Alzheimer-type dementia and verbal memory performances: influence of selegiline therapy

In a double blind randomized crossover trial lasting 6 months selegiline, a selective MAO-B inhibitor, was tested against placebo for activity on verbal memory performances in Alzheimer-type dementia (DAT). Verbal memory was assessed with the Rey-Auditory-Verbal Learning Test at the start of treatment, at the time scheduled for crossover (90 days) and at the end of the trial (180 days). The results suggest that selegiline possesses significant activity on some memory parameters, which seems to depend on an improvement both in information processing abilities and in learning strategies at the moment of acquisition

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Sommario In uno studio doppio cieco cross-over, randomizzato verso placebo della durata di sei mesi, è stata analizzata l'influenza della selegilina, inibitore selettivo delle MAO-B, sulle prestazioni di memoria verbale di 22 pazienti con diagnosi clinica di demenza tipo Alzheimer (DAT). L'esame della memoria verbale è stato effettuato con il Rey-Auditory Verbal Learning test all'inizio del trattamento, dopo 90 giorni, momento previsto per il cross-over, e dopo 180 giorni, al termine della sperimentazione. I risultati suggeriscono una significativa efficacia della selegilina su alcuni parametri di memoria, che sembrano riconducibili ad un miglioramento sia delle capacità di elaborazione delle informazioni, sia delle strategie di apprendimento al momento dell'acquisizione.

     

司来吉兰合用苄丝肼左旋多巴治疗帕金森病的临床疗效

目的 :研究司来吉兰合用苄丝肼 左旋多巴治疗帕金森病的临床疗效和安全性。方法 :采用开放性自身治疗前后对照。 2 5例帕金森病病人经苄丝肼 左旋多巴治疗后出现疗效减退、症状波动者 ,加用司来吉兰 5～ 7.5mg·d- 1,早晨、中午各服 1次。临床疗效采用帕金森运动功能量表 (MDR SPD)评分标准 ,同时检测血、尿常规 ,肝、肾功能及心电图。结果 :MDRSPD量表的临床总有效率84 % ,“开”期潜伏期缩短 (13±s 10 )min ,“开”期持续时间延长 (0 .7± 0 .5 )h ,不良反应轻微。结论 :司来吉兰合用苄丝肼 左旋多巴治疗中晚期帕金森病疗效确切 ,安全性高。     

Zydis selegiline in the management of Parkinson's disease

Selegiline, a selective monoamine oxidase-B inhibitor, has been used for decades in the treatment of Parkinson's disease. The recent development of an orally disintegrating dosage form using Zydis technology allows pregastric drug absorption and, thus, greatly improving the pharmacodynamic and pharmacokinetic drug profiles. This new formulation provides higher drug bioavailability and a substantially reduced concentration of active metabolites. As an adjunct to levodopa, Zydis selegiline is shown to be a safe and effective therapy in patients with motor fluctuations and wearing off. This review outlines the advantages of a Zydis formulation in Parkinson's disease and the evidence supporting the use of Zydis selegiline for motor fluctuations.     

Absorption and Presystemic Metabolism of Selegiline Hydrochloride at Different Regions in the Gastrointestinal Tract in Healthy Males

Purpose. The absorption and disposition of selegiline (SEL) and its metabolites N-desmethylselegiline (DMS), L-methamphetamine (MET), and L-amphetamine (AMP) were assessed in 8 healthy male volunteers at proximal and distal regions of the intestine relative to oral administration (in the stomach) to determine if intestinal site dependence contributed to the erratic oral absorption of selegiline hydrochloride which is manifest as low and variable bioavailability. Methods. An open-label, four-way crossover, single dose pharmacokinetic study comparing the bioavailability of 10 mg selegiline hydrochloride administered to healthy young males as a solution by the oral route (in the stomach) and by a nasoenteric tube to the following three sites: duodenum, jejunum and terminal ileum was conducted. Infusions were administered over a 1 minute interval and a two week washout was observed between treatments. Samples were taken over 96 hours and analyzed by LC/MS/MS. Results. Selegiline exposure was greatest following administration to the stomach (~150% > duodenum or jejunum) and least in the terminal ileum (~33% less than duodenum or jejunum). Duodenal and jejunal sites were equivocal based on selegiline absorption and subsequent metabolism. While both AMP and MET exposure was equivalent at all dosing sites, DMS exposure was less (~18%) at the terminal ileum. Conclusions. The oral absorption of selegiline is neither permeability-limited or intestinal site-dependent. Stomach absorption may bypass presystemic metabolism. The reduced DMS exposure at the terminal ileum is consistent with the theorized presystemic formation of DMS via luminal P450 enzymes and the density of these enzymes in the duodenum and jejunum relative to the ileum. AMP and MET metabolites were insensitive to dosing site consistent with their hepatic formation. The true magnitude of these effects would require multiple dosing as single dose pharmacokinetics do not predict the extent of multiple dose selegiline exposure.     

