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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 838-844, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694094

RESUMO

Objective: To compare the efficacy and safety profiles of tiotropium/olodaterol with the mono-components in Chinese and total study population from TONADO trial. Methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase Ⅲ TONADO studies (TONADO 1+2), patients received tiotropium/olodaterol, tiotropium, or olodaterol via the Respimat(®) Inhaler (Boehringer Ingelheim, Germany). Primary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0 to 3 hours (AUC(0-3h)) response and trough FEV(1) response, and St George's respiratory questionnaire (SGRQ) total score at 24 weeks. Adverse events were also collected. This subgroup analysis only focused on the efficacy and safety of the drug at the approved dose in China. Results: 548 Chinese patients were randomized, aged 41 to 82 years [mean age, (63±8) years] and most were male (526, 96%), 111 received tiotropium/olodaterol 5/5 µg, and 127 received tiotropium 5 µg and 95 received olodaterol 5 µg. The baseline characteristics of these groups were similar. After 24 weeks, treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg and olodaterol 5 µg resulted in an adjusted mean FEV(1) AUC(0-3h) response of 0.240, 0.157 and 0.079 L, and trough FEV(1) response of 0.117, 0.068 and-0.001 L, respectively. Tiotropium/olodaterol 5/5 µg significantly improved SGRQ scores in Chinese patients compared with olodaterol 5 µg (32.729 and 37.202, respectively). Generally, the safety profile of tiotropium/olodaterol was comparable with mono-components in 52 weeks. Conclusion: Compared with tiotropium or olodaterol, tiotropium/olodaterol in Chinese patients provided significant improvement in lung function and quality of life, and the safety profiles were similar.


Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/uso terapêutico , Broncodilatadores/uso terapêutico , China/epidemiologia , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Brometo de Tiotrópio/uso terapêutico , Resultado do Tratamento
2.
Medicine (Baltimore) ; 98(44): e17753, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689832

RESUMO

INTRODUCTION: Stable coronary artery disease (SCAD) is a common clinical style in patients with coronary artery disease. Inflammation and immune injury in SCAD have been proven. Current interventions can relieve patients' symptoms, but none are stable to improve the immune damage significantly. Chinese herb is used to treat stable angina pectoris as an alternative therapy. Taoren Honghua Jian granule (THJG) is a classical formula from which patients can benefit, but lack convincing evidence. Therefore, we report a protocol of high-quality randomized controlled trial. METHODS/DESIGN: We will conduct a randomized, double-blind, placebo-controlled clinical trial to assess the effect of THJG in relief of symptoms and blood immune indexes. A total of 80 patients with SCAD will be enrolled, and treated with THJG or placebo for 4 weeks. The primary outcome measurement is change of integral traditional Chinese medicine (TCM) syndrome score from baseline to 4 weeks' treatment. The 2nd outcome measurements include change of integral TCM syndrome scores from baseline to 2 weeks' treatment and another 4 weeks' follow-up, inflammation indexes at baseline and 4 weeks' treatment. It also includes Seattle Angina Questionnaire, major adverse cardiovascular events, Athens Insomnia scale, and 36-item short form health survey score from baseline to 2 weeks' and 4 weeks' treatment, and another 4 weeks' follow-up. Adverse events will be evaluated throughout the trial. DISCUSSION: The results of this trial will prove whether THJG could alleviate symptoms, control inflammation, and improve quality of life in patients with SCAD. TRIAL REGISTRATION: ChiCTR1900021772, registered 8 March, 2019.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional Chinesa/métodos , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Adulto Jovem
3.
Rev Med Suisse ; 15(670): 2058-2061, 2019 Nov 06.
Artigo em Francês | MEDLINE | ID: mdl-31696682

RESUMO

N-of-1 trials therapeutic tests allow an objective evaluation of treatment efficacy in a single patient. Thereby, they can support off-label prescriptions, or promote treatment safety and efficiency in chronic patients through the deprescription of useless drugs. They also encourage active participation of patients in their medical care. Practically a treatment is compared to a placebo in double blind during a series of randomly alternating periods. Statistical analysis comparing measurements performed in the patient throughout the test enable to evaluate objectively treatment efficacy. The performance of this type of test is now offered to patients and practitioners by the Service of Clinical Pharmacology in the University Hospital of Lausanne.


