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1.
J Affect Disord ; 325: 264-272, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36608852

RESUMO

BACKGROUND: While literature has suggested that the duration of a major depressive episode (MDE) may affect both symptomatic and functional outcomes in major depressive disorder (MDD), study designs are limited in their ability to isolate a causal relationship. METHODS: A targeted literature review was conducted using the MEDLINE database to assess whether there was an association between (1) shorter duration of an MDE, or (2) increased rapidity of symptom improvement, and MDD outcomes in adult patients. Given findings from the literature, we hypothesized that rapid symptom improvement could be associated with other longer-term clinical outcomes and used a previously-developed microsimulation model to test this hypothesis. The base case of the model replicated step-therapy treatment patterns, for 10,000 simulated patients, based on lines of therapy related to standard of care, observed remission rates, and observed time to relapse from the STAR*D study. In alternative scenario analyses, the step 1 remission rate was varied by +25 % and +50 % from the base case value to simulate the potential impact of improved earlier remission on disease trajectory and patient-level clinical outcomes. RESULTS: The literature review (N = 35 studies) suggests a statistically significant relationship between the duration of MDE or early symptom improvement and MDD outcomes. The microsimulation model corroborated these findings and demonstrated that increasing the rate of remission in step 1 results in patients experiencing decreased number of treatment steps, faster time to remission, decreased rate of reaching treatment-resistant depression, and delayed time to relapse. LIMITATIONS: Rates of relapse in STAR*D were deemed unreliable due to the high-loss of follow-up; rates of relapse for the MDD DTM were instead derived using parametric extrapolation methods (i.e., exponential, Weibull, log-logistic, Gaussian, log-normal, logistic). Adherence to treatment was assumed to be 100 %; however, non-adherence is expected to result in lower cumulative remission rates. CONCLUSION: Findings from the literature, coupled with quantification through a novel microsimulation model, demonstrate the potential impact of increased remission on disease trajectory and patient outcomes in MDD. While additional analyses with the model may be warranted to explore the impact of novel interventions on population health, including long-term outcomes (i.e., 5-year follow-up, lifetime follow-up), efforts by clinicians to increase remission early in the disease trajectory may improve long-term outcomes.


Assuntos
Transtorno Depressivo Maior , Adulto , Humanos , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/diagnóstico , Resultado do Tratamento , Depressão , Doença Crônica , Recidiva
2.
Artigo em Inglês | MEDLINE | ID: mdl-36638539

RESUMO

Objective: To identify and summarize data that describe the impact of effectively treating major depressive disorder (MDD) on the severity or risk of serious comorbidities.Data Sources: MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several congresses were searched. Searches included terms related to MDD, randomized controlled trials (RCTs), and physical comorbidities and were restricted to English-language publications. Searches were conducted in November 2019 for the previous 2 years for conference proceedings; no date restriction was applied to the database searches.Study Selection: Included studies were RCTs or meta-analyses that assessed depression therapies. Studies were required to report a statistically significant improvement in depression scores as well as the concurrent impact on comorbidities. A total of 1,997 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: A total of 30 studies, including 24 RCTs (N = 6,333) and 6 meta/pooled analyses of RCTs, were included. Findings in several comorbidity categories were mixed; for example, in half (4 of 8) of the identified studies in people with cardiovascular disease and depression, individuals who received treatment leading to reduced depressive symptoms compared with a control arm also had a significantly decreased incidence of cardiovascular events or significantly improved cardiac disease symptom/severity scores compared with controls. Significant improvements in comorbid disease severity observed alongside improvements in depressive symptoms were also noted in studies of comorbid Parkinson's disease, multiple sclerosis, chronic pain and fibromyalgia, and chronic obstructive pulmonary disease.Conclusions: Effective treatment of MDD may lead to a reduction in the severity of certain serious comorbidities. These results highlight the importance of appropriate and timely treatment of MDD.


