An open-randomized clinical trial of selegiline in amyotrophic lateral sclerosis

Based on the hypothesis that free radicals play a general role in the neurodegenerative process in motor neuron disease, we tested selegiline in a group of patients affected by amyotrophic lateral sclerosis (ALS) to examine whether it might modify the progression of the disease. Patients were admitted if they were 25–80 years old and had a confirmed diagnosis of ALS with symptoms lasting no longer than 24 months. Patients with familial ALS, pure progressive bulbar palsy, primary lateral sclerosis or progressive muscle atrophy were excluded; a total of 111 patients were recruited. Fifty-three patients were randomly assigned to receive the drug (selegiline 10 mg/day orally for 6 months) and the remaining 58 were considered ALS controls. Mortality was similar in the two groups (4 and 5 patients respectively), though the difference was not statistically significant. Among the survivors, mean MRC and Norris disability scores and forced vital capacity were fairly similar in the two groups at all times and no statistically significant difference between treated and untreated patients was found. The results did not change when the data were related to age, duration and characteristics of onset of the disease. The rate of progression was significantly more rapid in patients with bulbar symptoms in both groups. Our data do not show any significant effect of selegiline in modifying the progression of ALS.     

Selegiline Transdermal System (STS): Assessments of Dermal Safety in Human

The selegiline transdermal system (STS) is being developed to treat major depressive disorder. In a Phase I clinical study, the STS (20 mg/20 cm²) produced mild dermal irritability and demonstrated a low potential for contact allergenicity. In Phase III multicenter studies in major depression, over 1800 patients have been evaluated for dermal safety to reveal an overall rate of application site reactions (ASRs) with STS of 21.8% compared with a placebo rate of 9.7%. Discontinuation rates due to dermal adverse events in clinical studies were low (3.5%). Overall, the STS demonstrated good tolerability regarding ASRs and the potential for delayed contact hypersensitivity.     

Predictors of relapse in patients with major depressive disorder in a 52-week,fixed dose,double blind,randomized trial of selegiline transdermal system (STS)

Objective

We investigated patient and disease characteristics predictive of relapse of MDD during a 52-week placebo controlled trial of selegiline transdermal system (STS) to identify patient characteristics relevant for STS treatment.

Method

After 10 weeks of open-label stabilization with STS, 322 remitted patients with MDD were randomized to 52-weeks of double-blind treatment with STS (6 mg/24 h) or placebo (PLB). Relapse was defined as Hamilton Depression Rating Scale (HAMD-17) score of ≥14 and a CGI-S score of ≥3 with at least 2-point increase from the beginning of the double blind phase on 2 consecutive visits. Cox's proportional hazards regression was used to examine the effect of potential predictors (age, sex, age at onset of first MDD, early response pattern, number of previous antidepressant trials, severity of index episode, number of previous episodes, melancholic features, atypical features and anxious feature) on outcome. Exploratory analyses examined additional clinical variables (medical history, other psychiatric history, and individual items of HAM-D 28) on relapse.

Results

For all predictor variables analyzed, treatment Hazard Ratio (HR=0.48~0.54) was significantly in favor of STS (i.e., lower relapse risk than PLB). Age of onset was significantly predictive of relapse. Type, duration, and severity of depressive episodes, previous antidepressant trials, or demographic variables did not predict relapse. In additional exploratory analysis, eating disorder history and suicidal ideation were significant predictors of relapse after controlling for the effect of treatment in individual predictor analysis.

Conclusions

While age of onset, eating disorder history and suicidal ideation were significant predictors, the majority of clinical and demographic variables were not predictive of relapse. Given the post-hoc nature of analysis, the findings need confirmation from a prospective study. It appears that selegiline transdermal system was broadly effective in preventing relapse across different subtypes and symptoms clusters of MDD.     

天麻钩藤颗粒联合司来吉兰治疗帕金森病的临床研究

目的研究天麻钩藤颗粒联合盐酸司来吉兰片治疗帕金森病的临床疗效。方法选取2016年12月—2017年9月在郯城县妇幼保健计划生育服务中心进行治疗的帕金森病患者78例为研究对象,采用Excel表法随机分为对照组和治疗组,每组各39例。对照组患者于早餐后1 h口服盐酸司来吉兰片,第1~3天,1片/次,1次/d,第4天后若无异常则调整剂量至2片/次,1次/d。治疗组患者在对照组治疗的基础上口服天麻钩藤颗粒,5 g/次,3次/d。两组患者均持续治疗12周。观察两组的临床疗效,比较两组患者的自主神经症状量表(SPOCA-AUT)评分、帕金森病综合评分量表(UPDRS)评分、改良Webster评分、血清学指标和不良反应情况。结果治疗后,对照组和治疗组的总有效率分别为76.9%、92.3%,两组比较差异有统计学意义(P0.05)。治疗后,两组SPOCA-AUT、UPDRS和改良Webster评分均显著下降,同组治疗前后比较差异具有统计学意义(P0.05);且治疗后治疗组评分明显低于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组患者血清肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、丙二醛(MDA)和血清胱抑素C(Cys-C)水平均显著降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗后治疗组血清学指标水平明显低于对照组,两组比较差异有统计学意义(P0.05)。对照组和治疗组的不良反应率分别为7.7%、10.3%,两组不良反应率比较没有统计学意义。结论天麻钩藤颗粒联合盐酸司来吉多片治疗帕金森疗效显著,可降低机体炎症程度,改善患者神经功能、认知功能和运动能力,且安全性较好,具有一定的临床推广运用价值。     

