Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Play in advance against neurodegeneration: exploring enteric glial cells in gut-brain axis during neurodegenerative diseases

Introduction: New investigations have shown that ‘activated’ enteric glial cells (EGCs), astrocyte-like cells of the enteric nervous system (ENS), represent a possible extra-CNS trigger point of the neurodegenerative processes in impaired intestinal permeability conditions. The early modulation of enteric glia-mediated neuroinflammation might optimize neuroprotective treatments outcomes currently used in neurodegenerative diseases.

Areas covered: We discussed recent clinical and preclinical data existing on the Pubmed database, concerning the glial role in neurodegeneration. We focused on the gut as possible “entrance door” for endoluminal neurotoxic agents that induce neurological impairments during leaky gut conditions. Moreover, we reviewed the paradigmatic studies linking the leaky gut-induced priming of EGCs to the induction of late neurodegenerative processes in Parkinson’s disease and other neurodegenerative disorders.

Expert opinion: The previous appearance of neuropathological markers in the ENS emphasizes the extra-CNS origin of neurodegenerative disorders, by directing their therapies toward peripheral management of neurodegeneration. In light of the EGCs changes resulting from a switch-on of activated phenotype in leaky gut syndrome, EGCs sampling could be predictive for neuropathological conditions detection, anticipating their symptomatic manifestation in the CNS.     

Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington’s disease

Introduction: Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disorder. Despite the severe motor, psychiatric and cognitive symptoms and the great socioeconomic burden caused by the disease, available treatment is mainly symptomatic.

The kynurenine pathway (KP) is the main metabolic route of tryptophan degradation, in the course of which several neuroactive compounds are generated. The imbalance of the neurotoxic and neuroprotectant metabolites can lead to excitotoxicity and overproduction of reactive oxygen species, which both contribute to the progression of HD. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of the KP that has various immune modulatory roles.

Areas covered: Current knowledge of the involvement of KP in HD pathogenesis with a particular focus on IDO1. By reviewing the diverse roles of the enzyme in kynurenine production, immune modulation, and serotonin metabolism, we elucidate the factors that make this enzyme a therapeutic target.

Expert opinion: Due to the complexity of HD and the various effects that IDO1 exerts, targeting this enzyme, while highly profitable, may be a great challenge. Through IDO1 activity, neurodegeneration, inflammatory processes and depressive symptoms, often related to HD, can be modulated. Ongoing trials of IDO1 inhibitors in other areas of medicine offer advantages for initiating approaches toward this enzyme as a therapeutic target.     

Th17 cells: a promising therapeutic target for Parkinson’s disease?

Introduction: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder caused by the progressive loss of neurons in the midbrain and other brain regions. Only symptomatic treatment is currently available. Mounting evidence suggests that T cells are a key contributor to PD pathogenesis and neurodegeneration by a mechanism that requires further elucidation.

Areas covered: We discuss the evidence of imbalanced activation of effector T cell populations in PD and summarize the data of Th17 involvement and Th17-regulated mechanisms in PD pathology. Moreover, possible Th17-related molecular targets as possible neuroprotective immunomodulatory therapeutic targets for PD are examined.

Expert Opinion: Existing data show that Th17 cells, their effector molecules, and signaling pathways are potentially effective therapeutic targets for neuroprotective immunomodulation in PD treatment. However, specificity of action within Th17-mediated signaling pathways for PD requires careful consideration.     

Research and development of anti-Parkinson’s drugs: an analysis from the perspective of technology flows measured by patent citations

Introduction: By 2020, nearly one million people will live with Parkinson’s disease (PD) in the U.S. This disorder has a significant impact on patients’ quality of life and is a burden on families and society. Protracted efforts have been made to treat the disease. Cumulative technological innovations are encapsulated by patents, and patent citations have been used to analyze technology diffusion processes in R&D, which is essential to identifying technology evolution trends and providing a review of PD treatment from the perspective of technology flows.

Areas covered: A patent citation network was utilized to analyze technology flows. Patents related to anti-PD drugs were collected from the U.S. Patent and Trademark Office (U.S. PTO) database. A total of 1,231 patents and 2,995 internal citations granted between 1988 and 2017 were included and analyzed.

Expert opinion: To launch drugs with greater efficiency and safety, approaches such as long-acting sustained release, controlled osmotic release, and other novel drug delivery systems should be emphasized. Multi-target agents could effectively reduce side effects in mono-drug therapy and are worth further exploration. Investors should keep an eye on alpha-synuclein–related therapy, gene therapy, and other experimental therapies that might trigger a historic revolution in the treatment domain.     