Assuntos
Dor Crônica , Transtorno Depressivo Maior , Humanos , Comorbidade , Depressão/complicações , Depressão/epidemiologia , Depressão/terapia , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/terapia , Revisões Sistemáticas como Assunto
3.
J Clin Psychiatry ; 83(6)2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36264099

RESUMO

Objective: To summarize the breadth of data exploring the relationship between major depressive disorder (MDD) and both the incidence and the disease course of a range of comorbidities.Data Sources: The authors searched MEDLINE, Embase, PsycINFO, Cochrane Database of Systematic Reviews, and several prespecified congresses. Searches included terms related to MDD and several comorbidity categories, restricted to those published in the English language from 2005 onward.Study Selection: Eligibility criteria included observational studies within North America and Europe that examined the covariate-adjusted impact of MDD on the risk and/or severity of comorbidities. A total of 6,811 articles were initially identified for screening.Data Extraction: Two investigators extracted data and assessed study quality.Results: In total, 199 articles were included. Depression was significantly (P < .05) associated with an increased incidence of dementia and Alzheimer's disease as well as cognitive decline in individuals with existing disease; increased incidence and worsening of cardiovascular disease/events (although mixed results were found for stroke); worsening of metabolic syndrome; increased incidence of diabetes, particularly among men, and worsening of existing diabetes; increased incidence of obesity, particularly among women; increased incidence and worsening of certain autoimmune diseases; increased incidence and severity of HIV/AIDS; and increased incidence of drug abuse and severity of both alcohol and drug abuse.Conclusions: The presence of MDD was identified as a risk factor for both the development and the worsening of a range of comorbidities. These results highlight the importance of addressing depression early in its course and the need for integrating mental and general health care.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Transtorno Depressivo Maior , Feminino , Humanos , Masculino , Doença de Alzheimer/complicações , Disfunção Cognitiva/complicações , Comorbidade , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/complicações
4.
J Affect Disord ; 308: 19-26, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35378149

RESUMO

BACKGROUND: Major depressive disorder (MDD), a disabling, potentially life-threatening condition, negatively affects health-related quality of life (HRQoL). This secondary analysis aimed to understand the impact of the neuroactive steroid zuranolone on HRQoL using the Short Form-36v2 Health Survey (SF-36v2). METHODS: Adult patients with MDD and 17-item Hamilton Rating Scale for Depression total score ≥22 were randomized 1:1 to receive zuranolone 30 mg or placebo for 2 weeks, with 4 weeks follow-up. SF-36v2 scores were assessed at Day 15 across 8 domains (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and 2 summary scores (Physical and Mental Component), using a mixed-effects model for repeated measures. Correlations between SF-36v2 scores and clinician-reported efficacy endpoints were assessed using Pearson's correlation. RESULTS: Eighty-nine patients were treated with zuranolone 30 mg (n = 45) or placebo (n = 44). In zuranolone-treated patients, HRQoL improved across all SF-36v2 domains and summary scores at Day 15. Improvements exceeding established minimally important difference thresholds were observed in Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health scores. Improvements in General Health, Vitality, Mental Health, and Mental Component Summary were statistically significant versus placebo (p ≤ 0.025). Clinician-rated endpoints negatively correlated with SF-36v2 scores. LIMITATIONS: The small unipolar depression sample may not be representative of all US MDD patients. HRQoL measures could be impacted by factors unrelated to depression. CONCLUSIONS: Zuranolone-treated patients reported rapid and significant improvements in HRQoL versus placebo at Day 15. HRQoL improvements correlated with improvements in clinician-rated assessments. TRIAL REGISTRATION: clinicaltrials.gov:NCT03000530; https://clinicaltrials.gov/ct2/show/NCT03000530.


Assuntos
Transtorno Depressivo Maior , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Humanos , Dor , Medidas de Resultados Relatados pelo Paciente , Pregnanos , Pirazóis , Qualidade de Vida/psicologia , Inquéritos e Questionários
5.
JAMA Psychiatry ; 78(9): 951-959, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34190962

RESUMO

Importance: Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. Objective: To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. Design, Setting, and Participants: This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019. Interventions: Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. Main Outcomes and Measures: Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. Results: Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. Conclusions and Relevance: In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD. Trial Registration: ClinicalTrials.gov Identifier: NCT02978326.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Moduladores GABAérgicos/farmacologia , Pregnanos/farmacologia , Pirazóis/farmacologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Moduladores GABAérgicos/administração & dosagem , Moduladores GABAérgicos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Período Pós-Parto , Gravidez , Terceiro Trimestre da Gravidez , Pregnanos/administração & dosagem , Pregnanos/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Adulto Jovem
6.
J Affect Disord ; 285: 112-119, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33640861

