Selegiline combined with enriched-environment housing attenuates spatial learning deficits following focal cerebral ischemia in rats

Selegiline (l-deprenyl) is an irreversible monoamine oxidase B (MAO-B) inhibitor that is suggested to have neuroprotective and neuronal rescuing properties. The present study investigated whether systemic administration of selegiline facilitates behavioral recovery after transient focal cerebral ischemia in rats using a combination of different behavioral tests (limb placing, foot slip, water maze, and Montoya's staircase test) to measure the outcome of recovery. Selegiline (0.5 mg/kg, SC) or 0.9% NaCl was administered once a day, beginning on the second day after induction of ischemia and continuing for 30 days. Selegiline administration combined with enriched-environment housing attenuated ischemia-induced spatial learning deficits in a water-maze task and enhanced performance of both the contralateral affected and ipsilateral nonaffected forelimbs in a staircase test. Selegiline administration alone was not beneficial in any of the tests. Subsequent histologic examination revealed that the infarct volumes were not different between the experimental ischemic groups. Thus, these results suggest that selegiline combined with enriched-environment housing reduces behavioral and cognitive deficits without affecting infarct size.     

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.     

Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin.     

Human growth hormone and dopaminergic drugs, with special reference to deprenyl (selegiline): a summary of studies on volunteers.

ABSTRACT — The tubero-infundibular dopaminergic tract of the hypothalamus has a stimulatory effect on growth hormone (GH) secretion. In healthy volunteers levodopa, through the released dopamine and direct dopamine receptor agonists, therefore induces transient GH secretion. The indirect effect of levodopa at the presynaptic level can be modulated by inhibitory GABAergic drugs and by the potentiating deprenyl, for example. The GH response to direct postsynaptic dopamine receptor agonists like apomorphine is unaffected by these modulators. Below the dopamine level, the inhibitory effect of somatostatin and the negative feedback of the GH itself come into play. These regulatory mechanisms place limitations on dopamine-GH studies in man.     

Cardiovascular responses to combined treatment with selective monoamine oxidase type B inhibitors and L-DOPA in the rat

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.     

Integrated pharmacokinetic and metabolic modeling of selegiline and metabolites after transdermal administration

Selegiline (SEL) 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. Selegiline hydrochloride (HCl) undergoes significant first-pass metabolism following oral administration. Transdermal delivery avoids the first-pass effect and provides greater and more prolonged levels of unchanged SEL and reduced levels of metabolites (N-desmethylselegiline (DES), L-amphetamine (AMP), and L-methamphetamine (MET)) compared to the oral regimen. An integrated pharmacokinetic–metabolic model which predicts plasma concentrations of SEL and metabolites following a single 24 h application of a selegiline transdermal system (STS) is proposed. The model is based on the metabolic conversion of SEL to DES and MET and subsequently to AMP. The input function is described by a zero-order constant for the delivery of SEL from the STS system based on in vitro studies of penetration of SEL across human skin. The elimination–non-metabolic constants for each analyte account for the urinary elimination. Plasma concentration data from a pilot pharmacokinetic study in which six healthy male volunteers were administered single 24 h applications of a 1·8 mg cm², 10 cm² STS were used to examine this model. The coefficient of determination was 0·98 and model selection criterion was 3·4 for mean data fits, supporting the goodness of fit of the model. The pharmacokinetic parameters obtained by non-compartmental analysis were comparable to those predicted by a compartmental model. The model also predicted urinary recoveries for AMP and MET and negligible recovery for SEL and DES consistent with recent studies with the STS in which urine was collected. The metabolic conversion constant from SEL to DES was significantly lower than the conversion constant from SEL to MET, indicating that metabolism of SEL is primarily driven towards MET following transdermal administration. The metabolic conversion from MET to AMP was less than the conversion from DES to AMP. This simultaneous prediction of the SEL and metabolites is essential as the metabolic ratios have been linked to the neuroprotective effects of SEL. These findings support the proposed regional delivery advantage attributed to the transdermal route compared to the conventional therapy with the oral tablet. Future model applications may also help identify significant covariates (i.e. age, gender, and disease state) in upcoming clinical trials. © 1997 John Wiley & Sons, Ltd.     

司来吉兰的临床研究进展及安全性

通过文献回顾,详细描述单胺氧化酶-B抑制剂司来吉兰的研究历史、化学结构、药动学及临床研究的进展,并从多方面阐述其安全性。司来吉兰10 mg·d-1单药治疗能改善早期帕金森病(PD)患者的运动徐缓/少动症状,延迟左旋多巴的应用,延迟疾病的进展。司来吉兰与左旋多巴合用可改善晚期PD患者症状,减少左旋多巴服药次数和剂量,改善和减少与左旋多巴剂量相关的症状波动。除PD外,研究发现司来吉兰能有效治疗儿童和成人的注意力缺陷多动症;改善阿尔茨海默病和额颞痴呆患者的认知功能和日常生活能力;减少发作性睡病的突发睡眠次数;减少睡眠中周期性肢体运动的肌阵挛发作次数;有效治疗PD伴发抑郁,且对戒烟有帮助。司来吉兰的治疗剂量安全性佳。     

丙炔苯丙胺治疗帕金森病30例临床观察

兹对我院１９９４—１９９６年ＰＤ专病门诊中长期应用丙炔苯丙胺（ｄｅｐｒｅｎｙｌ）治疗观察的３０例（２４例ＰＤ，６例ＰＤＳ）进行回顾并复习文献。原有抗ＰＤ治疗药物不变，加用丙炔苯丙胺渐至每日１０ｍｇ。以改良Ｗｅｂｓｔｅｒ计分表评价病情，按治疗前后进步率计算结果。本组大部分对肌强直、震颤、少动等有改善。其疗效与治疗前病程、病情程度无明确关系；对早期ＰＤ应用丙炔苯丙胺可推迟左旋多巴的应用。副反应少，且为暂时性的。较安坦、金刚烷胺、左旋多巴类易于耐受，不失为可选用的药物之一     

The systemic administration of tacrine or selegiline facilitate spatial learning in aged fisher 344 rats

Summary When compared to young Fisher 344 rats, aged Fisher 344 rats were impaired in their acquisition of the water maze task as indicated by longer escape latencies and distances to find a hidden platform. In a free swim trial which was performed after the training period, young rats had a better spatial bias, since they spent more time swimming in the previous training quadrant. Tacrine 3mg/kg, an anticholinesterase, and selegiline 0.25mg/kg, a MAO-B inhibitor, partially reversed the acquisition deficit in aged rats when administered on their own, and drug-treated aged rats swam more in the previous training quadrant than vehicle-treated aged rats during the free swim trial. Aged rats also swam slower than young rats. Tacrine, but not selegiline, increased swimming speed in aged rats. Taken as a whole, these data support the proposal that tacrine may be effective at alleviating age-related learning impairment and confirm the role of cholinergic dysfunction in the spatial learning deficit in aged rats.