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.     

Evidence that Formulations of the Selective MAO-B Inhibitor,Selegiline, which Bypass First-Pass Metabolism,also Inhibit MAO-A in the Human Brain

Selegiline (L-deprenyl) is a selective, irreversible inhibitor of monoamine oxidase B (MAO-B) at the conventional dose (10 mg/day oral) that is used in the treatment of Parkinson''s disease. However, controlled studies have demonstrated antidepressant activity for high doses of oral selegiline and for transdermal selegiline suggesting that when plasma levels of selegiline are elevated, brain MAO-A might also be inhibited. Zydis selegiline (Zelapar) is an orally disintegrating formulation of selegiline, which is absorbed through the buccal mucosa producing higher plasma levels of selegiline and reduced amphetamine metabolites compared with equal doses of conventional selegiline. Although there is indirect evidence that Zydis selegiline at high doses loses its selectivity for MAO-B, there is no direct evidence that it also inhibits brain MAO-A in humans. We measured brain MAO-A in 18 healthy men after a 28-day treatment with Zydis selegiline (2.5, 5.0, or 10 mg/day) and in 3 subjects receiving the selegiline transdermal system (Emsam patch, 6 mg/day) using positron emission tomography and the MAO-A radiotracer [¹¹C]clorgyline. We also measured dopamine transporter (DAT) availability in three subjects from the 10 mg group. The 10 mg Zydis selegiline dose significantly inhibited MAO-A (36.9±19.7%, range 11–70%, p<0.007)) but not DAT; and while Emsam also inhibited MAO-A (33.2±28.9 (range 9–68%) the difference did not reach significance (p=0.10)) presumably because of the small sample size. Our results provide the first direct evidence of brain MAO-A inhibition in humans by formulations of selegiline, which are currently postulated but not verified to target brain MAO-A in addition to MAO-B.     

Orally disintegrating selegiline for the treatment of Parkinson's disease

The selective monoamine oxidase type B inhibitor selegiline is commonly administered as medical treatment to patients suffering from Parkinson's disease. The clinical value of conventional selegiline is, however, compromised by extensive first-pass metabolism, which reduces its bioavailability and leads to the production of possibly harmful methamfetamine metabolites. This review aims to evaluate a novel, orally disintegrating formulation of selegiline by examining scientific evidence from previous pharmacological and clinical studies. As a result of improved bioavailability, orally disintegrating selegiline can be administered at lower doses than conventional selegiline with similar clinical effect. It also leads to less variable selegiline blood concentrations and produces significantly less methamfetamine metabolites. We conclude that this novel formulation offers an interesting treatment option, especially for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.     

Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson's disease

ABSTRACT

Objective: Patients receiving levodopa for Parkinson's disease experience motor fluctuations and immobility (‘off’ episodes) between doses. This study assessed adjunctive Zelapar^? (selegiline orally disintegrating tablet (ODT)) for managing off episodes and for long-term safety.

Methods: This open-label extension evaluated long-term safety, efficacy, and tolerability of adjunctive selegiline ODT 2.5?mg in patients who completed either of two large phase 3 double-blind studies. The study was to end after 12 months but was amended to be open-ended. Investigators could increase levodopa doses and introduce controlled-release formulations of levodopa or dopamine agonists if warranted. Additionally, results of a small randomized trial of open-label selegiline ODT 1.25?mg in comparison to conventional selegiline was added only to the safety analysis. Efficacy variables included changes in daily off time and Patient's Global Impression of Improvement (PGI-I) and Clinical Global Impressions Severity of Disease (CGI-S) ratings. Safety assessments included adverse events and oropharyngeal findings.

Results: This study enrolled 254 patients: 248 from the large phase 3 studies (efficacy analysis) and an additional six from the prior open-label comparison (safety analysis) in order to evaluate a larger population for safety purposes. Mean reduction from baseline in daily off time was 9.4% (1.6?h) for patients previously given selegiline ODT, 6.0% (1.2?h) for those switched from placebo, and 8.1% (1.4?h) overall. PGI-I and CGI-S ratings indicated little or no change from baseline. Treatment-related adverse events occurred in 132 (52%) patients. No severe oral irritations were attributed to selegiline ODT or prompted discontinuation.

Conclusions: Long-term selegiline ODT 2.5?mg/day was effective, safe, and well tolerated in patients with Parkinson's disease experiencing off episodes during levodopa therapy.     