RESUMO

BACKGROUND: Zuranolone (SAGE-217) is a novel, investigational positive allosteric modulator of GABAA receptors being investigated in major depressive disorder (MDD). This analysis of phase 2 data quantified the benefit and risk of zuranolone (30mg) versus placebo and antidepressants in terms of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Rates of response, remission, and all-cause discontinuation for zuranolone and 11 antidepressant comparators were obtained from the zuranolone phase 2 clinical study (N=89) and a published network meta-analysis, respectively. An indirect treatment comparison was conducted using the Bucher method to compare zuranolone to standard-of-care. RESULTS: Zuranolone demonstrated greater benefit compared to placebo on Day 3 (NNT range for response=4-5, NNT for remission=10) and at Day 15 (NNT=3 for response and remission). Compared to SSRIs and SNRIs, zuranolone at Day 15 showed improved treatment response (NNT=4 [95% CI = 3; 16] and 5 [95% CI = 3; 25], respectively) and remission (NNT=4 [95% CI = 2; 13] and 4 [95% CI = 2; 18], respectively). This was accompanied by a reduction in all-cause discontinuation, with negative NNH values (-57 and -28), respectively. LIMITATIONS: Variations in study design across the included trials may limit the generalizability of results. CONCLUSIONS: With a small positive NNT as early as Day 3 indicating robust benefit and a negative NNH indicating reduced harm, this analysis based on a phase 2 study suggests that patients with MDD may benefit from the benefit-to-risk profile of zuranolone.


Assuntos
Transtorno Depressivo Maior , Antidepressivos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Transtorno Depressivo Maior/tratamento farmacológico , Humanos , Pregnanos/uso terapêutico , Pirazóis/uso terapêutico
7.
Mult Scler J Exp Transl Clin ; 5(1): 2055217318822148, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30729026

RESUMO

BACKGROUND: Flu-like symptoms are common adverse events associated with interferon beta relapsing multiple sclerosis therapies. OBJECTIVES: To evaluate the incidence and severity of flu-like symptoms after transitioning from non-pegylated interferons to peginterferon beta-1a and assess flu-like symptom mitigation using naproxen. METHODS: ALLOW was a phase 3b open-label study in relapsing multiple sclerosis patients. Patients had received non-pegylated interferon for 4 or more months immediately before beginning a 4-week screening period. At baseline, patients switched to peginterferon beta-1a and were randomly assigned (1:1) to continue their current flu-like symptoms management regimen or start twice-daily naproxen 500 mg for 8 weeks. Patients then switched to their preferred regimen and were followed for 48 weeks in total. RESULTS: Of 201 patients, 89.6% did not experience new/worsening flu-like symptoms during their first 8 weeks on peginterferon beta-1a. Flu-like symptom severity remained low in current-regimen and naproxen patients, with no significant between-group differences. Median flu-like symptom duration per injection was 3.2 hours longer with peginterferon beta-1a versus prior interferon, but the 4-week cumulative duration was reduced 49-78%. No new safety signals were identified. CONCLUSION: Most patients who switched from non-pegylated interferon to peginterferon beta-1a did not experience new/worsening flu-like symptoms. Flu-like symptom duration per injection increased, but the cumulative duration significantly decreased. These data may inform flu-like symptom management guidance.

