Impact of medication therapy management in patients with Parkinson’s disease

Background Since the new German Apothekenbetriebsordnung was released, medication therapy management (MTM) has increased in importance. MTM is intended to improve the quality of life of patients. Objectives The aim of this study was to improve the quality of life of patients with Parkinson’s disease through an MTM by a community pharmacist. Setting The patients were recruited in cooperation with the Deutsche Parkinson Vereinigung e.V. (dPV) in Germany. Methods All patients were evaluated at baseline (t0) and after a follow-up of 4 months (t1). During the intervention period, the pharmacists implemented an MTM with standardized pharmaceutical care. Main outcome measure The effects of the interventions were measured by the Unified Parkinson Disease Rating Scale (UPDRS) and the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS). Results In this study, 90 patients with Parkinson’s disease were included. The most common intervention was to find a therapy for untreated comorbidities. The UPDRS or MDS-UPDRS improved significantly after the intervention period by a median change rate of 1 (p < 0.05) or rather 2 (p < 0.05) compared to the baseline. Conclusion The study shows that the quality of life in Parkinson’s disease patients improved significantly through MTM.     

Management of constipation in Parkinson’s disease

Introduction: Constipation is a frequent non-motor feature of Parkinson’s disease (PD). It is the most common gastrointestinal symptom of the disease and it can precede motor symptoms by as much as 20 years. Constipation can produce discomfort and affect activities of daily living, productivity and quality of life, thus warranting early diagnosis and treatment.

Areas covered: In this review, the safety and efficacy of traditional and novel strategies for constipation management will be discussed. A treatment algorithm for constipation in PD will be presented.

Expert opinion: Polyethylene glycol and lubiprostone are first-line compounds recommended by evidence-based medicine guidelines for the treatment of constipation due to slow colonic transit in PD. Management of constipation secondary to defecatory dysfunction due to pelvic floor dyssynergia can be done by levodopa or apomorphine injections, botulinum toxin type A injection into the puborectalis muscle, and nonpharmacological interventions, like biofeedback therapy or functional magnetic stimulation, which showed some benefit in PD patients with constipation, but in general more extensive studies are warranted.     

Pharmacological interventions for psychosis in Parkinson’s disease patients

Introduction: Psychosis is a common problem for people treated for Parkinson’s disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required.

Areas covered: This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed.

Expert opinion: Clozapine and pimavanserin have proven efficacy for Parkinson’s disease psychosis (PDP), without impairing motor function. In clozapine’s favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4–6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials.     

Advances in understanding genomic markers and pharmacogenetics of Parkinson’s disease

Introduction: The inheritance pattern of Parkinson’s disease (PD) is likely multifactorial (owing to the interplay of genetic predisposition and environmental factors). Many pharmacogenetic studies have tried to establish a possible role of candidate genes in PD risk. Several studies have focused on the influence of genes in the response to antiparkinsonian drugs and in the risk of developing side-effects of these drugs.

Areas covered: This review presents an overview of current knowledge, with particular emphasis on the most recent advances, both in case-control association studies on the role of candidate genes in the risk for PD as well as pharmacogenetic studies on the role of genes in the development of side effects of antiparkinsonian drugs. The most reliable results should be derived from meta-analyses of case-control association studies on candidate genes involving large series of PD patients and controls, and from genome-wide association studies (GWAS).

Expert opinion: Prospective studies of large samples involving several genes with a detailed history of exposure to environmental factors in the same cohort of subjects, should be useful to clarify the role of genes in the risk for PD. The results of studies on the role of genes in the development of side-effects of antiparkinsonian drugs should, at this stage, only be considered preliminary.     

New and emerging medical therapies in Parkinson’s disease

Introduction: Parkinson’s disease (PD) is one of the most challenging neurodegenerative disorders to treat as it manifests with a large variety of troublesome, and often disabling, motor and non-motor symptoms. Despite limitations, such as motor and other complications, levodopa remains the most effective drug in the treatment of PD.

Areas covered: In this review, we focus on phase 2 and 3 studies describing new and emerging medical therapies in PD. We discuss new formulations of levodopa, medications that prolong levodopa response and ameliorate levodopa-induced dyskinesias, and innovative delivery methods that are currently being evaluated in clinical trials or are in development with the promise of better efficacy and tolerability. We also describe novel non-dopaminergic drugs that have been identified for treatment of motor and non-motor symptoms. A specific section is designated for potential disease modifying therapies.

Expert Opinion: Alternative formulations of levodopa appear to be promising especially to help with the motor fluctuations either by providing sustained benefits with controlled released formulations or ameliorate sudden OFF by formulations such as inhaled levodopa. Several different medications affecting non-dopaminergic pathways are being evaluated which may aide levodopa. As the understanding of the disease grows further, numerous novel neuroprotective or disease modifying therapies have been suggested. This along with development of medications to treat various non-motor symptoms will help improve quality of life of patients with PD.     

