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1.
Neurol Sci ; 42(10): 4085-4094, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34346015

RESUMO

BACKGROUND AND PURPOSE: Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson's disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. METHODS: A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. RESULTS: Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02-1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04-2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. CONCLUSIONS: Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.


Assuntos
Discinesias , Doença de Parkinson , Catecol O-Metiltransferase/genética , Humanos , Levodopa/efeitos adversos , Monoaminoxidase/genética , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética
3.
J Youth Adolesc ; 50(10): 2079-2095, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34259955

RESUMO

Ample evidence suggested that parental responsiveness, demandingness, and autonomy granting protect adolescents from depressive symptoms. However, what is less well understood is how parenting practices reduce the risk of depressive symptoms. This study tested the protective effects of parenting practices and inhibitory control on depressive symptoms, along with the mediating role of inhibitory control and the moderating role of the COMT gene in linking parenting practices to depressive symptoms. The study utilized cross-sectional data from a community sample of Chinese Han adolescents (N = 943, Mage = 15.25 years, SD = 0.70 years; 51.9% girls). Results showed that parental responsiveness and autonomy granting promoted higher inhibitory control, which in turn was associated with lower depressive symptoms. Further, the mediation effects were moderated by the COMT gene. For adolescents with ValVal homozygotes, both responsiveness and autonomy granting were related to higher levels of inhibitory control, which reduced risk for depressive symptoms, but the mediation effects were not observed among Met allele carriers. The mediating role of inhibitory control did not hold in the parental demandingness model. Findings support the cognitive theory that inhibitory control is a proximal factor linking parenting practices to depressive symptoms exclusively in ValVal homozygotes. These results also suggested that differentiating different dimensions of parenting practices may help to further clarify the processes by which parenting practices eventuate depressive symptoms.


Assuntos
Catecol O-Metiltransferase , Poder Familiar , Adolescente , Catecol O-Metiltransferase/genética , Criança , Educação Infantil , Estudos Transversais , Depressão/genética , Feminino , Humanos , Masculino
4.
Genes (Basel) ; 12(6)2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199792

RESUMO

It has been previously shown that the serotonin and dopamine neurotransmitter systems might influence the predisposition to suicidal behavior. This study aims to estimate the contribution of 11 polymorphisms in the genes SLC6A4 (5HTT), HTR1A, HTR2A, HTR1B, SLC6A3 (DAT1), DRD4, DRD2, COMT, and BDNF to suicidal behavior and severity of symptoms of depression and anxiety in the Russian population. The study was performed on 100 patients with repeated suicide attempts and 154 controls. We first found an association between SLC6A3 (DAT1) 40 bp VNTR locus and suicidal behavior. This association was significant; when using the codominant (p = 0.006), dominant (p = 0.001), overdominant (p = 0.004), and log-additive (p = 0.004) models, LL genotype played a protective role (OR = 0.48, 0.29-0.82, p = 0.005). Difference in the distribution of COMT rs4680 genotypes was significant in the codominant (p = 0.04), dominant (p = 0.013), and log-additive (p = 0.02) models, and AA genotype might protect against suicide (OR = 0.49, 0.26-0.91, p = 0.025). SLC6A4 5-HTTLPR + rs25531 locus was significant in the recessive model (p = 0.024), and also affected the severity of symptoms of depression (p = 0.044) and personal anxiety (p = 0.029). Our results suggest that allelic variants of SLC6A3, COMT, and SLC6A4 genes might be considered as risk factors for suicidal attempts.


Assuntos
Depressão/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Tentativa de Suicídio/estatística & dados numéricos , Adulto , Catecol O-Metiltransferase/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
5.
Transl Psychiatry ; 11(1): 389, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253715