8.
Clin J Pain ; 34(8): 691-699, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29443722

RESUMO

BACKGROUND AND AIM: Trigeminal neuralgia (TN) is a rare orofacial disorder characterized by severe unilateral paroxysmal pain in the region of the fifth cranial nerve. Clinical guidelines recommend carbamazepine (only US Food and Drug Administration-approved drug for TN) and oxcarbazepine as first-line therapies. We utilized the US Truven Health MarketScan database to examine treatment patterns among patients with TN. METHODS: Included patients were aged 18 years and above, newly diagnosed with TN (≥2 TN diagnoses ≥14 days apart; no diagnosis in the previous year), continuously enrolled 1 year before index, with ≥3 years' follow-up postindex. We assessed utilization of selected pharmacotherapies (carbamazepine, oxcarbazepine, pregabalin, gabapentin, baclofen, duloxetine, topiramate), surgery (posterior fossa, radiosurgery), and injections (peripheral anesthetic injections, Gasserian ganglion procedures) for TN. RESULTS: In total, 3685 patients were included (2425 commercial, 1260 Medicare; 71.8% female; age, mean [SD], 59 [15] y). Overall, 72.5% of patients received at least 1 studied medication, most commonly carbamazepine (51.7%) or gabapentin (48.6%). In total, 65% of pharmacologically treated patients had ≥2 treatment episodes; 41.6% had ≥3 (defined by a change in pharmacotherapy [monotherapy/combination] regimen). Overall, 12.3% had surgery and 7.3% injections; 42.9% received opioids for TN. CONCLUSIONS: In the 3 years after diagnosis, patients with TN in the United States receive a variety of pharmacological treatments, including opioids, despite carbamazepine being the only approved medication. A notable proportion utilize surgeries/injections. A high proportion of pharmacologically treated patients receive multiple treatment episodes, suggesting frequent therapy switching, perhaps because of suboptimal efficacy/tolerability. Our data suggest a high burden of illness associated with TN.


Assuntos
Neuralgia do Trigêmeo/terapia , Idoso , Analgésicos/uso terapêutico , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Estudos Retrospectivos , Neuralgia do Trigêmeo/epidemiologia , Estados Unidos
9.
Neurodegener Dis Manag ; 7(1): 39-47, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28071330

RESUMO

AIM: The objective of this Delphi analysis was to obtain consensus on injection-site reaction (ISR) experience and mitigation strategies for patients with relapsing-remitting multiple sclerosis switching from nonpegylated interferons (IFNs) to peginterferon ß-1a in the ALLOW Phase IIIb trial using a three-step approach. METHODS: Study investigators and coordinators from investigative sites enrolling four or more patients in ALLOW participated in three rounds of questionnaires and interviews. RESULTS: Respondents (n = 37) agreed that the most common ISR, erythema, was not disruptive to daily activities. Patient education, as a conversation with a clinician about ISR potential, was recommended. CONCLUSION: The consensus of Delphi respondents on ISR experience and ISR management after switching from nonpegylated IFNs to peginterferon ß-1a can help inform treatment decisions and manage patient expectations.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Toxidermias/etiologia , Interferon beta/efeitos adversos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Adjuvantes Imunológicos/administração & dosagem , Adulto , Idoso , Técnica Delphi , Toxidermias/terapia , Humanos , Interferon beta/administração & dosagem , Pessoa de Meia-Idade , Naproxeno/administração & dosagem , Naproxeno/efeitos adversos , Polietilenoglicóis/administração & dosagem , Resultado do Tratamento
10.
Br J Clin Pharmacol ; 82(2): 380-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27060836

RESUMO

AIM: Subcutaneous (s.c.) peginterferon beta-1a injected once every 2 weeks and s.c. interferon beta-1a injected three times per week (Rebif®) have demonstrated efficacy in relapsing-remitting multiple sclerosis, but direct comparisons of pharmacological activity and tolerability between the two products are lacking. COMPARE was an open label, crossover, pharmacokinetic (PK) study evaluating drug exposure and the safety and tolerability of s.c. peginterferon beta-1a and s.c. interferon beta-1a, over 2 weeks in healthy subjects. METHODS: Thirty healthy subjects received one dose of peginterferon beta-1a (125 µg s.c.) or six doses of interferon beta-1a (44 µg s.c.) over 2 weeks, followed by the alternate treatment after a 2 week washout period. Drug concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and PK parameters including cumulative area under the concentration-time curve (AUC0-336h ) over 2 weeks and maximum observed serum concentrations (Cmax ) were estimated using a non-compartmental analysis. RESULTS: The PK analysis population comprised 26 subjects for each treatment. Drug exposure (AUC0-336h ) was 60% higher with s.c. peginterferon than with s.c. interferon beta-1a (117.4 ng ml(-1) h, 95% confidence interval 95.6, 144.3 vs. 73.1 ng ml(-1) h, 95% confidence interval 61.2, 87.3, respectively; P < 0.0001). Injection-site reactions (ISRs) were the most common adverse events (AEs) observed with both treatments. Numerically lower frequencies and incidence rates of ISRs, headache, myalgia and chills were observed with s.c. peginterferon beta-1a. CONCLUSIONS: One dose of s.c. peginterferon delivered significantly greater drug exposure than s.c. interferon beta-1a three times a week over 2 weeks, and a lower frequency of AEs.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Interferon beta-1a/administração & dosagem , Interferon beta/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Estudos Cross-Over , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Injeções Subcutâneas , Interferon beta-1a/efeitos adversos , Interferon beta-1a/farmacocinética , Interferon beta/efeitos adversos , Interferon beta/farmacocinética , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Adulto Jovem
11.
J Sex Med ; 9(3): 812-20, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22239825