Drug treatment of non-motor symptoms in Parkinson’s disease

Non-motor symptoms may considerably reduce parkinsonian quality of life, particularly in advanced stages of the disease. Autonomic features, such as seborrhoea, hyperhidrosis, orthostatic hypotension, excessive salivation, bladder dysfunction and GI disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis and dementia, appear in the course of Parkinson’s disease. Pharmacotherapy of these non-motor symptoms complicates long-term antiparkinsonian combination drug therapy due to possible drug interactions, side effects and changes in metabolism. Moreover, antiparkinsonian compounds themselves contribute to the onset of these non-motor symptoms to a considerable extent. This complicates differentiation between the disease process itself and drug-related effects, thus influencing therapeutic options, which are often limited because of comorbidity and polypharmacy. Therefore, standardised recommendations are questionable, since drug tolerability and response differ between patients. Nevertheless, this review tries to provide a survey of possible therapeutic options for the treatment of the symptoms of Parkinson’s disease other the dopamine-sensitive motor features.     

Recent important trials of pharmacotherapy in Parkinson’s disease

Parkinson’s disease (PD) affects ~ 1% of individuals > 60 years. Of these PD patients ～ 40% suffer dementia in later life. Levodopa is commonly used in the treatment of PD. Experimental evidence suggests that the dopamine synthesised from levodopa may contribute to the further degeneration of dopaminergic neurons. The results of the clinical outcome part of the Earlier Versus Later Levodopa Therapy in PD study suggest that levodopa slows the progression of PD. In contrast, the single photon emission-computed tomography imaging substudy was not conclusive but suggested that levodopa hastened the progression of PD. Thus, further studies of the effects of levodopa on the progression of PD are needed before it can be proved that levodopa does not have a detrimental effect on dopaminergic neurons. In a clinical trial of the anticholinesterase rivastigmine, a small improvement was observed in some patients suffering from dementia associated with PD. This small benefit has to be balanced against cholinergic side effects and a possible loss of efficacy of antimuscarinic agents used for motor control in PD.     

A review of pramipexole and its clinical utility in Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex^®, Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.     

Established therapies and novel targets in the treatment of Parkinson’s disease

Parkinson’s disease affects more than 1% of individuals older than 60 years of age. The gold standard of its symptomatic treatment is levodopa therapy, which in time leads to motor fluctuations and dyskinesia due to noncontinuous receptor stimulation. Dopamine agonists and monoamine oxidase-B inhibitors are recommended as initial therapy, but they are less effective in the advanced stages of the disease. Treatment should be individualized for the patient, dependent on the stage, with attention to nonmotor symptoms. No effective neuroprotective therapy for Parkinson’s disease is yet available, and there is currently substantial interest in the development of new nondopaminergic agents. Analogs of kynurenic acid and inhibitors of the enzymes involved in the synthesis of quinolinic acid may exert a neuroprotective effect.     

Higher dopamine transporter density in Parkinson’s disease patients with depression

Rationale

Depression is a frequent non-motor symptom in Parkinson’s disease (PD) with increasing rates with the progression of the disease. Molecular imaging studies have shown a reduction of dopamine transporter (DAT) density in depressed PD patients (dPD); however, DAT role in the pathophysiology of PD depression is not clear since clinical matching was inappropriate and DAT reduction could be attributed to PD severity.

Objectives

To further examine the role of DAT in PD depression, this study compared thoroughly matched depressed vs. non-depressed PD patients (ndPD).

Materials and methods

Twenty PD patients (n?=?10 ndPD; n?=?10 dPD) matched for age and disease severity were submitted to brain SPECT imaging with [^99mTc]-TRODAT-1, a DAT radioligand. DAT-binding potential was calculated using regions of interest bilaterally drawn in the striatum, caudate, and putamen. Depression was defined according to Beck Depression Inventory (BDI; cut-off >18).

Results

Mean BDI scores were higher in dPD (25.0?±?5.6) than in ndPD patients (8.0?±?1.9, p?<?0.0001). DAT density was greater on dPD especially in the left caudate (dPD 0.87?±?0.19 vs. ndDP 0.69?±?0.18, p?=?0.02) and right putamen (dPD 0.37?±?0.07 vs. ndPD 0.28?±?0.13, p?=?0.03) than in ndPD patients.

Conclusion

Our results suggest that in vivo DAT density is increased in dPD patients as compared to ndPD, suggesting that DAT is implicated in the pathophysiology of PD depression.     