RESUMO

Post-traumatic stress disorder (PTSD) leads to impairments in both cognitive and affective functioning. Animal work suggests that chronic stress reduces dopamine tone, and both animal and human studies argue that changes in dopamine tone influence working memory, a core executive function. These findings give rise to the hypothesis that increasing cortical dopamine tone in individuals with greater PTSD symptomatology should improve working memory performance. In this pharmacological functional magnetic resonance imaging (fMRI) study, 30 US military veterans exhibiting a range of PTSD severity completed an emotional working memory task. Each subject received both placebo and the catechol-O-methyl transferase inhibitor tolcapone, which increases cortical dopamine tone, in randomized, double-blind, counterbalanced fashion. Mnemonic discriminability (calculated with d', an index of the detectability of working memory signals) and response bias were evaluated in the context of task-related brain activations. Subjects with more severe PTSD showed both greater tolcapone-mediated improvements in d' and larger tolcapone-mediated reductions in liberally-biased responding for fearful stimuli. FMRI revealed that tolcapone augmented activity within bilateral frontoparietal control regions during the decision phase of the task. Specifically, tolcapone increased cortical responses to fearful relative to neutral stimuli in higher severity PTSD subjects, and reduced cortical responses to fearful stimuli for lower severity PTSD subjects. Moreover, tolcapone modulated prefrontal connectivity with areas overlapping the default mode network. These findings suggest that enhancing cortical dopamine tone may represent an approach to remediating cognitive and affective dysfunction in individuals with more severe PTSD symptoms.


Assuntos
Dopamina , Transtornos de Estresse Pós-Traumáticos , Encéfalo/metabolismo , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase , Humanos , Imageamento por Ressonância Magnética , Memória de Curto Prazo , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico
6.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281267

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease. METHODS: We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review. RESULTS: We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings. CONCLUSIONS: This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Antiparkinsonianos/efeitos adversos , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/metabolismo , Inibidores de Catecol O-Metiltransferase/farmacologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Genótipo , Humanos , Levodopa/efeitos adversos , Levodopa/metabolismo , Levodopa/farmacologia , Inibidores da Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/metabolismo , Farmacogenética/métodos , Farmacogenética/tendências , Variantes Farmacogenômicos , Pesquisa Médica Translacional
8.
BMJ Open ; 11(6): e045969, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162645

RESUMO

INTRODUCTION: Migraine is the most common neurological disorder and one of the major causes of years lived with disability. Its treatment (especially of chronic forms) is often challenging and accompanied with adverse effects. Although new therapeutic approaches have recently emerged (eg, calcitonin gene-related peptide antibodies), these are linked to strict prescribing guidelines and therefore limited to only a minority of patients. Recently, randomised controlled trials have demonstrated that open-label placebo treatments can lead to significant and clinically relevant improvements of chronic pain conditions. METHODS AND ANALYSIS: This multicentre, randomised controlled clinical trial following a parallel group between-subject design aims to systematically investigate the impact of a 12-week open-label placebo treatment on moderate to severe headache days (primary outcome) in patients with episodic and chronic migraine in addition to treatment as usual. Secondary outcomes comprise the number of migraine days, pain intensity, intake of acute medication, quality of life, disability, global impression of change, tolerability and a responder rate. To systematically address potential predictors of placebo responses in patients with migraine, this study assesses potential psychometric predictors, salivary cortisol and alpha-amylase awakening responses, catechol-o-methyltransferase Val158Met polymorphisms, as well as functional and structural brain connectivity (ie, resting state functional MRI, diffusion tensor imaging). The data analysis will be performed on basis of the general linear model considering repeated measures (mixed model). ETHICS AND DISSEMINATION: This protocol and all corresponding documents were approved with regard to their content and compliance with ethical regulations by the Ethics Committee of the Medical Faculty of the University Duisburg-Essen, Germany and the Ethics Committee of the Landesärztekammer Hessen. The results from this study will be actively disseminated through manuscript publications and conference presentations. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (DRKS00021259).