Assuntos
Ensaios Clínicos como Assunto/métodos , Prática Clínica Baseada em Evidências/métodos , Método Duplo-Cego , Humanos , Uso Off-Label , Suíça , Resultado do Tratamento
5.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
6.
N Engl J Med ; 381(21): 2009-2019, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31693803

RESUMO

BACKGROUND: Dengue, a mosquito-borne viral disease, was designated a World Health Organization top 10 threat to global health in 2019. METHODS: We present primary efficacy data from part 1 of an ongoing phase 3 randomized trial of a tetravalent dengue vaccine candidate (TAK-003) in regions of Asia and Latin America in which the disease is endemic. Healthy children and adolescents 4 to 16 years of age were randomly assigned in a 2:1 ratio (stratified according to age category and region) to receive two doses of vaccine or placebo 3 months apart. Participants presenting with febrile illness were tested for virologically confirmed dengue by serotype-specific reverse-transcriptase polymerase chain reaction. The primary end point was overall vaccine efficacy in preventing virologically confirmed dengue caused by any dengue virus serotype. RESULTS: Of the 20,071 participants who were given at least one dose of vaccine or placebo (safety population), 19,021 (94.8%) received both injections and were included in the per-protocol analysis. The overall vaccine efficacy in the safety population was 80.9% (95% confidence interval [CI], 75.2 to 85.3; 78 cases per 13,380 [0.5 per 100 person-years] in the vaccine group vs. 199 cases per 6687 [2.5 per 100 person-years] in the placebo group). In the per-protocol analyses, vaccine efficacy was 80.2% (95% CI, 73.3 to 85.3; 61 cases of virologically confirmed dengue in the vaccine group vs. 149 cases in the placebo group), with 95.4% efficacy against dengue leading to hospitalization (95% CI, 88.4 to 98.2; 5 hospitalizations in the vaccine group vs. 53 hospitalizations in the placebo group). Planned exploratory analyses involving the 27.7% of the per-protocol population that was seronegative at baseline showed vaccine efficacy of 74.9% (95% CI, 57.0 to 85.4; 20 cases of virologically confirmed dengue in the vaccine group vs. 39 cases in the placebo group). Efficacy trends varied according to serotype. The incidence of serious adverse events was similar in the vaccine group and placebo group (3.1% and 3.8%, respectively). CONCLUSIONS: TAK-003 was efficacious against symptomatic dengue in countries in which the disease is endemic. (Funded by Takeda Vaccines; TIDES ClinicalTrials.gov number, NCT02747927.).


Assuntos
Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Doenças Endêmicas/prevenção & controle , Adolescente , Américas/epidemiologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Ásia/epidemiologia , Criança , Pré-Escolar , Dengue/epidemiologia , Dengue/imunologia , Vacinas contra Dengue/efeitos adversos , Vírus da Dengue/isolamento & purificação , Método Duplo-Cego , Feminino , Humanos , Incidência , Masculino , Sorogrupo , Resultado do Tratamento
7.
JAMA ; 322(19): 1887-1898, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742631

RESUMO

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine. Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack. Design, Setting, and Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month. Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity. Main Outcomes and Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication. Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]). Conclusions and Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.


Assuntos
Analgésicos/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Analgésicos/efeitos adversos , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Manejo da Dor , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Adulto Jovem
8.
Medicine (Baltimore) ; 98(45): e17848, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702643