RESUMO

INTRODUCTION: Little is known about Hypoactive Sexual Desire Disorder (HSDD) in men. AIM: To provide the first comprehensive characterization of men diagnosed with HSDD (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [DSM-IV-TR]) using established patient-reported outcomes (PROs) and new PROs developed in line with U.S. Food and Drug Administration (U.S. FDA) guidance. METHODS: This 4-week non-treatment study recruited men (N=200) with or without symptoms of low sexual desire and related distress. Men with erectile dysfunction, serum testosterone <300 ng/dL, or depression were excluded. Men completed assessments of sexual desire and sex-related distress and underwent structured clinical interviews for the diagnosis of HSDD. MAIN OUTCOME MEASURES: Primary endpoints were scores on the Sexual Desire Inventory (SDI), Male Desire Scale (MDS), Sexual Concerns Inventory-Male (SCI-M), and Sexual Desire Relationship Distress Scale (SDRDS) on day 28, and University of California, Los Angeles (UCLA) Psychosexual Diary on days 21-27. Scores are presented as median (interquartile range). RESULTS: There were no clinically relevant differences in age, serum testosterone, depressive symptomatology, erectile function, concomitant illness, or medication use between men with HSDD (N=109) and men without HSDD (N=91). However, clinically meaningful differences between men with and without HSDD were observed in sexual desire according to SDI score (40.0 [21.0] vs. 65.0 [25.0]) and MDS sexual desire domain score (18.0 [8.0] vs. 31.0 [13.0]), in sex-related distress according to SCI-M score (22.0 [12.0] vs. 6.0 [12.0]) and SDRDS score (36.0 [17.0] vs. 10.0 [16.0]), and in UCLA Psychosexual Diary sexual activity domain score (2.6 [2.7] vs. 4.9 [3.9]) (P<0.0001, for all). CONCLUSIONS: Based on a brief structured interview, diagnosis according to DSM-IV-TR criteria for HSDD identified a population of men comparable with men without HSDD in age, serum testosterone, concomitant illness and medication use but distinct in their experience of sexual desire and distress associated with low desire. These controlled data characterize HSDD in men as a distinct sexual dysfunction.


Assuntos
Disfunções Sexuais Psicogênicas/diagnóstico , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Disfunções Sexuais Psicogênicas/psicologia , Inquéritos e Questionários
12.
Bioorg Med Chem Lett ; 18(6): 1994-9, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18291646

RESUMO

Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Indóis/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-Atividade
14.
Proc Natl Acad Sci U S A ; 104(15): 6353-8, 2007 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-17395714

RESUMO

p38 MAPK and MAPK-activated protein kinase 2 (MK2) are key components of signaling pathways leading to many cellular responses, notably the proinflammatory cytokine production. The physical association of p38alpha isoform and MK2 is believed to be physiologically important for this signaling. We report the 2.7-A resolution crystal structure of the unphosphorylated complex between p38alpha and MK2. These protein kinases bind "head-to-head," present their respective active sites on approximately the same side of the heterodimer, and form extensive intermolecular interactions. Among these interactions, the MK2 Ile-366-Ala-390, which includes the bipartite nuclear localization signal, binds to the p38alpha-docking region. This binding supports the involvement of noncatalytic regions to the tight binding of the MK2:p38alpha binary assembly. The MK2 residues 345-365, containing the nuclear export signal, block access to the p38alpha active site. Some regulatory phosphorylation regions of both protein kinases engage in multiple interactions with one another in this complex. This structure gives new insights into the regulation of the protein kinases p38alpha and MK2, aids in the better understanding of their known cellular and biochemical studies, and provides a basis for understanding other regulatory protein-protein interactions involving signal transduction proteins.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Moleculares , Complexos Multiproteicos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Clonagem Molecular , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Camundongos , Complexos Multiproteicos/química , Fosforilação , Ligação Proteica , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Difração de Raios X , Proteínas Quinases p38 Ativadas por Mitógeno/química
15.
J Biochem ; 141(3): 353-62, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17234686

