Population pharmacokinetics and pharmacodynamics of oral levodopa in parkinsonian patients

Objective: The population pharmacokinetics and pharmacodynamics of a standardised oral test dose of levodopa have been determined in patients with mild to severe Parkinson’s disease using parametric, non-linear mixed effect modelling with the program NONMEM. Levodopa plasma concentration data and motor effect behaviour (tapping times) were obtained from 46 patients, for whom a total of 970 observations were available (approximately 21 pharmacokinetic and pharmacodynamic observations per patient). The pharmacokinetic-pharmacodynamic model used was a one-compartment first-order absorption model linked to the sigmoid E_Max representation of the Hill equation via an equilibration rate-constant, ke₀. The model was also tested via a reduction in the number of pharmacokinetic and pharmacodynamic data points to a total of four to eight per patient. Results: In the final regression models the Hoehn and Yahr (HY) status of the patient and duration of disease (DUR) were found to be important determinants of the pharmacodynamic parameters for levodopa. The pharmacokinetic parameters were not significantly affected by any covariates. A test group of 16 additional parkinsonian patients was used to evaluate the predictive performance of the population parameters. The predictive performance of the pharmacokinetic-pharmacodynamic modelling using the full and reduced data sets was evaluated in NONMEM using posthoc, Bayesian forecasting. Statistically insignificant bias existed among predicted and observed levodopa concentrations, whereas the pharmacodynamic model underpredicted the observed tapping times. There was little difference in the pharmacokinetic-pharmacodynamic predictive performance among results for the full and the reduced data sets. Conclusion: In a clinical setting knowledge of the population pharmacokinetic and pharmacodynamic parameters for oral levodopa may prove useful in estimating the duration of the drug’s beneficial motor activity in patients with mild to severe Parkinson’s disease (Hoehn and Yahr status I–IV). Received: 13 November 1995/Accepted in revised form: 13 February 1996     

天麻钩藤颗粒联合左旋多巴治疗帕金森病的疗效观察

目的观察天麻钩藤颗粒联合左旋多巴治疗帕金森病的临床疗效。方法选取2015年7月—2016年6月监利县人民医院收治的帕金森患者88例,随机分为对照组和治疗组,每组各44例。对照组口服左旋多巴片,125 mg/次,2次/d,每周调整药物用量,逐渐增量至250 mg/次,3次/d,每日总剂量不超过6 g;治疗组在对照组的基础上口服天麻钩藤颗粒,5 g/次,3次/d。两组均治疗3个月。治疗后,观察两组的临床疗效,比较两组日常生活能力和运动能力评分和不良反应情况。结果治疗后,对照组和治疗组的总有效率分别为61.36%、72.27%,两组比较差异有统计学意义(P0.05)。治疗后,两组日常生活能力和运动能力评分均显著下降,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些评分明显低于对照组,两组比较差异具有统计学意义(P0.05)。两组不良反应发生率比较差异无统计学意义。结论天麻钩藤颗粒联合左旋多巴治疗帕金森病,临床疗效确切,症状改善明显,值得临床推广。     

Unwanted effects and interaction of intrajejunal levodopa/carbidopa administration

Introduction: Levodopa is the most effective treatment for Parkinson's disease. After a number of years on treatment, fluctuations and dyskinesias may develop. Hence, invasive treatment measures are often needed (escalation therapy).

Areas covered: Twenty years ago, a levodopa/carbidopa intestinal gel (LCIG) that can be infused directly into the jejunum was developed. This provides for continuous dopaminergic stimulation. For the past 10 years, LCIG has been licensed in some countries and its marketing approval is pending in the USA. It is endowed with very good efficacy, and in studies, it has proven to be superior to oral drug treatment. Continuous dopaminergic stimulation is also assured, and fluctuations and dyskinesias are significantly reduced. However, this technique involves an invasive procedure with percutaneous endoscopic gastrostomy and attendant surgical and postsurgical complications. Besides, there are problems related to the pump and tube. Vitamin deficiency and polyneuropathies are other drawbacks.