Assuntos
Transtornos de Enxaqueca , Qualidade de Vida , Catecol O-Metiltransferase , Imagem de Tensor de Difusão , Método Duplo-Cego , Alemanha , Cefaleia , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
9.
Psychiatry Res ; 302: 114011, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051678

RESUMO

There is a need to identify the subset of individuals with borderline personality disorder (BPD) symptoms at greatest risk for transitioning from suicidal ideation to a suicide attempt. Contemporary models of suicide risk propose that the capability for suicide is necessary for moving from suicidal ideation to a suicide attempt. Few studies have examined dispositional capability factors for suicide, especially among individuals with BPD symptoms. One candidate may be the catechol-o-methyltransferase (COMT) Val158Met polymorphism given its influence on pain sensitivity and fear. This study examined the interactive relation of BPD symptoms and the COMT Val158Met polymorphism to suicidal ideation and suicide attempts. Fifty-nine treatment-seeking patients were recruited. Participants were administered a series of clinical interviews to evaluate BPD symptoms and suicidal thoughts and behaviors. Saliva samples were collected for genotyping. The relation between BPD symptoms and suicidal ideation was not influenced by the Val158Met polymorphism. However, among Val/Val carriers, the probability of a lifetime suicide attempt increased as BPD symptom severity increased. Findings provide preliminary support for the Val/Val variant as a dispositional factor that may increase risk for suicide attempts in BPD; however, results must be interpreted with caution until replication of findings occurs in larger samples.


Assuntos
Transtorno da Personalidade Borderline , Tentativa de Suicídio , Transtorno da Personalidade Borderline/genética , Catecol O-Metiltransferase/genética , Humanos , Polimorfismo Genético , Ideação Suicida
10.
J Enzyme Inhib Med Chem ; 36(1): 1079-1087, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34030574

RESUMO

Inhibitors of COMT are clinically used for the treatment of Parkinson's disease. Here, we report the first natural pentacyclic triterpenoid-type COMT inhibitors and their structure-activity relationships and inhibition mechanism. The most potent compounds were found to be oleanic acid, betulinic acid and celastrol with IC50 values of 3.89-5.07 µM, that acted as mixed (uncompetitive plus non-competitive) inhibitors of COMT, representing a new skeleton of COMT inhibitor. Molecular docking suggested that they can specifically recognise and bind with the unique hydrophobic residues surrounding the catechol pocket. Furthermore, oleanic acid and betulinic acid proved to be less disruptive of mitochondrial membrane potential (MMP) compared to tolcapone, thus reducing the risk of liver toxicity. These findings could be used to produce an ideal lead compound and to guide synthetic efforts in generating related derivatives for further preclinical testing.


Assuntos
Produtos Biológicos/farmacologia , Catecol O-Metiltransferase/metabolismo , Inibidores Enzimáticos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Cinética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Conformação Molecular , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
11.
Orv Hetil ; 162(21): 839-847, 2021 05 23.
Artigo em Húngaro | MEDLINE | ID: mdl-34023813

