Parkinson's Disease: Advances in Treatment and the Syntheses of Various Classes of Pharmaceutical Drug Substances.

An overview of Parkinson's disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug products and the syntheses of various drug substances are summarized based on published literature.

Performance of Force-Field- and Machine Learning-Based Scoring Functions in Ranking MAO-B Protein-Inhibitor Complexes in Relevance to Developing Parkinson's Therapeutics.

Monoamine oxidase B (MAOB) is expressed in the mitochondrial membrane and has a key role in degrading various neurologically active amines such as benzylamine, phenethylamine and dopamine with the help of Flavin adenine dinucleotide (FAD) cofactor. The Parkinson's disease associated symptoms can be treated using inhibitors of MAO-B as the dopamine degradation can be reduced. Currently, many inhibitors are available having micromolar to nanomolar binding affinities. However, still there is demand for compounds with superior binding affinity and binding specificity with favorable pharmacokinetic properties for treating Parkinson's disease and computational screening methods can be majorly recruited for this. However, the accuracy of currently available force-field methods for ranking the inhibitors or lead drug-like compounds should be improved and novel methods for screening compounds need to be developed. We studied the performance of various force-field-based methods and data driven approaches in ranking about 3753 compounds having activity against the MAO-B target. The binding affinities computed using autodock and autodock-vina are shown to be non-reliable. The force-field-based MM-GBSA also under-performs. However, certain machine learning approaches, in particular KNN, are found to be superior, and we propose KNN as the most reliable approach for ranking the complexes to reasonable accuracy. Furthermore, all the employed machine learning approaches are also computationally less demanding.

Problem based review: a patient with Parkinson's disease.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease characterized by bradykinesia, tremor and/ or rigidity, often with gait disturbance and postural instability. In addition to these typical features, patients with PD may experience further problems related to the disease itself or to the medications used to treat it. These comorbid problems include neuropsychiatric conditions (including psychosis, hallucinations, excessive daytime sleepiness, anxiety, depression, fatigue and dementia) as well as problems associated with autonomic nervous system function such as bowel and bladder function. PD can also present in emergency situations with a 'neuroleptic malignant like picture' and acute psychosis. It is not uncommon to see motor fluctuations due to drug interactions and 'withdrawal' symptoms following dose reduction of dopamine agonists. In patients with PD, disturbances of mental state constitute some of the most difficult treatment challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability and poor quality of life. While some of these symptoms may be alleviated by antiparkinsonian medication, especially if they are 'off-period' related, treatment-related phenomena are usually exacerbated by increasing the number or dosage of antiparkinsonian drugs. Elimination of exacerbating factors and simplification of drug regimens are the first and most important steps in improvement of such symptoms.

Emerging therapies for Parkinson's disease.

PURPOSE OF REVIEW: The experimental therapeutics of Parkinson's disease are reviewed, highlighting the current pipeline of emerging therapeutic approaches. RECENT FINDINGS: This review includes novel approaches to dopaminergic drug delivery such as intraintestinal infusions or new extended-release formulations of levodopa and also intrapulmonary delivery of apomorphine as well as novel dopaminergic agents like the monoamine oxidase-B inhibitor safinamide or novel catechol-O-methyl transferase inhibitors. An even greater number of ongoing clinical trials assess the efficacy and safety of nondopaminergic approaches to enhance motor control or reduce motor complications like fluctuations and dyskinesias. These include adenosine A2A antagonists, α-adrenergic and serotonergic agonists as well as drugs acting on the glutamatergic system. Gene-based or cell-based intrastriatal delivery of therapeutic principles that enhance striatal dopaminergic transmission directly or via the stimulation of trophic activity has also reached phase II clinical development with encouraging results in some studies. Finally, a wide spectrum of agents with a potential for slowing disease progression is currently tested. SUMMARY: A variety of medical and nonmedical interventions in different phases of clinical development provide an interesting and promising portfolio of emerging therapies for Parkinson's disease.

The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease.