2,3-吲哚醌对帕金森病模型小鼠抗氧化酶活性的影响研究

目的:探讨2,3-吲哚醌(ISA)神经保护作用的可能机制。方法:40只C57BL/6J小鼠分为空白对照组、模型组、ISA(200mg.kg-1灌胃)组和司来吉兰(0.5mg.kg-1腹腔注射)组。各组给予相应药物10d,后3组腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)制备帕金森病(PD)模型,随后处死小鼠测定各组小鼠血浆和脑组织中单胺氧化酶B(MAO-B)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-px)的活性。结果:与空白对照组比较,模型组MAO-B活性略有升高,SOD、GSH-px活性降低(P<0.01);与模型组比较,ISA、司来吉兰组MAO-B活性明显降低,SOD、GSH-px活性明显升高(P<0.01或P<0.05)。结论:ISA对MPTP造成多巴胺能神经元损伤的保护作用可能与其抑制MAO-B活性,减少毒性产物量,提高自由基清除能力,减少氧化性应激损伤有关。     

促渗剂对司来吉兰贴片透皮性能的影响

目的:考察不同质量分数的氮酮、油酸和肉豆蔻酸异丙酯3种促渗剂对司来吉兰贴片经离体豚鼠皮渗透性的影响。方法:采用Franz扩散池进行体外经皮渗透试验,利用高效液相色谱法为浓度测定方法,以不含促渗剂的司来吉兰贴片为对照计算氮酮、油酸和肉豆蔻酸异丙酯的增渗比及表观扩散系数比较促渗剂渗透效果。结果:与对照组比较,质量分数为3%的3种促渗剂增渗倍数分别为1.53、1.37和1.26,表观扩散系数分别增至2.37、1.65、1.13倍。结论:3种促渗剂均可提高司来吉兰贴片的透皮性能,其中以3%氮酮的促渗效果较好。     

Neuroprotective and neurotoxic effects of monoamine oxidase-B inhibitors and derived metabolites under ischemia in PC12 cells.

Selegiline and rasagiline are selective and irreversible monoamine oxidase-B inhibitors that exert neuroprotective effects in various preclinical models. The aim of the present study was to examine the effect of selegiline and its major metabolite, L-methamphetamine in comparison to rasagiline and its major metabolite, 1-R-aminoindan on oxygen-glucose deprivation induced cell death in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells. Our results show that selegiline reduces oxygen-glucose deprivation induced cell death by 30%. When the cultures were treated with rasagiline at similar concentrations, cell death induced by oxygen-glucose deprivation was reduced by 45-55%. L-methamphetamine, a major selegiline metabolite, but not 1-R-aminoindan, the major rasagiline metabolite, enhanced oxygen-glucose deprivation-induced cell death by 70%. Under normoxic conditions, both metabolites lack neurotoxicity. Concomitant exposure of the cultures under oxygen-glucose deprivation, to a combination of either selegiline and L-methamphetamine or rasagiline and 1-R-aminoindan, indicated that L-methamphetamine, but not 1-R-aminoindan, blocked the neuroprotective effect of the parental drug. These results suggest there may be a neuroprotective advantage of rasagiline over selegiline.     

SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Several factors such as inhibition of the mitochondrial respiration, generation of hydroxyl radicals and reduced free radical defense mechanisms causing oxidative stress, have been postulated to contribute to the degeneration of dopaminergic neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated animals is a useful experimental model of PD, exhibiting most of the clinical features, as well as the main biochemical and pathologic symptoms of the disease. In the present study, we have examined a dopaminergic (D1) receptor agonist, SKF-38393 HCl (SKF) for its possible neuroprotective action against MPTP-induced insults on dopaminergic neurons. MPTP is converted by monoamine oxidase-B (MAO-B) to its neurotoxic metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which is then taken up into the dopaminergic neurons. SKF-38393 had no effects either on total or monoamine oxidase B in the striatum. SKF-38393 blocked the MPTP-induced depletion of glutathione and attenuated MPTP-induced depletion of dopamine. Furthermore, it enhanced the activity of superoxide dismutase and hence mimicked the action of selegiline. The results of these studies are interpreted to suggest that SKF-38393 may prove a valuable drug in the treatment of Parkinson's disease.     

