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1.
Drugs Today (Barc) ; 56(9): 583-598, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33025952

RESUMO

Acute bacterial skin and skin structure infections (ABSSSIs) are one of the most common types of infections due to methicillin-resistant Staphylococcus aureus (MRSA). The standard of care for ABSSSI includes glycopeptides such as vancomycin, teicoplanin, oxazolidinones and fluoroquinolones, which are potent broad-spectrum antibacterial agents. Unfortunately, due to indiscriminate utilization, resistance to these agents is rising and identification of novel agents is an urgent unmet medical need. In this context, levonadifloxacin (WCK-771) is a novel, hydrate arginine salt of nadifloxacin with improved bactericidal activity against MRSA as well as fluoroquinolone-resistant S. aureus by targeting bacterial DNA supercoiling enzymes DNA gyrase and topoisomerase IV. Levonadifloxacin displays a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria, atypical bacteria, anaerobic bacteria and bioterror pathogens with a very low frequency of mutation. Levonadifloxacin also displays improved activity under low pH biofilm environments. The drug has successfully completed phase I, phase II and phase III clinical trials in India. The U.S. Food and Drug Administration (FDA) granted a Qualified Infectious Disease Product (QIDP) designation to levonadifloxacin for the treatment of MRSA infections in August 2014.


Assuntos
Antibacterianos/uso terapêutico , Quinolizinas/uso terapêutico , Quinolonas/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
3.
Cochrane Database Syst Rev ; 8: CD010285, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820536

RESUMO

BACKGROUND: Pelvic inflammatory disease (PID) affects 4% to 12% of women of reproductive age. The main intervention for acute PID is broad-spectrum antibiotics administered intravenously, intramuscularly or orally. We assessed the optimal treatment regimen for PID.  OBJECTIVES: To assess the effectiveness and safety of antibiotic regimens to treat PID. SEARCH METHODS: In January 2020, we searched the Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which included randomized controlled trials (RCTs) from 1944 to 2020, located through hand and electronic searching; CENTRAL; MEDLINE; Embase; four other databases; and abstracts in selected publications. SELECTION CRITERIA: We included RCTs comparing antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. We limited our review to a comparison of drugs in current use that are recommended by the 2015 US Centers for Disease Control and Prevention guidelines for treatment of PID. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the quality of evidence. MAIN RESULTS: We included 39 RCTs (6894 women) in this review, adding two new RCTs at this update. The quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision. None of the studies reported quinolones and cephalosporins, or the outcomes laparoscopic evidence of resolution of PID based on physician opinion or fertility outcomes. Length of stay results were insufficiently reported for analysis. Regimens containing azithromycin versus regimens containing doxycycline We are uncertain whether there was a clinically relevant difference between azithromycin and doxycycline in rates of cure for mild-moderate PID (RR 1.18, 95% CI 0.89 to 1.55; 2 RCTs, 243 women; I2 = 72%; very low-quality evidence). The analyses may result in little or no difference between azithromycin and doxycycline in rates of severe PID (RR 1.00, 95% CI 0.96 to 1.05; 1 RCT, 309 women; low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.71, 95% CI 0.38 to 1.34; 3 RCTs, 552 women; I2 = 0%; low-quality evidence). In a sensitivity analysis limited to a single study at low risk of bias, azithromycin probably improves the rates of cure in mild-moderate PID (RR 1.35, 95% CI 1.10 to 1.67; 133 women; moderate-quality evidence), compared to doxycycline.  Regimens containing quinolone versus regimens containing cephalosporin The analysis shows there may be little or no clinically relevant difference between quinolones and cephalosporins in rates of cure for mild-moderate PID (RR 1.05, 95% CI 0.98 to 1.14; 4 RCTs, 772 women; I2 = 15%; low-quality evidence), or severe PID (RR 1.06, 95% CI 0.91 to 1.23; 2 RCTs, 313 women; I2 = 7%; low-quality evidence). We are uncertain whether there was a difference between quinolones and cephalosporins in adverse effects leading to discontinuation of treatment (RR 2.24, 95% CI 0.52 to 9.72; 6 RCTs, 1085 women; I2 =  0%; very low-quality evidence). Regimens with nitroimidazole versus regimens without nitroimidazole There was probably little or no difference between regimens with or without nitroimidazoles (metronidazole) in rates of cure for mild-moderate PID (RR 1.02, 95% CI 0.95 to 1.09; 6 RCTs, 2660 women; I2 = 50%; moderate-quality evidence), or severe PID (RR 0.96, 95% CI 0.92 to 1.01; 11 RCTs, 1383 women; I2 = 0%; moderate-quality evidence). The evidence suggests that there was little to no difference in in adverse effects leading to discontinuation of treatment (RR 1.05, 95% CI 0.69 to 1.61; 17 studies, 4021 women; I2 = 0%; low-quality evidence). . In a sensitivity analysis limited to studies at low risk of bias, there was little or no difference for rates of cure in mild-moderate PID (RR 1.05, 95% CI 1.00 to 1.12; 3 RCTs, 1434 women; I2 = 0%; high-quality evidence). Regimens containing clindamycin plus aminoglycoside versus quinolone We are uncertain whether quinolone have little to no effect in  rates of cure for mild-moderate PID compared to clindamycin plus aminoglycoside (RR 0.88, 95% CI 0.69 to 1.13; 1 RCT, 25 women; very low-quality evidence). The analysis may result in little or no difference between quinolone vs. clindamycin plus aminoglycoside in severe PID (RR 1.02, 95% CI 0.87 to 1.19; 2 studies, 151 women; I2 =  0%; low-quality evidence). We are uncertain whether quinolone reduces adverse effects leading to discontinuation of treatment (RR 0.21, 95% CI 0.02 to 1.72; 3 RCTs, 163 women; I2 =  0%; very low-quality evidence). Regimens containing clindamycin plus aminoglycoside versus regimens containing cephalosporin We are uncertain whether clindamycin plus aminoglycoside improves the rates of cure for mild-moderate PID compared to cephalosporin (RR 1.02, 95% CI 0.95 to 1.09; 2 RCTs, 150 women; I2 =  0%; low-quality evidence). There was probably little or no difference in rates of cure in severe PID with clindamycin plus aminoglycoside compared to cephalosporin (RR 1.00, 95% CI 0.95 to 1.06; 10 RCTs, 959 women; I2= 21%; moderate-quality evidence). We are uncertain whether clindamycin plus aminoglycoside reduces adverse effects leading to discontinuation of treatment compared to cephalosporin (RR 0.78, 95% CI 0.18 to 3.42; 10 RCTs, 1172 women; I2 =  0%; very low-quality evidence). AUTHORS' CONCLUSIONS: We are uncertain whether one treatment was safer or more effective than any other for the cure of mild-moderate or severe PID Based on a single study at a low risk of bias, a macrolide (azithromycin) probably improves the rates of cure of mild-moderate PID, compared to tetracycline (doxycycline).