The objective was to update previous evidence-based medicine reviews of treatments for motor symptoms of Parkinson's disease published between 2002 and 2005. Level I (randomized, controlled trial) reports of pharmacological, surgical, and nonpharmacological interventions for the motor symptoms of Parkinson's disease between January 2004 (2001 for nonpharmacological) and December 2010 were reviewed. Criteria for inclusion, clinical indications, ranking, efficacy conclusions, safety, and implications for clinical practice followed the original program outline and adhered to evidence-based medicine methodology. Sixty-eight new studies qualified for review. Piribedil, pramipexole, pramipexole extended release, ropinirole, rotigotine, cabergoline, and pergolide were all efficacious as symptomatic monotherapy; ropinirole prolonged release was likely efficacious. All were efficacious as a symptomatic adjunct except pramipexole extended release, for which there is insufficient evidence. For prevention/delay of motor fluctuations, pramipexole and cabergoline were efficacious, and for prevention/delay of dyskinesia, pramipexole, ropinirole, ropinirole prolonged release, and cabergoline were all efficacious, whereas pergolide was likely efficacious. Duodenal infusion of levodopa was likely efficacious in the treatment of motor complications, but the practice implication is investigational. Entacapone was nonefficacious as a symptomatic adjunct to levodopa in nonfluctuating patients and nonefficacious in the prevention/delay of motor complications. Rasagiline conclusions were revised to efficacious as a symptomatic adjunct, and as treatment for motor fluctuations. Clozapine was efficacious in dyskinesia, but because of safety issues, the practice implication is possibly useful. Bilateral subthalamic nucleus deep brain stimulation, bilateral globus pallidus stimulation, and unilateral pallidotomy were updated to efficacious for motor complications. Physical therapy was revised to likely efficacious as symptomatic adjunct therapy. This evidence-based medicine review updates the field and highlights gaps for research.

Diagnosis and initiation of treatment in Parkinson's disease.

Parkinson's disease (PD) is the most common cause of parkinsonism, yet the diagnosis and management can be a challenge. The United Kingdom Parkinson's Disease Society Brain Bank Clinical Diagnostic Criteria and dopamine transporter/single-photon emission computed tomography (DaT-SPECT) are diagnostic aids that can improve diagnostic accuracy. Even though PD is a progressive disease, for years, physicians and patients have delayed treatment until functional disability occurs. However, studies of monoamine oxidase-type B (MAO-B) inhibitors, dopamine agonists, and levodopa, all of which can be used as initial therapy, have demonstrated that PD patients receiving treatment do better than those who do not receive treatment, and some studies have shown that those receiving treatment earlier do better long term. Therefore, the management strategy for PD has moved toward earlier initiation of treatment. Although treatment for each patient should be individualized and based on their specific symptoms, severity, and lifestyle, in general MAO-B inhibitors may be used initially to treat mild symptoms, adding a dopamine agonist in younger patients or levodopa in older patients, as symptoms become more severe.

The evidence for disease modification in Parkinson's disease.

Disease modification or slowing the progression of any neurodegenerative disorder represents a dire unmet need. There have been trials for several decades specifically designed to help evaluate whether a specific therapy might be able to slow the progression of Parkinson's disease (PD) or be disease modifying. Trials evaluating the use of coenzyme Q10, pramipexole, and levodopa suggest that these medications offer symptomatic benefit uniquely, while other studies reveal that rasagiline and selegiline may be disease modifying. This review will discuss in detail the design and results of clinical trials for varied medical therapies that were specifically undertaken to discern whether a particular treatment might be disease modifying in the treatment of PD.

Advances in the treatment of Parkinson's disease.

Parkinson's disease (PD) affects one in every 100 persons above the age of 65 years, making it the second most common neurodegenerative disease after Alzheimer's disease. PD is a disease of the central nervous system that leads to severe difficulties with body motions. The currently available therapies aim to improve the functional capacity of the patient for as long as possible; however they do not modify the progression of the neurodegenerative process. The need for newer and more effective agents is consequently receiving a great deal of attention and consequently being subjected to extensive research. This review concisely compiles the limitations of currently available therapies and the most recent research regarding neuroprotective agents, antioxidants, stem cell research, vaccines and various surgical techniques available and being developed for the management of PD.

Impact of newer pharmacological treatments on quality of life in patients with Parkinson's disease.

