Evaluation of rotigotine transdermal patch for the treatment of depressive symptoms in patients with Parkinson’s disease

Objective: To evaluate the dopamine receptor agonist, rotigotine, for improving depressive symptoms in patients with Parkinson’s disease (PD).

Methods: Patients were randomized 1:1 to rotigotine or placebo, titrated for ≤7 weeks, and maintained at optimal/maximum dose for 8-weeks. Primary efficacy variable: 17- item Hamilton Depression Rating Scale (HAM-D 17) total score change from baseline to end-of-maintenance. Secondary variables: changes in Beck Depression Inventory-II, Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living [ADL]) and III (motor) subscores, UPDRS II+III total, patient-rated Apathy Scale (AS), and Snaith-Hamilton Pleasure Scale.

Results: Of 380 patients randomized, 149/184 (81.0%) rotigotine-treated and 164/196 (83.7%) placebo-treated patients completed the study. Patients: mean (±SD) age 65.2 (±8.5) years; time since PD-diagnosis 2.74 (±3.08) years; 42.6% male. The treatment difference (LS mean [95% CI]) in change from baseline HAM-D 17 was ?1.12 (?2.56, 0.33; p = 0.1286). UPDRS II, III, II+III and AS scores improved numerically with rotigotine versus placebo. Common adverse events with higher incidence with rotigotine: nausea, application/instillation site reactions, vomiting, and pruritus. Forty-one (10.8%) patients discontinued owing to adverse events (25 rotigotine/16 placebo).

Conclusions: No statistically significant improvement in depressive symptoms were observed with rotigotine versus placebo. ADL, motor function, and patient-rated apathy improved numerically.

ClinicalTrials.gov: NCT01523301     

Safinamide for the treatment of Parkinson’s disease

Introduction: The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification.

Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD.

Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.     

Filgotinib for the treatment of Crohn’s disease

Introduction: Inflammatory bowel diseases, such as Crohn’s disease (CD) and ulcerative colitis (UC), are widespread diseases (with an estimated 2.2 million Europeans affected), and even populations previously considered ‘low risk’ (such as Japan and India) are witnessing an increasing incidence. CD is a chronic, progressive immunologically driven disease, with an evolution characterized by succession of periods of progression and remission. New physiopathological pathways are continuously being discovered, the more we understand about how the disease appears and progresses, the more targets become available for the development of novel therapies.

Areas covered: Filgotinib is one of these promising new therapies; this article discusses the currently available data. We used an exhaustive search of the PubMed database to corroborate information regarding its chemical characteristics, and the studies evaluating clinical efficacy and safety.

Expert opinion: Up to now, the phase-II study evaluating Filgotinib yielded very promising results in moderate to severe CD patients, with good clinical response, mucosal healing, while having few and moderate adverse effects, both in anti-TNF naïve and resistant patients. Phase-III studies are still ongoing and will help decide whether Filgotinib will be a worthwhile drug in the treatment of CD and the best way to use it.     

Safinamide for the treatment of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease caused by a complex interaction of loss of dopaminergic and non-dopaminergic neurotransmitter systems. Drugs acting on the dopaminergic pathways are the mainstay of treatment for motor symptoms today. Safinamide (NW-1015) is a novel drug with multiple actions. It is a monoamine oxidase B inhibitor and improves dopaminergic transmission. In addition, it has antiglutamatergic effects and can thus reduce dyskinesias, which is a side effect limiting most dopaminergic therapy. In Phase III trials, safinamide has been found to be a useful adjunctive to dopamine agonists in early PD and has been shown to increase time without increasing troublesome dyskinesias when used as an adjunct to levodopa in patients with advanced PD. A possible neuroprotective role in inhibiting PD disease progression is envisaged and warrants future studies.     

Pridopidine for the treatment of Huntington’s disease

Introduction: Huntington’s disease is a rare dominantly-inherited neurodegenerative disease with motor, cognitive and behavioral manifestations. It results from an expanded unstable trinucleotide repeat in the coding region of the huntingtin gene. Treatment is symptomatic, but a poor evidence baseguides selection of therapeutic agents. Non-choreic derangements in voluntary movement contribute to overall motor disability and are poorly addressed by current therapies. Pridopidine is a novel agent in the dopidine class believed to have ‘state dependent’ effects at dopamine receptors, thus show promise in the treatment of these disorders of voluntary movement.