A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition

Summary. Seven randomised comparative studies were conducted in healthy volunteers to compare the pharmacokinetic and pharmacodynamic profiles of selegiline hydrochloride in a new formulation designed for buccal absorption Zydis Selegiline (1.25–10mg) with conventional selegiline hydrochloride tablets conventional selegiline tablets (10mg). A total of 156 healthy volunteers participated in these studies. Plasma concentrations of selegiline and its primary metabolites, N-desmethylselegiline (DMS), l-amphetamine (AMT), and l-methamphetamine (MET) were measured using Gas Chromatography Mass Spectrometry (GCMS) and gas liquid chromatography (GLC) assays. Inhibition of monoamine-oxidase type B (MAO-B) and monoamine oxidase type A (MAO-A) activity was determined by measurement of as -phenylethylamine (PEA) by GCMS and 5-hydroxyindoleacetic acid (5-HIAA) by High Performance Liquid Chromatography (HPLC) assays. Almost a third (2.96mg) of a 10mg selegiline dose in Zydis Selegiline was absorbed pre-gastrically (predominantly buccally) within 1 minute. Mean [SD] area-under-the curve (AUC_0–) values following Zydis Selegiline 10mg (5.85 [7.31] ng·h/mL) were approximately five times higher than those following conventional selegiline tablets 10mg (1.16 [1.05] ng·h/mL). In contrast, plasma concentrations of metabolites were significantly (p<0.001) lower following Zydis Selegiline 10mg than following conventional selegiline tablets 10mg.Plasma concentrations of selegiline and its metabolites increased in a dose-dependent manner over the dose-range Zydis Selegiline 1.25–5mg. Bioavailability was determined using AUC and peak plasma concentrations (C_max). The C_max of selegiline was similar following administration of Zydis Selegiline 1.25mg (1.52ng/mL) or conventional selegiline tablets 10mg (1.14mg/mL). The range of values for AUC_0– and C_max following Zydis Selegiline 1.25mg were entirely contained within the range following conventional selegiline tablets 10mg, with a much higher variability of plasma selegiline concentrations occurring after conventional selegiline tablets than after Zydis Selegiline. As expected, peak plasma concentrations for DMS, AMT and MET were consistently lower after Zydis Selegiline 1.25mg (1.19, 0.34, 0.93ng/ml, respectively) than after conventional selegiline tablets 10mg (18.37, 3.60, 12.92ng/ml, respectively). A significant (r=0.0001) correlation between daily PEA excretion (a measure of brain MAO-B inhibition) and the log-transformed AUC_(0–t) for selegiline was demonstrated. Mean daily PEA excretion was similar following Zydis Selegiline 1.25mg and conventional selegiline tablets 10mg (13.0µg versus 17.6µg). In contrast, there was no correlation between PEA excretion and selegiline metabolites, indicating that selegiline metabolites do not significantly inhibit MAO-B. Urinary excretion of 5-HIAA (used as a marker for MAO-A inhibition) was unrelated to plasma concentrations of selegiline or DMS following single or repeat dosing of Zydis Selegiline 1.25mg or conventional selegiline tablets 10mg. However, comparison of treatment groups revealed a significantly lower excretion of 5-HIAA in the conventional selegiline tablets 10mg group than in the Zydis Selegiline 1.25mg group after repeated administration over 13 days.In summary, by reducing the opportunity for first-pass metabolism, the absorption of selegiline from Zydis Selegiline was more efficient and less variable than from conventional selegiline tablets. Compared with conventional selegiline tablets 10mg, Zydis Selegiline 1.25mg yielded similar plasma concentrations of selegiline and degree of MAO-B inhibition, but markedly reduced concentrations of the principal metabolites. Thus, the lower but equally MAO-B inhibitory dose of selegiline in Zydis Selegiline 1.25mg, which is associated with lower concentrations of potentially harmful metabolites, could offer a safer and more predictable treatment in the management of patients with Parkinsons disease.Present address: Cephalon UK Ltd., Surrey Research Park, Guildford, United KingdomPresent address: Biogen Ltd., Maidenhead, Berks, United KingdomPresent address: Safetymednet, Ruscombe, United KingdomPresent address: Oxford Glycosciences (UK) Ltd., Abingdon, United KingdomPresent address: Pfizer UK Ltd., High Wycombe, United KingdomReceived December 3, 2002; accepted June 30, 2003     