Parkinson's disease is a common progressive neurodegenerative condition with multiple motor and nonmotor features contributing to impairment of health-related quality of life (HR-QOL). Pharmacological treatments have been directed primarily at dopamine replacement with levodopa and agents to improve its bioavailability, including DOPA decarboxylase inhibitors, catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors, as well as synthetic dopamine agonists. These treatments to restore motor function are often very successful in early Parkinson's disease, with objective improvement and concomitant improvement in subjective HR-QOL scores. However, as the disease progresses, motor complications and nonmotor symptoms predominate and are often refractory to therapeutic interventions. Antiparkinsonian medications have been shown to improve motor severity and motor complications of advancing disease, and there is increasing evidence that this can be translated into subjective improvement of HR-QOL from a patient's point of view. However, the degree of improvement is less marked on HR-QOL scores than on motor scores, and some studies do not show improvement of HR-QOL in parallel to motor improvements. A number of explanations are possible, including limitations of the scales used, trial designs and lack of clinical improvement from the patients' point of view. This review concentrates on clinical trials with an index of HR-QOL as an outcome measure, with particular emphasis on well designed, randomized, double-blind, placebo-controlled or active comparator-controlled methodology. Drugs that have been more recently added to the armamentarium of Parkinson's disease, including the oral (pramipexole, ropinirole and piribedil) and transdermal (rotigotine) non-ergotamine-derived dopamine agonists, the novel MAO-B inhibitor rasagiline and the COMT inhibitors tolcapone and entacapone, were included. The effect of each of these agents on overall HR-QOL and depression, a factor that has been shown to significantly contribute to HR-QOL in several multivariate analyses, is discussed.Overall, the literature search revealed 14 double-blind, placebo- or active comparator-controlled trials with an index of HR-QOL as an outcome measure. Entacapone resulted in HR-QOL improvement in nonfluctuating patients (one study) but not clearly in those with motor fluctuations (two studies). Tolcapone was only tested in patients with motor fluctuations and resulted in significant improvement in two of four studies using HR-QOL as an outcome measure. Rasagiline improved HR-QOL as monotherapy in early Parkinson's disease (one study), but not clearly in more advanced disease (one study). Rotigotine improved HR-QOL in both early Parkinson's disease (one study) and more advanced disease with motor fluctuations (one study). The impact of ropinirole and pramipexole on HR-QOL as monotherapy in early Parkinson's disease versus placebo has not been assessed, but both agents have resulted in improved HR-QOL in patients with motor fluctuations (ropinirole one study, pramipexole one study). The evidence for antidepressant efficacy of antiparkinsonian medications is limited.

Antiparkinsonian therapy modifications in PD patients after STN DBS: a retrospective observational analysis.

OBJECTIVE: This study reports a retrospective analysis of 67 consecutive parkinsonian patients to assess changes in antiparkinsonian medications after Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN). METHODS: All antiparkinsonian drugs, including levodopa, dopamine agonists, associated drugs such as COMT and MAO inhibitors, amantadine and anticholinergics, were evaluated pre- and post-operatively at 1 and 3 years follow-up. RESULTS: The levodopa mean daily dose was reduced approximately 60% after 1 year and remained stable after 3 years. Apomorphine, bromocriptine, tolcapone, entacapone and selegiline were withdrawn after STN DBS. Three years post-operatively, 9 patients (13.4%) no longer required levodopa and 6 patients (8.9%) completely stopped all dopaminergic medications. More patients were on monotherapy of either levodopa or dopamine agonist and fewer patients required a combined treatment of dopamine agonist and levodopa, compared to the pre-surgical condition. CONCLUSIONS: STN DBS treated PD patients experience a significant long-term reduction and simplification of the pharmacological treatment.

[Prescribing patterns of antiparkinson drugs in a group of Colombian patients, 2015].

