catechol-O-methyltransferase Inhibitor Research Articles

In vitro effects of opicapone on activity of human UDP-glucuronosyltransferases isoforms

Catechol-O-methyltransferase (COMT) inhibitors are widely used as an add-on treatment to levodopa in adults with Parkinson’s disease. It has been evidenced that the second-generation COMT inhibitors entacapone and tolcapone are potent inhibitors on human UDP-glucosyltransferases (UGTs), while the effect of the third-generation COMT inhibitor opicapone on human UGTs activities is unclear. The purpose of this study is to systemically investigate the effects of opicapone on human UGTs activities, and also to assess the potential risk of drug-drug interactions (DDIs) associated with opicapone. Our results indicated that opicapone is a broad-spectrum inhibitor of UGTs. Particularly, opicapone exhibited potent inhibition against UGT1A1, 1A7, 1A8, 1A9, and 1A10, with a range of inhibition constant Ki values of 1.31–10.58 µM. Furthermore, the DDI risk was quantitatively predicted by using the in vitro-in vivo extrapolation (IVIVE). The prediction suggested that co-administration of opicapone at 25 mg/day or 50 mg/day with drugs primarily cleared by hepatic UGT1A9 or intestinal UGT1A1, 1A7, 1A8, 1A9, or 1A10 might result in potential DDI via inhibition of intestinal or hepatic UGTs.

Differential analyte derivatization enables unbiased MALDI-TOF-based high-throughput screening: A proof-of-concept study for the discovery of catechol-o-methyltransferase inhibitors.

Recent advances in label-free high-throughput screening via matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) offer unprecedented opportunities for the identification of novel chemical starting points in target-based drug discovery. A clear advantage of the technology is the possibility for label-free, direct quantification of analytes with high precision and robustness. Here we have expanded the range of analytes and biology that can be addressed via MALDI-TOF HTS, by developing a method based on post-reaction pyrylium-based derivatization to detect 3-methoxytyramine, the physiological enzyme product of the catechol-O-methyltransferase (COMT) enzyme. The introduction of pyrylium-type reagents as universal derivatization strategy under aqueous conditions for molecules containing primary amines represents a valuable addition to the toolbox of MALDI-TOF assay development. Characterization of COMT's enzymatic activity and inhibition by reference inhibitors, and comparison of the results obtained in our assay with data from previous mechanistic studies validated the performance of this new method. To address the problem of isobaric interference, a source of false results in MALDI-TOF assays measuring low molecular weight analytes, we devised a differential derivatization workflow which can potentially replace other counter- or orthogonal assays in future screening campaigns. Finally, we report on the first label-free HTS campaign for the identification of COMT inhibitors performed in miniaturized 1536-well microtiter plate format via MALDI-TOF MS analysis.

Opicapone as an Add-on to Levodopa in Patients with Parkinson's Disease Without Motor Fluctuations: Rationale and Design of the PhaseIII, Double-Blind, Randomised, Placebo-Controlled EPSILON Trial.

IntroductionLevodopa remains the cornerstone treatment for Parkinson’s disease (PD) but its use is associated with the development of ‘wearing-off’ fluctuations and other motor and non-motor complications over time. Adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/dopa decarboxylase (DDC) inhibitor therapy reduces fluctuations in the profile of plasma levodopa levels following oral dosing, and can therefore be beneficial for the management of motor complications. The objective of the EPSILON study is to investigate the efficacy of opicapone (OPC; a third-generation, once-daily COMT inhibitor) in enhancing the clinical benefit of levodopa in patients in earlier stages of PD, without end-of-dose motor fluctuations.MethodsEPSILON is a phase III, double-blind, randomised, placebo-controlled and parallel-group study, designed to evaluate the efficacy and safety of OPC as add-on to levodopa/DDC inhibitor therapy in patients with early PD who do not exhibit signs of motor complications. Eligible patients will be randomised (1:1) to receive OPC 50 mg or placebo, in addition to their existing levodopa/DDC inhibitor therapy, over a 24-week, double-blind treatment period, after which they will have the option of entering an additional 1-year, open-label extension period, during which all patients will receive OPC 50 mg.Planned OutcomesThe primary efficacy endpoints are change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score from baseline to the end of the double-blind period (double-blind phase) and change in MDS-UPDRS Part IV total score from open-label baseline to the end of the open-label period (open-label phase). Secondary outcomes during the double-blind phase will include other measures of PD symptoms, including quality of life, non-motor symptoms, and development of motor fluctuations. Safety assessments will include evaluation of treatment-emergent adverse events, laboratory safety parameters, suicidality and impulse control disorders.Trial RegistrationEuropean Union Drug Regulating Authorities Clinical Trials Database (number 2020-005011-52).