Assuntos
Antibacterianos/uso terapêutico , Doença Inflamatória Pélvica/tratamento farmacológico , Adolescente , Adulto , Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/uso terapêutico , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Azitromicina/uso terapêutico , Cefalosporinas/efeitos adversos , Cefalosporinas/uso terapêutico , Clindamicina/efeitos adversos , Clindamicina/uso terapêutico , Doxiciclina/efeitos adversos , Doxiciclina/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Doença Inflamatória Pélvica/microbiologia , Viés de Publicação , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
4.
PLoS One ; 15(7): e0235638, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687499

RESUMO

IMPORTANCE: Sinonasal symptoms in patients suffering from cystic fibrosis can negatively influence the quality of life and sinuses can be a niche for pathogens causing infection and inflammation leading to a decrease of lung function. Ivacaftor, a potentiator of the Cystic Fibrosis Transmembrane Conductance Regulator protein, has shown improvement in pulmonary function in cystic fibrosis patients with different forms of class III gating mutations. However, the effects of ivacaftor on sinonasal pathology have hardly been studied. OBJECTIVE: To determine the impact of ivacaftor therapy on sinonasal pathology in patients with cystic fibrosis with an S1251N mutation. DESIGN: Prospective observational mono-center cohort study, between June 2015 and December 2016. SETTING: A tertiary referral center in Utrecht, The Netherlands. PARTICIPANTS: Eight patients with cystic fibrosis with an S1251N mutation, treated with the potentiator ivacaftor were investigated. EXPOSURES: Ivacaftor (Kalydeco, VX-770) therapy. Computed tomography imaging of paranasal sinuses. Nasal nitric oxide concentration measurements and nasal endoscopy. MAIN OUTCOMES AND MEASURES: Primary outcome is opacification of paranasal sinuses examined with computed tomography scan analysis and scaled by the modified Lund-Mackay score before and one year after treatment. Secondary outcomes are nasal nitric oxide concentration levels, sinonasal symptoms and nasal endoscopic findings before and approximately two months and in some cases one year after treatment. RESULTS: Computed tomography scan analysis showed a significant decrease in opacification of the majority of paranasal sinuses comparing the opacification score per paranasal sinus before and after one year of treatment with ivacaftor. Median nasal nitric oxide levels significantly improved from 220.00 (IQR:136.00-341.18) to 462.84 (IQR:233.17-636.25) (p = 0.017) parts per billion. Likewise, the majority of sinonasal symptoms and nasal endoscopic pathology decreased or resolved at two months after the use of ivacaftor. CONCLUSION AND RELEVANCE: Ivacaftor appears to improve sinonasal outcome parameters and thereby sinonasal health in patients with cystic fibrosis with an S1251N mutation.