INTRODUCTION: Parkinson's disease, whose prevalence in Colombia is 4.7 per 1,000 inhabitants, is a public health problem and a therapeutic challenge for health professionals. OBJECTIVE: To determine the prescribing patterns of antiparkinson drugs and the variables associated with its use in a population from Colombia. MATERIALS AND METHODS: We conducted a descriptive cross-sectional study. We selected patients who had been given antiparkinson drugs uninterruptedly between January 1st and March 31st, 2015 from a systematized database of approximately 3.5 million people affiliated to the Colombian health system. We included sociodemographic, pharmacologic and comedication variables. For the multivariate analysis, we used the IBM SPSS™-22 software. RESULTS: A total of 2,898 patients was included; the mean age was 65.1years, and 50.7% were men; 69.4% (n=2010) of people received monotherapy and 30.6% combination therapy with two to five antiparkinson drugs. The most frequently prescribed drugs were: levodopa 45.5% (n=1,318 patients), biperiden 23.1% (670), amantadine 18.3% (531) and pramipexole 16.3% (471). The most commonly used association was levodopa/carbidopa + entacapone (n=311; 10.7%). Multivariate analysis showed that being male (OR=1.56; 95%CI: 1.321-1.837), over 60 years (OR=1.41; 95%CI 1.112-1.782) and receiving treatment in the city of Barranquilla (OR=2.23; 95%CI 1.675-2.975) were statistically associated with a greater risk of using combination therapy; 68.2% (n=1,977) patients were given concomitant treatment with other drugs. CONCLUSIONS: Prescribing habits of drugs with high therapeutic value predominated, mainly in antiparkinson drugs monotherapy. Most were employed in the usual recommended doses. It is necessary to explore the clinical effectiveness of the medications studied and differentiate between disease and parkinsonian syndromes subtypes.

Medical management of levodopa-associated motor complications in patients with Parkinson's disease.

Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity. Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa. Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility. All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.

Treatment of Parkinson's disease: a survey of patients and neurologists.

BACKGROUND: The treatment of Parkinson's disease (PD) is complex and highly individual. The choice between available treatment options depends on clinical characteristics such as the patient's age, disease severity and presence of comorbidities, lifestyle characteristics and preferences, costs of different medications and awareness and perception of available treatment options, and education of the treating physician. The impact of PD treatment regimens on patients' health-related quality of life (QOL) is also an important healthcare feature. The objective of the present study was to assess treatment options, treatment satisfaction and opinions about treatment improvements in patients with PD and neurologists treating the disease. METHODS: Two surveys using face-to-face interviews and an additional phone survey were carried out in the US and five European countries (France, Germany, Italy, Spain and the UK). Patients with early and advanced stages of PD were included. To participate in the neurologist survey, neurologists were required to personally treat ten or more PD patients per month, including both early and advanced stage patients. Interviews consisted of a mix of closed and open-ended questions; some of these questions involved show cards. RESULTS: Of the 500 patients who were surveyed, 49% had early and 51% had advanced PD. Early-stage PD patients, both in the US and Europe, take a mean of 3.2 tablets daily of PD-medication. In contrast, the mean daily tablet load of PD medication is much higher for advanced-stage patients (9.9 and 8.4 tablets in the US and Europe, respectively). Tablet load was perceived as a major problem; the majority of patients wished to see improvements regarding daily medication intake and expressed interest in other delivery systems such as patches. Overall, patients rated their treatment with a score of 6.6 points (6.7 for early-stage and 6.6 for advanced-stage patients) [scale of 1-10; 10 being highest]. Physicians (n = 592) were satisfied with a number of current PD medications and assumed they improve the QOL of the patients. They regarded efficacy and safety as the most important features for the improvement of PD medication. CONCLUSION: Further research is needed into PD treatment options not only for symptom alleviation but for better delivery systems that could improve compliance and QOL for patients with PD. Treatment guidelines need to incorporate QOL aspects and general communication between the health professional and the patient.

Non-dopaminergic treatment of cognitive impairment and dementia in Parkinson's disease: a review.

OBJECTIVE: To review the clinical management of cognitive impairment and dementia related to Parkinson's disease (PD), with emphasis on pharmacologic intervention strategies such as cholinesterase inhibitors. DATA SOURCES: A MEDLINE, EMBASE, PsychINFO, and Cochrane Collaboration search of English language literature from 1970 to 2004 was performed to identify reviews, studies, case reports, and letters pertaining to the treatment of cognitive impairment in PD. The bibliographies of selected articles were reviewed for additional references. STUDY SELECTION: Human studies or case reports in adults with PD describing the use of drug and other therapies for the treatment of cognitive impairment in PD. DATA EXTRACTION: Studies were reviewed for study design, number of subjects, outcome measures, dosage, side-effects, particularly, worsening of PD motor symptoms. CONCLUSION: The strongest evidence for the pharmacological treatment of cognitive impairment and dementia in PD supports the use of cholinesterase inhibitors. Evidence for the efficacy and safety of other agents in PD dementia is either insufficient or inconclusive, but offers intriguing clues for potential future treatments. No reports from the Cochrane Collaboration were found.