A new low-dose formulation of selegiline: clinical efficacy,patient preference and selectivity for MAO-B inhibition

Summary. Three studies were performed using a fast dissolving formulation of selegiline hydrochloride designed for buccal absorption Zydis Selegiline. The aim of the first study was to compare the therapeutic efficacy of Zydis Selegiline (1.25mg or 10mg) with conventional selegiline hydrochloride tablets conventional selegiline tablets (10mg) in patients with Parkinsons disease (PD) who were previously treated with conventional selegiline tablets as an adjunct to levodopa/dopamine agonist therapy. Patients were observed for 4 weeks to ensure that they were stable. Stable patients (n=197) were then randomised to continue with conventional selegiline tablets 10mg (n=68), or to treatment with Zydis Selegiline 1.25mg (n=64) or Zydis Selegiline 10mg (n=62) for 12 weeks in this randomised, parallel group study. A further aim was to establish the acceptability of Zydis Selegiline compared with conventional selegiline tablets. Patient preference for Zydis Selegiline was also evaluated in a second study, a single-dose, randomised, two-way crossover study conducted in patients with PD (n=148). Patients were stratified by the presence or absence of swallowing and salivation problems and were randomised to either Zydis Selegiline 5mg or a placebo fast-dissolving formulation. In a third study, the degree of potentiation of the tyramine pressor effect following Zydis Selegiline was compared with that following conventional selegiline tablets in healthy volunteers. A total of 24 healthy volunteers were randomised to receive Zydis Selegiline 1.25mg or conventional selegiline tablets 10mg for 14–16 days in an open-label, randomised parallel group study.Both Zydis Selegiline (1.25mg and 10mg) treatments were shown to be therapeutically equivalent to conventional selegiline tablets 10mg based on comparison of mean total Unified Parkinsons Disease Rating Scale (UPDRS) scores. Therapeutic equivalence was defined a priori as the 90% confidence interval (CI) for the difference in total UPDRS scores between groups to lie entirely within the range ±5. The difference (90% CI) in mean adjusted total UPDRS between Zydis Selegiline 1.25mg and conventional selegiline tablets 10mg was –2.50 (–4.84, –0.17), and for Zydis Selegiline 10mg and conventional selegiline tablets 10mg, 0.04 (–2.30, 2.38). For the motor subscores of the UPDRS, differences between adjusted means (90% CI) compared with the conventional selegiline tablets group were: Zydis Selegiline 1.25mg, –2.14 (–3.94, –0.33) and Zydis Selegiline 10mg, –0.90 (–2.70, +0.91). Patients who switched from conventional selegiline tablets to Zydis Selegiline 1.25mg showed a slight improvement in UPDRS scores following 12 weeks of treatment (standard error of difference 1.039; p=0.01).In the single-dose crossover study, most (61%) patients liked Zydis Selegiline 5mg; a significantly greater proportion than the null hypothesis of 50% (p<0.002). However, only 62 patients (46%) indicated that they liked the taste of Zydis Selegiline. Nevertheless, the proportion of patients who preferred Zydis Selegiline (65%) to their usual medication was significantly greater than the null hypothesis of 50% (p<0.001).Similar findings were demonstrated in the 12-week study where a higher proportion of patients who received up to 3 months of treatment indicated a preference for either Zydis Selegiline 1.25mg (90%) or Zydis Selegiline 10mg (86%) over conventional selegiline tablets 10mg. More than 90% of patients found Zydis Selegiline easy to take, with 61% rating it as extremely easy. Most (81%) patients taking Zydis Selegiline 1.25mg liked the taste compared with 45% taking Zydis Selegiline 5mg (in the previous study).Zydis Selegiline did not potentiate the tyramine effect: a pressor effect was elicited after 400mg tyramine both before and after 14 days of treatment with Zydis Selegiline 1.25mg. In contrast, after 14 days treatment with conventional selegiline tablets 10mg, the threshold dose required to elicit the tyramine pressor response was significantly (p<0.0001) reduced from 400mg to 200mg.In summary, Zydis Selegiline at doses of 1.25mg and 10mg was therapeutically equivalent to conventional selegiline tablets 10mg. The Zydis Selegiline formulation was well-liked by all patients, with most preferring Zydis Selegiline 1.25mg to their usual selegiline tablet. Furthermore, Zydis Selegiline was well tolerated and, unlike conventional selegiline tablets, appeared to retain specificity for inhibition of monoamine oxidase type B (MAO-B), since it did not potentiate the pressor response to tyramine.Present address: Cephalon UK Ltd., Surrey Research Park, Guildford, United KingdomPresent address: Safetymednet, Ruscombe, United KingdomPresent address: Oxford Glycosciences (UK) Ltd., Abingdon, United KingdomReceived December 3, 2002; accepted July 23, 2003