Prediction of COMT Inhibitors Using Machine Learning and Molecular Dynamics Methods.

Catechol O-methyltransferase (COMT) plays a vital role in deactivating neurotransmitters like dopamine, norepinephrine, etc., by methylating those compounds. However, the deactivation of an excess amount of neurotransmitters leads to serious mental ailments such as Parkinson's disease. Molecules that bind inside the enzyme's active site inhibit this methylation mechanism by methylating themselves, termed COMT inhibitors. Our study is focused on designing these inhibitors by various machine learning methods. First, we have developed a classification model with experimentally available COMT inhibitors, which helped us generate a new data set of small inhibitor-like molecules. Then, to predict the activity of the new molecules, we have applied regression techniques such as Random Forest, AdaBoost, gradient boosting, and support vector machines. Each of the regression models yielded an R2 value > 70% for both training and test data sets. Finally, to validate our models, 200 ns long molecular dynamics (MD) simulations of the two known inhibitors with known IC50 values and the resultant inhibitors were performed inside the binding pockets to check their stability within. The free energy barrier of the methyl transfer from S-adenosyl-l-methionine (SAM) to each inhibitor was determined by combining steered molecular dynamics (SMD) and umbrella sampling using the quantum mechanics/molecular mechanics (QM/MM) method.

Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

1-Hydroxy-2(1H)-pyridinone-Based Chelators with Potential Catechol O-Methyl Transferase Inhibition and Neurorescue Dual Action against Parkinson's Disease.

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1H)-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson’s disease: they are designed to be inhibitors of catechol O-methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their pKa and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood–brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation.

Catechol-O-methyltransferase activity does not influence emotional processing in men.

Background:Catechol-O-methyltransferase (COMT) regulates cortical dopaminergic transmission and prefrontal-dependent cognitive function. However, its role in other cognitive processes, including emotional processing, is relatively unexplored. We therefore investigated the separate and interactive influences of COMT inhibition and Val158Met (rs4680) genotype on performance on an emotional test battery.Methods:We recruited 74 healthy men homozygous for the functional COMT Val158Met polymorphism. Volunteers were administered either a single 200 mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a double-blind, randomised manner. Emotional processing was assessed using the emotional test battery, and mood was rated using visual analogue scales and the Profile of Mood States (POMS) questionnaire across the test day.Results:There were no main or interactive effects of Val158Met genotype or tolcapone on any of the emotional processing measures or mood ratings.Conclusions:Our findings suggest that, at least in healthy adult men, COMT has little or no effect on emotional processing or mood. These findings contrast with several neuroimaging studies that suggest that COMT modulates neural activity during emotional processing. Thus, further studies are required to understand how COMT impacts on the relationship between behavioural output and neural activity during emotional processing. Nevertheless, our data suggest that novel COMT inhibitors under development for treating cognitive dysfunction are unlikely to have acute off target effects on emotional behaviours.

Efficacy and Safety of Opicapone for Motor Fluctuations as an Adjuvant to Levodopa Therapy in Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis.