Assuntos
Aminofenóis/uso terapêutico , Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Seios Paranasais/patologia , Quinolonas/uso terapêutico , Adolescente , Adulto , Estudos de Coortes , Fibrose Cística/genética , Fibrose Cística/patologia , Feminino , Genótipo , Humanos , Masculino , Óxido Nítrico/metabolismo , Seios Paranasais/diagnóstico por imagem , Seios Paranasais/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Centros de Atenção Terciária , Tomografia Computadorizada por Raios X , Adulto Jovem
5.
Medicine (Baltimore) ; 99(25): e20620, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569191

RESUMO

BACKGROUND: Chronic atrophic gastritis (CAG) is defined as an important precancerous disease with high risk of gastric cancer. Rebamipide is a mucosal protective agent widely used in the treatment of chronic gastritis. The aim of this systematic review is to assess the efficacy and safety of rebamipide for the treatment of patients with CAG. METHODS AND ANALYSIS: We will perform a comprehensive retrieval in the following electronic databases: PubMed, Embase, MEDLINE, Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI) database, Wanfang Data Knowledge Service Platform, Chinese Scientific Journals Database (VIP), Chinese Biomedical Literature Service System (SinoMed) and other sources. Two trained researchers will select the qualified studies for data extraction and assess the quality and risk of bias, independently. Then the meta-analyses will be conducted by using the RevMan 5.2 and stata 14.0. The heterogeneity of data will be investigated by Cochrane X and I tests. Sensitivity analysis will be conducted to evaluate the stability of the results. Funnel plot analysis and Egger test will be used to assess the publication bias. Finally, the quality of evidence will be assessed by the GRADE system. RESULTS: The results of our research will be published in a peer-reviewed journal. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether rebamipide is an effective intervention for patient with CAG. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/BKC3E.


Assuntos
Alanina/análogos & derivados , Antiulcerosos/uso terapêutico , Gastrite Atrófica/tratamento farmacológico , Quinolonas/uso terapêutico , Alanina/uso terapêutico , Humanos , Metanálise como Assunto , Revisões Sistemáticas como Assunto
6.
Ter Arkh ; 92(1): 89-95, 2020 Jan 15.
Artigo em Russo | MEDLINE | ID: mdl-32598669

RESUMO

The main goals of COPD therapy are to achieve clinical stability with minimal clinical manifestations and low risk of relapse. The proposed COPD control concept by analogy with asthma has not been quite well characterized yet. COPD control is defined as "the long - term maintenance of a clinical situation with a low impact of symptoms on the patient's life and absence of exacerbations." The situation of clinical control in COPD is considered desirable and potentially achievable for most patients with COPD. Pharmacotherapeutic options for COPD are constantly expanding. The control concept may be useful when the decision on treatment of COPD is made for dynamic adjustment of the therapy volume.


Assuntos
Indanos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Humanos
7.
Gan To Kagaku Ryoho ; 47(3): 441-444, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32381911

RESUMO

OBJECTIVE: The aim of this study is to assess prophylactic prescriptions for febrile neutropenia(FN)caused by chemotherapy. INVESTIGATION: We retrospectively surveyed prophylactic antibiotic prescriptions administered to 930 cancer treatment naive outpatients at Showa University Hospital. Factors associated with prophylactic antibiotic prescriptions were assessed based on patient characteristics, intensity of chemotherapy regimens, laboratory data and diagnoses using logistic regression analysis. RESULTS: The number of patients given prophylactic antibiotic prescriptions was significantly higher in high-risk regimens(n= 349)compared to low-risk regimens(n=288), with an odds ratio of 8.93(6.07-13.14). In logistic regression analysis, significant factors affecting the prophylactic prescription of antibiotics were high-risk regimens(OR: 2.05, p=0.009), age(+ 1 year, OR: 0.98, p=0.002), female sex(OR: 7.10, p<0.001), WBC count(+1.0×10 / 3mL, OR: 1.19, p=0.013)and operation history before and after chemotherapy(OR: 23.19, p<0.001). CONCLUSIONS: Physicians(including pharmacists)should therefore pay attention to the prophylactic prescriptions especially in high-risk female cancer patients with operation history. This prescription pattern provides basic information needed for the proper use of antibiotics in cancer patients.