RESUMO

BACKGROUND: Lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) are one of the most common conditions seen in middle-aged and elderly men and threaten their quality of life. Since conventional pharmacotherapy for LUTS/BPH can lead to sexual side effects, herbal therapies are widely used as complementary and alternative treatments worldwide. HT080 is an herbal extract of Cinnamomum cassia and Rosa Laevigata, both of which have been used to treat symptoms typically associated with BPH in traditional Asian medicine. The aims of this trial are to assess whether HT080 can alleviate LUTS/BPH in middle-aged and elderly men, and to investigate the safety of HT080. METHODS/DESIGN: A double-blind, randomized, placebo-controlled, two-arm parallel group trial will be conducted in men with moderate LUTS/BPH. A total of 100 eligible men aged 40 to 75 years with an International Prostate Symptom Score of 8 to 19 will be randomized in a 1:1 ratio and receive either HT080 (500 mg) or placebo twice a day for 12 weeks. All participants will be evaluated for efficacy and safety at baseline and weeks 6 and 12. The primary endpoint is the change in International Prostate Symptom Score between baseline and week 12. The secondary efficacy variables are uroflowmetry parameters (maximal urinary flow rate and post-void residual volume), serum prostate-specific antigen, testosterone, and dihydrotestosterone levels, the International Index of Erectile Function score, and participant-reported global response assessment scores. The safety assessments include adverse events, laboratory tests results, vital signs, and physical examination. DISCUSSION: This is a first-in human trial designed to investigate the efficacy and safety of HT080 among middle-aged and elderly men with LUTS/BPH. This prospective study with a double-blind randomized design will provide high-quality evidence supporting the use of HT080 for LUTS/BPH. TRIAL REGISTRATION: Korean Clinical Research Information Service (KCT0004286) Registered September 6, 2019.


Assuntos
Cinnamomum aromaticum/química , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Hiperplasia Prostática/tratamento farmacológico , Rosa/química , Adulto , Idoso , Método Duplo-Cego , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Medicina Tradicional Coreana , Pessoa de Meia-Idade , Extratos Vegetais/efeitos adversos , Estudos Prospectivos , Hiperplasia Prostática/complicações , Resultado do Tratamento
9.
Medicine (Baltimore) ; 98(45): e17922, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702673

RESUMO

BACKGROUND: The prevalence of excessive body weight has rapidly increased worldwide over the past decades; however, medications are intended for moderately and severely obese patients and are associated with side effects. As an alternative approach, the use of traditional herbal medicines has gained increasing popularity among overweight individuals in recent years in East Asia. HT048 is an herbal extract of Citrus unshiu and Crataegus pinnatifida, and HT077 is an herbal extract of Nelumbo nucifera and Prunus persica. These 4 herbs have been used widely for body weight reduction in China and Korea. The aims of this trial are to investigate whether HT048 and HT077 are effective at reducing body fat and weight in overweight adults, and to determine the safety of HT048 and HT077. METHODS/DESIGN: A double-blind, randomized, placebo-controlled, 3-arm parallel group trial will be conducted in adults with a body mass index (BMI) of 25 to <30 kg/m. A total of 120 eligible participants will be randomized in a 1:1:1 ratio to receive either HT048 (1000 mg), HT077 (400 mg), or matching placebo twice daily for 12 weeks, and will be monitored for an additional 4-week follow-up period after the treatment. All participants will be assessed for efficacy and safety of the investigational product at baseline and weeks 4, 8, 12, and 16. The primary endpoint is the change in body fat mass and percent body fat measured by dual-energy X-ray absorptiometry at week 12 from the baseline. The secondary efficacy variables are abdominal fat area measured by computed tomography, body fat mass and percent body fat measured by bioelectrical impedance analysis, body weight, BMI, and serum lipids and adipocytokines concentrations. Safety will be evaluated on the basis of reported adverse events, abnormal laboratory results, vital signs, and physical examination findings. DISCUSSION: This is a first-in-human trial of HT048 and HT077 to assess the efficacy and safety in overweight subjects. The results will provide high-quality evidence of the therapeutic benefits of HT048 and HT077 for weight management and the prevention of obesity. TRIAL REGISTRATION: Korean Clinical Research Information Service (KCT0004271) Registered September 2, 2019.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Sobrepeso/tratamento farmacológico , Perda de Peso/efeitos dos fármacos , Adulto , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , República da Coreia
10.
Brain Nerve ; 71(11): 1261-1269, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722312

RESUMO

High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Vitamina B 12/análogos & derivados , Método Duplo-Cego , Humanos , Japão , Estudos Prospectivos , Vitamina B 12/uso terapêutico
11.
Brain Nerve ; 71(11): 1279-1288, 2019 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-31722314