Background:Long-term levodopa administration for treating Parkinson’s disease (PD) may shorten the duration of effect and cause dyskinesias, inducing the need for catechol-O-methyltransferase (COMT) inhibitors as adjuvant therapy.Objective:We provide pooled scientific evidence highlighting the efficacy and safety of opicapone, a newly approved COMT inhibitor, as an adjuvant to levodopa.Methods:We searched Ovid Medline, Embase, and Cochrane databases for relevant reports. Efficacy and safety were evaluated as off-time reduction and risk ratio (RR) of dyskinesia, respectively. Data were independently extracted using predefined criteria. Selected placebo-controlled trials were divided into double-blind and open-label periods. Using a random-effects model, the mean difference (MD) of the off-time reduction (efficacy), RR for the occurrence of dyskinesia, and on-time without/with troublesome dyskinesia (TD; safety assessment) were compared between opicapone and placebo groups.Results:Five studies from three randomized controlled trials were included, and a meta-analysis was performed with 407 patients receiving opicapone 50 mg and 402 patients receiving placebo. Compared with the placebo, opicapone (50 mg) reduced off-time by 49.91 min during the double-blind period (95% confidence intervals [CIs] = –71.39, –28.43; I2 = 0%). The RR of dyskinesia was 3.43 times greater in the opicapone 50 mg group than in the placebo group (95% CI = 2.14, 5.51; I = 0%). Compared with the placebo, opicapone increased the on-time without TD by 44.62 min (95% CI = 22.60, 66.64; I2 = 0%); the on-time increase with TD did not differ between treatments.Conclusion:Opicapone can play a positive role as an adjuvant to levodopa in patients with PD by reducing off-time and prolonging on-time without PD.

Integrated Mass Spectrometry Reveals Celastrol As a Novel Catechol-O-methyltransferase Inhibitor.

Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear. Here, we used multiple mass-spectrometry-based approaches to identify catechol-O-methyltransferase (COMT) as a major binding target of celastrol and characterized their interaction comprehensively. Celastrol was found to inhibit the enzymatic activity of COMT and increased the dopamine level in neuroendocrine chromaffin cells significantly. Our study not only revealed a novel binding target of celastrol but also provided a new scaffold and cysteine hot spot for developing new generation COMT inhibitors in combating neurological disorders.

Treatment practice of patients with Parkinson's disease in Saxony : A secondary data-based analysis of utilization in the observation period 2011-2019

The consequences of demographic change are already noticeable in Saxony, the federal state with the highest average age in Germany and predominantly rural areas. In order to improve medical care for patients with Parkinson's disease (PwP), astatus quo analysis of current care practice is required. To what extent does the utilization of medical services by PwP differ a)between urban and rural areas in Saxony and b)between PwP with and without neurologist contact in the observation period from 2011 to 2019? The cohort study was based on extensive routine data for Saxony from the health insurance company AOK PLUS from 2010 to 2019. Acohort of 15,744 PwP (n = 67,448patient-years) was compared to amatched cohort (n = 674,480patient-years; criteria: year of birth, gender, year of insurance, place of residence: urban/rural) without an ICD-10 coding of amovement disorder. Overall, there was asteady increase in the number of PwP in the dynamic cohort from 2011 (n = 6829) to 2019 (n = 8254). Urban-rural differences included asmaller proportion of patients being seen by aneurologist in rural areas. The PwP had a3.5 to 4‑fold higher risk of dying compared to those in the comparison cohort. Changes in drug therapy for Parkinson's disease (i.e., increases in COMT and MAO inhibitors) and in remedy delivery (i.e., increases in occupational therapy and speech therapy) over the observation period were primarily seen in PwP who were seen by aneurologist. The study identified increased morbidity and mortality in PwP who are suitable targets for innovative care concepts. The increasing number of patients and the described differences document the need for this. At the same time, changes in prescription practice show that innovative forms of treatment are being used by neurologists in outpatient care.

COMT Inhibitors in the Management of Parkinson's Disease.