Assuntos
Neutropenia Febril , Neoplasias , Quinolonas/uso terapêutico , Neutropenia Febril/prevenção & controle , Humanos , Pacientes Ambulatoriais , Estudos Retrospectivos
8.
PLoS One ; 15(5): e0223464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379830

RESUMO

Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/metabolismo , Integrase de HIV/genética , Integrase de HIV/metabolismo , HIV-1/enzimologia , Compostos Heterocíclicos com 3 Anéis/metabolismo , Mutação , Sequência de Aminoácidos , Domínio Catalítico/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica/genética , Estabilidade Proteica , Quinolonas/metabolismo , Quinolonas/uso terapêutico , Raltegravir Potássico/metabolismo , Raltegravir Potássico/uso terapêutico , África do Sul , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
9.
BMJ Case Rep ; 13(4)2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32317365

RESUMO

Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder among Caucasian populations. The majority of CF cases are diagnosed in childhood; however, increasing numbers of adults are being diagnosed with the condition. We present the case of a 65-year-old Irish woman presenting with a chronic cough and a history of recurrent respiratory tract infections. Staphylococcus aureus, Scedosporium apiospermum and Stenotrophomonas maltophilia were grown from bronchoalveolar lavage raising suspicion for CF. Sweat testing was negative; however, genetic testing revealed the presence of ∆F508 and R117H CF mutations, the latter mutation conferring a milder form of CF. The patient commenced treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) potentiator medication ivacaftor to good effect. Novel CFTR potentiators and modulators have significant potential to benefit morbidity and mortality in this group. In this case, the microbiological results were key in pursuing genetic testing and diagnosing CF.


Assuntos
Aminofenóis/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Quinolonas/uso terapêutico , Idoso , Feminino , Testes Genéticos , Humanos , Mutação , Scedosporium/patogenicidade , Staphylococcus aureus/patogenicidade , Stenotrophomonas maltophilia/patogenicidade
10.
Leuk Res ; 91: 106337, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200189

RESUMO

The tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML) and BCR-ABL1 inhibitors form the mainstay of CML treatment. Although patients with CML generally do well under TKI therapy, there is a subgroup of patients who are resistant and/or intolerant to TKIs. In these group of patients, there is the need of additional treatment strategies. In this review, we provide an update on the current knowledge of these novel treatment approaches that can be used alone and/or in combination with TKIs.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Everolimo/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/imunologia , Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Humanos , Imunoterapia/métodos , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , Proteínas Recombinantes/uso terapêutico
11.
Z Gastroenterol ; 58(2): 160-170, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32050286

RESUMO

Typhoid fever and paratyphoid fever are systemic infectious diseases of global significance caused by Salmonella enterica subspecies enterica Serovar Typhi (short name: Salmonella Typhi) or Serovar Paratyphi (short name: Salmonella Paratyphi). The course of these fecal-orally transmitted diseases is mainly characterized by a high fever. Left untreated, the course of typhoid fever can be severe and lethal. The infection is almost always acquired outside of Europe (mainly in India) and is notifiable in Germany, Austria and Switzerland. Paratyphoid is an attenuated disease of typhoid fever caused by Salmonella Paratyphi. Available vaccines only protect against Salmonella Typhi. Antibiotic resistance reflects the situation in endemic countries and shows a worrying increase of multi-drug resistant isolates. Currently, third-generation cephalosporins such as ceftriaxone are recommended as first-line therapy; if sensitive to quinolones, fluoroquinolones such as ciprofloxacin may continue to be administered. Crucial preventive measures for travelers to endemic regions include consistent water and food hygiene as well as vaccination, whereby only protection rates of 50-70 % are achieved by currently available vaccines. In the light of increasing multi-drug resistance, a more effective conjugate vaccine against Salmonella Typhi with cross-reactivity against Salmonella Paratyphi is needed more than ever.


Assuntos
Antibacterianos/farmacologia , Febre Paratifoide/tratamento farmacológico , Febre Paratifoide/prevenção & controle , Salmonella paratyphi A/efeitos dos fármacos , Salmonella typhi/efeitos dos fármacos , Febre Tifoide/tratamento farmacológico , Febre Tifoide/prevenção & controle , Vacinas Conjugadas/administração & dosagem , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Fluoroquinolonas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Febre Paratifoide/diagnóstico , Febre Paratifoide/microbiologia , Quinolonas/uso terapêutico , Salmonella enterica , Salmonella paratyphi A/isolamento & purificação , Salmonella typhi/isolamento & purificação , Febre Tifoide/diagnóstico , Febre Tifoide/microbiologia
12.
Psychopharmacology (Berl) ; 237(5): 1459-1470, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32002559