RESUMO

Összefoglaló. Bevezetés: Az elorehaladott Parkinson-kór bizonyos fázisában a motoros komplikációk már nem befolyásolhatók hatékonyan a hagyományos orális, illetve transdermalis gyógyszerekkel. Ilyenkor meg kell fontolni, komplex felmérési és döntési folyamatot követoen, az invazív eszközös terápiák bevezetését. Célkituzés: A döntéshozatal és a fontosabb klinikai paraméterek elemzése levodopa-karbidopa intestinalis géllel kezelt betegeinknél az elfogadás idotartamának függvényében. Módszer: Retrospektíven vizsgáltuk azon betegeink adatait, akiknél a marosvásárhelyi 2. Sz. Ideggyógyászati Klinikán 2011. június 1. és 2019. december 31. között vezettük be a levodopa-karbidopa intestinalis géllel történo terápiát. A kezelés elfogadásához szükséges idointervallum szerint két csoportot alkottunk: egy hónap vagy annál rövidebb, illetve egy hónapnál több ido az elso, célzott kivizsgálás és a tesztelés megkezdése között. Eredmények: A vizsgált idoszakban 163 betegnél teszteltük orrszondán a kezelés hatékonyságát, közülük 127 esetben történt meg a terápia véglegesítése. A döntéshozatal 56 betegnél egy hónap vagy annál rövidebb idot, míg 71 betegnél egy hónapnál több idot igényelt. A dyskinesisek átlagos idotartamának szempontjából szignifikáns különbséget találtunk a két csoport között (3,1 ± 0,7 vs. 2,8 ± 0,8 óra, p = 0,02). Az eszközös terápia bevezetése elotti levodopa-átlagadag 821,5 ± 246,6 mg volt, naponta átlagosan 5-ször adagolva. A kiegészíto terápiák alkalmazási arányai: a dopaminagonisták 80,3%-ban, a katechol-O-metiltranszferáz-gátlók 62,2%-ban, illetve a monoaminoxidáz-B-gátlók 68,5%-ban. Az átlagos off idotartam 4,7 ± 1,1 óra volt, és 85 betegünknél tapasztaltunk 2,9 ± 0,8 óra átlag-idotartamú dyskinesist. Következtetés: Hamarabb fogadják el az eszközös terápiát azok az elorehaladott Parkinson-kóros betegek, akiknek hosszabb idotartamú a napi dyskinesisük, illetve régebbi a betegségük. A terápiás irányelvek gyakorlatba ültetésekor figyelembe kell venni a helyi sajátosságokat: a kiegészíto gyógyszerekhez, illetve az eszközös terápiákhoz való hozzáférést. Orv Hetil. 2021; 162(21): 839-847. INTRODUCTION: In advanced stages of Parkinson's disease, motor complications cannot be effectively controlled with conventional therapies. In such cases, the complex assessment and decision-making process that leads to device-aided therapies should be considered. OBJECTIVE: To analyze the decision-making and key clinical parameters, as a function of duration of acceptance, patients treated with levodopa-carbidopa intestinal gel. METHOD: We retrospectively examined the data of patients who started levodopa-carbidopa intestinal gel therapy at the 2nd Department of Neurology Târgu Mures, between 1 June 2011 and 31 December 2019. Two groups were formed: less than one month and more than one month between the first targeted examination and the start of testing. RESULTS: Therapeutic efficiency was tested with nasal tube on 163 patients, out of whom 127 patients remained on treatment. Decision-making took one month or less for 56 patients and more than a month for 71 patients. Duration of dyskinesias was significantly different between the two groups (3.1 ± 0.7 vs 2.8 ± 0.8 hours, p = 0.02). Mean dose of levodopa prior to the introduction of device-aided therapy was 821.5 ± 246.6 mg, administered 5 times daily. Dopamine agonists were used in 80.3%, catechol-O-methyltransferase inhibitors in 62.2%, and monoamine oxidase-B inhibitors in 68.5% of cases. The mean off-time was 4.7±1.1 hours and data from 85 patients showed 2.9 ± 0.8 hours of dyskinesia. CONCLUSION: Device-aided therapy is adopted sooner by patients with advanced Parkinson's disease with longer disease duration and more dyskinesias. Local specificities, such as access to add-on medication and device-aided therapies, must be taken into account when implementing therapeutic guidelines. Orv Hetil. 2021; 162(21): 839-847.


Assuntos
Doença de Parkinson , Catecol O-Metiltransferase , Humanos , Masculino , Doença de Parkinson/tratamento farmacológico , Estudos Retrospectivos
12.
Child Obes ; 17(5): 365-370, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33826421

RESUMO

Background: Gestational diabetes mellitus (GDM) is a major macrosomia risk factor. Variations in the catechol-O-methyltransferase (COMT; rs4680) genotypes are associated with heightened susceptibility to environmental exposures and nutritional conditions. However, macrosomia risks associated with COMT genetics, epigenetics, and the interaction between genetic and epigenetics among children with and without exposure to GDM are unknown. Methods: Data from women/children pairs (n = 1087) who participated in the Tianjin Gestational Diabetes Birth Cohort were used to examine the odds of being born with macrosomia associated with COMT-genotypes, 55 CpG sites located on the COMT gene, and genetic and epigenetic interactions. Odds of macrosomia associated with COMT genetic, epigenetic, genetic and epigenetic interactions, and moderations with GDM were tested using adjusted logistic regression models. Results: Overall, 16.1% (n = 175) of children were born with macrosomia. Models showed that children with at least one copy of the minor allele (A) had higher odds of macrosomia (odds ratio, 1.82; 95% confidence interval 1.25-2.64) compared with children with the GG-genotype. After false discovery rate corrections, none of the 55 CpG sites located on the COMT gene was associated with odds of macrosomia. The genetic and epigenetic associations were not modified by exposure to GDM. Conclusion: Findings suggest carriers of the COMT GG-genotype had lower odds of macrosomia, and this association was not modified by epigenetics or exposure to GDM.