Chemical management of levodopa-induced dyskinesia in Parkinson’s disease patients

Introduction: Levodopa-induced dyskinesias (LID) appears in more than 50% of Parkinson’s disease patients after 5 years of treatment and clinicians always have to ensure that there is a balance between the beneficial effect of the treatment and the potential complications.

Areas covered: In this review, the authors discuss the treatment of LID. Treatment can be divided into strategies for preventing their occurrence, modification of dopaminergic therapy, and providing more continuous dopaminergic stimulation as well as the use of nondopaminergic drugs.

Expert opinion: Amantadine is currently considered the most effective drug for the treatment of LID. Several compounds developed to target adenosine, adrenergic, glutamatergic, and serotonergic receptors have shown to significantly decrease dyskinesias in animal models. However, despite promising preclinical results, translation to clinical practice remains challenging and majority of these compounds failed to decrease LID in randomized controlled trials with moderate–to-advanced parkinsonian patients. Despite promising results with nondopaminergic drugs, treatment of dyskinesias is still challenging and largely due to their side effects. Future research should focus on developing treatments that can provide continuous dopaminergic delivery throughout the day in a noninvasive manner. Studies on the impact of the early administration of long-acting formulations of levo-3,4-dihydroxy-phenylalanine on dyskinesias are also necessary.     

Droxidopa for the treatment of neurogenic orthostatic hypotension in neurodegenerative diseases

Introduction: L-threo-3,4-dihydroxyphenylserine (droxidopa), a pro-drug metabolized to norepinephrine in nerve endings and other tissues, has been commercially available in Japan since 1989 for treating orthostatic hypotension symptoms in Parkinson’s disease (PD) patients with a Hoehn & Yahr stage III rating, as well as patients with Multiple System Atrophy (MSA), familial amyloid polyneuropathy, and hemodialysis. Recently, the FDA has approved its use in symptomatic neurogenic orthostatic hypotension (NOH).

Areas covered: The authors review the effects of droxidopa in NOH with a focus on the neurodegenerative diseases PD, MSA, and pure autonomic failure (PAF).

Expert opinion: A few small and short placebo-controlled clinical trials in NOH showed significant reductions in the manometric drop in blood pressure (BP) after posture changes or meals. Larger Phase III studies showed conflicting results, with two out of four trials meeting their primary outcome and thus suggesting a positive yet short-lasting effect of the drug on OH Questionnaire composite score, light-headedness/dizziness score, and standing BP during the first two treatment-weeks. Results appear essentially similar in PD, MSA, and PAF. The FDA granted droxidopa approval in the frame of an ‘accelerated approval program’ provided further studies are conducted to assess its long-term effects on OH symptoms.     

Nanotheranostics,a future remedy of neurological disorders

Introduction: Effective therapy of various neurological disorders is hindered on account of the failure of various therapeutics crossing blood-brain-barrier (BBB). Nanotheranostics has emerged as a cutting-edge unconventional theranostic nanomedicine, capable of realizing accurate diagnosis together with effective and targeted delivery of therapeutics across BBB to the unhealthy regions of the brain for potential clinical success.

Areas covered: We have tried to review the current status of nanotheranostic based approaches followed to manage neurological disorders. The focus has been majorly laid on to explore various theranostic nanoparticles and their application potential towards image-guided neurotherapies. Additionally, the usefulness of exceptional diagnostic, imaging techniques including magnetic resonance imaging and fluorescence imaging are being discussed by highlighting their promising opportunities in the detection, diagnosis, and treatment of the neurological disorders.

Expert opinion: Inimitable diagnostic and therapeutic potential of nanotheranostics have accomplished the aim of personalized therapies by governing the therapeutic efficacy of the system along with facilitating patient pre-selection grounded on non-invasive imaging, thereby predicting the responses of patients to nanomedicine treatments. While these accomplishments are encouraging, they are still the minority and demands for a continuous effort to improve sensitivity and precision in screening/diagnosis along with improving therapeutic efficacy in various neural disorders.     

The P2X7 receptor: a new therapeutic target in Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a neurodegenerative illness with genetic risk as an etiological factor in a subset of cases. In AD with autosomal dominant inheritance, the extracellular β-amyloid (Aβ) aggregates and intracellular neurofibrillary tangles which consist of hyperphosphorylated tau, appear to be involved in the neuronal damage; however, other forms of AD may have a polygenetic causality. Microglial cells orchestrate pathophysiological events responsible for neuronal damage in AD. They surround Aβ aggregates and the stimulation of microglial P2X7 receptors (P2X7Rs) by high local concentrations of ATP which originates from damaged CNS cells, results in degeneration of nearby neurons.