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.     

The effects of oral selegiline hydrochloride on learning and training in the dog: a psychobiological interpretation

1. Twenty two healthy, non-problem dogs were assessed for their acquisition of three different learning tasks on consecutive days and on the extinction of the response in the third. In Task 1, dogs were trained to walk in a circle on command. In Task 2, dogs were trained to retreat and sit on a mat. In Task 3, dogs were assessed for the acquisition and extinction of an operant response (pawing a panel).

2. Dogs were orally administered a placebo or selegiline hydrochloride at a dose of 0.5mg/kg for a period of three weeks prior to testing and during the test period.

3. Dog's treated with selegiline tended to perform better at tasks which were clearly lured with a motivationally significant cue, performing a first correct response sooner and requiring fewer reinforcements to reach the success criterion. They were also significantly more likely to walk over a novel object placed on the floor of the test arena. In the absence of a significant lure, the selegiline treated dogs took significantly longer to reach the required performance criterion for the operant task. These dogs also extinguished their response more rapidly than the control group

4. In the third task, selegiline treated dogs were significantly less likely to look away and throughout all tasks these dogs tended to be less distracted than the placebo group.

5. These findings and other reports associated with the effects of selegiline on learning may be explained by reference to the effects of selegiline on dopaminergic structures associated with positive incentive motivation.

Combination of a dopamine agonist, MAO-B inhibitor and levodopa — a new strategy in the treatment of early Parkinson's disease

Abstract– During 3 years'treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.     

Selegiline and levodopa in early or moderately advanced Parkinson's disease: a double-blind controlled short- and long-term study

Abstract– Selegiline 10 mg per day was compared to placebo as an adjunct to levodopa treatment in this double-blind study of early or moderately advanced Parkinson's disease. Thirty-eight patients completed an initial cross-over trial comprising two treatment periods, each of eight weeks, with a four weeks'wash-out period between them. Thirty of the patients continued in a long-term, double-blind parallel trial with a mean duration of 16 months (range 6–30 months). Selegiline treatment allowed a significant reduction of the necessary daily levodopa dose in both parts of the study and of the daily dosing frequency in the long-term investigation. In spite of this reduction of levodopa dose, an improvement was noted in tremor during the short-term selegiline periods. The side-effects were slight and related to dopamine effects and disappeared after reduction of levodopa-dose. The results support the use of selegiline as an early adjunctive treatment in Parkinson's disease.     

Monoamine oxidase, dopamine and Parkinson's disease

Four aspects about monoamine oxidase (MAO; E.C. 1.4.3.4) are of obvious interest in relation to Parkinson's disease and its treatment with the irreversible and selective MAO-B inhibitor L-deprenyl and are discussed in this review: 1) To what extent the two forms of MAO are of importance for the deamination of dopamine and to what degree MAO localised inside and outside of dopaminergic nerve terminals contributes 2) The kinetics of the MAO-protein, i.e. the rate of recovery of MAO after irreversible inhibition. 3) To what extent MAO may be changed as a consequence of the pathophysiological processes. 4) To what extent MAO may be involved as a force in the pathophysiological processes.     

Selegiline as primary treatment in early phase Parkinson's disease — an interim report

Abstract– We are carrying out a double-blind parallel trial comparing the effect of selegiline monotherapy and placebo in de novo parkinsonian patients. Fifty-six patients (28 in both groups) are included in the trial. This interim analysis reports the results of the first 52 evaluable patients who have had at least one follow-up visit after entering the trial. The efficacy of treatment was assessed using the Columbia University Rating Scale, the North-Western University Disability Scale and the Webster Rating Scale and followed until the addition of levodopa therapy became necessary. The data were analysed at follow-up times of up to twelve months (34 patients evaluable at the end of the period). The overall disability scores of all the rating scales used were significantly smaller in the selegiline group than in the placebo group. Levodopa treatment had become necessary in 12 patients (46%) in the selegiline group and in 14 patients (54%) in the placebo group. The side-effects were mild and similar in both treatment groups. According to the present results selegiline monotherapy seems to have therapeutic efficacy in the early phase of Parkinson's disease. Whether selegiline is able to slow down the progression of Parkinson's disease needs further clarification.