Influences of levodopa on adipose tissue and skeletal muscle metabolism in patients with idiopathic Parkinson’s disease

OBJECTIVE: The substantial weight loss in Parkinson's patients may be related to direct influences of levodopa treatment on fat mobilization/oxidation. We assessed systemic and local metabolic responses to levodopa/benserazide in patients with idiopathic Parkinson's disease. METHODS: We studied 10 Parkinson's disease patients and examined adipose tissue and skeletal muscle metabolism directly with microdialysis. We monitored dialysate concentrations of ethanol, glucose, lactate, pyruvate, and glycerol to assess tissue blood flow and metabolism before and after levodopa/benserazide intake. We also conducted in vitro studies on adipocytes from healthy women. RESULTS: Levodopa/benserazide increased serum levodopa, 3,4-dihydroxyphenylacetic acid (DOPAC), and norepinephrine (P < 0.01). Serum adipose tissue and skeletal muscle glycerol did not change or decreased. Adipose tissue glycerol was inversely correlated with serum levodopa concentrations (P < 0.05). In isolated adipocytes, levodopa attenuated isoproterenol-induced glycerol release (P < 0.05). CONCLUSION: Levodopa/benserazide elicits pronounced metabolic changes in both adipose tissue and skeletal muscle with a switch from lipid to carbohydrate metabolism. In adipose tissue, levodopa/benserazide failed to activate lipolysis. Therefore, we suggest that levodopa/benserazide does not induce fat wasting through direct and acute influences on adipose tissue metabolism.     

Discontinuation of ropinirole and pramipexole in patients with Parkinson’s disease: clinical practice versus clinical trials

Objective  To compare characteristics and incidence of discontinuation of Parkinson’s disease (PD) patients starting ropinirole or pramipexole in clinical practice with data from randomised controlled clinical trials (RCTs). Methods  Included in the retrospective clinical-practice cohort were first-time users of ropinirole or pramipexole diagnosed with PD before 2005. Baseline characteristics and incidence of discontinuation were compared between the clinical-practice cohort and RCTs. Treatment discontinuation was defined as more than 180 days between two refills of ropinirole or pramipexole. The incidence of discontinuation in RCTs was based on the reported rate of discontinuation for any cause. Results  Included were 45 patients who started with ropinirole and 59 patients who started with pramipexole. Treatment was discontinued within 3 years in 51% (ropinirole) and 60% (pramipexole) of the patients. Ten RCTs with ropinirole and 12 with pramipexole were identified. Baseline characteristics did not differ between the clinical-practice cohort and RCTs. RCTs reported discontinuation rates comparable with those at the same timepoint in the clinical practice until 1 year of follow-up. Conclusion  This study shows that the overall incidence of discontinuation of ropinirole and pramipexole between the patients in our clinical-practice cohort and patients in the RCTs was comparable for the short term. However for the long term, discontinuation in practice is possibly higher.     

Novel pharmaceuticals in the treatment of psychosis in Parkinson’s disease

Parkinson’s disease (PD) affects 10 million people worldwide. Half will develop psychosis, the majority experiencing hallucinations rather than delusions. Emergence of psychosis increases the likelihood of institutionalization and mortality. Where pharmacological treatment is warranted, options are limited. Most currently licensed atypical antipsychotics are ineffective or worsen motor symptoms in people with PD. This review of provides an overview of the current landscape of treatments and the opportunities in emerging research. Clozapine is the only licensed antipsychotic with proven efficacy, although the associated side effects limit its use. With recent advances in understanding the role of serotonin, rational drug design approaches have delivered a novel pharmacological treatment with recently proven efficacy in clinical trials of people with PD and psychosis. Pimavanserin represents an important addition to treatment.     

Recent developments in the pharmacological treatment of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.     

Safety and effectiveness of istradefylline in patients with Parkinson’s disease: interim analysis of a post-marketing surveillance study in Japan

ABSTRACT

Background: Istradefylline is a first-in-class, non-dopaminergic, selective adenosine A_2A receptor antagonist for the treatment of Parkinson’s disease (PD) in patients experiencing the wearing-off phenomenon with levodopa (L-DOPA). The authors present an interim report from a post-marketing surveillance (PMS) evaluating the safety and effectiveness of long-term istradefylline in a real-world setting.

Research design and methods: Istradefylline safety was assessed by the incidence of adverse events (AE) and adverse drug reactions (ADRs). Effectiveness was assessed using the physician’s assessment of off-time, off-time symptoms and motor dysfunction, unified PD rating scale (UPDRS) Part III score, and the physician’s global assessment.

Results: This analysis evaluated 476 patients. Istradefylline was generally well tolerated, despite dyskinesia and hallucination being the most common ADRs. Reduction in off-time was observed in 38.2% of patients, off-time symptoms were improved or markedly improved in 44.7%, and motor dysfunction was improved or markedly improved in 48.5%. The mean UPDRS Part III score decreased from 33.7 to 30.3 at the end of the study. The physician’s global assessment rated the drug as effective in 61.3% of patients.