RESUMO

Our laboratory previously established spinal motor neurons (MN) from induced-pluripotent stem cells (iPSCs) prepared from both sporadic and familial ALS patients, and successfully recapitulated disease-specific pathophysiological processes. We next searched for effective drugs capable of slowing the progression of ALS using a drug library of 1232 existing compounds and discovered that ropinirole hydrochloride prevented MN death. In December 2018, we started an investigator-initiated clinical trial testing ropinirole hydrochloride extended-release tablets in ALS patients. This is an on-going phase I/IIa randomized, double-blind, placebo-controlled, single-center, open-label continuation clinical trial (UMIN000034954). The primary aim is to assess the safety and tolerability of ropinirole hydrochloride in patients with ALS. We will also perform an efficacy evaluation using patient-derived iPSCs/MN. Major inclusion criteria were as follows: 1) 'clinically possible and laboratory-supported ALS', 'clinically probable ALS' or 'clinically definite ALS', according to the criteria for the diagnosis of ALS (El Escorial revised) and within 60 months after disease onset; 2) change in ALSFRS-R score of -2 to -5 points during the 12-week run-in period. Finally, 15 patients will be assigned to the active drug and 5 patients to the placebo. Our trial will be a touchstone trial for iPSC-based drug development strategies.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Indóis/uso terapêutico , Células-Tronco Pluripotentes Induzidas , Neurônios Motores/citologia , Método Duplo-Cego , Humanos
12.
N Engl J Med ; 381(19): 1831-1842, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31693806

RESUMO

BACKGROUND: Patients who are treated with targeted temperature management after out-of-hospital cardiac arrest with shockable rhythm are at increased risk for ventilator-associated pneumonia. The benefit of preventive short-term antibiotic therapy has not been shown. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving adult patients (>18 years of age) in intensive care units (ICUs) who were being mechanically ventilated after out-of-hospital cardiac arrest related to initial shockable rhythm and treated with targeted temperature management at 32 to 34°C. Patients with ongoing antibiotic therapy, chronic colonization with multidrug-resistant bacteria, or moribund status were excluded. Either intravenous amoxicillin-clavulanate (at doses of 1 g and 200 mg, respectively) or placebo was administered three times a day for 2 days, starting less than 6 hours after the cardiac arrest. The primary outcome was early ventilator-associated pneumonia (during the first 7 days of hospitalization). An independent adjudication committee determined diagnoses of ventilator-associated pneumonia. RESULTS: A total of 198 patients underwent randomization, and 194 were included in the analysis. After adjudication, 60 cases of ventilator-associated pneumonia were confirmed, including 51 of early ventilator-associated pneumonia. The incidence of early ventilator-associated pneumonia was lower with antibiotic prophylaxis than with placebo (19 patients [19%] vs. 32 [34%]; hazard ratio, 0.53; 95% confidence interval, 0.31 to 0.92; P = 0.03). No significant differences between the antibiotic group and the control group were observed with respect to the incidence of late ventilator-associated pneumonia (4% and 5%, respectively), the number of ventilator-free days (21 days and 19 days), ICU length of stay (5 days and 8 days if patients were discharged and 7 days and 7 days if patients had died), and mortality at day 28 (41% and 37%). At day 7, no increase in resistant bacteria was identified. Serious adverse events did not differ significantly between the two groups. CONCLUSIONS: A 2-day course of antibiotic therapy with amoxicillin-clavulanate in patients receiving a 32-to-34°C targeted temperature management strategy after out-of-hospital cardiac arrest with initial shockable rhythm resulted in a lower incidence of early ventilator-associated pneumonia than placebo. No significant between-group differences were observed for other key clinical variables, such as ventilator-free days and mortality at day 28. (Funded by the French Ministry of Health; ANTHARTIC ClinicalTrials.gov number, NCT02186951.).


Assuntos
Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Antibacterianos/uso terapêutico , Parada Cardíaca Extra-Hospitalar/complicações , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Adulto , Idoso , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Antibacterianos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções Intravenosas , Unidades de Terapia Intensiva , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/mortalidade , Pneumonia Associada à Ventilação Mecânica/etiologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Resultado do Tratamento , Desmame do Respirador
13.
N Engl J Med ; 381(20): 1918-1928, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31722152

RESUMO

BACKGROUND: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS: A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS: In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Úlceras Orais/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Talidomida/análogos & derivados , Administração Oral , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Área Sob a Curva , Síndrome de Behçet/complicações , Método Duplo-Cego , Feminino , Humanos , Masculino , Úlceras Orais/etiologia , Inibidores da Fosfodiesterase 4/efeitos adversos , Qualidade de Vida , Talidomida/efeitos adversos , Talidomida/uso terapêutico
14.
N Engl J Med ; 381(19): 1809-1819, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697873

RESUMO

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).