Expert opinion: LCIG is a beneficial and very useful treatment option as escalation therapy for Parkinson's disease. While the side effects are not insignificant, they are justifiable in view of the severity of the disease. Attention must be paid, in particular, to malabsorption, with monitoring at baseline and in the course of treatment.     

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.     

吡贝地尔联合左旋多巴治疗帕金森病的Meta分析

目的 系统评价吡贝地尔联合左旋多巴治疗帕金森病（Parkinson’s disease,PD）的有效性与安全性。方法 检索Cochrane library、PubMed、ScienceDirect英文数据库和CNKI、WanFang、VIP中文数据库,检索时间从建库至2015年9月,收集吡贝地尔联用左旋多巴治疗PD的随机对照试验（randomized controlled trial,RCT）。由2名研究者严格按照纳入与排除标准独立筛选文献、提取资料并评价质量,使用RevMan5.3软件进行Meta分析。结果 最终纳入9个随机对照试验,共计697例PD患者。Meta分析结果显示,吡贝地尔联合左旋多巴在改善统一帕金森病评定量表（unified Parkinson’s disease rating scale,UPDRS）总评分、UPDRS运动评分、UPDRS日常活动评分方面优于左旋多巴联合安慰剂或左旋多巴单药治疗,差异具有统计学意义[UPDRS总评分：MD=-9.20,95% CI（-11.28,-7.12）,P<0.000 01;UPDRS运动评分：随访时间≤6月,MD=-3.04,95% CI（-4.92,-1.16）,P=0.002;随访时间>6个月,MD=-10.81,95% CI（-14.76,-6.86）,P<0.000 01;UPDRS日常活动评分：MD=-1.28,95% CI（-2.31,-0.26）,P=0.01];在胃肠道不良反应发生率方面,左旋多巴联合安慰剂或左旋多巴单药治疗优于吡贝地尔联合左旋多巴,其差异有统计学意义[OR=1.86,95% CI（1.04,3.31）,P=0.04]。结论 吡贝地尔联用左旋多巴治疗PD,可显著改善UPDRS总评分、UPDRS运动评分、UPDRS日常活动评分,同时应重视其胃肠道不良反应。     

Clinical drug monitoring by microdialysis: application to levodopa therapy in Parkinson's disease

1 We describe the first application of microdialysis to monitor the pharmacokinetics of a drug in the blood of man.
2 The aims of the study were to ascertain patient acceptability and tolerability of a new microdialysis probe and to assess its accuracy in determining the pharmacokinetics of levodopa and its principal plasma metabolite 3-O-methyldopa (3-OMD).
3 Eight patients with parkinsonism on chronic levodopa therapy were investigated.
4 After an overnight fast, a flexible microdialysis probe, perfused with isotonic saline, was inserted into a forearm vein and a blood sampling cannula was inserted in a forearm vein of the other arm. After ingestion of a levodopa preparation (Madopar Dispersible^}}rm), dialysate was collected over 5 or 10  min periods and blood samples were taken every 15 or 30  min for 2–6  h.
5 Dialysate drug profiles were similar to those of plasma, and levodopa and 3-OMD concentrations exhibited significant ( P <0.001) correlation with those observed in the corresponding plasma samples.
6 The mean (±s.d.) blood dialysate concentrations for levodopa and 3-OMD were 36.1±9.2% and 43.4±8.4% respectively of the plasma content.
7 The tolerability of the probe was excellent, and all eight patients found it preferable to conventional blood sampling.
8 Microdialysis of blood is less invasive than frequent intermittent direct blood sampling, and can readily be used to continuously monitor levodopa pharmacokinetics. In a clinical setting, a combination of drug monitoring by this technique together with clinical evaluation of motor function can be used to optimize levodopa treatment in patients with Parkinson's disease.     