Animal Models of Parkinsonism

The discovery of profound dopamine depletion of basal ganglia in patients with Parkinson's disease and the development of antiparkinsonian drug therapy were largely based on animal models. The behavioural changes caused by cholinergic drugs, reserpine and related agents, and unselective neuronal lesions were the first widely used animal models for Parkinson's disease. The crucial breakthrough was the observation of the circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model still is one of the basic animal models of Parkinson's disease. It is suitable for the screening of new potential antiparkinsonian agents with the classic spectrum. The parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and the monkey is the latest and the best animal model for Parkinson's disease. Especially when given to the monkey, MPTP causes biochemical, behavioural and neuropathological changes which largely mimick those of Parkinson's disease in man. The MPTP-induced parkinsonism in the monkey can be used for the study of the neurobiology and new forms of drugs therapy of Parkinson's disease. However, because the MPTP monkey model is expensive and laborious, it is not particularly convenient for the screening of new drugs. Recently, a new approach in the treatment of Parkinson's disease is to develop drugs which might prevent or retard the disease progression. The prevention of behavioural changes of aged rodents is used as an animal model and promising results with selegiline have been obtained.     

Selegiline. A review of its pharmacology, symptomatic benefits and protective potential in Parkinson's disease.

Selegiline (deprenyl) is a selective inhibitor of cerebral monoamine oxidase type B at the dosage (10 mg/day) used in patients with Parkinson's disease. Through this activity, the drug increases nigrostriatal dopamine levels, and may protect neurons against damage by free radicals and possibly exogenous neurotoxins. Selegiline also inhibits dopamine reuptake from the synaptic cleft. Because of its selectivity, selegiline 10mg daily does not prevent the breakdown and exacerbate the indirect pressor effects of dietary amines such as tyramine; it is devoid of the 'cheese' effect. Following oral administration, selegiline is rapidly metabolised to L-methamphetamine and L-amphetamine, which may account for the euphoria and insomnia seen in many patients, although potentiation of dopaminergic activity with concurrent levodopa appears more likely. The drug is a useful adjunct to levodopa in Parkinsonism, improving 'end-of-dose' fluctuations, producing modest improvements in motor function, and allowing a reduction in levodopa dosage. Indeed, if levodopa dosages are not decreased when selegiline is added to the therapeutic regimen, peak concentration dyskinesias due to levodopa are often exacerbated. However, symptomatic benefits are rarely maintained for more than a year and selegiline is relatively ineffective in allaying the abrupt swings in response to levodopa ('on/off' effects). When used alone in patients with mild disease, selegiline appears to slow the rate of symptom progression and may extend survival, through either neuroprotection or symptom relief. Whichever mechanism(s) is responsible, there is strong evidence to suggest that selegiline should be considered both in patients newly diagnosed with Parkinson's disease in an attempt to delay symptom progression, and in those experiencing dose-dependent fluctuations in response to levodopa.     

临床药师在晚期帕金森病伴复杂运动并发症中的药学服务

目的探讨临床药师在晚期帕金森病伴复杂运动并发症中的药学监护。方法临床药师参与1例晚期帕金森病伴复杂运动并发症治疗的案例,分析总结临床药师在该疾病治疗中的药学服务模式。结果临床药师对该患者的药物选择进行了分析及建议,并对药物治疗中出现的不良反应进行了处理和监护的综合管理,使患者的症状得到了改善。结论临床药师为帕金森病患者提供药学服务,可有效提高患者用药安全。     

Community and long-term care management of Parkinson's disease in the elderly: focus on monoamine oxidase type B inhibitors

Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes.     

Apomorphine therapy in Parkinson's disease: a review

Motor fluctuations are common and distressing for patients with advanced Parkinson's disease. Subcutaneous apomorphine injections can be an extremely valuable adjunctive therapy. In this review, the authors discuss the history, pharmacology, efficacy, safety and proper administration of apomorphine for treating ‘off’ states in Parkinson's disease, with a focus on intermittent subcutaneous administration.     