Assuntos
Aminofenóis/administração & dosagem , Benzodioxóis/administração & dosagem , Agonistas dos Canais de Cloreto/administração & dosagem , Fibrose Cística/tratamento farmacológico , Indóis/administração & dosagem , Mutação , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Pirrolidinas/administração & dosagem , Quinolonas/administração & dosagem , Adolescente , Adulto , Aminofenóis/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Agonistas dos Canais de Cloreto/efeitos adversos , Cloretos/análise , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Genótipo , Humanos , Indóis/efeitos adversos , Masculino , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirrolidinas/efeitos adversos , Quinolonas/efeitos adversos , Suor/química , Adulto Jovem
15.
Braz J Cardiovasc Surg ; 34(5): 517-524, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31719005

RESUMO

OBJECTIVE: To evaluate the effect of high-dose vitamin C on cardiac reperfusion injury and plasma levels of creatine kinase-muscle/brain (CK-MB), troponin I, and lactate dehydrogenase (LDH) in patients undergoing coronary artery bypass grafting (CABG). METHODS: This is a double-blind randomized clinical trial study. Fifty patients (50-80 years old) who had CABG surgery were selected. The intervention group received 5 g of intravenous vitamin C before anesthesia induction and 5 g of vitamin C in cardioplegic solution. The control group received the same amount of placebo (normal saline). Arterial blood samples were taken to determine the serum levels of CK-MB, troponin I, and LDH enzymes. Left ventricular ejection fraction was measured and hemodynamic parameters were recorded at intervals. RESULTS: High doses of vitamin C in the treatment group led to improvement of ventricular function (ejection fraction [EF]) and low Intensive Care Unit (ICU) stay. The cardiac enzymes level in the vitamin C group was lower than in the control group. These changes were not significant between the groups in different time intervals (anesthesia induction, end of bypass, 6 h after surgery, and 24 h after surgery) for CK-MB, LDH, and troponin I. Hemodynamic parameters, hematocrit, potassium, urinary output, blood transfusion, arrhythmia, and inotropic support showed no significant difference between the groups. CONCLUSION: Vitamin C has significantly improved the patients' ventricular function (EF) 72 h after surgery and reduced the length of ICU stay. No significant changes in cardiac biomarkers, including CK-MB, troponin I, and LDH, were seen over time in each group. IRCT CODE: IRCT2016053019470N33.


Assuntos
Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Ponte de Artéria Coronária/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Arritmias Cardíacas/prevenção & controle , Biomarcadores/sangue , Creatina Quinase Forma BB/sangue , Creatina Quinase Forma MM/sangue , Método Duplo-Cego , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Unidades de Terapia Intensiva , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão Miocárdica/sangue , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Troponina I/sangue , Função Ventricular/efeitos dos fármacos
16.
Braz J Cardiovasc Surg ; 34(5): 588-595, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31719010

RESUMO

OBJECTIVE: To evaluate the efficacy of triclosan-coated suture for the reduction of infection in saphenectomy wounds of patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: A total of 508 patients who underwent saphenectomy in CABG surgery were included in a prospective, randomized, double-blind trial from February/2011 to June/2014. Patients were randomized into the triclosan-coated suture group (n= 251) and the conventional non-antibiotic suture group (n=257). Demographic (gender and age), clinical (body mass index, diabetes, and use of analgesics), and intraoperative (cardiopulmonary bypass and cross-clamp times) variables and those related to the saphenectomy wound (pain, dehiscence, erythema, infection, necrosis, and hyperthermia) were measured and analyzed. RESULTS: Of the 508 patients who underwent saphenectomy, 69.9% were males and 40.2% were diabetic. Thirty-three (6.5%) patients presented infection: 13 (5.3%) with triclosan and 20 (7.9%) with conventional suture (P=0.281). Among diabetic patients (n=204), triclosan suture was used in 45.1% with four cases of infection; conventional suture was used in 54.9% of them, with 11 cases of infection. Most patients (94.3%) underwent on-pump CABG. Wound pain was observed in 9.9% of patients with triclosan-coated suture and in 17.9% with conventional suture (P=0.011). Wound hyperthermia was found in 1.6% of patients with triclosan-coated suture and in 5.4% of those with conventional suture (P=0.028). CONCLUSION: Triclosan-coated suture shows lower infection rate in saphenectomy of patients undergoing CABG, although the differences were not statistically significant. Pain and wound hyperthermia were less frequent in patients with triclosan-coated sutures compared with conventional sutures.


