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BMC Pulm Med ; 20(1): 119, 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366249


BACKGROUND: Batefenterol (BAT) is a bi-functional molecule with both muscarinic antagonist and ß2-adrenoceptor agonist pharmacology. This Phase II, randomized, placebo-controlled, double-blind study evaluated the safety and tolerability of BAT 300 µg with fluticasone furoate (FF) 100 µg administered via the ELLIPTA inhaler (BAT/FF 300/100). METHODS: Subjects with stable chronic obstructive pulmonary disease were randomized 2:1 to receive BAT/FF 300/100 or placebo once daily for 6 weeks. The primary endpoint was change from baseline in 0-4-h weighted mean (WM) heart rate (HR, measured by electrocardiogram [ECG]) on Day 42. Other endpoints included WM and maximum 0-4-h corrected QT interval (ECG on Days 1, 28, and 42), HR measured by Holter monitoring (Day 42), and standard safety assessments. Study protocol was approved by an Investigational Review Board. RESULTS: Sixty-two patients were randomized and received ≥1 dose of study medication (BAT/FF 300/100 n = 42; placebo n = 20). Mean age was 62.5 years (standard deviation [SD] 8.17). Study completion rates were 83% (BAT/FF 300/100) and 100% (placebo). Screening mean (SD) post-bronchodilator percentage-predicted forced expiratory volume in 1 s was 57.57 (11.42) in the BAT/FF 300/100 group and 55.68 (14.03) in the placebo group. BAT/FF 300/100 was non-inferior to placebo for the primary endpoint, treatment difference: - 2.2 beats per minute (bpm), 95% confidence interval [CI]: - 6.2, 1.7). There were no clinically relevant differences between treatment groups in WM or maximum 0-4-h corrected QT interval, or mean HR based on Holter monitoring on Day 42 (BAT/FF 300/100: 76.3 bpm [SD 11.38]; placebo: 84.8 bpm [SD 9.87]). Adverse events (AEs) occurred in 38% (BAT/FF 300/100) and 35% (placebo) of patients. AEs in ≥2 subjects with BAT/FF 300/100 were dysgeusia (10%), diarrhea (7%), nasopharyngitis (7%), and cough (5%). AEs leading to discontinuation occurred in two subjects who received BAT/FF 300/100: post-treatment severe pneumonia (serious AE) and non-serious AEs of moderate vomiting and severe gastroenteritis; both were not considered drug-related. No deaths occurred. CONCLUSIONS: Six weeks of BAT/FF 300/100 treatment was non-inferior to placebo for change from baseline in HR, with no new clinically relevant general or cardiovascular safety signals. TRIAL REGISTRATION: NCT02573870 (submitted October 12, 2015).

ChemistryOpen ; 8(9): 1204-1208, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31523608


The synthesis of a Cu4(OH)4 cube which is coordinated by four molecules of the dipyridyl ligand 1,6-[di(pyridin-4-yl)hex-3-ene] is reported. This compound has a trans double bond which restricts the conformational freedom of the ligand and favours coordination within a unique copper cube. The structure was solved by an X-Ray single crystal structure determination and low temperature magnetic susceptibility measurements examined its magnetic properties. The cube classification corresponds to the type I classification of Mergehenn and Haase and the short/long distribution of Cu ⋅⋅⋅ Cu separations in the cube as defined by Ruiz. The magnetic susceptibility measurements show paramagnetic behaviour down to 50 K but below this the copper cube shows weak ferromagnetic exchange interactions. The low temperature magnetic susceptibility characteristics are examined in detail then modelled and compared to other similar Cu4O4 copper cubes.

Artigo em Inglês | MEDLINE | ID: mdl-30880951


Background: Batefenterol is a novel bifunctional muscarinic antagonist ß2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose-response of batefenterol and select a dose for Phase III development. Patients and methods: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0-6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose-response modeling, respectively, on day 42. Results: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1-292.8 and 182.2-244.8 mL, respectively), with a relatively flat dose-response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed. Conclusion: Batefenterol 300 µg may represent the optimal dose for Phase III studies.

Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Carbamatos/administração & dosagem , Inaladores de Pó Seco , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Carbamatos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Alemanha , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/efeitos adversos , África do Sul , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
J Am Med Dir Assoc ; 6(6): 367-74, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16286057


BACKGROUND: Antiviral chemoprophylaxis effectiveness for influenza control has not been prospectively established for unvaccinated residents of long-term care facilities. This study evaluated the efficacy and tolerability of zanamivir against the standard of care (no intervention, ie, placebo) for influenza outbreak control in a largely unvaccinated institutionalized population. OBJECTIVE: To evaluate the efficacy and tolerability of zanamivir versus placebo for influenza outbreak control in long-term care facilities. METHODS: This double-blind, randomized, placebo-controlled study prospectively enrolled/followed residents of long-term care facilities (LTCF) at 12 centers for 1 to 3 influenza seasons (1997 to 2000). Following influenza outbreak declaration, asymptomatic subjects were randomized for prophylaxis to inhaled zanamivir 10 mg or inhaled placebo given once daily for 14 days. The proportion of randomized subjects who during prophylaxis developed symptomatic, laboratory-confirmed influenza (SLCI) was the primary end point. RESULTS: Influenza outbreaks were explosive. The attack rates varied from 9.5 to 14.8 per 100 residents. Of 1763 consents given and resulting in 494 randomizations, 49% received zanamivir and 51% placebo; 66% were elderly and 9% were vaccinated. SLCI occurred in 6% of zanamivir and 9% of placebo subjects (P = .355; protective efficacy for zanamivir = 29%, 95% confidence interval 31% to 62%), and symptomatic influenza confirmed by culture in 2% and 6%, respectively (P = .052; protective efficacy = 65%, 95% confidence interval 8.5% to 86%). Zanamivir use was also associated with a 70% (95% confidence interval 13% to 89%) reduction in laboratory-confirmed influenza with fever (2% vs 6%, P = .043). Influenza B was not detected. Zanamivir was well tolerated. No virus isolate demonstrated zanamivir resistance. CONCLUSIONS: The protective efficacy of zanamivir versus placebo for SLCI was marginal, for all laboratory confirmed illnesses, but significant against culture proven and febrile influenza, suggesting zanamivir can be effective for outbreak control and symptom reduction of unvaccinated institutionalized residents. Zanamivir had an acceptable safety profile in elderly, high-risk LTCF residents and was not associated with the emergence of resistant strains.

Antivirais/administração & dosagem , Infecção Hospitalar/prevenção & controle , Surtos de Doenças/prevenção & controle , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Casas de Saúde , Zanamivir/administração & dosagem , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Quimioprevenção , Infecção Hospitalar/virologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vacinação , Zanamivir/efeitos adversos