姜黄素治疗帕金森病的作用机制研究进展

帕金森病是好发于中老年人的神经退行性疾病。目前治疗帕金森病的常用药物是左旋多巴,但是患者在服用几年之后会出现一系列的不良反应。姜黄素是一种提取自姜黄科、天南星科等植物中的疏水性多酚类成分,在帕金森病的研究和治疗中展现出潜在的疗效。研究表明,姜黄素可以通过保护多巴胺能神经元、抗炎、抗氧化、抗细胞凋亡、抗线粒体损伤、调节自噬等多种途径在帕金森病中发挥神经保护作用。总结了姜黄素在帕金森病治疗中涉及到的不同作用机制,为进一步开发安全可靠的药物提供参考。     

The safety of dopamine agonists in the treatment of Parkinson's disease

Dopamine agonists are highly effective as adjunctive therapy to levodopa in advanced Parkinson's disease. These drugs have rapidly gained popularity as a monotherapy in the early stages of Parkinson's disease for patients < 65 – 70 years old, because they are about as effective as levodopa, but patients demonstrate a lower tendency to develop motor complications. However, dopamine agonists could have peripheral and central side effects, which are often the reason for the discontinuation of the treatment. This review focuses on the potential negative effects related to the use of dopamine agonists in the treatment of Parkinson's disease.     

Apomorphine in the treatment of Parkinson's disease

Motor fluctuations, refractory to conventional medical management, are one of the most troubling aspects of Parkinson's disease. Apomorphine is a dopaminergic agent that has been known to the medical community for more than a century, but has only recently been developed to treat such motor fluctuations. In this article, the authors review the historical background, structure, mechanism of action, pharmacologic properties, clinical trials, indications and side effects, as well as avenues of further research, of apomorphine.     

临床路径中药物治疗方案的优化探索——以南京鼓楼医院帕金森病药物治疗路径为例

药物治疗路径是对临床路径在用药方案方面的完善和补充，对于减轻患者经济负担，促进医院药事管理高质量发展，适应医保支付改革新趋势，实现卫生资源的优化配置等方面具有积极的意义。现行临床路径中的药物治疗方案往往描述得不够详尽，从而影响临床路径的实施。以帕金森病为例，从南京鼓楼医院现有药品的实际情况出发，制定药物治疗路径。通过对帕金森病药物治疗路径的重新整理，明确了各个药物的选择优先级别及治疗地位，从而避免不必要的治疗方案调整，也减少了帕金森病的单病种治疗费用。     

Current drug therapy for Parkinson's disease. A review.

The impact of neuropharmacology has been greatest in 2 areas of clinical treatment: epilepsy and Parkinson's disease. This article covers the drug treatment of Parkinson's disease, a condition which characteristically affects the elderly population. The 5 drugs or groups of drugs used in the treatment of Parkinson's disease are: (a) anticholinergic drugs; (b) amantadine; (c) levodopa plus a peripheral decarboxylase inhibitor; (d) dopamine agonists; and (e) selegiline. Levodopa is still the most effective anti-Parkinsonian drug for most patients and is often combined with selegiline which may retard the rate of disease progression. The early use of dopamine agonists (such as bromocriptine) may prevent the subsequent development of response fluctuations. Once fluctuations have developed, they may be helped by the use of slow release levodopa preparations and, in the most severe cases, subcutaneous apomorphine.     

Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson's disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently l-dopa is the gold standard treatment for Parkinson's disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson's disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces l-dopa-induced dyskinesias, a side effect of l-dopa therapy that may be as incapacitating as Parkinson's disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of l-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson's disease progression and for the management of the dyskinesias that arise with l-dopa therapy.     

线粒体损伤相关的帕金森病分子机制及其药物靶标

帕金森病（Parkinson’s disease，PD）的主要病理特征是中脑黑质多巴胺能神经元的丢失，其疾病进程与年龄增长、环境毒物、家族遗传等诸多风险因素有关。大量研究表明，线粒体的损伤或功能障碍是多巴胺能神经元应答于多种致病因素，并引起神经元功能退化或死亡的重要病理事件。因此，解析线粒体损伤相关的PD分子机制有助于发现新的药物靶标和拓宽新药研发思路。并且，干预线粒体损伤相关的分子机制能够有效延缓疾病的发生和发展，是提高PD临床治疗效果和改善PD患者生活质量的重要途径。本文综述了目前较为新颖的有关线粒体损伤的PD分子机制，并讨论了由此衍生的可能药物靶标和候选药物，以期为PD的防治和新药研发提供新的理论依据。     

Drug-delivery Products and the Zydis Fast-dissolving Dosage Form*

Many patients find it difficult to swallow tablets and hard gelatin capsules and do not take their medication as prescribed. It is estimated that 50% of the population is affected by this problem which results in a high incidence of non-compliance and ineffective therapy. The difficulty is experienced in particular by paediatric and geriatric patients, but it also applies to people who are ill in bed and to those active working patients who are busy or travelling, especially those who have no access to water. Such problems can be resolved by means of the Zydis dosage form which does not require water to aid swallowing. The Zydis fast-dissolving dosage form is a unique freeze dried medicinal tablet, made from well known and acceptable materials. When Zydis units are put into the mouth, the freeze dried structure disintegrates instantaneously releasing the drug which dissolves or disperses in the saliva. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach. In these cases, the bioavailabilities of drugs from Zydis formulations are significantly greater than those observed from standard dosage forms. This paper deals with the formulation and process technology of the Zydis dosage form. The bioavailability characteristics of Zydis products are summarized, and in particular, the design of Zydis products for the enhancement of oral bioavailability and the improvement of clinical activity, through transmucosal delivery and pregastric absorption, is discussed.     

Orally disintegrating selegiline for the treatment of Parkinson's disease

The selective monoamine oxidase type B inhibitor selegiline is commonly administered as medical treatment to patients suffering from Parkinson's disease. The clinical value of conventional selegiline is, however, compromised by extensive first-pass metabolism, which reduces its bioavailability and leads to the production of possibly harmful methamfetamine metabolites. This review aims to evaluate a novel, orally disintegrating formulation of selegiline by examining scientific evidence from previous pharmacological and clinical studies. As a result of improved bioavailability, orally disintegrating selegiline can be administered at lower doses than conventional selegiline with similar clinical effect. It also leads to less variable selegiline blood concentrations and produces significantly less methamfetamine metabolites. We conclude that this novel formulation offers an interesting treatment option, especially for patients who report adverse events after initial treatment with conventional selegiline or who suffer from swallowing difficulties.     

A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP

BACKGROUND AND PURPOSE

In Parkinson''s disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation.

EXPERIMENTAL APPROACH

We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson''s disease, and Parkinson''s disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated.

KEY RESULTS

PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1β, TNF-α and cyclooxygenase-2 and blocked nuclear translocation of NF-κB. In the mouse model of Parkinson''s disease, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg⁻¹ and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection.

CONCLUSIONS AND IMPLICATIONS

These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson''s disease.     

Catechol-O-methyltransferase inhibitors: Clinical potential in the treatment of Parkinson's disease

Substitution therapy with levodopa and a peripheral inhibitor of aromatic L-amino acid decarboxylase (AADC) is the cornerstone in the treatment of Parkinson's disease. Chronic therapy with levodopa, however, is associated with the occurrence of motor complications that are partially related to the pharmacokinetics of levodopa. The formation of 3-O-methyldopa (3-OMD), a long-lived metabolite that confers no clinical benefit, is catalyzed by catechol-O-methyltransferase (COMT), an enzyme that is particularly abundant in the gastrointestinal tract, liver, and kidneys. Potent, reversible, selective, and orally active COMT inhibitors have become available. The nitrocatechols, entacapone and tolcapone, have undergone extensive clinical testing as adjuncts to levodopa in the therapy of Parkinson's disease. Studies in healthy subjects and parkinsonian patients have shown the inhibitory effect of both drugs on the formation of 3-OMD, leading to an increase in levodopa bioavailability and elimination half-life, without a change in peak plasma concentrations (C_max) or time to reach C_max (t_max). In patients, COMT inhibitors significantly prolong and smooth, i.e., reduce peak-trough fluctuations, the effects of levodopa, as reflected in improved motor scores and lengthened duration of ON time (periods of good response) without an influence on the time to onset of action or the peak effect. Entacapone 200 mg is given in conjunction with each levodopa dose, whereas tolcapone is administered in a fixed 100 to 200 mg t.i.d. dosing regimen. The tolerability profiles of the two drugs are similar, with urine discoloration and an increase in dopaminergic side effects such as nausea, orthostatic hypotension, and dyskinesias being most prominent. Tolcapone induces a higher incidence of diarrhea and liver enzyme abnormalities. It is anticipated that COMT inhibitors will prove beneficial in extending and smoothing the effects of levodopa in patients with Parkinson's disease and end-of-dose wearing-off fluctuations. Drug Dev. Res. 42:1–25, 1997. © 1997 Wiley-Liss, Inc.