Assuntos
Anti-Infecciosos Locais/uso terapêutico , Ponte de Artéria Coronária/métodos , Poliglactina 910/uso terapêutico , Veia Safena/cirurgia , Infecção da Ferida Cirúrgica/prevenção & controle , Técnicas de Sutura , Triclosan/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Ponte de Artéria Coronária/efeitos adversos , Complicações do Diabetes , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
17.
J Indian Soc Pedod Prev Dent ; 37(4): 378-382, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31710013

RESUMO

Aim: The aim of the study was to compare the effectiveness of probiotic milk and fluoride mouthwash on salivary Streptococcus mutans (SM) counts and plaque index (PI) scores in children. Materials and Methods: Thirty children of 8-13 years with zero decayed, missing, and filled teeth (dmft)/DMFT were randomly divided into two equal groups of 15 each; baseline saliva samples were collected, and plaque scores were recorded. Group A received probiotic milk and Group B received fluoride mouthwash for 7 days, and then, saliva samples were collected for colony counting, and plaque scores were recorded on the 8th day. Study Design: This was a double-blind experimental in vivo study and randomized sample selection. Results: The results showed that there was statistically significant reduction in both salivary SM counts and plaque scores in both the groups after 7 days period. Intergroup comparison showed that there was no statistically significant difference between the two groups (i.e., both groups are equally effective in caries reduction). Conclusion: Probiotic milk was as effective as fluoride mouthwash in reducing SM counts and PI scores.


Assuntos
Anti-Infecciosos , Cárie Dentária , Probióticos , Animais , Criança , Método Duplo-Cego , Fluoretos , Humanos , Leite , Antissépticos Bucais , Saliva , Streptococcus mutans
18.
N Engl J Med ; 381(18): 1718-1727, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31566307

RESUMO

BACKGROUND: Preclinical data have suggested that nintedanib, an intracellular inhibitor of tyrosine kinases, inhibits processes involved in the progression of lung fibrosis. Although the efficacy of nintedanib has been shown in idiopathic pulmonary fibrosis, its efficacy across a broad range of fibrosing lung diseases is unknown. METHODS: In this double-blind, placebo-controlled, phase 3 trial conducted in 15 countries, we randomly assigned patients with fibrosing lung disease affecting more than 10% of lung volume on high-resolution computed tomography (CT) to receive nintedanib at a dose of 150 mg twice daily or placebo. All the patients met criteria for progression of interstitial lung disease in the past 24 months despite treatment and had a forced vital capacity (FVC) of at least 45% of the predicted value and a diffusing capacity of the lung for carbon monoxide ranging from 30 to less than 80% of the predicted value. Randomization was stratified according to the fibrotic pattern (a pattern of usual interstitial pneumonia [UIP] or other fibrotic patterns) on high-resolution CT. The primary end point was the annual rate of decline in the FVC, as assessed over a 52-week period. The two primary populations for analysis were the overall population and patients with a UIP-like fibrotic pattern. RESULTS: A total of 663 patients were treated. In the overall population, the adjusted rate of decline in the FVC was -80.8 ml per year with nintedanib and -187.8 ml per year with placebo, for a between-group difference of 107.0 ml per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). In patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was -82.9 ml per year with nintedanib and -211.1 ml per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). Diarrhea was the most common adverse event, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group. CONCLUSIONS: In patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo. Diarrhea was a common adverse event. (Funded by Boehringer Ingelheim; INBUILD ClinicalTrials.gov number, NCT02999178.).