Areas covered: This review discusses the pharmacokinetics and pharmacodynamics of pridopidine and reviews clinical trials supporting development of the drug for HD. This information was culled from literature searches for dopidines, pridopidine, and HD experimental therapeutics in PubMed and at http://www.clinicaltrials.org.

Expert opinion: There is a compelling need to discover new treatments for motor disability in HD, particularly for non-choreic motor symptoms. While pridopidine failed to achieve its primary efficacy outcomes in 2 large trials, reproducible effects on secondary motor outcomes have fueled an ongoing trial studying higher doses and more focused clinical endpoints. This and phase III trials will define define the utility of pridopidine for HD.     

Opicapone for the treatment of Parkinson’s disease

Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disease. The currently available treatment options only have a symptomatic effect. With disease progression almost all antiparkinsonian pharmacological classes are tried, but the gold standard of pharmacological management is still L-dopa. Various strategies can be used to raise the dopaminergic tone. Catechol-O-methyltransferase (COMT) inhibitors attain this goal by decreasing L-dopa peripheral metabolism.

Areas covered: Opicapone (Ongentys®) is a new COMT inhibitor developed to fulfill the need for more potent, safer and longer acting COMT inhibitors. This review puts into context opicapone’s indications, its chemical and preclinical data, the pharmacodynamics and pharmacokinetic characteristics, and the efficacy and safety results delivered by clinical trials.

Expert opinion: Opicapone is an efficacious COMT inhibitor. Its proprieties make it adequate for a once-a-day oral dose regimen. It has proved to reduce the off-time and to increase the on-time without troublesome dyskinesias in PD patients with motor fluctuations. The reported adverse events suggest an overall safe and well-tolerated profile. The most common adverse events were dyskinesia, and there were no issues of concern for hepatotoxicity, severe diarrhoea or chromaturia. Further evidence is still needed to conclude how it compares with other drugs for the treatment of motor fluctuations.     

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.     

Abnormal hippocampal neurogenesis in Parkinson’s disease: relevance to a new therapeutic target for depression with Parkinson’s disease

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by motor dysfunction, including bradykinesia, tremor, rigidity, and postural instability. Recent clinical findings recognize PD as a complex disease with diverse neuropsychiatric complications. Depression is the most frequent non-motor psychiatric symptom experienced in PD, and it is associated with poor quality of life. While the pathophysiology of PD-associated depression is not directly related to neurodegenerative processes in the substantia nigra, underlying mechanisms remain unclear and there are few symptomatic treatments. Altered adult hippocampal neurogenesis is considered crucial for the development and treatment of depression. In genetic animal models and human postmortem studies of PD, severely impaired adult neurogenesis has been observed, with patients showing hippocampal atrophy and disrupted hippocampal neurogenesis. Because adult newborn neurons appear to exert various functions, which relate to non-motor symptoms observed in PD, there might be a close correlation between malformation of newborn neurons in the adult hippocampus and depressive symptoms. Here, we discuss current concepts regarding impaired hippocampal neurogenesis and non-motor symptoms of PD, and review PD-associated pathophysiological factors regulating neurogenesis, including inflammatory signaling and autophagy. We present a novel framework for targeting adult hippocampal neurogenesis, which could provide a promising treatment for PD-associated depression.     

Active treatment of patients with “incurable disease”: what’s the point?

What is active treatment of patients with “incurable disease”? I believe that it is not limited to the care of the patients’ symptoms, but goes further. We can and must control pain, breathlessness, nausea and vomiting, intestinal obstruction, insomnia… but something else remains for us to face, something paradoxically made more evident by the absence of symptoms: the patients’ emotional suffering, suffering deep in their heart, the most hidden, but which becomes apparent in the season of death. So, what can we do? We must be able to understand their needs and to stay with them, protecting the uniqueness of their person in the face of an imminent death.     

Rasagiline for the treatment of Parkinson’s disease: an update

Introduction: Rasagiline is a potent, selective, irreversible Monoamine Oxidase-B (MAO-B) inhibitor, developed to prolong the action of dopamine in the brain. It has been demonstrated that rasagiline can improve motor and some non-motor symptoms (NMS) in both early and advanced Parkinson’s disease (PD) patients, and it also exhibits neuroprotective and antiapoptotic properties.