Levodopa treatment remains the gold standard for Parkinson's disease, but shortcomings related to the pharmacological profile, notably, oral administration and the consequent occurrence of motor complications, have led to the development of several add-on levodopa treatments or to research to improve the method of delivery. Motor fluctuations, and to a lesser extent non-motor fluctuations, concern half of the patients with Parkinson's disease after 5 years of disease and patients identified them as one of their most bothersome symptoms. Catechol-O-methyl transferase inhibitors (COMT-Is) are one of the recommended first-line levodopa add-on therapies for the amelioration of end-of dose motor fluctuations in patient with advanced Parkinson's disease. Currently, two peripheral COMT-Is are considered as first-line choices - entacapone (ENT), which was approved by the US Food and Drug Administration in 1999 and the European Committee in 1998; and opicapone (OPC), which was approved by the European Committee in 2016. A second-line COMT-I that requires regular hepatic monitoring, tolcapone (TOL), was approved by the Food and Drug Administration in 1998 and the European Committee in 1997. Of note, OPC also received Food and Drug Administration approval in 2021, but it is still only marketed in a few countries, including Germany, UK, Spain, Portugal, Italy, Japan, and USA, while ENT and TOL have a wider market. Our narrative review summarizes the pharmacokinetic/pharmacodynamic properties, clinical efficacy in terms of motor fluctuations, motor/non-motor symptoms, quality of life, and safety data of these three COMT-Is, as evidenced by randomized clinical trials, as well as by real-life observational studies. Overall, a phase III non-inferiority trial showed a similar effect between ENT and OPC on off-time (-60.8 min/day and -40.3 min/day, vs placebo, respectively), with a possible additional off-time reduction of 39 min/day, obtained when there is a switch from ENT to OPC. Concomitantly, TOL can reduce off-time by an average of 98 min/day. A significant though discrete concomitant reduction on the Unified Parkinson's Disease Rating Scale motor section (2-3 points) is obtained with all three drugs vs placebo. Data on quality of life are fewer and more heterogeneous, with positive results obtained especially in open-label studies. Effects on non-motor symptoms were investigated as secondary outcome only in a few studies, frequently by means of non-specific scales and a benefit was observed in open-label studies. Dopaminergic adverse effects were the most frequent, dyskinesia being the most common for the three drugs eventually requiring levodopa dose reductions. No urine discoloration and a very low incidence of diarrhea were found with OPC compared with ENT and TOL. Regular hepatic monitoring is needed only for TOL. A combination of COMT-Is with new formulations of levodopa, including the subcutaneous, intrajejunal, or new extended-release formulation, merits further exploration to improve the management of both mild and severe motor fluctuations.

Opicapone: Once-Daily COMT Inhibitor for the Treatment of Wearing Off in Parkinson's Disease.

Objective To provide a review of opicapone as a treatment for end-of-dose wearing off associated with long-term levodopa therapy in patients with Parkinson's disease (PD). Data Sources PubMed, Web of Science, and Google Scholar were searched for relevant literature using the following terms: management, treatment, opicapone, BIA 9-1067, entacapone, and tolcapone. Current guidelines and the manufacturer's package inserts were also reviewed. Study Selection/Data Extraction Recent literature and published studies of opicapone in the management of wearing off. Data Synthesis Long-term use of levodopa is associated with known complications of motor fluctuations and dyskinesia. The addition of a drug with fewer daily administrations may reduce the complexity of the current medication regimen, improve adherence, and reduce the risk of adverse events in older people with PD. The Food and Drug Administration (FDA) approved a new catechol-O-methyltransferase (COMT) inhibitor opicapone in combination with levodopa/carbidopa to treat wearing off in PD patients on April 24, 2020. Conclusion Opicapone offers patients with PD a once-daily option with a favorable side effect profile, increased exposure to levodopa, and reduction in "off" time. It may be an appropriate second line option in patients who are intolerant or do not respond with entacapone.

Relevance of COMT inhibitors in the treatment of motor fluctuations

Catechol O‑methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of aworking group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.

