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.     

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.     

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.     

Nanotechnology-based drug delivery of ropinirole for Parkinson’s disease

A new drug delivery system is developed for ropinirole (RP) for the treatment of Parkinson’s disease (PD) consisting of biodegradable poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs). The formulation selected was prepared with 8?mg RP and 50?mg PLGA 502. This formulation exhibited mean encapsulation efficiency of 74.8?±?8.2%, mean particle size lower than 155?nm, the zeta potential of ?14.25?±?0.43?mV and zero-order in vitro release of RP (14.13?±?0.17?μg/h/10?mg NPs) for 5?d. Daily doses of the neurotoxin rotenone (2?mg/kg) given i.p. to male Wistar rats induced neuronal and behavioral changes similar to those of PD. Once neurodegeneration was established (15?d) animals received RP in saline (1?mg/kg/d for 35?d) or encapsulated within PLGA NPs (amount of NPs equivalent to 1?mg/kg/d RP every 3 d for 35?d). Brain histology and immunochemistry (Nissl-staining, glial fibrillary acidic protein and tyrosine hydroxylase immunohistochemistry) and behavioral testing (catalepsy, akinesia, rotarod and swim test) showed that RP-loaded PLGA NPs were able to revert PD-like symptoms of neurodegeneration in the animal model assayed.     

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.     

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.     

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 budesonide in the treatment of Crohn’s disease

Introduction: Crohn’s disease (CD) is a chronic inflammatory disorder that commonly affects the terminal ileum and proximal colon. Although systemic corticosteroids such as prednisone and methylprednisolone are widely used for treatment of CD, these agents have a high incidence of adverse drug reactions due to off-target effects. Budesonide is a locally acting corticosteroid with enhanced formulation properties that offer a superior therapeutic index in comparison to conventional members of the class.

Areas covered: This review focuses on budesonide for the treatment of CD. The pharmacological and pharmacokinetics of the drug are summarized, along with clinical efficacy and safety data. We also indicate the role of budesonide in therapeutic algorithms.

Expert opinion: Budesonide has an important role as an induction therapy in patients with mild to moderately active CD of the ileum and proximal colon. The most distinctive advantage of budesonide over conventional corticosteroids is a substantially reduced risk of corticosteroid-related side effects.     

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.     

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.     

Modulation of microglial pro-inflammatory and neurotoxic activity for the treatment of Parkinson’s disease

Parkinson's disease (PD) is a debilitating movement disorder resulting from a progressive degeneration of the nigrostriatal dopaminergic pathway and depletion of neurotransmitter dopamine in the striatum. Molecular cloning studies have identified nearly a dozen genes or loci that are associated with small clusters of mostly early onset and genetic forms of PD. The etiology of the vast majority of PD cases remains unknown, and the precise molecular and biochemical processes governing the selective and progressive degeneration of the nigrostriatal dopaminergic pathway are poorly understood. Current drug therapies for PD are symptomatic and appear to bear little effect on the progressive neurodegenerative process. Studies of postmortem PD brains and various cellular and animal models of PD in the last 2 decades strongly suggest that the generation of pro-inflammatory and neurotoxic factors by the resident brain immune cells, microglia, plays a prominent role in mediating the progressive neurodegenerative process. This review discusses literature supporting the possibility of modulating the activity of microglia as a neuroprotective strategy for the treatment of PD.     

Prospects for the treatment of Parkinson’s disease using neurotrophic factors

Parkinson’s disease (PD) is a debilitating neurodegenerative condition that is characterised by a progressive loss of dopaminergic neurones of the substantia nigra pars compacta (SNpc) and the presence of α-synuclein cytoplasmic inclusions (Lewy bodies). Cardinal symptoms include tremor, bradykinesia, and rigidity, although cognitive and autonomic disturbances are not uncommon. Pharmacological treatment targeting the dopaminergic network is relatively effective at ameliorating these symptoms, especially in the early stages of the disease, but none of these therapies are curative and they generate their own problems. As dopaminergic neuronal death in PD occurs in a gradual manner, it is amenable to treatments that can either protect remaining dopaminergic neurones or prevent death of those neurones that have begun to die. Use of neurotrophic factors is a potential candidate, as various factors have been shown to increase dopaminergic neuronal survival in culture and promote survival and axonal growth in animal models of PD. Glial cell line-derived neurotrophic factor (GDNF) is currently the most effective substance that has been intensively studied and shown to have a specific ‘dopaminotrophic’ effect. This review will therefore focus on studies that have investigated GDNF and discuss the potential for neurotrophic factor treatment in PD.     