普拉克索联合左旋多巴治疗帕金森病的临床疗效及安全性

目的 探讨左旋多巴联合普拉克索治疗帕金森病的临床疗效及安全性。方法 选取2015年8月—2017年12月于南通市第一人民医院神经内科门诊或住院诊治的帕金森病患者150例,采用随机法分为观察组（80例）和对照组（70例）,对照组患者仅给予左旋多巴进行治疗,观察组患者给予左旋多巴联合普拉克索进行治疗,持续服药12周,比较两组患者帕金森病综合评估量表（UPDRS）Ⅱ和UPDRS Ⅲ、汉密顿抑郁量表（HAMD）及不良反应的发生率。结果 治疗前,两组患者的UPDRS Ⅱ和UPDRS Ⅲ评分相比,差异无统计学意义;经治疗后,两组患者UPDRS Ⅱ和UPDRS Ⅲ评分均显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;与对照组相比,观察组患者UPDRS Ⅱ和UPDRS Ⅲ评分显著低于对照组,差异有统计学意义（P<0.05）。治疗后,两组患者的HAMD评分显著降低,同组治疗前后比较差异有统计学意义（P<0.05）;与对照组治疗后相比,观察组患者的HAMD评分显著降低,差异具有统计学意义（P<0.05）。观察组患者不良反应发生率为13例（16.25%）,对照组患者不良反应发生率为9例（12.86%）,差异无统计学意义。结论 左旋多巴联合普拉克索治疗帕金森病的临床疗效较好,且安全可靠。     

Istradefylline for the treatment of Parkinson's disease

In recent years, research into bipolar depression has increased. Each year, more studies are published using different agents to treat this condition. In addition to effectiveness and tolerability, bipolar depression research has sought agents that do not induce cycling or mania. This paper evaluates an open-label pilot study on zonisamide for bipolar depression that examined the effectiveness and tolerability of this agent while observing for any switch to mania. Zonisamide was found to have a very low switch rate and modest effectiveness. However, a high dropout rate was observed – mostly due to side effects. Until further research is available, zonisamide is not recommended as a first-line treatment for bipolar depression.     

Levodopa in Parkinson's disease: from the past to the future

Importance of the field: Levodopa is the mainstay of symptomatic treatment for Parkinson's disease (PD). Although other treatments have been developed in the last 30 years, most patients use levodopa in view of its superior efficacy in controlling PD symptoms. Unfortunately, levodopa is associated with long-term motor complications (motor fluctuations and dyskinesias). The main causes of these undesirable effects are the narrowing of the therapeutic window with the natural progression of the disease, pulsatile dopaminergic stimulation due to the short half-life of the drug and erratic absorption. Several studies suggest that PD control could be enhanced by changing the mode of levodopa delivery so as to ensure continuous and stable supply of the drug to the brain. The objective of this text is to review the ascertained strengths and limitations of levodopa in PD, starting from its history, and propose novel modes of usage designed to cover currently unmet medical needs.

Areas covered in this review: Medline literature search (from 1973 to date).

What the reader will gain: A perspective on the evolution of PD pharmacological treatment.

Take home message: Levodopa still is the best treatment for PD. Truly stable and controlled formulations that ensure clinical response should be developed to reduce the undesirable effects that restrict its efficacy.     

Recent Progress of Imaging Agents for Parkinson's Disease

Parkinson''s disease (PD) is a common progressive, neurodegenerative brain disease that is promoted by mitochondrial dysfunction, oxidative stress, protein aggregation and proteasome dysfunction in the brain. Compared with computer tomography (CT) or magnetic resonance imaging (MRI), non-invasive nuclear radiopharmaceuticals have great significance for the early diagnosis of PD due to their high sensitivity and specificity in atypical and preclinical cases. Based on the development of coordination chemistry and chelator design, radionuclides may be delivered to lesions by attaching to PD-related transporters and receptors, such as dopamine, serotonin, and others. In this review, we comprehensively detailed the current achievements in radionuclide imaging in Parkinson’s disease.     