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Diarreia/induzido quimicamente , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Capacidade Vital/efeitos dos fármacos
19.
Medicine (Baltimore) ; 98(40): e16950, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577697

RESUMO

BACKGROUND: Anorexia is a common cause of malnutrition and is associated with negative effects on the quality of life (QOL) for patients with cancer. Management of appetite is the key to improving both the QOL and the prognosis for such patients. Yukgunja-tang (YGJT) is a traditional herbal medicine extensively prescribed in Korea as a remedy for various gastrointestinal syndromes. Currently, no standardized herbal medicine treatment exists for patients with cancer who are suffering from anorexia after surgery, chemotherapy, and/or radiotherapy. For that reason, this study aims to examine the efficacy and the safety of using YGJT to treat anorexia in such patients and to establish whether or not YGJT can be recommended as the primary therapy. METHODS: We will enroll 52 cancer patients diagnosed with anorexia. The enrolled participants will be randomly allocated to 2 groups: The control group will receive nutrition counseling, and the YGJT group will receive nutrition counseling and be administered YGJT at a dose of 3 g twice a day for 4 weeks (a total of 56 doses of 3.0 g per dose). The primary outcome of this study is the change in the score on the anorexia/cachexia subscale (A/CS) of the Functional Assessment of Anorexia/Cachexia Therapy (FAACT). The secondary outcomes are the changes in the FAACT score with the A/CS score excluded, the score on the Visual Analogue Scale (VAS) for appetite, the weight and the body mass index (BMI), and laboratory tests for compounds such as leptin, tumor necrosis factor-α (TNF-α), ghrelin, and IL-6. All variables related to the safety assessment, such as vital signs, electrocardiography results, laboratory test results (CBC, chemistry, urine test), and adverse events, will be documented on the case report form (CRF) at every visit. CONCLUSION: This study is the first randomized controlled trial to investigate the efficacy and the safety of using YGJT for treating patients with cancer-related anorexia in Korea. We designed this study based on previous research about YGJT. This study will serve as a pilot and provide data for planning further clinical trials on herbal medicine and cancer-related anorexia. TRIAL REGISTRATION: Clinical Research Information Service (CRIS), Republic of Korea, ID: KCT0002847. Registered retrospectively on 3 April 2018.


Assuntos
Anorexia/tratamento farmacológico , Anorexia/etiologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Apetite , Índice de Massa Corporal , Peso Corporal , Método Duplo-Cego , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Qualidade de Vida , República da Coreia , Projetos de Pesquisa , Adulto Jovem
20.
J Int Soc Sports Nutr ; 16(1): 44, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31623659

RESUMO

BACKGROUND: The ergogenic properties of acute caffeine (CAF) and sodium bicarbonate (NaHCO3) ingestion on athletic performance have been previously investigated. However, each sport has unique physiological and technical characteristics which warrants optimizing supplementations strategies for maximizing performance. This study examined the effects of CAF and NaHCO3 ingestion on physiological responses and rate of perceived exertion during a Karate-specific aerobic test (KSAT) in competitive karatekas. METHODS: In a double-blind, crossover, randomized placebo-controlled trial, eight Karatekas underwent five experimental conditions including control (CON), placebo (PLA), CAF, NaHCO3, and CAF + NaHCO3 before completing KSAT. Capsules containing 6 mg/kg BW CAF were consumed 50 min prior to a KSAT whilst 0.3 g/kg BW NaHCO3 was consumed for 3 days leading to and 120, 90, and 60 min prior to a KSAT. Time to exhaustion (TTE), rate of perceived exertion (RPE), and blood lactate (BL) were measured before, immediately after and 3 min following KSAT. RESULTS: TTE was significantly greater following CAF, NaHCO3, and CAF + NaHCO3 consumption compared to PLA and CON. However, the differences between CAF, NaHCO3, and CAF + NaHCO3 were not statistically significant (p > 0.05). BL increased significantly from baseline to immediately after and 3 min following KSAT in all conditions (p < 0.01), while RPE at the end of KSAT was not significantly different between conditions (p = 0.11). CONCLUSIONS: Karate practitioners may benefit from the ergogenic effects of CAF and NaHCO3 when consumed separately or together.


Assuntos
Desempenho Atlético/fisiologia , Cafeína/farmacologia , Artes Marciais/fisiologia , Substâncias para Melhoria do Desempenho/farmacologia , Bicarbonato de Sódio/farmacologia , Adolescente , Estudos Cross-Over , Método Duplo-Cego , Humanos , Adulto Jovem
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