RESUMO

RATIONALE: What is the difference between aripiprazole and brexpiprazole? OBJECTIVES: This systematic review, network meta-analysis of randomized trials evaluated the efficacy and safety/tolerability of aripiprazole and brexpiprazole for treating acute schizophrenia. METHODS: We searched Scopus, MEDLINE, and Cochrane Library from inception until May 22, 2019. The response rate was set as the primary outcome. Other outcomes were discontinuation rate and incidence of individual adverse events. The risk ratio (RR) and 95% credible interval (95%CrI) were calculated. RESULTS: Fourteen studies were identified (n = 3925). Response rates of both aripiprazole and brexpiprazole were superior to that of the placebo (RR [95%CrI]: aripiprazole = 0.84 [0.78, 0.92], brexpiprazole = 0.84 [0.77, 0.92]). Aripiprazole and brexpiprazole were associated with a lower incidence of all-cause discontinuation (0.80 [0.71, 0.89], 0.83 [0.72, 0.95]), adverse events (0.67 [0.47, 0.97], 0.64 [0.46, 0.94]), and inefficacy (0.56 [0.40, 0.77], 0.68 [0.48, 0.99]) compared with the placebo. Although brexpiprazole was associated with a lower incidence of schizophrenia as an adverse event compared with the placebo (0.57 [0.37, 0.85]), aripiprazole and brexpiprazole were associated with a higher incidence of weight gain compared with the placebo (2.12 [1.28, 3.68], 2.14 [1.35, 3.42]). No significant differences were found in other individual adverse events, such as somnolence, akathisia, extrapyramidal symptoms, and dizziness between aripiprazole or brexpiprazole and placebo. Any outcome between aripiprazole and brexpiprazole were not different. CONCLUSIONS: Differences in short-term efficacy and safety for acute schizophrenia were not apparent between aripiprazole and brexpiprazole. Future studies are warranted to evaluate whether there are differences in the long-term outcome between treatments.


Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Quinolonas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiofenos/uso terapêutico , Doença Aguda , Acatisia Induzida por Medicamentos/diagnóstico , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Humanos , Metanálise em Rede , Quinolonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Esquizofrenia/diagnóstico , Tiofenos/efeitos adversos , Ganho de Peso/efeitos dos fármacos , Ganho de Peso/fisiologia
13.
Intern Med ; 59(2): 193-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31941869

RESUMO

Objective Hemorrhagic pneumonia due to Stenotrophomonas maltophilia (SM) in severely immunocompromised patients has a very poor prognosis. However, the risk factors for hemorrhagic pneumonia are not clear. Methods This study assessed the predictive factors of hemorrhagic pneumonia caused by SM. The medical records of patients admitted to Osaka City University Hospital with SM bacteremia between January 2008 and December 2017 were retrospectively reviewed. Patients All patients who had positive blood cultures for SM were included in this study. They were categorized into two groups: the SM bacteremia with hemorrhagic pneumonia group and the SM bacteremia without hemorrhagic pneumonia group. The clinical background characteristics and treatments were compared between these groups. Results The 35 patients with SM bacteremia included 4 with hemorrhagic pneumonia and 31 without hemorrhagic pneumonia. Hematologic malignancy (p=0.03) and thrombocytopenia (p=0.04) as well as the prior use of quinolone within 30 days (p=0.04) were more frequent in the SM bacteremia patients with hemorrhagic pneumonia than in those without hemorrhagic pneumonia. The mortality of the SM bacteremia patients with hemorrhagic pneumonia was higher than that of those without hemorrhagic pneumonia group (p=0.02). Conclusion Patients with SM bacteremia who have hematologic malignancy, thrombocytopenia, and a history of using quinolone within the past 30 days should be treated with deliberation.


Assuntos
Infecções por Bactérias Gram-Negativas/complicações , Hemorragia/microbiologia , Pneumonia Bacteriana/complicações , Stenotrophomonas maltophilia/imunologia , Adulto , Feminino , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Neoplasias Hematológicas/complicações , Hemoptise/microbiologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Pneumonia Bacteriana/tratamento farmacológico , Prognóstico , Quinolonas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Trombocitopenia/complicações , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
14.
J Med Chem ; 63(4): 1612-1623, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31971798

RESUMO

Inhibition of mutant IDH1 is being evaluated clinically as a treatment option for oncology. Here we describe the structure-based design and optimization of quinoline lead compounds to identify FT-2102, a potent, orally bioavailable, brain penetrant, and selective mIDH1 inhibitor. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model. This compound has been selected as a candidate for clinical development in hematologic malignancies, solid tumors, and gliomas with mIDH1.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Isocitrato Desidrogenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Quinolonas/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Feminino , Humanos , Isocitrato Desidrogenase/metabolismo , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ligação Proteica , Quinolonas/síntese química , Quinolonas/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cochrane Database Syst Rev ; 1: CD013056, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902139