海藻糖治疗帕金森病的作用机制研究进展

帕金森病是一种常见的神经变性疾病,特征性病理改变主要是黑质多巴胺能神经元丢失和路易小体的形成。路易小体中主要成分是纤维化的α-突触核蛋白,研究表明多巴胺能神经元中异常的蛋白质沉积可能与溶酶体自噬途径的失调有关。自噬调节剂的治疗潜力已在帕金森病动物模型中得到证实。海藻糖是一种天然双糖,被认为是治疗神经退行性疾病的新候选药物。它具有类似伴侣活性,防止蛋白质错误折叠或聚集,并有助于通过促进自噬去除积聚的蛋白质。总结异常自噬在帕金森病疾病发展过程中的潜在机制,讨论使用海藻糖对抗帕金森病的促进自噬、蛋白质稳定和抗神经炎症作用。     

Pharmacokinetics and effects of levodopa in advanced Parkinson's disease

Summary Five patients with severe Parkinson's disease were characterized with respect to their pharmacokinetic and pharmacodynamic responses to levodopa given: orally, intravenously (three different infusion rates) and intraduodenally. The best therapeutic infusion rate in the intravenous study was used for the intraduodenal infusion of levodopa. A lag time between plasma concentration and effect following oral administration was seen in three of the five patients and this disequilibrium was estimated as the rate constant k_e0 using model-independent analysis.The plasma concentration-effect relationship was similar for the three modes of administration and in all patients the therapeutic plasma concentration for full mobility was >4–5 g·ml^–1. The disequilibrium half-life for development of effect after oral administration was calculated to be about 30 min.The patients remained clinically stable during the period of the intraduodenal infusion.     

早期肠道菌群干预对帕金森病患者便秘症状及多巴丝肼疗效的影响

目的 探讨早期肠道菌群干预对帕金森病（PD）患者肠道便秘症状及多巴丝肼疗效的影响,为临床治疗提供参考。方法 纳入2015月1月至2017年10月我院神经内科初次诊断的PD患者114例,随机分为肠道菌群干预组（n=57）与对照组（n=57）,两组均予多巴丝肼片常规初始治疗,干预组在此基础上加用三联活菌制剂调理肠道菌群,采用便秘患者生活质量量表（PAC-QOL）等评估患者便秘症状及满意度,采用统一帕金森病评定量表（UPDRS-Ⅲ）等评估两组患者治疗前后的运动症状及心理状态。结果 1干预组较治疗前及较对照组的PAC-QOL,Bristol粪便性状量表（BSFS）评分改善显著,差异有统计学意义（P<0.05）;2两组患者较治疗前UPDRS-Ⅲ运动评分均有改善,差异有统计学意义（P<0.05）,干预组较对照组4周时UPDRS-Ⅲ评分有下降,差异有统计学意义（P<0.05）;3干预组较对照组治疗后医院焦虑量表（HAD-A）、医院抑郁量表（HAD-D）、匹兹堡睡眠质量指数（PSQI）评分均有下降,差异有统计学意义（P<0.05）。结论 早期肠道菌群干预能有效改善PD患者的便秘症状及焦虑睡眠等心理状态,可能有早期增强多巴丝肼制剂对运动症状的疗效,但远期影响仍有待研究。     

Pharmacoeconomic considerations of treating patients with advanced Parkinson's disease

Introduction: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. In the later (advanced) stages of PD, the initial treatment of early PD becomes less effective and long-term side effects of dopaminergic treatment become apparent. In advanced PD, motor and non-motor complications occur, which increase treatment costs. Increasing disability and impaired activities of daily living concomitantly raise indirect costs, due to loss in productivity. Hence, the economic burden of advanced PD is substantial for both the society and the patients with their caregivers.

Areas covered: A systematic literature search was performed involving the databases NHS CRD (National Health Service Centre for Reviews and Dissemination) and PubMed until July 15, 2011. “Parkinson” [Mesh] and “cost” were used as search terms in PubMed and only “Parkinson” in the CRD database.

