RESUMO
BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).
Assuntos
Antivirais/administração & dosagem , Desoxicitidina/análogos & derivados , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sinciciais Respiratórios , Administração Oral , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Área Sob a Curva , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/farmacocinética , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Muco , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Vírus Sinciciais Respiratórios/fisiologia , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID50) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of â¼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.).
Assuntos
Anticorpos Monoclonais/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , Influenza Humana/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Neutralizantes/farmacologia , Antivirais/farmacocinética , Farmacorresistência Viral/efeitos dos fármacos , Voluntários Saudáveis , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Vírus da Influenza A Subtipo H3N2/patogenicidade , Influenza Humana/virologia , Masculino , Doenças Nasofaríngeas/virologia , Resultado do Tratamento , Carga Viral , Eliminação de Partículas Virais , Adulto JovemRESUMO
BACKGROUND: Six distinct genetic variants (genotypes 1 - 6) of hepatitis C virus (HCV) exist globally. Certain genotypes are more prevalent in particular countries or regions than in others but, globally, genotype 3 (GT3) is the second most common. Patients infected with HCV GT1, 2, 4, 5 or 6 recover to a greater extent, as measured by sustained virological response (SVR), following treatment with regimens based on direct-acting antivirals (DAAs) than after treatment with older regimens based on pegylated interferon (Peg-IFN). GT3, however, is regarded as being more difficult to treat as it is a relatively aggressive genotype, associated with greater liver damage and cancer risk; some subgroups of patients with GT3 infection are less responsive to current licensed DAA treatments. Newer DAAs have become available or are in development. METHODS: According to PRISMA guidance, we conducted a systematic review (and descriptive statistical analysis) of data in the public domain from relevant clinical trial or observational (real-world) study publications within a 5-year period (February 2011 to May 2016) identified by PubMed, Medline In-Process, and Embase searches. This was supplemented with a search of five non-indexed literature sources, comprising annual conferences of the AASLD, APASL, CROI, EASL, and WHO, restricted to a 1-year period (April 2015 to May 2016). RESULTS: Of the all-oral regimens, the efficacy (SVR12 ≥ 90%) of sofosbuvir plus daclatasvir- and velpatasvir-based regimens in clinical trials supports and reinforces their recommendation by guidelines. Other promising regimens comprise grazoprevir + elbasvir + sofosbuvir, and ombitasvir + paritaprevir/ribavirin + sofosbuvir. Newer regimens incorporating pibrentasvir + glecaprevir or grazoprevir + ruzasvir + MK-3682 (uprifosbuvir), offer all-oral, ribavirin-free SVR12 rates consistently greater than 95%. Observational studies report slightly lower overall SVR rates but reflect corresponding clinical trial data in terms of treatments most likely to achieve good responses. CONCLUSIONS: On the basis of SVR12, we established that for treating GT3 infections (i) regimens incorporating newer DAAs are more effective than those comprising older DAAs, and (ii) ribavirin may be of less benefit in newer DAA regimens than in older DAA regimens. The analysis provides evidence that DAA regimens can replace Peg-IFN-based regimens for GT3 infection.
Assuntos
Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Quimioterapia Combinada , Genótipo , Hepacivirus/isolamento & purificação , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Pirrolidinas , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina/análogos & derivadosRESUMO
BACKGROUND AND OBJECTIVE: Gastro-oesophageal reflux has been implicated in the pathogenesis of chronic cough. Guidelines on management suggest a therapeutic trial of anti-reflux medication. Esomeprazole is a proton pump inhibitor licensed for the long-term treatment of acid reflux in adults and we compared the effects of esomeprazole and placebo on patients with chronic cough. METHODS: This was a prospective, single-centre, randomized, double-blind, placebo-controlled, parallel group study conducted over 8weeks. Fifty adult non-smokers with chronic cough and normal spirometry were randomized. Patients completed cough-related quality-of-life and symptom questionnaires and subjective scores of cough frequency and severity at the beginning and end of the study. They also kept a daily diary of symptom scores. Citric acid cough challenge and laryngoscopic examination were performed at baseline and the end of the study. The primary outcome was improvement in cough score. RESULTS: There were no differences in cough scores in the placebo and treatment arms of the study although some significant improvements were noted when compared to baseline. In the cough diary scores there was a trend towards greater improvement in the treatment arm in patients with dyspepsia. CONCLUSIONS: Esomeprazole did not have a clinically important effect greater than placebo in patients with cough. It suggests a marked placebo effect in the treatment of cough.
Assuntos
Tosse/etiologia , Esomeprazol/uso terapêutico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Doença Crônica , Método Duplo-Cego , Esomeprazol/administração & dosagem , Feminino , Refluxo Gastroesofágico/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Bomba de Prótons/administração & dosagem , Qualidade de Vida , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Influenza and its associated diseases are a major cause of morbidity and mortality. The United States Advisory Committee on Immunization Practices recommends influenza vaccination for everyone over 6 months of age. The failure of the flu vaccine in 2014-2015 demonstrates the need for a model that allows the rapid development of novel antivirals, universal/intra-seasonal vaccines, immunomodulators, monoclonal antibodies and other novel treatments. To this end we manufactured a new H3N2 influenza virus in compliance with Good Manufacturing Practice for use in the Human Viral Challenge Model. METHODS AND STRAIN SELECTION: We chose an H3N2 influenza subtype, rather than H1N1, given that this strain has the most substantial impact in terms of morbidity or mortality annually as described by the Centre for Disease Control. We first subjected the virus batch to rigorous adventitious agent testing, confirmed the virus to be wild-type by Sanger sequencing and determined the virus titres appropriate for human use via the established ferret model. We built on our previous experience with other H3N2 and H1N1 viruses to develop this unique model. HUMAN CHALLENGE AND CONCLUSIONS: We conducted an initial safety and characterisation study in healthy adult volunteers, utilising our unique clinical quarantine facility in London, UK. In this study we demonstrated this new influenza (H3N2) challenge virus to be both safe and pathogenic with an appropriate level of disease in volunteers. Furthermore, by inoculating volunteers with a range of different inoculum titres, we established the minimum infectious titre required to achieve reproducible disease whilst ensuring a sensitive model that can be translated to design of subsequent field based studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT02525055.
