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International Journal of Molecular... Mar 2017Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging... (Review)
Review
Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson's disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin-proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol--methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the "wearing-off phenomenon", with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing dopaminergic neurotransmission. Since biochemical changes and therapeutic outcomes are highly dependent upon the genomic profiles of PD patients, personalized treatments should rely on pharmacogenetic procedures to optimize therapeutics.
Topics: Adult; Aged; Aged, 80 and over; Animals; Antiparkinson Agents; Disease Susceptibility; Dopaminergic Neurons; Humans; Middle Aged; Oxidative Stress; Parkinson Disease; Pharmacogenetics; Pharmacogenomic Variants; Risk Factors
PubMed: 28273839
DOI: 10.3390/ijms18030551 -
Journal of Neural Transmission (Vienna,... Jun 2023Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong... (Review)
Review
Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson's disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson's disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Monoamine Oxidase; Catechol O-Methyltransferase; Levodopa; Catechol O-Methyltransferase Inhibitors; Monoamine Oxidase Inhibitors
PubMed: 36964457
DOI: 10.1007/s00702-023-02623-8 -
Circulation Research May 2021Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the... (Review)
Review
Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.
Topics: Aging; Alkylating Agents; Amyloid; Amyloid Neuropathies, Familial; Amyloidosis; Antibodies, Monoclonal; Benzoates; Benzoxazoles; Bridged Bicyclo Compounds, Heterocyclic; Cardiomyopathies; Catechol O-Methyltransferase Inhibitors; Heart Transplantation; Humans; Immunomodulating Agents; Oligonucleotides; Proteasome Inhibitors; Protein Folding; Pyrazoles; RNA, Small Interfering; Stem Cell Transplantation; Sulfonamides; Tolcapone
PubMed: 33983835
DOI: 10.1161/CIRCRESAHA.121.318187 -
European Heart Journal Supplements :... Nov 2022The therapy of transthyretin (TTR)-related cardiac amyloidosis consists, on the one hand, of the prevention and management of complications (supportive therapy) and on...
The therapy of transthyretin (TTR)-related cardiac amyloidosis consists, on the one hand, of the prevention and management of complications (supportive therapy) and on the other of treatments aimed at interrupting or slowing down the production and deposition of fibrils (disease-modifying therapy). This definition includes drugs that act on different phases of amyloidogenesis: (i) silencing of the gene encoding TTR (small interfering RNA: patisiran, vutrisiran; antisense oligonucleotides: inotersen, eplontersen; new CRISPR Cas-9 drug technology for editing DNA); (ii) stabilization of circulating TTR to inhibit its dissociation and subsequent assembly of the resulting monomers in amyloidotic fibrils (tafamidis, acoramidis, and tolcapone); (iii) destruction and re-absorption of already formed amyloid tissue deposits. Drugs related to the latter strategy (antibodies) are still the subject of Phase 1 or 2 studies.
PubMed: 36380794
DOI: 10.1093/eurheartjsupp/suac104 -
Current Neuropharmacology 2022Despite increasing worldwide incidence of Parkinson's disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient...
BACKGROUND
Despite increasing worldwide incidence of Parkinson's disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient treatment, the poor adherence in advanced patients, and varied response. Proper intake of medications regarding food and managing drug-food interactions may optimize Parkinson's disease treatment.
OBJECTIVES
We investigated potential effects that food, beverages, and dietary supplements may have on the pharmacokinetics and pharmacodynamics of drugs used by parkinsonian patients; identified the most probable interactions; and shaped recommendations for the optimal intake of drugs regarding food.
METHODS
We performed a systematic review in adherence to PRISMA guidelines, and included a total of 81 studies in the qualitative synthesis.
RESULTS AND CONCLUSION
We found evidence for levodopa positive interaction with coffee, fiber and vitamin C, as well as for the potential beneficial impact of low-fat and protein redistribution diet. Contrastingly, high-protein diet and ferrous sulfate supplements can negatively affect levodopa pharmacokinetics and effectiveness. For other drugs, the data of food impact are scarce. Based on the available limited evidence, all dopamine agonists (bromocriptine, cabergoline, ropinirole), tolcapone, rasagiline, selegiline in tablets, safinamide, amantadine and pimavanserin can be taken with or without a meal. Opicapone and orally disintegrating selegiline tablets should be administered on an empty stomach. Of monoamine oxidase B inhibitors, safinamide is the least susceptible for interaction with the tyramine-rich food, whereas selegiline and rasagiline may lose selectivity to monoamine oxidase B when administered in supratherapeutic doses. The level of presented evidence is low due to the poor studies design, their insufficient actuality, and missing data.
Topics: Antiparkinson Agents; Dietary Supplements; Humans; Levodopa; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline
PubMed: 34784871
DOI: 10.2174/1570159X19666211116142806 -
Psychopharmacology Apr 2018The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
The prefrontal cortex (PFC) and basal ganglia (BG) have been associated with cognitive stability and cognitive flexibility, respectively. We hypothesized that increasing PFC dopamine tone by administering tolcapone (a catechol-O-methyltransferase (COMT) inhibitor) to human subjects should promote stability; conversely, increasing BG dopamine tone by administering bromocriptine (a D2 receptor agonist) should promote flexibility.
OBJECTIVE
We assessed these hypotheses by administering tolcapone, bromocriptine, and a placebo to healthy subjects who performed a saccadic eye movement task requiring stability and flexibility.
METHODS
We used a randomized, double-blind, within-subject design that was counterbalanced across drug administration sessions. In each session, subjects were cued to prepare for a pro-saccade (look towards a visual stimulus) or anti-saccade (look away) on every trial. On 60% of the trials, subjects were instructed to switch the response already in preparation. We hypothesized that flexibility would be required on switch trials, whereas stability would be required on non-switch trials. The primary measure of performance was efficiency (the percentage correct divided by reaction time for each trial type).
RESULTS
Subjects were significantly less efficient across all trial types under tolcapone, and there were no significant effects of bromocriptine. After grouping subjects based on Val158Met COMT polymorphism, we found that Met/Met and Val/Met subjects (greater PFC dopamine) were less efficient compared to Val/Val subjects.
CONCLUSIONS
Optimal behavior was based on obeying the environmental stimuli, and we found reduced efficiency with greater PFC dopamine tone. We suggest that greater PFC dopamine interfered with the ability to flexibly follow the environment.
Topics: Adult; Attention; Bromocriptine; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Cognition; Dopamine Agonists; Double-Blind Method; Female; Humans; Male; Prefrontal Cortex; Reaction Time; Saccades; Tolcapone; Young Adult
PubMed: 29427081
DOI: 10.1007/s00213-018-4845-4