RESUMO

BACKGROUND: Chronic suppurative otitis media (CSOM), sometimes referred to as chronic otitis media (COM), is a chronic inflammation and infection of the middle ear and mastoid cavity, characterised by ear discharge (otorrhoea) through a perforated tympanic membrane. The predominant symptoms of CSOM are ear discharge and hearing loss. Antibiotics and antiseptics kill or inhibit the micro-organisms that may be responsible for the infection. Antibiotics can be applied topically or administered systemically via the oral or injection route. Antiseptics are always directly applied to the ear (topically). OBJECTIVES: To assess the effectiveness of antibiotics versus antiseptics for people with chronic suppurative otitis media (CSOM). SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL; 2019, Issue 4, via the Cochrane Register of Studies); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 1 April 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with at least a one-week follow-up involving patients (adults and children) who had chronic ear discharge of unknown cause or CSOM, where ear discharge had continued for more than two weeks. The intervention was any single, or combination of, antibiotic agent, whether applied topically (without steroids) or systemically. The comparison was any single, or combination of, topical antiseptic agent, applied as ear drops, powders or irrigations, or as part of an aural toileting procedure. Two comparisons were topical antiseptics compared to: a) topical antibiotics or b) systemic antibiotics. Within each comparison we separated where both groups of patients had received topical antibiotic a) alone or with aural toilet and b) on top of background treatment (such as systemic antibiotics). DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methodological procedures. We used GRADE to assess the certainty of the evidence for each outcome. Our primary outcomes were: resolution of ear discharge or 'dry ear' (whether otoscopically confirmed or not), measured at between one week and up to two weeks, two weeks to up to four weeks, and after four weeks; health-related quality of life using a validated instrument; and ear pain (otalgia) or discomfort or local irritation. Secondary outcomes included hearing, serious complications and ototoxicity measured in several ways. MAIN RESULTS: We identified seven studies (935 participants) across four comparisons with antibiotics compared against acetic acid, aluminium acetate, boric acid and povidone-iodine. None of the included studies reported the outcomes of quality of life or serious complications. A. Topical antiseptic (acetic acid) versus topical antibiotics (quinolones or aminoglycosides) It is very uncertain if there is a difference in resolution of ear discharge with acetic acid compared with aminoglycosides at one to two weeks (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.72 to 1.08; 1 study; 100 participants; very low-certainty evidence). No study reported results for ear discharge after four weeks. It was very uncertain if there was more ear pain, discomfort or local irritation with acetic acid or topical antibiotics due to the low numbers of participants reporting events (RR 0.16, 95% CI 0.02 to 1.34; 2 RCTs; 189 participants; very low-certainty evidence). No differences between groups were reported narratively for hearing (quinolones) or suspected ototoxicity (aminoglycosides) (very low-certainty evidence). B. Topical antiseptic (aluminium acetate) versus topical antibiotics No results for the one study comparing topical antibiotics with aluminium acetate could be used in the review. C. Topical antiseptic (boric acid) versus topical antibiotics (quinolones) One study reported more participants with resolution of ear discharge when using topical antibiotics (quinolones) compared with boric acid ear drops at between one to two weeks (risk ratio (RR) 1.56, 95% confidence interval (CI) 1.27 to 1.92; 1 study; 409 participants; moderate-certainty evidence). This means that one additional person will have resolution of ear discharge for every five people receiving topical antibiotics (compared with boric acid) at two weeks. No study reported results for ear discharge after four weeks. There was a bigger improvement in hearing in the topical antibiotic group compared to the topical antiseptic group (mean difference (MD) 2.79 decibels (dB), 95% CI 0.48 to 5.10; 1 study; 390 participants; low-certainty evidence) but this difference may not be clinically significant. There may be more ear pain, discomfort or irritation with boric acid compared with quinolones (RR 0.56, 95% CI 0.32 to 0.98; 2 studies; 510 participants; low-certainty evidence). Suspected ototoxicity was not reported. D. Topical antiseptic (povidone-iodine) versus topical antibiotics (quinolones) It is uncertain if there is a difference between quinolones and povidone-iodine with respect to resolution of ear discharge at one to two weeks (RR 1.02, 95% CI 0.82 to 1.26; 1 RCT, 39 participants; very low-certainty evidence). The study reported qualitatively that there were no differences between the groups for hearing and no patients developed ototoxic effects (very low-certainty evidence). No results for resolution of ear discharge beyond four weeks, or ear pain, discomfort or irritation, were reported. E. Topical antiseptic (acetic acid) + aural toileting versus topical + systemic antibiotics (quinolones) One study reported that participants receiving topical and oral antibiotics had less resolution of ear discharge compared with acetic acid ear drops and aural toileting (suction clearance every two days) at one month (RR 0.69, 95% CI 0.53 to 0.90; 100 participants). The study did not report results for resolution of ear discharge at between one to two weeks, ear pain, discomfort or irritation, hearing or suspected ototoxicity. AUTHORS' CONCLUSIONS: Treatment of CSOM with topical antibiotics (quinolones) probably results in an increase in resolution of ear discharge compared with boric acid at up to two weeks. There was limited evidence for the efficacy of other topical antibiotics or topical antiseptics and so we are unable to draw conclusions. Adverse events were not well reported.