[The prevalence and pharmacological cost of Parkinson's disease in Spain]. / Prevalencia y coste farmacológico de la enfermedad de Parkinson en España.

INTRODUCTION: Parkinson's disease is the second most frequent neurodegenerative disease. AIM: To analyze the dispensation of antiparkinsonian agents in Spain and to estimate the Parkinson's disease prevalence. MATERIALS AND METHODS: Dispensation of antiparkinsonian agents were studied in Spain during two years (October 1998 to September 2000). Results were expressed in defined daily dosages per 1,000 inhabitants per day (DID). Levodopa's DID was used to estimate the prevalence of the disease. The cost per 1,000 inhabitants per day (CID) and the daily treatment cost was also valued. RESULTS: The most frequently used drugs are levodopa, biperiden and selegiline. The total cost reached values of 116,346,589.30 euros during the study period. The CID was 4,14 euros. It was very high the daily treatment cost of pramipexol and entacapone. The prevalence of Parkinson's disease is considered in 1.7 per 1,000 inhabitants in Spain. There is an important geographical variability; regions as Castilla-Leon, Galicia and La Rioja have a higher prevalence than Andalucia or Murcia. The number of patients in Spain can be considered in 69,571 people. CONCLUSION: There are some differences between the autonomous communities in the antiparkinsonian drugs' utilization.

Modes of drug delivery used to manage Parkinson's disease.

Parkinson's disease is the second most frequent neurodegenerative condition after Alzheimer's disease and with an ageing population, the burden of care will only increase. This article presents an overview of the condition, its pharmacological and care management, and novel treatment approaches.

Pharmacotherapy of Parkinson's disease in Germany.

Treatment standards or guidelines have been developed for most features of Parkinson's disease (PD). However, data on the actual treatment that is put into practice are scarce. In 2000, a nationwide survey on the topic of sudden onset of sleep (SOS) in PD was initiated among the members of the German patient support group (deutsche Parkinson-Vereinigung, dPV). A part of this mailed questionnaire survey covering the antiparkinsonian and concomitant medication of the participants is presented here. This study analyses data sets from more than 6,500 PD patients. The mean dopaminergic dose was equivalent to 599 +/- 387 mg levodopa/die. The most frequently administered drugs were levodopa (94.2 %), dopamine agonists (DA) (71.7 %), amantadine (40.1 %), selegiline (27.6 %), entacapone (20.4 %), budipine (12.3 %), and anticholinergics (11.8 %). Costs of pharmacotherapy were estimated to be approximately 399 million/year in Germany. PD drug therapy in general strongly depended on age, disease duration, and the level of care. The treatment guidelines were apparently not consistently followed underlining the need for their continuous propagation throughout the medical community. In addition our data suggest that non-motor symptoms in PD are not adequately treated and that concomitant sedative medication contributes to the occurrence of SOS.

Association of daytime sleepiness with COMT polymorphism in patients with parkinson disease: a pilot study.

STUDY OBJECTIVES: To evaluate an association between catechol-O-methyltransferase (COMT) genotype and subjective daytime sleepiness in patients with Parkinson disease. DESIGN: Structured questionnaire study. SETTING: Tertiary Parkinson disease care center and sleep outpatients' department at the university hospital neurology department. PARTICIPANTS: All nondemented patients with idiopathic Parkinson disease who had been part of a previous study of D4-receptor polymorphisms in 1997 were eligible to participate. From the original sample of 113 patients, 46 participated in the study, 22 met exclusion criteria, and 43 were not available. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 46 patients were included (27 men, 19 women; 68.4 +/- 9.9 years of age; symptomatic disease duration, 12.2 +/- 5.2 years; Hoehn and Yahr stage in "on" of 2.6 +/- 0.8). Out of the 46 patients, 13 had LL genotype, 22 LH, and 11 HH. The Epworth Sleepiness Scale scores were 9.5 +/- 4.8 in LL, 8.5 +/- 4.7 in LH, and 6.8 +/- 3.1 in HH (mean +/- SD) (NS). LL and LH were grouped together. The Epworth Sleepiness Scale score was 11 or more in 40% of the LL+LH group, compared to 9.1% of the HH group (P = .039). The levodopa or dopamine-agonist doses and types did not differ between the LL+LH group versus the HH group. CONCLUSIONS: These preliminary data suggest an association of the Lallele and daytime sleepiness in patients with Parkinson disease.