Assuntos
Diabetes Gestacional , Obesidade Pediátrica , Catecol O-Metiltransferase/genética , Criança , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/genética , Epigênese Genética , Feminino , Macrossomia Fetal/epidemiologia , Macrossomia Fetal/genética , Genótipo , Humanos , Gravidez
14.
PLoS One ; 16(4): e0250547, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33909692

RESUMO

Previous research has shown a consistent association among genetic factors, psychological symptoms and pain associated with fibromyalgia. However, how these symptoms interact to moderate genetic factors in fibromyalgia has rarely been studied to date. The present research investigates whether psychological symptoms can moderate the effects of catechol-O-methyltransferase on pain and fatigue. A total of 108 women diagnosed with fibromyalgia and 77 healthy control participants took part in the study. Pain, fatigue, and psychological symptoms (anxiety, depression, pain catastrophizing, fear of pain and fear of movement) were measured by self-report questionnaires. Two types of statistical analyses were performed; the first was undertaken to explore the influences of COMT genotypes on clinical symptoms by comparing patients with fibromyalgia and healthy controls. In the second analysis, moderation analyses to explore the role of psychological symptoms as potential factors that moderate the relationship between pain/fatigue and COMT genotypes were performed. The main results indicated that patients carrying the Met/Met genotype reported significantly higher levels of fatigue than heterozygote carriers (i.e., Met/Val genotype) and higher levels of fatigue, but not significantly different, than Val homozygote carriers. Among patients with fibromyalgia carrying methionine alleles (i.e., Met/Met + Met/Val carriers), only those who scored high on medical fear of pain, experienced an intensified feeling of fatigue. Thus, the present research suggests that fear of pain, as a psychological symptom frequently described in fibromyalgia may act as a moderating factor in the relationship between the Met allele of the COMT gene and the increase or decrease in self-reported fatigue. Although further research with wider patient samples is needed to confirm the present findings, these results point out that the use of psychological interventions focused on affective symptomatology might be a useful tool to reduce the severity of fibromyalgia.


Assuntos
Catecol O-Metiltransferase/genética , Fibromialgia/genética , Predisposição Genética para Doença , Dor/genética , Adulto , Idoso , Alelos , Fadiga/complicações , Fadiga/genética , Fadiga/fisiopatologia , Medo/fisiologia , Feminino , Fibromialgia/complicações , Fibromialgia/fisiopatologia , Humanos , Metionina/genética , Pessoa de Meia-Idade , Dor/complicações , Dor/fisiopatologia , Autorrelato
15.
J Med Econ ; 24(1): 563-569, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33866942

RESUMO

AIMS: To assess from a US payer perspective the relative cost-effectiveness of the catechol-O-methyltransferase inhibitors opicapone and entacapone when used adjunctively to levodopa/carbidopa (LD/CD) in patients with Parkinson's disease (PD), based on the drugs' effects to reduce absolute OFF-time hours in PD patients. MATERIALS AND METHODS: A Markov model was created to estimate cost-effectiveness of adjunctive opicapone treatment compared with adjunctive entacapone treatment in a synthetic cohort of 1,000 patients with PD taking LD/CD. Clinical inputs were derived from clinical trials, published literature, and expert opinion. Cost data (in 2018 US dollars) were obtained from the Centers for Medicare & Medicaid Services, the Kaiser Family Foundation, and Analy$ource. Cost-effectiveness outcomes included incremental cost per OFF-time hours avoided, cost per life year gained, and cost per quality-adjusted life year (QALY) gained. Outcomes were projected over a 25-year lifetime horizon and discounted at 3% annually. RESULTS: Opicapone treatment was associated with an average of 1,187 fewer OFF-time hours per patient and an increase of 0.07 QALYs compared with entacapone. Total lifetime costs for opicapone were $3,100 higher than entacapone, resulting in an incremental cost-effectiveness ratio of $46,900 per QALY. One-way sensitivity analyses showed the model was most sensitive to mean OFF-time hours associated with opicapone and entacapone. Probabilistic sensitivity analysis suggested a 60-65% probability that opicapone was cost-effective relative to entacapone at any willingness-to-pay threshold ≥$5,000. LIMITATIONS: There exists a single head-to-head clinical trial comparing the effectiveness of opicapone with entacapone, thus the clinical inputs regarding relative treatment effect of the drugs to reduce OFF-time hours in PD patients receiving LD/CD were derived from that single non-inferiority trial. CONCLUSIONS: Add-on treatment with opicapone in PD patients receiving LD/CD appeared to be cost-effective compared with entacapone.