Areas covered: We discuss the pathogenesis of Alzheimer’s disease, the role of P2X7 receptors and their potential as therapeutic targets. We also address the fundamental hurdles in the development of new therapeutic strategies for Alzheimer’s disease.

Expert opinion: There are many difficulties associated with the development of efficient pharmacological strategies for AD; the lack of good animal and cellular models for this illness is a key obstacle. None of the pharmacological strategies developed so far have led to an improvement of the treatment of AD. Hence, the consideration of blood-brain barrier-permeable P2X7R antagonists as possible therapeutic agents in AD is a must.     

Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1?year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90?mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300?mg. For clinical remission, ustekinumab 90?mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300?mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1?year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.     

Tau immunotherapies for Alzheimer’s disease

Introduction: Alzheimer’s dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular β-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of β-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward.

Areas covered: All clinical trials that have targeted β-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as ‘tauons’. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons.

Expert opinion: A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.     

Safety of drugs used for the treatment of Crohn’s disease

Introduction: Medications in treating Crohn’s disease (CD) have evolved over the last two decades, particularly with the use of biologic agents. There are, however, concerns about the safety and adverse events associated with these medications. The authors review the safety profile of immunosuppressive medications used in Crohn’s disease in adult patients.

Areas covered: The authors performed a literature search until October 2018 to examine safety data on thiopurines, methotrexate, anti-TNFα agents, vedolizumab and ustekinumab. The authors focused on ‘trial’ and ‘real-world’ data for the biologic agents. Safety in pregnancy and the elderly are also presented.

Expert opinion: Available data in CD suggest that immunosuppressive medications are relatively safe, although there are concerns about an elevated risk of serious infections, skin cancer and lymphoma particularly with thiopurines and anti-TNFα agents. Data on vedolizumab and ustekinumab suggest these newer biologic agents are well tolerated; however, longer term data in CD are required to identify risks with extended use. Apart from methotrexate, there appear to be no adverse congenital outcomes with exposure of drugs during pregnancy.     

Gender,subclinical organ damage and cardiovascular risk stratification in hypertensive patients

Background: The aims of the study were to assess subclinical organ damage in men and women with hypertension and its subsequent effect on cardiovascular risk, and use of new statistical methods for more precise estimation of cardiovascular risk using vascular cardiovascular risk factors: ankle–brachial index (ABI), intima–media thickness (IMT) and pulse wave velocity (PWV).

Methods: We studied 200 patients: 100 hypertensive and 100 normotensive. The parameters we evaluated included: patient age, ABI, IMT, PWV, serum uric acid and serum C-reactive protein (CRP). In addition, the cardiovascular risk according to the SCORE and Framingham scales was assessed.

Results: In the hypertensive group, there were significant correlations between ABI and the Framingham scale in both sexes. In hypertensive women, there were also significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

In normotensive women, there were significant correlations between ABI and the SCORE scale risk, and between ABI and the Framingham scale risk. In normotensive men, there were significant correlations between PWV and the SCORE scale risk, and between PWV and the Framingham scale risk. Lastly, in the group of normotensive men, there were significant correlations between IMT and the SCORE scale risk, and IMT and the Framingham scale risk.

The possibility of correctly classifying a patient into the high-risk category by a logistic regression model using synchronous ABI, IMT and PWV was high – 74% for the risk according to the SCORE scale (66% in men, 88% in women), and 98% for the Framingham scale.

Conclusions: The addition of recognized subclinical target organ damage tests to the estimation of cardiovascular risk can significantly strengthen the prevention of cardiovascular disease.

Cardiovascular risk estimation follow-up with ABI, PWV and IMT increased the probability of correctly classifying people, especially women, into an at least high-risk category according to the SCORE scale, which has valuable therapeutic implications.     

Alcohol use,regular use,disorder and remission from use disorders in Northern Ireland: a prevalence study

Background: This study presents prevalence estimates and ages of onset for alcohol use, regular use, use disorders and remission from use disorders in Northern Ireland, and the time for transitioning between these stages.

Methods: Data on alcohol use, lifetime history, and remission from alcohol conditions as defined by the DSM-IV were collected using the Composite International Diagnostic Interview.

Results: By the age of 17 years 50% of the age cohort had started taking alcohol. By 19 years of age 67% of the cohort were regular users, and by 20 years of age 45% of the cohort were abusing alcohol. Remission from abuse/dependence was related to the number of years since commencing the use of alcohol, with women being more likely than men to move to remission sooner, and the cohort in which the person had commenced alcohol consumption also influenced the move to remission.