Areas covered: The objective of this review, performed by a Medline search on the most recent papers investigating the therapeutic effects of rasagiline, is to describe the role of rasagiline in the schedule of treatment of early and advanced PD patients. It will then focus on its role in treating NMS, fatigue, early morning off and cognitive decline, which heavily affect quality of life for PD patients.

Expert opinion: Rasagiline is an efficacious, well-tolerated, easy to use drug. The drug has been extensively studied and has proven its efficacy in monotherapy and in combination with any other antiparkinsonian therapy. It proved to be efficacious in reducing ‘off’ time and in improving early morning ‘off’ but also some NMS, thus enhancing the therapeutic approach to PD.     

The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson’s disease

Rotigotine (Neupro®) is a non-ergoline dopamine agonist developed for the once daily treatment of Parkinson’s disease (PD) using a transdermal delivery system (patch) which provides patients with the drug continuously over 24 h. To fully understand the pharmacological actions of rotigotine, the present study determined its extended receptor profile. In standard binding assays, rotigotine demonstrated the highest affinity for dopamine receptors, particularly the dopamine D₃ receptor (K _i?=?0.71 nM) with its affinities to other dopamine receptors being (K _i in nM): D_4.2 (3.9), D_4.7 (5.9), D₅ (5.4), D₂ (13.5), D_4.4 (15), and D₁ (83). Significant affinities were also demonstrated at α-adrenergic (α_2B, K _i?=?27 nM) and serotonin receptors (5-HT_1A K _i?=?30 nM). In newly developed reporter-gene assays for determination of functional activity, rotigotine behaved as a full agonist at dopamine receptors (rank order: D_3?>?D_2L?>?D₁?=?D_5?>?D_4.4) with potencies 2,600 and 53 times higher than dopamine at dopamine D₃ and D_2L receptors, respectively. At α-adrenergic sites, rotigotine acted as an antagonist on α_2B receptors. At serotonergic sites, rotigotine had a weak but significant agonistic activity at 5-HT_1A receptors and a minor or nonexistent activity at other serotonin receptors. Thus, in respect to PD, rotigotine can be characterized as a specific dopamine receptor agonist with a preference for the D₃ receptor over D₂ and D₁ receptors. In addition, it exhibits interaction with D₄ and D₅ receptors, the role of which in relation to PD is not clear yet. Among non-dopaminergic sites, rotigotine shows relevant affinity to only 5-HT_1A and α_2B receptors. Further studies are necessary to investigate the contribution of the different receptor subtypes to the efficacy of rotigotine in Parkinson’s disease and possible other indications such as restless legs syndrome.     

Zinc acetate for the treatment of Wilson’s disease

Zinc acetate (Galzin^®, Gate Pharmaceutical Co.) has been developed for the treatment of Wilson’s disease, an inherited disease of copper accumulation and copper toxicity in the brain and liver. Zinc acetate has been approved by the US FDA for maintenance therapy of adult and paediatric Wilson’s disease patients but also has efficacy in the treatment of pregnant patients and pre-symptomatic patients from the beginning. It also has value as adjunctive therapy for the initial treatment of symptomatic patients. Zinc’s mechanism of action involves induction of intestinal cell metallothionein (Mt), which blocks copper absorption from the intestinal track. A negative copper balance is caused by blockade not only of absorption of food copper but the blockade of reabsorption of the considerable amount of endogenously secreted copper in saliva, gastric juice and intestinal secretions. Zinc is completely effective in controlling copper levels and toxicity in Wilson’s disease, as are other anticopper agents. Zinc’s major advantage over other anticopper agents is its extremely low level of toxicity. The only side effect is some degree of initial gastric irritation in ~10% of patients, which usually decreases and becomes insignificant over time. As with all long-term therapies, compliance is a problem in some patients and dictates regular monitoring with 24 h urine copper and zinc measurements. As with all anticopper therapies, over a long period of time, overtreatment and induction of copper deficiency can occur. This is to be avoided particularly in children because copper is required for growth.     