Assuntos
Levodopa , Doença de Parkinson , Idoso , Antiparkinsonianos/uso terapêutico , Carbidopa/uso terapêutico , Catecol O-Metiltransferase , Catecóis , Análise Custo-Benefício , Humanos , Medicare , Nitrilas , Oxidiazóis , Doença de Parkinson/tratamento farmacológico , Estados Unidos
16.
Ann Rheum Dis ; 80(9): 1227-1235, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33926923

RESUMO

BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. RESULTS: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca 2+ transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. CONCLUSIONS: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.


Assuntos
ATPases Transportadoras de Cálcio/genética , Dor Crônica/genética , Dor Musculoesquelética/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Catecol O-Metiltransferase/genética , Dor Crônica/fisiopatologia , Depressão/genética , Feminino , Fibromialgia/fisiopatologia , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Dor Musculoesquelética/fisiopatologia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920326

RESUMO

Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Dopaminérgicos/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Antiparkinsonianos/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Inibidores da Colinesterase/síntese química , Ensaios Clínicos como Assunto , Simulação por Computador , Dopaminérgicos/síntese química , Desenho de Fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica , Humanos , Fármacos Neuroprotetores/síntese química , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Sirtuínas/antagonistas & inibidores , Sirtuínas/genética , Sirtuínas/metabolismo
18.
ACS Chem Neurosci ; 12(9): 1552-1562, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33871963

RESUMO

Methamphetamine (MA), a potent central nervous system stimulant, mainly affects the brain dopaminergic and serotoninergic systems. Monoamine oxidase, catechol-O-methyltransferase, and aldehyde dehydrogenase 2 (ALDH2) are important enzymes in the metabolism of dopamine (DA) and serotonin (5-HT); however, the role of ALDH2 in MA addiction remains unclear. This study focused on the real-time changes in DA, 5-HT, and their metabolites, including 3,4-dihydroxyphenylacetic aldehyde and salsolinol, which are metabolites directly related to ALDH2, to examine the effects of the inhibition of ALDH2 on hyperlocomotion induced by MA. Locomotor activity was evaluated in rats after administration of MA and/or CVT-10216 (a selective ALDH2 inhibitor). Moreover, the simultaneous quantification of DA, 5-HT, and their metabolites in brain microdialysates of the rats was performed using a derivatization-assisted LC-MS/MS method after full validation. The validation results proved the method to be selective, sensitive, accurate, and precise, with acceptable linearity within calibration ranges. Intraperitoneal (i.p.) administration of 10 or 20 mg/kg of CVT-10216 significantly decreased MA-induced hyperlocomotion (1 mg/kg, i.p.). The analytical results of rat brain microdialysates demonstrated that the administration of CVT-10216 significantly downregulated DA levels, which were increased upon exposure to MA. Moreover, the increase in 3-methoxytyramine levels following coadministration of CVT-10216 and MA could play a potential role in antagonizing the hyperlocomotion induced by MA. All of these findings suggest that the inhibition of ALDH2 protects against MA-induced hyperlocomotion and has therapeutic potential in MA addiction.