Assuntos
Antibacterianos/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Otite Média Supurativa/tratamento farmacológico , Administração Tópica , Humanos , Quinolonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
Pediatr Pulmonol ; 55(3): 654-659, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899860

RESUMO

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients have greatly increased in prevalence in the past two decades and may lead to a more rapid rate of lung function decline. The objective of this study was to determine the impact of a MRSA eradication protocol on long-term culture results and clinical outcomes of pediatric CF patients in a real-world setting. METHODS: This was a single-center, retrospective study of children age 30 days to 17 years. Eradication followed the STAR-too study protocol. The primary outcome was the percent of patients with MRSA-negative cultures at 12 months. Secondary outcomes were the percent of patients with negative cultures at 3, 6, and greater than 12 months and changes in clinical outcomes compared to individual baseline. RESULTS: Of the 55 patients who met inclusion criteria, 10 received protocol eradication. Baseline characteristics were similar between eradication and control groups except more eradication patients were on ivacaftor (30% vs 4%; P = .037). Two eradication patients did not receive rifampin due to ivacaftor use. Eradication did not significantly increase the percent of MRSA-negative cultures at 3 months (P = .122), 6 months (P = .058), or 12 months (P = .108); however, did increase culture negativity at greater than 12 months (P = .008). Eradication resulted in no significant differences in clinical outcomes compared to control. CONCLUSIONS: An extensive eradication protocol may lead to an increased clearance rate of long-term CF respiratory cultures but does not appear to affect clinical outcomes. Eradication may be reasonable to attempt; however, more data is needed before routine recommendation in all patients.


Assuntos
Aminofenóis/uso terapêutico , Antibacterianos/uso terapêutico , Fibrose Cística/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina , Quinolonas/uso terapêutico , Rifampina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Fibrose Cística/microbiologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
18.
Clin Ther ; 42(1): 77-93, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928831

RESUMO

PURPOSE: Brexpiprazole is an oral atypical antipsychotic (OAA) for the treatment of schizophrenia (SCZ). This study compared all-cause and psychiatric inpatient hospitalization and medical costs in adult patients with SCZ newly treated with brexpiprazole versus other US Food and Drug Administration-approved OAAs in a real-world setting. METHODS: This retrospective cohort study analyzed data from: (1) the IBM MarketScan Commercial and Medicare Supplemental databases, and the MarketScan Multi-State Medicaid database; and (2) the de-identified Optum Clinformatics Datamart. Adult patients were identified if they had SCZ and initiated either brexpiprazole or another OAA during the study identification period (July 1, 2015, to September 30, 2016, for MarketScan Commercial and Medicare Supplemental and for Optum; July 1, 2015, to June 30, 2016, for MarketScan Multi-State Medicaid) and had ≥12 months of continuous enrollment before (baseline) and after (follow-up) the first treatment date. Linear regression analyses were performed to test associations between treatment groups (brexpiprazole vs another OAA) and costs (total and medical); negative binomial regression models were used to estimate number of hospitalizations per year, adjusting for baseline characteristics and medication adherence to index treatment during the 12-month follow-up. FINDINGS: The final study sample consisted of 6254 patients with SCZ: 176 initiated brexpiprazole; 391, ziprasidone; 453, paliperidone; 523, lurasidone; 786, aripiprazole; 1234, quetiapine; 1264, olanzapine; and 1427, risperidone. Controlling for baseline characteristics and medication adherence, the adjusted number of hospitalizations (both all-cause and psychiatric), all-cause total costs, and all-cause medical costs did not differ across groups. Brexpiprazole users had the lowest mean psychiatric costs among all OAA users ($12,013; 95% bootstrap CI, 7488-16,538). Compared with brexpiprazole users, paliperidone (incidence rate ratio [95% CI], 1.52 [1.05-2.19]; P = 0.027) and quetiapine (incidence rate ratio [95% CI], 1.47 [1.04-2.07]; P = 0.029) users had more psychiatric hospitalizations per year. Paliperidone had higher psychiatric costs than brexpiprazole (total, $32,066 [95% bootstrap CI, 28,779-35,353] vs $23,851 [18,907-28,795]; medical, $19,343 [16,294-22,392] vs $12,013 [7488-16,538]). Psychiatric medical costs were also $6744 higher in olanzapine users (95% bootstrap CI, 1694-11,795; P = 0.009) than in brexpiprazole users. IMPLICATIONS: Patients with SCZ treated with brexpiprazole had fewer psychiatric hospitalizations and lower psychiatric costs than those treated with paliperidone. Differences in the number of all-cause hospitalizations and medical costs among treatments were not statistically significant. Although treatment decisions are driven by a number of factors (eg, clinical circumstances and drug costs), choice of OAA may affect health care costs.