Conclusions: The consumption of alcohol is high within Northern Ireland with some 83% of the population consuming alcohol, and with over 90% of this group taking alcohol on a regular basis. The abuse of alcohol was particularly marked amongst students and males, with dependence showing a higher prevalence amongst those with the lowest level of educational attainment, and where the commencement of alcohol consumption was at an early age. Transitions between stages of lifetime alcohol use, regular use, and use disorders were associated with the early commencement of alcohol use, education, cohort use and being male.     

An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment

Purpose: Oral isotretinoin (13-cis retinoic acid, 13-cis RA) was approved for severe acne treatment by the FDA in 1982. The ocular side effects associated with oral isotretinoin use are mostly dose-dependent. Numerous ocular pathologies affect peripapillary choroidal layer primarily or indirectly.

Objective: Evaluation of the peripapillary choroidal layer in the patients receiving oral isotretinoin therapy may aid in explaining the pathophysiology of ocular side effects.

Methods: In this study, peripapillary choroidal thickness was assessed in the patients receiving oral isotretinoin treatment via optical coherent tomography technique.

Results: Significant difference was found in the superotemporal and temporal areas.

Conclusion: Oral isotretinoin treatment may affect the thickness of the peripapillary choroidal layer.     

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles – development,characterisation, and in vitro assessment of bioactivity for cardiac applications

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP).

Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method.

Results: Spherical MPs showed an average particle size of 2?µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15?days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit⁺ cells.

Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.     

Current state on tryptophan 2,3-dioxygenase inhibitors: a patent review

Introduction: Tryptophan-2, 3-dioxygenase (TDO2) is a tryptophan-degrading enzyme constitutively expressed in the liver and to a lesser extend in the brain. Before its link to cancer immunotherapy was discovered in 2011, the search for TDO2 inhibitors was initially driven by depression therapy. In the recent years, TDO2 has drawn an increasing attention as a promising target in both cancer and neuropsychiatric diseases.

Areas covered: Patent literature regarding Tryptophan-2, 3-dioxygenase inhibitors is reviewed. Compounds are categorized by chemical structure. Representative examples of each category are presented with their inhibitory activity and, when available, structure-activity relationships. Data from patent literature is deepened with relevant peer-reviewed literature.

Expert opinion: Very few selective and potent inhibitors were to this day reported and there are currently no TDO2 inhibitors in clinical trials. Despite the challenges in their discovery, the search for TDO2 inhibitors is a very active area of research, as such molecules may prove to be of great interest in not only cancer immunotherapy drug arsenal, but also in neurodegenerative diseases.     

Optimisation of the microencapsulation of lavender oil by spray drying

Background: Lavender oil consists of around 100 components and is susceptible to volatilisation and degradation reactions.

Aim: Microencapsulate lavender oil by spray drying using a biocompatible polymeric blend of gum acacia and maltodextrin to protect the oil components. Effect of total polymer content, oil loading, gum acacia, and maltodextrin proportions on the size, yield, loading, and encapsulation efficiency of the microparticles was investigated.

Methods: Morphology and oil localisation within microparticles were assessed by confocal laser scanning electron microscope. Structural preservation and compatibility were assessed using Fourier transform infra-red spectroscopy, differential scanning calorimetry, and gas chromatography–mass spectrometry.

Results: Lavender microparticles of size 12.42?±?1.79?µm prepared at 30 w/w% polymer concentration, 16.67 w/w% oil loading, and 25w/w% gum acacia showed maximum oil protection at high loading (12?mg w/w%), and encapsulation efficiency (77.89 w/w%).

Conclusion: Lavender oil was successfully microencapsulated into stable microparticles by spray drying using gum acacia/maltodextrin polymeric blend.     

Current pharmacotherapeutic options for primary dyslipidemia in adults

Introduction: Atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations, remain a leading cause of death and disability worldwide. One of the major risk factors of ASCVD is dyslipidemia and all the available guidelines suggest the importance of strategies for lipid control in a remarkable proportion of the general population.

Areas covered: This review focuses on the therapeutic options available for the management of lipid disorders in adults.

Expert opinion: A large body of evidence supports that statins are still the first-line option for the management of hypercholesterolemia in a large percentage of patients. Statins should be given at the appropriate dose and considering the differences in lipid-lowering potency across the different medications. The main current challenge in the treatment of lipid disorders is the need of improving patient adherence and persistence to lipid-lowering treatments beyond the drug choice and the target lipid component. To achieve this goal, the best strategy would be to treat the patients by using the appropriate drugs given at adequate doses to reach the treatment target. We should also avoid drug interactions, monitor possible untoward side effects and promote adherence to treatment by tailoring treatment strategies to each patient.