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.     

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.     

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

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Future directions in the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) remains the most common of the neurodegenerative disorders. In the elderly, it represents the most frequently occurring form of dementia, especially if considered alongside concomitant cerebrovascular disease. Current treatment involves the use of acetylcholinesterase inhibitors, which have shown symptomatic benefits in the recognised domains of cognition, function and behaviour. While they may have intrinsic disease-modifying activity, this is yet to be proven, and strategies to alter the fundamental neuropathological changes in AD continue to be sought. Much of the evidence suggests that the accumulation of amyloid-β may play a pivotal role, therefore the bulk of current research is focused on possible intervention along the amyloid pathways. However, the abnormal phosphorylation of tau is also a reasonable target and as the molecular basis of AD is better delineated, more targeted treatment approaches are being proposed. This paper reports on the current data that is setting the future directions for research into AD.     

The pharmacology of donepezil: a new treatment for Alzheimer’s disease

Donepezil (donepezil hydrochloride, E-2020, Aricept?, Eisai), launched in March 1997, was the first drug to be marketed for the symptomatic treatment of Alzheimer’s disease (AD) in the UK. It had been launched a year earlier in the US where clinicians had already had experience of tacrine (THA). Donepezil is a piperidine based, potent, specific, non-competitive and reversible inhibitor of acetylcholinesterase (AChE). It is structurally dissimilar from other established cholinesterase inhibitors, namely THA (an acridine compound) and the carbamates, physostigmine and rivastigmine and has a pharmacokinetic and tolerability profile distinct from these agents. Experimentally, donepezil inhibits AChE activity in human erythrocytes and increases extracellular acetylcholine levels in the cerebral cortex and the hippocampus of the rat. Pharmacologically, donepezil has a half-life of approximately 70 h lending itself to once daily administration. The most common adverse events reported in clinical trials have been gastrointestinal, typically nausea, vomiting, diarrhoea and constipation. Headache, dizziness and sleep disturbance have also been reported; there has been no evidence of hepatotoxicity. Clinically a number of placebo-controlled trials have shown that donepezil 5 or 10 mg daily was associated with significant improvements in cognitive function, as assessed by the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS cog) after 12 or 24 weeks treatment. Significant improvements in global function and activities of daily living have also been demonstrated after 24 weeks treatment compared with placebo in patients with mild to moderate AD. Donepezil was the first rational treatment available in the UK for this disabling condition and as such received considerable attention. Much of the original attention was negative, ostensibly based on the scientific view that there was not enough published evidence to justify widespread use, but this was driven by concerns about the potentially high drug costs if all patients with AD were eligible to receive it. Considerable data have now been produced from Phase II, III and post-marketing surveillance. This drug evaluation will review the basic pharmacology of donepezil and place it in context with the trial data and the author’s clinical experience with the drug.     

The safety of istradefylline for the treatment of Parkinson’s disease

Introduction: Antagonism of the A_2A receptor improves motor behavior in patients with Parkinson’s disease (PD), according to results of clinical studies which confirm findings of previous experimental research. The xanthine derivative, istradefylline, has the longest half-life out of the available A_2A receptor antagonists. Istradefylline easily crosses the blood–brain barrier and shows a high affinity to the human A_2A receptor.

Areas covered: This narrative review aims to discuss the safety and tolerability of istradefylline against the background of the currently available drug portfolio for the treatment of PD patients.

Expert opinion: Istradefylline was safe and well tolerated in clinical trials, which have focused on l-DOPA-treated PD patients. The future of istradefylline as a complementary drug for modulation of the dopaminergic neurotransmission also relies on its potential to act like an l-DOPA plus dopamine agonist sparing future treatment alternative and to reduce the risk of predominant l-DOPA-related onset of motor complications in addition to its direct ameliorating effect on motor symptoms. Dopamine-substituting drugs may dose-dependently produce systemic side effects, particularly onset of hypotension and nausea by peripheral dopamine receptor stimulation. Istradefylline does not interfere with these peripheral receptors and therefore shows a good safety and tolerability profile.     

Transdermal rotigotine: a new non-ergot dopamine agonist for the treatment of Parkinson’s disease

An important conceptual development to avoid the occurrence of motor dyskinesias in Parkinson’s disease is continuous dopaminergic stimulation. Studies in animal models and humans suggest that continuous dopaminergic stimulation could be achieved by the infusions of different dopamine agonists or levodopa, and may significantly reduce the risk of dyskinesias associated with treatment strategies utilising pulsatile treatment options. However, so far, these techniques have either necessitated frequent intake of oral therapy or invasive parenteral treatment. The rotigotine transdermal delivery system represents a significant development that allows a constant delivery of a non-ergot dopamine agonist using a once-daily regimen, achieving steady plasma levels. Clinical trials demonstrate the efficacy of rotigotine in early and advanced Parkinson’s disease, with important implications for treatment of non-motor symptoms of Parkinson’s disease.     

Novel disease-modifying therapeutics for the treatment of Alzheimer’s disease

Alzheimer’s disease is the most common cause of dementia and is becoming a global health concern. Despite a well-established understanding of the molecular mechanism involved in its pathogenesis, and millions of dollars of investment in drug discovery and clinical trials, no single molecule has yet been approved for its treatment since the advent of cholinesterase inhibitors and memantine. This review examines first the optimal use of currently approved agents and then explores in detail the current Phase II and III clinical trial landscape, while spending some time on the mechanistic details. Driven by the increasing knowledge gleaned from numerous Phase III failures and improvements in early detection and biomarkers, there is renewed enthusiasm that a cure is taking shape along the visible horizon.