Anti-Parkinson Drug from Chemical Medicines and Herbal Medicines: A Review

Parkinson's disease (PD) is a disease of the central nervous system. It is a progressive disorder, meaning it gets worse over time. PD usually characterized by tremor, rigidity, akinesia and postural autonomic instability. In addition, it may also cause a series of non-motor symptoms (NMSs). This disease affects a small area of cells in the middle of the brain. This area is called the substantia nigra (SNc). The cells slowly lose their ability to produce a chemical called dopamine. The disease usually appears in the age over 60 years. Nowadays, a lot of anti-Parkinson drugs have been found either from that of chemicals or herbs. In this essay anti-Parkinson drugs from chemical medicine and herbal medicines especially from china will be discussed. Anti-Parkinson's drugs are derived from chemical medicines include levodopa (l-dopa), dopamine agonists, MAO-B inhibitors, catechol O-methyltransferase (COMT) inhibitors, anticholinergics and amantadine. Meanwhile, anti-Parkinson drugs derived from herbal medicine include Scutellaria baicalensis Georgi, Polygonum cuspidatum Sieb. et Zucc., green tea (Camellia sinensis L.), Panax ginseng C. A. Mey., Cistanche deserticola Y. C. Ma, Panax Notoginseng Wall. var notoginseng (Burkill.) F.H. Chen, Gastrodia elata Blume and Polygala tenuifoliaWilld.. These drugs have the same effects to help ease symptoms of Parkinson’s and can increase the amount of dopamine in substantia nigra pars compacta (SNc). However, some chemical drugs have more side effects although herbal medicines are less clear, more tests need to be planned.

Parkinson’s Disease: A Neurodegenerative Disease

Parkinson’s disease is characterized by tremor, stiffness, rigid muscles, bradykinesia, slowness of movement, instability leading to falls, memory and talking difficulties, fatigue, writing modifications (micrography) and dementia. In addition, depression, urinary (bladder) problems, constipation, decreased ability to smell and sleep disruption are among the symptoms associated to the PD. As Parkinson’s cannot be eradicate, treatments are oriented toward a slow decline and deterioration and therefore, only palliative care predominates. Mutations of 6 genes (SNCA, LRRK2, PRKN, DJ1, PINK1 and ATP13A2), are the cause of familial Parkinsonism. They are playing a role in the metabolism of α-synucleine, in mitochondrial control, oxidative stress, lysosomal functions, transport and recycling of proteins and immunologic activities. Five stages with increased gravity have been identified. From stage 1 to 3, symptoms may be treated with pharmacological drugs. At stages 4 and 5, the patient needs assistive help and an ambulatory walker device. L-dopa is transformed in dopamine in the brain. Treatments for speech disorders increase the disability of these symptoms. Dopamine agonists, MAO-B and COMT inhibitors contribute to help break down dopamine, an anticholinergic drug aiming to reduce tremors and muscle rigidity. Death is occurring within 7 to 15 years.

Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson's Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies.

A pharmacophore-based virtual screening methodology was used to discover new catechol-O-methyltransferase (COMT) inhibitors with interest in Parkinson’s disease therapy. To do so, pharmacophore models were constructed using the structure of known inhibitors and then they were used in a screening in the ZINCPharmer database to discover hit molecules with the desired structural moieties and drug-likeness properties. Following this, the 50 best ranked molecules were submitted to molecular docking to better understand their atomic interactions and binding poses with the COMT (PDB#6I3C) active site. Additionally, the hits’ ADMET properties were also studied to improve the obtained results and to select the most promising compounds to advance for in-vitro studies. Then, the 10 compounds selected were purchased and studied regarding their in-vitro inhibitory potency on human recombinant membrane-bound COMT (MBCOMT), as well as their cytotoxicity in rat dopaminergic cells (N27) and human dermal fibroblasts (NHDF). Of these, the compound ZIN27985035 displayed the best results: For MBCOMT inhibition an IC50 of 17.6 nM was determined, and low cytotoxicity was observed in both cell lines (61.26 and 40.32 μM, respectively). Therefore, the promising results obtained, combined with the structure similarity with commercial COMT inhibitors, can allow for the future development of a potential new Parkinson’s disease drug candidate with improved properties.