Expert opinion: Economic evaluations are scarce and heterogeneous, and their interpretation may be limited due to methodological shortcomings. Dopamine agonists, COMT and MAO-B inhibitors as well levodopa infusion and deep brain stimulation are reported to be cost-effective in the respective decision frameworks. However, these results are heavily dependent on assumptions of drug costs and effect sizes used in the models. More detailed real-life information from long-term clinical trials is needed to feed the economic models, especially for head-to-head comparisons. To date, no economic evaluation has been undertaken for possible neuroprotective/disease modifying effects, and further research is needed for evaluations of interventions for non-motor symptoms.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.     

养心定悸胶囊联合多巴丝肼治疗帕金森病的临床研究

目的 探讨养心定悸胶囊联合多巴丝肼片对帕金森病患者的临床疗效。方法 选择定州市人民医院2017年8月-2019年8月收治的帕金森病患者60例作为研究对象,采用随机原则将患者分为观察组与对照组,每组各30例。对照组采用多巴丝肼片治疗,初始剂量0.25 g/次,3次/d,1周后逐渐根据病情调整用量,直到达到适合患者的治疗量为止,最高剂量不超过1 g/d,分3~4次服用。观察组在对照组治疗的基础上联合养心定悸胶囊,3 g/次,2次/d。两组治疗时间均为12周。观察两组患者的临床疗效,同时比较两组治疗前后的帕金森评定量表（UPDRS）、自主神经症状量表（SCOPT-AUT）、帕金森生活质量问卷（PDQ-39）评分及神经递质水平。结果 治疗后,观察组患者总有效率90.00%,显著高于对照组66.67%（P<0.05）。治疗后,两组UPDRS、SCOPT-AUT、PDQ-39评分均显著降低,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后,观察组各评分显著低于对照组,两组比较差异具有统计学意义（P<0.05）。治疗后,两组血清血清5-羟色胺（5-HT）、去甲肾上腺素（NE）、多巴胺（DA）水平比较显著升高,同组治疗前后比较差异具有统计学意义（P<0.05）;且治疗后,观察组5-HT、NE、DA水平显著高于对照组,两组比较差异具有统计学意义（P<0.05）。结论 养心定悸胶囊联合多巴丝肼片治疗帕金森病效果显著,能够显著缓解症状,改善自主神经功能和神经递质水平,有利于患者生活质量的提高,且具有较好的安全性。     

Epidemiological assessment of levodopa use in Cuba: 1993-1998

PURPOSE: The purpose of this study is to describe and evaluate the use of levodopa in Cuba in order to provide a basis for intervention aimed at improving pharmacological treatment of individuals presenting with Parkinson's disease (PD). METHODS: We studied the amount of levodopa, both plain and combined, distributed by the central laboratory to hospital and community pharmacies in Cuba in the period 1993-1998. An internationally established drug-classification system and a reported method for epidemiological assessment of levodopa sales were applied. Sweden in 1994 served as the reference population. RESULTS: National crude rates of levodopa use basically remained stable since 1994, and in 1998 stood at 0.11 defined daily dose (DDD) per 1000 inhabitants/day, approximately 15 times lower than the corresponding figure for the reference population. Annual provincial use of levodopa showed considerable geographical variation, with the lowest rates in the eastern provinces and the highest rates in Havana City (Ciudad de La Habana). Adjustment for age reduced such differences by approximately 50%. CONCLUSIONS: Levodopa use in Cuba is low and consistent with the reported low prevalence of the diagnosis of PD. Results suggest that the diagnosis and treatment of PD can be improved, with emphasis on better detection of PD.     

1例帕金森病伴部分精神障碍患者的用药分析和药学监护

目的 探讨临床药师在帕金森病伴部分精神障碍患者治疗过程中的作用。方法 临床药师结合患者疾病特点、用药史、药物相互作用及药品不良反应等情况,对患者进行药学监护并提出优化治疗方案的建议。结果 临床药师参与患者治疗方案的制订,进行用药指导和出院教育,促进合理用药。结论 临床药师可利用自身专业知识,积极参与临床药物治疗工作,协同医师优化临床给药方案。     

Unravelling mitochondrial pathways to Parkinson's disease

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson''s disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson''s disease models. However, identification of the recessive genes implicated in Parkinson''s disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson''s disease.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8