Lomustine’s nanoemulsion as nose-to-brain drug delivery system for CNS tumor treatment

Nose-to-brain delivery allows the direct targeting of drug molecules bypassing the Blood Brain Barrier and systemic effect. Nanoemulsion is one of the novel strategies to deliver drug in this route due to its simplicity in manufacturing, long-term stability, and strong solubilization property for drug. The anticancer drug lomustine had poor oral bioavailability in addition to its serious side effect, therefore, developing more effective drug delivery with direct targeting towards the brain through intra-nasal administration applying nanoemulsion technology is a promising alternative. The work involved lomustine solubility screening in oils, surfactants and cosurfactants as well as emulsifier ratio (Smix) nanoemulsion area was identified using pseudo-ternary phase diagrams. Eighteen nanoemulsion formulas were produced for optimization, then characterized for droplet size, polydispersity index, zeta potential, entrapment efficiency, conductivity, transmittance, dilution, visual transparency, physical stability and in vitro release. The optimum NE formula showed droplet size, zeta potential, polydispersity index, entrapment efficiency, %transmittance, conductivity of 31.31 nm, −30.65 mV, 0.159, 98.12%, 99.08%, and 951 us/cm, respectively. The best formula released 100% lomustine within 15 min which is a promising potential drug delivery system that may deliver the drug quickly and directly to the brain as a safe and effective alternative to oral delivery.     

Thiazolidinediones under preclinical and early clinical development for the treatment of Parkinson’s disease

Introduction: Current treatment of Parkinson’s disease (PD) is limited to symptomatic dopaminergic therapy, while no interventions have been shown to slow down disease progression.

Areas covered: The following article highlights a group of PPAR-γ agonists called thiazolidinediones (TZDs), which are currently being tested for a putative disease-modifying benefit in PD, using pioglitazone as a prototypic compound. PPAR-γ is highly expressed in neurons of the substantia nigra and CNS immune cells. Preclinical data in rodent and primate support an effect of TZDs in preventing and/or arresting neurodegeneration and development of motor symptoms. Although no data on the neuroprotective effect of TZDs is currently available, a clinical trial is ongoing where the primary objective is to assess pioglitazone’s impact on the progression of PD. The trial is also evaluating the drug’s safety concerns.

Expert opinion: The efficacy data from clinical trials must be carefully weighed against the safety concerns. However, given the solid preclinical data, and since the safety data are not yet fully conclusive and limited to the diabetic population, PPAR-γ research in PD can continue with caution. Ideally, drug discovery and development efforts will lead to the identification of new compounds with reduced risk of peripheral side effects.     

A pharmacoeconomic evaluation of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) results in progressively worsening cognitive decline, leading to loss of functional ability, behavior/mood disturbances, institutionalization, and death. Current pharmaceutical therapies only treat the symptoms of cognitive decline yet can be expensive for payers.

Areas covered: The authors undertook a systematic review of economic evaluations of pharmaceutical therapies for AD. The literature search encompassed English-language studies indexed in PubMed (Medline), Cochrane Library Current, and Web of Science. The search included articles published between 1 January 1995 and 10 February 2018. The literature suggested AD medications generally dominated comparator treatments (e.g. placebo).

Expert opinion: The authors noted several limitations of the included economic evaluations. These limitations suggest the results of the economic evaluations should be interpreted with caution. Many economic models were not transparent with respect to sources of probabilities and cost data, and data collected in certain jurisdictions were applied to other jurisdictions without considering the validity of such applications. Measuring health utilities in cognitively impaired populations raises questions about the validity of quality-adjusted life years, but this issue was unaddressed in the included studies. Most included studies were sponsored by industry and the results tended to overwhelmingly support the manufacturer’s product.     

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.     

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.     

Mavoglurant as a treatment for Parkinson’s disease

Introduction: A major unresolved issue in the Parkinson’s disease (PD) treatment is the development of l-DOPA-induced dyskinesias (LIDs) as a side effect of chronic l-DOPA administration. Currently, LIDs are managed in part by reducing the l-DOPA dose or by the administration of amantadine. However, this treatment is only partially effective. A potential strategy, currently under investigation, is the coadministration of metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) and l-DOPA; a treatment that results in the improvement of dyskinesia symptoms and that permits reductions in l-DOPA dosage frequency.

Areas covered: The authors examine the role of mGluR5 in the pathophysiology of PD and the potential use of mGluR5 NAM as an adjuvant therapy together with a primary treatment with l-DOPA. Specifically, the authors look at the mavoglurant therapy and the evidence presented through preclinical and clinical trials.

Expert opinion: Interaction between mGluR5 NAM and l-DOPA is an area of interest in PD research as concomitant treatment results in the improvement of LID symptoms in humans, thus enhancing the patient’s quality of life. However, few months ago, Novartis decided to discontinue clinical trials of mavoglurant for the treatment of LID, due to the lack of efficacy demonstrated in trials NCT01385592 and NCT01491529, although no safety concerns were involved in this decision. Nevertheless, the potential application of mGluR5 antagonists as neuroprotective agents must be considered and further studies are warranted to better investigate their potential.