Assuntos
Metanfetamina , Aldeído Desidrogenase , Aldeído-Desidrogenase Mitocondrial , Animais , Encéfalo , Catecol O-Metiltransferase , Cromatografia Líquida , Isoflavonas , Microdiálise , Ratos , Espectrometria de Massas em Tandem
19.
Molecules ; 26(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916785

RESUMO

Nordihydroguaiaretic acid (NDGA) is a major lignan metabolite found in Larrea spp., which are widely used in South America to treat various diseases. In breast tissue, estradiol is metabolized to the catechol estrogens such as 4-hydroxyestradiol (4-OHE2), which have been proposed to be cancer initiators potentially involved in mammary carcinogenesis. Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol estrogens to their less toxic methoxy derivatives, such as 4-O-methylestradiol (4-MeOE2). The present study investigated the novel biological activities of NDGA in relation to COMT and the effects of COMT inhibition by NDGA on 4-OHE2-induced cyto- and genotoxicity in MCF-7 human breast cancer cells. Two methoxylated metabolites of NDGA, 3-O-methylNDGA (3-MNDGA) and 4-O-methyl NDGA (4-MNDGA), were identified in the reaction mixture containing human recombinant COMT, NDGA, and cofactors. Km values for the COMT-catalyzed metabolism of NDGA were 2.6 µM and 2.2 µM for 3-MNDGA and 4-MNDGA, respectively. The COMT-catalyzed methylation of 4-OHE2 was inhibited by NDGA at an IC50 of 22.4 µM in a mixed-type mode of inhibition by double reciprocal plot analysis. Molecular docking studies predicted that NDGA would adopt a stable conformation at the COMT active site, mainly owing to the hydrogen bond network. NDGA is likely both a substrate for and an inhibitor of COMT. Comet and apurinic/apyrimidinic site quantitation assays, cell death, and apoptosis in MCF-7 cells showed that NDGA decreased COMT-mediated formation of 4-MeOE2 and increased 4-OHE2-induced DNA damage and cytotoxicity. Thus, NDGA has the potential to reduce COMT activity in mammary tissues and prevent the inactivation of mutagenic estradiol metabolites, thereby increasing catechol estrogen-induced genotoxicities.


Assuntos
Inibidores de Catecol O-Metiltransferase/química , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Estrogênios de Catecol/metabolismo , Masoprocol/metabolismo , Masoprocol/farmacologia , Mutagênicos/toxicidade , Sítios de Ligação , Morte Celular/efeitos dos fármacos , Dano ao DNA , Estrogênios de Catecol/química , Estrogênios de Catecol/farmacologia , Humanos , Células MCF-7 , Masoprocol/química , Metilação , Simulação de Acoplamento Molecular , Proteínas Recombinantes/metabolismo , Especificidade por Substrato/efeitos dos fármacos
20.
Artigo em Inglês | MEDLINE | ID: mdl-33807669

RESUMO

(1) Background: Numerous studies suggest strong associations between childhood maltreatment and nonsuicidal self-injury (NSSI); this is also true for the roles of dopaminergic genes in the etiology of some psychopathologies related to NSSI. Investigating the interactions of environments and genes is important in order to better understand the etiology of NSSI. (2) Methods: Within a sample of 269 Chinese male adolescents (Mage = 14.72, SD = 0.92), childhood maltreatment and NSSI were evaluated, and saliva samples were collected for MAOA T941G and COMT Val158Met polymorphism analyses. (3) Results: The results revealed no primary effects attributable to MAOA T941G and COMT Val158Met polymorphism on NSSI. However, there was a significant three-way interaction between MAOA, COMT, and child abuse (ß = -0.34, p < 0.01) in adolescent NSSI. Except for carriers of the T allele of MAOA and the Met allele of COMT, all studied male adolescents displayed higher NSSI scores when exposed to a higher level of child abuse. A similar three-way interaction was not observed in the case of child neglect. (4) Conclusions: The results indicate that the MAOA gene and COMT gene play moderating roles in the association between child abuse and NSSI of male adolescents and suggest the polygenic underpinnings of NSSI.


Assuntos
Maus-Tratos Infantis , Comportamento Autodestrutivo , Adolescente , Alelos , Catecol O-Metiltransferase/genética , Criança , Genótipo , Humanos , Masculino , Monoaminoxidase/genética , Comportamento Autodestrutivo/epidemiologia , Comportamento Autodestrutivo/genética
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