Parkinson’s Disease Treatment and the Role of Genetic Polymorphisms in the Efficacy and Adverse Effects

Parkinson’s disease (PD) is a relentlessly growing neurodegenerative disorder clinically manifested by rigidity, tremors, and dyskinesia ascribed to loss of nigrostriatal dopaminergic innervation. Conventional therapies focus on alleviating disease symptoms as far as possible, yet lack the ability to halt the progression of the neurodegenerative process. A major historic turning point in PD therapy came through the inception of levodopa (l-dopa), however, its prolonged use is associated with complications and a decline in response. Some alternate modalities to treat PD are also available as dopamine agonists (DA), catechol-o-methyl transferase inhibitors (COMTIs), and non-dopaminergic drugs that could be used as a supportive therapy with l-dopa or alone. Nonetheless, these drugs are less effective than l-dopa in regulating motor symptoms. On the other hand, substantial inter-individual variations are observed in response to l-dopa. Although many factors can influence an individual’s response to therapy, a patient’s genetic makeup could be a starting point in creating precision medicine with greater safety and efficacy. Precision medicine that incorporates pharmacogenomics data can optimize patients’ response to PD drugs and facilitate treatment. In this review, we aim to present PD pathogenesis, challenges of current therapy, and pharmacogenetics aspects of levodopa.

Orthostatic Hypotension and Antiparkinsonian Drugs: A Systematic Review and Meta-analysis.

BackgroundOrthostatic hypotension (OH) is multifactorial in Parkinson’s disease (PD). Antiparkinsonian medication can contribute to OH, leading to increased risk of falls, weakness and fatigue.MethodsWe conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) of antiparkinsonian drugs associated with OH as an adverse effect, compared to placebo. We searched EMBASE, MEDLINE and Web of Science databases until November 2020. Analysis used fixed-effects models and the GRADE tool to rate quality of evidence. Meta-analysis was performed if 3 or more studies of a drug group were available.ResultsTwenty-one RCTs including 3783 patients were included comparing 6 PD drug groups to placebo (MAO-B inhibitors, dopamine agonists, levodopa, COMT inhibitors, levodopa and adenosine receptor antagonists). OH was recorded as an adverse event or measurement of vital signs, without further specification on how this was defined or operationalised. Meta-analysis was performed for MAO-B inhibitors and dopamine agonists, as there were 3 or more studies for these drug groups. In this analysis, compared with placebo, neither MAO-B inhibitors or dopamine agonists were associated with increased risk of OH, (OR 2.28 [95% CI:0.81–6.46]), (OR 1.39 [95% CI:0.97–1.98]).ConclusionsMost studies did not specifically report OH, or reporting of OH was limited, including how and when it was measured. Furthermore, studies specifically reporting OH included participants that were younger than typical PD populations without multimorbidity. Future trials should address this, for example,, by including individuals over the age of 75, to improve estimations of how antiparkinsonian medications affect risk of OH.

Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy

Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.

FEATURES OF DRUG TREATMENT FOR PARKINSON'S DISEASE

The article provides information about a study that studies the features of drug treatment of patients with Parkinson's disease among the population of the capital of Azerbaijan Republic- Baku. The study is based on data from 703 patients with Parkinson's disease diagnosed in outpatient clinics in Baku by the beginning of 2019. In the treatment of Parkinson's disease, all modern treatment options were used (Dopamine receptor agonists, Levodopa drugs, Antixolinergik drugs, COMT inhibitors, NMDA receptor antagonists, etc.). According to the study results, the standard approach is used in the treatment of Parkinson's disease in Baku, but in most cases, polytherapy is preferred (59.2±1.9 per 100 patients). In terms of frequency of use in treating Parkinson's disease, the first two places are occupied by dopamine precursors (63.2±1.8 per 100 patients) and dopadecarboxylase inhibitors (59.2±1.9 per 100 patients), respectively. Among the drugs used for the treatment of Parkinson's disease, Nakom (28.2±1.7 per 100 patients) and its combination with Cyclodol (10.4±1.2 per 100 patients) and Akineton (10.1±1.1 per 100 patients) prevail. Monotherapy is carried out only with Pronoran and Cyclodol (17.1±1.4 and 10.7±1.2 per 100 patients, respectively).