Conclusions: This PMS provides useful safety and effectiveness data for long-term treatment with istradefylline in a real-world setting for patients with PD exhibiting the wearing-off phenomenon with L-DOPA.     

Advances in the delivery of treatments for Parkinson’s disease

Innovative drug delivery in Parkinson’s disease (PD) has the potential to reduce or avoid many side effects of current treatment, such as wearing-off type fluctuations, dyskinesia, on-off phenomena or bouts of motor freezing. The traditional orally administered formulations of l-dihydroxyphenylalanine combined with a peripheral aromatic acid decarboxylase inhibitor remain the mainstay of treatments for PD. However, such combination therapies have been further formulated to extend their duration of action by including a catechol-O-methyltransferase inhibitor. Preventing the breakdown of dopamine has also been achieved by monoamine oxidase-B inhibition; this approach now having been formulated for sublingual use (Zelapar^®, Valeant Pharmaceuticals). An alternative approach bypasses the oral route of administration and instead relies on continuous duodenal infusion (Duodopa^®, Solvay, NeoPharma AB) for better therapeutic effect. The clinical use of dopamine agonists as antiparkinsonian drugs now incorporates a variety of delivery techniques. For example, apomorphine, which relies on parenteral administration for maximum bioavailability, may be delivered via rectal, intranasal, sublingual and subcutaneous (e.g., Apokyn^®, Mylan Bertek) routes. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches. Finally, the authors examine more experimental delivery techniques, including the delivery of genes via viral vectors or liposomes, intracranial transplant of a variety of cells and of l-dihydroxyphenylalanine by prodrug-dispensing liposomes or pulmonary delivery (AIR^®, Alkermes). The advent and application of these varied technologies will help encourage patient-specific means of treatment for PD.     

The treatment of gastroparesis,constipation and small intestinal bacterial overgrowth syndrome in patients with Parkinson’s disease

Introduction: Parkinson’s disease (PD) affects the nerves of the entire gastrointestinal (GI) tract and may result in profound gastrointestinal (GI) dysfunction leading to poor patient outcomes. Common GI disturbances in patients with PD include gastroparesis (GP), constipation and small intestinal bacterial overgrowth syndrome (SIBO). In particular, GP is difficult to treat due to the limited options available and precautions, contraindications and adverse effects associated with the approved treatments. Moreover, some commonly used medications can worsen pre-existing PD.

Areas covered: Our review will focus on treatment options for GP and SIBO with motilin agonists, dopamine receptor antagonists, Ghrelin agonists muscarinic agonists, 5-HT₄ receptor agonists, antibiotics, probiotics and herbal formulation such as iberogast. Constipation occurs in the majority of patients with PD and fortunately many treatments are now available. Our review is based on original papers or reviews selected from PUBMED search and Cochrane reviews.

Expert opinion: Motility disorders of the GI tract are found frequently in patients with PD and treating the underlying GI disorders caused by PD with various prokinetics and laxatives is paramount in achieving improvements in patient’s motor function. Various prokinetics and laxatives are now available to provide some relief of the GI morbidity caused by PD leading even to better absorption of even the PD treatments.     

Association of the DRD2 and DRD3 polymorphisms with response to pramipexole in Parkinson’s disease patients

Objective  To evaluate the impact of the DRD2 TaqIA and DRD3 Ser9Gly polymorphisms on the efficacy of pramipexole in treating patients with Parkinson’s disease (PD). Methods  Thirty patients with PD prospectively received pramipexole 0.25 mg three times daily for 2 months. Unified Parkinson Disease Rating Scale (UPDRS) assessments were conducted at baseline and 2 months after treatment initiation. Improvement by 20% or more in the total score on the UPDRS was considered to indicate responsiveness. The PCR–restriction fragment length polymorphism analysis was used to analyze the DRD2 Taq1A and DRD3 Ser9Gly genotype. Results  The DRD2 Taq1A allele frequencies were A141.7 (A1) and 58.3% (A2), and the DRD3 Ser9Gly allele frequencies were 68.3 (Ser) and 31.7% (Gly). When the subjects were grouped by the DRD3 Ser9Gly polymorphism, the response rates for pramipexole treatment were significantly higher in the Ser/Ser group (60%) than in the group containing the Gly allele (13%). There was a significant association between the DRD3 Ser9Gly polymorphism and response rate to pramipexole in PD patients (P = 0.024). When the subjects were grouped by the DRD2 Taq1A polymorphism, there were no significant differences among the three Taq1A genotypes. Conclusions  DRD3 Ser9Gly polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with PD. A large-scale and multi-dose group study in patients with PD is necessary for evaluating the impact of the genetic polymorphisms of the dopamine receptor on the therapeutic effects of pramipexole.     

Therapeutic strategies to prevent and manage dyskinesias in Parkinson’s disease

Introduction: Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life.

Areas covered: In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation.

Expert opinion: Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect.