将60例已用安坦、金刚烷胺、维生素E联合治疗的早期PD患者分为司来吉兰治疗组和空白对照组,前者在原用药物剂量不变的基础上添加盐酸司来吉兰片5mg/d,疗程8周。采用改良Webster评分评价药物疗效并观察不良反应。结果 司来吉兰组治疗后4周及8周时改良Webster评分较治疗前明显改善（均P〈0．01）,且明显低于空白对照组（均P〈0．05）;司来吉兰组总有效率为76．7％,明显优于空白对照组（P〈0．01）;未见明显不良反应。结论 司来吉兰是一种安全有效的早期PD治疗用药。     

Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline

Summary. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce parkinsonism in man and non-human primates. Monoamine-oxidase B (MAO-B) has been reported to be implicated in both MPTP-induced parkinsonism and Parkinson's disease, since selegiline (L-deprenyl), an irreversible MAO-B inhibitor, prevents MPTP-induced neurotoxicity in numerous species including mice, goldfish and drosophyla. However, one disadvantage of this substance relates to its metabolism to (−)-methamphetamine and (−)-amphetamine. Rasagiline (R-(+)-N-propyl-1-aminoindane) is a novel irrevesible MAO-B-inhibitor, which is not metabolized to metamphetamine and/or amphetamine. The present study compared the effects of high doses of selegiline and rasagiline (10 mg/kg body weight s.c.) on MPTP-induced dopaminergic neurotoxicity in a non-human primate (Callithrix jacchus) model of PD. Groups of four monkeys were assigned to the following six experimental groups: Group I: Saline, Group II: Selegiline/Saline, Group III: Rasagiline/Saline, Group IV: MPTP/Saline, Group V: Rasagiline/MPTP, Group VI: Selegiline/MPTP. Daily treatment with MAO-B-inhibitors (either rasagiline or selegiline, 10 mg/kg body weight s.c.) was initiated four days prior to MPTP-exposure (MPTP-HCl, 2 mg/kg body weight subcutaneously, separated by an interval of 24 hours for a total of four days) and was continued until the end of the experiment, i.e. 7 days after the cessation of the MPTP-injections, when animals were sacrificed. MPTP-treatment caused distinct behavioural, histological, and biochemical alterations: 1. significant reduction of motor activity assessed by clinical rating and by computerized locomotor activity measurements; 2. substantial loss (approx. 40%) of dopaminergic (tyrosine-hydroxylase-positive) cells in the substantia nigra, pars compacta; and 3. putaminal dopamine depletion of 98% and its metabolites DOPAC (88%) and HVA (96%). Treatment with either rasagiline or selegiline markedly attenuated the neurotoxic effects of MPTP at the behavioural, histological, and at the biochemical levels. There were no significant differences between rasagiline/MPTP and selegiline/MPTP-treated animals in respect to signs of motor impairment, the number of dopaminergic cells in the substantia nigra, and striatal dopamine levels. As expected, both inhibitors decreased the metabolism of dopamine, leading to reduced levels of HVA and DOPAC (by >95% and 45% respectively). In conclusion, rasagiline and selegiline at the dosages employed equally protect against MPTP-toxicity in the common marmoset, suggesting that selegiline-derived metabolites are not important for the neuroprotective effects of high dose selegiline in the non-human MPTP-primate model in the experimental design employed. However, unexpectedly, high dose treatment with both MAO-inhibitors caused a decrease of the cell sizes of nigral tyrosine hydroxylase positive neurons. It remains to be determined, if this histological observation represents potential adverse effects of high dose treatment with monoamine oxidase inhibitors. Received February 1, 2001; accepted May 30, 2001     

Selegiline (1-deprenyl) and low-dose levodopa treatment of Parkinson''s disease A double-blind crossover trial.

Fifteen parkinsonian patients previously untreated with levodopa were treated with daily doses of 200 mg Madopar and randomized to addition of 10 mg selegiline (1-deprenyl) in a double-blind, placebo controlled, crossover trial. According to the patients own evaluations 6 reported additional therapeutic effect from selegiline to Madopar; 2 reported possible additional effect, whereas a further 6 reported no improvement; 1 did not complete the trial. Statistically significant positive therapeutic effect of selegiline could not be found on Webster's rating scale or on a sensimotoric test designed for parkinsonian disabilities. Side effects of selegiline were minimal. It is concluded that selegiline may be of some value in addition to levodopa in early treatment of parkinsonian patients, but positive therapeutic effect has to be tested individually. Even in these patients the additional therapeutic effect of selegiline to levodopa seems to be quantitatively small.     

Zydis selegiline reduces off time in Parkinson's disease patients with motor fluctuations: a 3-month, randomized, placebo-controlled study.

Zydis selegiline dissolves on contact with saliva and undergoes pregastric absorption. This minimizes first-pass metabolism and provides high plasma concentrations of selegiline. In this study, the efficacy and safety of Zydis selegiline was assessed in Parkinson's disease (PD) patients who were experiencing motor fluctuations with levodopa. Patients were randomly assigned to either drug or placebo in a 2:1 ratio in this double-blind, multicenter trial. Significant reductions in daily off time occurred at 4 to 6 weeks with the 1.25 mg dose (9.9%, P = 0.003) and 10 to 12 weeks with the 2.5 mg dose (13.2%, P < 0.001). The total number of off hours was reduced by 2.2 hours at Week 12 from baseline (compared with 0.6 hours in the placebo group). The average number of dyskinesia-free on hours for the Zydis selegiline patients increased by 1.8 hours at Week 12. There was no change in mean percentage of "Asleep" time throughout the study. No apparent differences were detected in the occurrence of drug-related adverse events between the Zydis selegiline group and placebo-treated groups. Adverse events were consistent with known effects of levodopa therapy. Zydis selegiline safely reduces daily off time when used as adjunctive therapy with levodopa in patients with PD.     

New approaches in the use of selegiline for the treatment of Parkinson's disease

Abstract– Selegiline hydrochloride (deprenyl) is a safe, useful adjuvant therapy in patients with Parkinson's disease treated with L-dopa. The optimum time for its introduction into the treatment regimen of a patient remains controversial. A multi-centre long-term study being conducted by the Parkinson's Disease Research Group of the United Kingdom to attempt to answer whether selegiline improves the natural history of Parkinson's disease is discussed. In a separate study we have been unable to demonstrate that higher doses of selegiline (up to 40 mg a day) produce additional therapeutic benefit above the conventional dose of 10 mg a day in levodopa-treated patients with motor fluctuations. Preliminary data from a neuropsychological study is also presented which suggests that selegiline may have beneficial effects on the speed of psychomotor responses supporting the anecdotal clinical observations of increased mental energy and alacrity.     

Selegiline as the primary treatment of Parkinson's disease — a long-term double-blind study

Introduction – To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD). Material and methods – A randomized, prospective, double-blind study on 44 patients with PD needing levodopa therapy after the initial double-blind treatment with placebo or selegiline was carried out. The patients were followed-up for 5 years under combination therapy. Results – Selegiline induced a significant ( P < 0.001) slowing in the need to increase the daily levodopa dose in order to compensate for the progression of the disease. After 5 years of combination therapy the mean dose of levodopa was on average 320 mg lower in the selegiline group (405 ± 59 mg vs 725 ± 78 mg). The difference in the levodopa doses between the two groups increased along with follow-up time, as also the ratio of the levodopa doses (placebo/selegiline group). The number of daily levodopa doses needed to compensate for the occurrence of motor fluctuations was significantly lower in the selegiline group. The parkinsonian disability did not differ between the two groups because the clinical condition was kept as optimal as possible by adjusting the levodopa dosage. Nine patients in the placebo group needed initiation of additional dopaminergic therapy in comparison to one in the selegiline group ( P =0.004). During the 5-year follow-up period 11 patients were withdrawn from the selegiline group, 7 due to adverse events. There was no difference in mortality between the two groups. Conclusion – Selegiline therapy offers beneficial long-term effects in the treatment of PD.