Assuntos
Anticorpos Monoclonais/imunologia , Vírus da Influenza A Subtipo H3N2/genética , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Adulto , Animais , Anticorpos Antivirais/imunologia , Antivirais/química , Método Duplo-Cego , Feminino , Furões , Voluntários Saudáveis , Humanos , Vacinas contra Influenza/química , Influenza Humana/virologia , Londres , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Eliminação de Partículas Virais , Adulto JovemRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0145902.].
RESUMO
BACKGROUND: Gastroesophageal reflux is one of the most common causes of chronic cough in the general population. Reflux occurs frequently in patients with cystic fibrosis (CF). We undertook laparoscopic Nissen fundoplication in adult CF patients with a clinical diagnosis of reflux cough who had failed conventional medical therapies. OBJECTIVE: We determined the response to the surgical route in the treatment of intractable reflux cough in CF. METHOD: Patients with refractory cough were assessed by 24 h pH monitoring and oesophageal manometry. Pre-and post-operation cough, lung function and exacerbation frequency were compared. Cough was assessed by the Leicester Cough Questionnaire (LCQ), lung function by spirometry and exacerbation frequency was defined by comparing the postoperative epoch with a similar preoperatively. RESULTS: Significant abnormalities of oesophageal function were seen in all patients studied. 6 patients (2 females), with the mean age of 34.5 years consented to surgery. Their mean number of reflux episodes was 144.4, mean DeMeester score was 39.2, and mean lower oesophageal sphincter pressure 12.4 mmHg. There was a small change in the FEV1 from 1.03 L to 1.17 (P = 0.04), and FVC improved from 2.62 to 2.87 (P = 0.05). Fundoplication lead to a marked fall in cough with the total LCQ score increasing from 11.9 to 18.3 (P = 0.01). Exacerbation events were reduced by 50% post operatively. CONCLUSION: Whilst there is an obvious attention to respiratory causes of cough in CF, reflux is also a common cause. Fundoplication is highly effective in the control of reflux cough in CF. Significant reduction in exacerbation frequency may indicate that reflux with possible aspiration is a major unrecognised contributor to airway disease.
RESUMO
It is well documented that inhalation of sulfur mustard causes injury of the respiratory system. While all of the reports and surveys thoroughly document long-term pulmonary effects after significant exposure to mustard, there is no direct evidence that addresses the issue of long-term respiratory effects in individuals who were exposed to very low level of mustard and suffered no acute respiratory tract injury. Our subjects were selected among all those who were in chemically contaminated areas with chemical warfare agents (CWA) and had been registered for an annual checkup. Subclinical exposure's definition is the absence of any acute symptoms at the time of exposure. We used standard respiratory questionnaires, and chest HRCT examinations and a pulmonary function test were done. Based on exclusion criteria from total of 200 patients claiming respiratory problems, just 77 veterans entered the study. After performing HRCT for all our patients there were 13 (38.23%) veterans with no observable defect, 13 (38%) of them had just significant air trapping in their HRCTs. All the others had at least air trapping (AT), which added to other defects. Septal wall thickening was seen in five veterans (14.7%) and bronchiectasis was seen in three (8.8%) cases. This study suggest that exposure to CWA was responsible for the occurrence of the bronchiolitis obliterans syndrome observed in our patients. There are many civilian and military people who have been present in contaminated area without signs and symptoms at the time of exposure, and early detection of such a population could be lifesaving.
Assuntos
Substâncias para a Guerra Química/efeitos adversos , Guerra Química , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Adulto , Doença Crônica , Nível de Saúde , Humanos , Irã (Geográfico)/epidemiologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/fisiopatologia , Masculino , Radiografia Torácica , Testes de Função Respiratória , Inquéritos e Questionários , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Gastroesophageal junction cancer has increased over time in Western countries. Gastroesophageal reflux disease (GERD) is considered to be a major risk factor. We prospectively studied the prevalence of clinical, histological and endoscopic GERD, and premalignant changes among dyspeptic Iranian patients referred for upper gastrointestinal endoscopy (UGIE). METHODS: Consenting patients referred for UGIE to our clinic were enrolled. Their symptoms were recorded, UGIE was conducted, and biopsies from all suspicious lesions and across the Z-line were taken. RESULTS: Of the 344 enrolled patients, 269 (135 women, 134 men; mean age: 41.6 years) were evaluated. One major GERD symptom (heart burn, acid regurgitation, dysphagia and chest pain) was seen in 209 (77.6%) patients, and 207 patients (76.1%) had endoscopic esophagitis. Thirteen patients (5%) had specialized intestinal metaplasia at the gastrointestinal junction (SIM-GEJ), and three had glandular dysplasia (two low-grade, one high-grade). No symptom could predict the presence of histological or endoscopic findings. Patients with dysplasia had more advanced degrees of endoscopic esophagitis. CONCLUSION: Gastroesophageal reflux disease is common among Iranian patients referred for diagnostic endoscopy. The prevalence of SIM-GEJ among this population was comparable to that reported in Western countries.