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.     

Pharmacokinetic drug evaluation of opicapone for the treatment of Parkinson’s disease

Introduction: Opicapone (OPC) is a novel, potent, reversible, and purely peripheral third-generation COMT inhibitor, which provides an enhancement in levodopa (L-Dopa) availability. It represents adjunctive therapy for L-Dopa treated patients with PD and motor fluctuations.

Areas covered: The purpose of this study was to evaluate pharmacokinetic of OPC for the treatment of PD.

Expert commentary: Oral OPC exhibits linear, dose-dependent absorption. However, following concomitant ingestion of a high-fat, high-calorie meal, the maximum plasma concentration will be decreased. A once-daily bedtime administration of OPC 1 h after the last daily L-Dopa/AADCi, are considered to avoid any interaction during the L-Dopa absorption phase. There are no clinically relevant effects of age (in adults), renal impairment or race on the pharmacokinetics of OPC. OPC dose adjustment is not needed in patients with mild to moderate chronic hepatic impairment. Opicapone exhibits the lowest potential for cytotoxicity in comparison with other COMT inhibitors. It significantly decreases COMT activity, with half-life of COMT inhibition in human erythrocytes of 61.6 h and increases systemic exposure to L-Dopa. This provides an enhancement in L-Dopa availability that translates into clinical benefit for PD patients in terms of significant decrease of OFF periods and increase in ON-time without troublesome dyskinesia.     

Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson’s disease

A microsphere–gel in situ forming implant (MS–Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson’s disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM–MS prepared by a modified emulsion-phase separation method and optimized by Box–Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of in vitro drug release (60?days). An in vivo pharmacokinetic study indicated a significant reduction (p?in situ gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (p?p?in situ phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs.     

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.     

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

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.     

Pharmacokinetic drug evaluation of safinamide mesylate for the treatment of mid-to-late stage Parkinson’s disease

Introduction: Patients with Parkinson’s disease suffer from a heterogeneous expression of neurotransmitter deficits. They cause an individual variable expression of motor and non-motor symptoms. Thus, drugs with various mechanisms of actions are suitable to counteract these disease related neurotransmitter alterations.

Areas covered: This invited review suggests safinamide as an ideal compound for therapy of Parkinson’s disease, as its pharmacological profile includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and abnormal glutamate release. Safinamide may provide benefits effects on non-motor symptoms in addition to the demonstrated amelioration of motor impairment in levodopa treated patients with Parkinson’s disease. Safinamide was well tolerated and safe when administered in dose of 50 or 100 mg daily in pivotal trials.

Expert opinion: Clinical handling, safety and tolerability of Safinamide are better than of dopamine agonists or levodopa. Safinamide supplements the existing armamentarium of drugs for Parkinson’s disease. Safinamide will help to reduce dosing of levodopa but also of dopamine agonists during long term treatment in patients with Parkinson’s disease.     

Emerging drugs for Parkinson’s disease

Parkinson’s disease (PD) afflicts millions of people worldwide. There are numerous drugs available for PD; however, levodopa remains the gold standard of pharmacotherapy to which all other therapies are compared. Levodopa is quite effective for many motor symptoms (bradykinesia, tremor, rigidity) of PD; however, non-levodopa-responsive motor symptoms (postural instability) and nonmotor symptoms are frequently the most troublesome in middle and later stages of disease. Although motor symptoms remain an important focus for emerging drugs, current research is largely geared to identify and develop disease-slowing therapies. Another important area of focus has become treatment of the nonmotor symptoms of PD (especially depression and dementia). This review discusses emerging drugs in the management of the motor and nonmotor symptoms of PD and drugs under study as disease-slowing/neuroprotective agents.     

Transplantation therapy for Parkinson’s disease

This review paper will provide an overview of the advent of neural transplantation therapy and the milestones achieved over the last 20 years for its use in treating Parkinson’s disease. A discussion of technical factors that influence the outcome of neural transplantation is presented, with emphasis given on three sections dealing with immunosuppressants, alternative grafts and trophic factors which have recently been the focus of basic research and development of early phase clinical trials. Some views on the clinical assessment of transplanted Parkinson’s disease patients are given at the end of the paper, with a synopsis highlighting the importance of basic research in advancing the potential clinical benefits of neural transplantation therapy in the treatment of Parkinson’s disease.     