Pimavanserin for the treatment of Parkinson’s disease psychosis

Introduction: Parkinson´s disease (PD) is a synucleinopathy that affects millions of people worldwide and leads to progressive disability. Psychosis is highly prevalent in PD patients and is associated with poor prognosis. Until April 2016, there were no licensed drugs available in the United States of America (USA) for the treatment of PD psychosis (PDP). Pimavanserin is the first Food and Drug Administration approved medicine for the treatment of hallucinations and delusions associated with PDP.

Areas covered: A MEDLINE literature search, publicly available information provided by ACADIA Pharmaceuticals, and expert opinion were used for this review. A review of PDP, its current treatment and limitations is followed by the rationale for development of pimavanserin. The mechanism of action, preclinical data, pharmacokinetics, pharmacodynamics, and clinical data supporting the efficacy and safety of pimavanserin in PDP are reviewed. We also describe the potential benefits of pimavanserin in other contexts such as schizophrenia and sleep disorders.

Expert opinion: Pimavanserin is an antipsychotic with a unique mechanism of action (5-HT_2A receptor inverse agonist) and no measurable dopaminergic activity; it has been demonstrated to be efficacious, well tolerated and safe for the treatment of PDP.

The development of pimavanserin as an antipsychotic represents a major breakthrough in the pharmacotherapy of psychotic symptoms associated with PD.     

Evaluation of memantine for the treatment of Alzheimer’s disease

Increasing evidence suggests that disturbances in glutamatergic activity play an important role in Alzheimer’s disease (AD). Excessive glutamate-mediated activation of NMDA receptors, for example, may contribute to the neuronal death that characterises AD. On the other hand, physiological activation of the NMDA receptor appears necessary for normal cognitive function. Therefore, compounds that finely modulate NMDA receptor activity hold promise as treatments for AD. Memantine (Namenda^?, Axura^®, Ebixa^®; Forest Laboratories, Inc., Merz Pharmaceuticals GmbH, H. Lundbeck A/S) is a low-moderate affinity, uncompetitive NMDA-receptor antagonist that appears to block pathological, but not physiological, activation of the NMDA receptor. Consequently, therapeutic doses of the drug are well-tolerated and do not seem to interfere with the acquisition or processing of cognitive information. Memantine has been shown to improve symptoms and reduce the rate of clinical deterioration among patients with moderate-to-severe AD and was approved in the US for this indication in October 2003. This review provides a brief rationale for the development of memantine as a therapy for AD, as well as an overview of the pharmacology, clinical efficacy, safety and tolerability of this novel therapeutic agent.     

Polymorphisms in candidate genes: implications for the current treatment of Parkinson’s disease

Pharmacological treatment remains the cornerstone of therapy in Parkinson’s disease. A number of clinical and genetic factors may influence the therapeutic response and treatment-related complications. Some exploratory studies have suggested that genetic polymorphisms may influence an individual’s response to dopaminergic therapy and susceptibility to drug-related complications, such as hallucinations, dyskinesias, motor fluctuations and sudden onset of sleep episodes. This article provides a concise summary and discussion of the potential utility and limitation of studies that have examined the influence of genetic polymorphisms on drug-related response and complications in Parkinson’s disease.     

Advances in dopamine receptor agonists for the treatment of Parkinson’s disease

Introduction: Dopamine agonists (DA) are a class of agents which directly stimulate dopamine receptors mimicking the endogenous neurotransmitter dopamine. At first used as adjunctive therapy in the advanced phases of the disease, over the years a significant role was found for DA monotherapy as a first approach in the initial stage of Parkinson’s disease (PD). Several reviews have already reported efficacy and safety of DA in PD and differences between DA and levodopa. Therefore the objective of this review is to gather recent updates in DA therapy. A thorough knowledge of recent literature evidences, would help clinician in the management of treatment with DA.

Areas covered: Our review investigates recent updates on DA therapy, the role of these compounds in controlling non-motor symptoms (NMS) as well as new formulations under clinical evaluation and newly emerged post-marketing safety considerations. A literature search has been performed using Medline and reviewing the bibliographies of selected articles.

Expert opinion: DA represents a very important option in the treatment of PD, even though there are still some criticisms and unmet needs. A better knowledge of dopamine receptors could lead to identification of new compounds able to better balance clinical efficacy and side effects.     

Advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn’t effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn’t necessarily outweigh the associated risks.

Areas covered: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation.

Expert opinion: Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.