RESUMO

The Pim family of Ser/Thr kinases has been implicated in the process of lymphomagenesis and cell survival. Known substrates of Pim kinases are few and poorly characterized. In this study we set out to identify novel Pim-2 substrates using the Kinase Substrate Tracking and Elucidation (KESTREL) approach. Two potential substrates, eukaryotic initiation factor 4B (eIF4B) and apoptosis inhibitor 5 (API-5), were identified from rat thymus extracts. Sequence comparison of the Pim-2 kinase phosphorylation sites of eIF4B and mouse BAD, the only other known Pim-2 substrate, revealed conserved amino acids preceding the phosphorylated serine residue. Stepwise replacement of the conserved residues produced a consensus sequence for Pim kinase recognition: RXRHXS. Pim-1 and Pim-2 catalyzed the phosphorylation of this recognition sequence 20-fold more efficiently than the original (K/R-K/R-R-K/R-L-S/T-a; a = small chain amino acid) Pim-1 phosphorylation site. The identification of the novel Pim kinase consensus sequence provides a more sensitive and versatile peptide based assay for screening modulators of Pim kinase activity.


Assuntos
Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Sequência de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Sequência Consenso , Fatores de Iniciação em Eucariotos/metabolismo , Humanos , Ratos , Especificidade por Substrato , Timo/metabolismo
16.
J Comp Neurol ; 498(2): 217-26, 2006 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-16856138

RESUMO

During the development of multiple sclerosis the destruction of the myelin sheath surrounding the neurites is accompanied by citrullination of several central nervous system (CNS) proteins, including myelin basic protein and glial fibrillary acidic protein. In experimental autoimmune encephalomyelitis (EAE), a disease induced in animals by immunization with proteins or peptides from the CNS, the animals develop symptoms similar to multiple sclerosis (MS). The increased levels of citrullinated CNS proteins associated with MS are also observed during the development of EAE. To study the role of CNS protein citrullination in EAE development, we induced EAE with a peptide derived from myelin oligodendrocyte glycoprotein (MOG(35-55)) in mice lacking the peptidylarginine deiminase 2 (PAD2) protein, because this enzyme was the most likely candidate to be involved in catalyzing CNS protein citrullination in the diseased state. Even though the PAD2 knockout mice displayed a dramatic reduction in the amount of citrullination present in the CNS, indicating that PAD2 is indeed responsible for the majority of detectable citrullination observed in EAE, the development of EAE was not impaired by genetic deletion of PAD2, suggesting that PAD2 catalyzed citrullination is not essential to the development of EAE.


Assuntos
Encefalomielite Autoimune Experimental/fisiopatologia , Hidrolases/metabolismo , Animais , Citrulina/metabolismo , Humanos , Hidrolases/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Proteína-Arginina Desiminase do Tipo 2 , Desiminases de Arginina em Proteínas , Medula Espinal/citologia , Medula Espinal/metabolismo
17.
Biochemistry ; 43(37): 11658-71, 2004 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-15362850