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.     

Molecularly imprinted cyclodextrin nanosponges for the controlled delivery of L-DOPA: perspectives for the treatment of Parkinson’s disease

ABSTRACT

Background: L-DOPA is an amino acid precursor to the neurotransmitter dopamine that is extensively used as a prodrug for the treatment of Parkinson’s disease. However, L-DOPA is an unstable compound: when exposed to light or added to aqueous solutions, it may degrade, compromising its therapeutic properties.

Methods: In this work, a new type of drug-loaded cyclodextrin-based nanosponge, obtained using molecular imprinting, is described for the prolonged and controlled release of L-DOPA. The molecularly imprinted nanosponges (MIP-NSs) were synthesized by cross-linking β-cyclodextrin with 1,1?-carbonyldiimidazole in DMF in the presence of L-DOPA as a template molecule. TGA, DSC and FTIR analyses were performed to characterize the interactions between L-DOPA and the two nanosponge structures. Quantitative NMR spectroscopy was used to determine the amount and the affinity of L-DOPA entrapped in the nanosponges. The in vitro L-DOPA release kinetics from the NSs were quantitatively determined by HPLC analysis.

Results: The MIP-NSs show a slower and more prolonged release profile than the non-imprinted nanosponges. No degradation of the L-DOPA hosted in the MIP-NSs was observed after long-term storage at room temperature.

Conclusions: The MIP-NSs are a promising alternative for the storage and controlled delivery of L-DOPA.     

Epigenetic drug discovery for Alzheimer’s disease

Introduction: It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer’s disease (AD).

Areas covered: This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs.

Expert opinion: Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.     

Novel models for Parkinson’s disease and their impact on future drug discovery

Introduction: Parkinson’s disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson’s Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times.

Areas covered: The authors provide an outline of the various traditional models of Parkinson´s disease and address those that have been recently generated. They also discuss the utility of these models for the identification of drugs of potential therapeutic value for Parkinson´s Disease patients. From the cell based models and the well-known toxin-based animal models, to the recent genetic models and the increasingly used non-mammalian models, every model is worthwhile in the search for a better Parkinson´s Disease therapy.

Expert opinion: Almost 60 years after its discovery, levodopa is still the gold standard treatment for Parkinson's Disease patients. It seems unlikely that a single model can fully recapitulate the complexity of Parkinson's Disease in the same way it appears improbable that a unique treatment could relieve both the motor and non-motor symptoms of Parkinson's Disease altogether. Therefore treatment will probably require a combination of therapies.     

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.     

New treatments for the motor symptoms of Parkinson’s disease

Levodopa remains the most potent drug to treat motor symptoms in Parkinson’s disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using ‘levodopa-sparing agents’ and adding non-dopaminergic drugs. New options to ‘improve’ delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned.     

Non-oral drug delivery in Parkinson’s disease: a summary from the symposium at the 7th International Congress of Parkinson’s Disease and Movement Disorders

This symposium reviewed the issues of non-oral therapy in the late stage Parkinson’s disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy.     

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.     

Advances in prodrug design for Parkinson’s disease

Introduction: Parkinson’s Disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) characterized by motor dysfunctions, such as bradykinesia, rigidity, neuropsychiatric symptoms, and others. The pharmacological treatment of the disease is only symptomatic since, to date, there is no treatment to stop or slow PD. Currently, L-Dopa (LD) remains the gold standard therapy even though it undergoes peripheral metabolism causing several side effects, such as nausea, vomiting and orthostatic hypotension.

Areas covered: This review is focused on recent developments in strategies involving prodrugs to enhance DA and/or LD absorption, their chemical and enzymatic stabilities, and selective targeting to the central nervous system.

Expert opinion: The prodrug strategy remains one of the most promising approaches to improve pharmaceutical, pharmacokinetic, and pharmacodynamic properties of hydrophilic compounds, such as anti-Parkinson drugs (DA and LD). Prodrugs developed in recent years have demonstrated good pharmacokinetic profiles, affording a sustained release of LD and reducing its plasma level fluctuations. The development of new prodrugs that may reach the BBB unaltered and with a good ADME (Absorption, Distribution, Metabolism, Elimination) profile and pharmacological efficacy represents an exciting challenge for medicinal chemists.