RESUMO

A novel inhibitor of p38 mitogen-activated protein kinase (p38), CMPD1, identified by high-throughput screening, is characterized herein. Unlike the p38 inhibitors described previously, this inhibitor is substrate selective and noncompetitive with ATP. In steady-state kinetics experiments, CMPD1 was observed to prevent the p38alpha-dependent phosphorylation (K(i)(app) = 330 nM) of the splice variant of mitogen-activated protein kinase-activated protein kinase 2 (MK2a) that contains a docking domain for p38alpha and p38beta, but it did not prevent the phosphorylation of ATF-2 (K(i)(app) > 20 microM). In addition to kinetic studies, isothermal titration calorimetry and surface plasmon resonance experiments were performed to elucidate the mechanism of inhibition. While isothermal titration calorimetry analysis indicated that CMPD1 binds to p38alpha, CMPD1 was not observed to compete with ATP for p38alpha, nor was it able to interrupt the binding of p38alpha to MK2a observed by surface plasmon resonance. Therefore, deuterium exchange mass spectrometry (DXMS) was employed to study the p38alpha.CMPD1 inhibitory complex, to provide new insight into the mechanism of substrate selective inhibition. The DXMS data obtained for the p38alpha.CMPD1 complex were compared to the data obtained for the p38alpha.MK2a complex and a p38alpha.active site binding inhibitor complex. Alterations in the DXMS behavior of both p38alpha and MK2a were observed upon complex formation, including but not limited to the interaction between the carboxy-terminal docking domain of MK2a and its binding groove on p38alpha. Alterations in the D(2)O exchange of p38alpha produced by CMPD1 suggest that the substrate selective inhibitor binds in the vicinity of the active site of p38alpha, resulting in perturbations to regions containing nucleotide binding pocket residues, docking groove residues (E160 and D161), and a Mg(2+) ion cofactor binding residue (D168). Although the exact mechanism of substrate selective inhibition by this novel inhibitor has not yet been disclosed, the results suggest that CMPD1 binding in the active site region of p38alpha induces perturbations that may result in the suboptimal positioning of substrates and cofactors in the transition state, resulting in selective inhibition of p38alpha activity.


Assuntos
Compostos de Bifenilo/metabolismo , Inibidores Enzimáticos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Estrutura Terciária de Proteína , Fator 2 Ativador da Transcrição , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Compostos de Bifenilo/química , Calorimetria , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Inibidores Enzimáticos/química , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Proteína Quinase 14 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Fosforilação , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Especificidade por Substrato , Ressonância de Plasmônio de Superfície , Fatores de Transcrição/metabolismo
18.
Biochemistry ; 43(31): 9950-60, 2004 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-15287722

RESUMO

The p38 mitogen-activated protein kinase (p38) pathway is required for the production of proinflammatory cytokines (TNFalpha and IL-1) that mediate the chronic inflammatory phases of several autoimmune diseases. Potent p38 inhibitors, such as the slow tight-binding inhibitor BIRB 796, have recently been reported to block the production of TNFalpha and IL-1beta. Here we analyze downstream signaling complexes and molecular mechanisms, to provide new insight into the function of p38 signaling complexes and the development of novel inhibitors of the p38 pathway. Catalysis, signaling functions, and molecular interactions involving p38alpha and one of its downstream signaling partners, mitogen-activated protein kinase-activated protein kinase 2 (MK2), have been explored by steady-state kinetics, surface plasmon resonance, isothermal calorimetry, and stopped-flow fluorescence. Functional 1/1 signaling complexes (Kd = 1-100 nM) composed of activated and nonactivated forms of p38alpha and a splice variant of MK2 (MK2a) were characterized. Catalysis of MK2a phosphorylation and activation by p38alpha was observed to be efficient under conditions where substrate is saturating (kcat(app) = 0.05-0.3 s(-1)) and nonsaturating (kcat(app)/KM(app) = 1-3 x 10(6) M(-1) s(-1)). Specific interactions between the carboxy-terminal residues of MK2a (370-400) and p38alpha precipitate formation of a high-affinity complex (Kd = 20 nM); the p38alpha-dependent MK2a phosphorylation reaction was inhibited by the 30-amino acid docking domain peptide of MK2a (IC50 = 60 nM). The results indicate that the 30-amino acid docking domain peptide of MK2a is required for the formation of a tight, functional p38alpha.MK2a complex, and that perturbation of the tight-docking interaction between these signaling partners prevents the phosphorylation of MK2a. The thermodynamic and steady-state kinetic characterization of the p38alpha.MK2a signaling complex has led to a clear understanding of complex formation, catalysis, and function on the molecular level.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/química , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/fisiologia , Processamento Alternativo , Animais , Calorimetria , Catálise , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/fisiologia , Cinética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteína Quinase 14 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/fisiologia , Fosforilação , Ligação Proteica , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína/genética , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Termodinâmica , Ultracentrifugação
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