Assuntos
Antipsicóticos/economia , Hospitalização/economia , Quinolonas/economia , Esquizofrenia/economia , Tiofenos/economia , Administração Oral , Adulto , Antipsicóticos/uso terapêutico , Aripiprazol/economia , Aripiprazol/uso terapêutico , Feminino , Custos de Cuidados de Saúde , Humanos , Cloridrato de Lurasidona/economia , Cloridrato de Lurasidona/uso terapêutico , Masculino , Medicaid/economia , Medicare/economia , Pessoa de Meia-Idade , Olanzapina/economia , Olanzapina/uso terapêutico , Palmitato de Paliperidona/economia , Palmitato de Paliperidona/uso terapêutico , Piperazinas/economia , Piperazinas/uso terapêutico , Fumarato de Quetiapina/economia , Fumarato de Quetiapina/uso terapêutico , Quinolonas/uso terapêutico , Risperidona/economia , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiazóis/economia , Tiazóis/uso terapêutico , Tiofenos/uso terapêutico , Estados Unidos
19.
Infection ; 48(2): 213-221, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31713814

RESUMO

BACKGROUND: Weight gain after initiation of combination antiretroviral therapy (cART) is a possible side effect of all antiretroviral regimens, but it seems to be more evident in association with integrase strand transfer inhibitors (INSTIs). So, we aimed to evaluate weight change associated with an initial cART including one INSTI or darunavir-ritonavir (DRV/r). METHODS: A retrospective, observational, cohort study of antiretroviral therapy-naive adult HIV-positive patients starting an initial cART including raltegravir (RAL), dolutegravir (DTG), elvitegravir-cobicistat (EVG), or DRV/r. We compared changes in weight and body mass index (BMI) across the four groups during a 12-month follow-up. RESULTS: As a whole, 680 patients (470 males, mean age 42.1 years) were enrolled: 196 starting RAL, 174 DTG, 158 EVG/c, and 152 DRV/r. Baseline mean CD4 lymphocyte count was 455 cells/mm3 and 7.3% had an AIDS diagnosis. After 12 months, mean increase in body weight was 1.93 kg in the RAL group, 2.38 kg in the DTG group, 2.14 kg in the EVG group, and 1.85 in the DRV/r group. Mean increase in BMI was 0.71, 0.84, 0.77 and 0.63 kg/m2, respectively (p > 0.05 for each comparison). Therefore, no significant increases in weight and BMI were reported in each group, and no significant differences in weight and BMI changes were described across the four treatment groups. CONCLUSIONS: In our study, patients starting an initial cART including one INSTI or DRV/r after 12 months showed a small and comparable, but not significant, increase in body weight, whose long-term clinical consequences are unknown.


Assuntos
Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Inibidores de Integrase/uso terapêutico , Ritonavir/uso terapêutico , Ganho de Peso , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Cobicistat/efeitos adversos , Cobicistat/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Inibidores de Integrase/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Estudos Retrospectivos
20.
Int J Infect Dis ; 91: 1-8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31730926

RESUMO

OBJECTIVES: To evaluate condition-specific antibiotic prescription rates and the appropriateness of antibiotic use in outpatient settings in Japan. METHODS: Using Japan's national administrative claims database, all outpatient visits with infectious disease diagnoses were linked to reimbursed oral antibiotic prescriptions. Prescription rates stratified by age, sex, prefecture, and antibiotic category were determined for each infectious disease diagnosis. The proportions of any antibiotic prescription to all infectious disease visits and the proportions of first-line antibiotic prescriptions to all antibiotic prescriptions were calculated for each infectious disease diagnosis. RESULTS: Of the 659 million infectious disease visits between April 2012 and March 2015, antibiotics were prescribed in 266 million visits (704 prescriptions per 1000 population per year). Third-generation cephalosporins, macrolides, and quinolones accounted for 85.9% of all antibiotic prescriptions. Fifty-six percent of antibiotic prescriptions were directed toward infections for which antibiotics are generally not indicated. The diagnoses with frequent antibiotic prescription were bronchitis (184 prescriptions per 1000 population per year), viral upper respiratory infections (166), pharyngitis (104), sinusitis (52), and gastrointestinal infection (41), for which 58.3%, 40.6%, 58.9%, 53.9%, and 26.1% of visits antibiotics were prescribed, respectively. First-line antibiotics were rarely prescribed for pharyngitis (8.8%) and sinusitis (9.8%). More antibiotics were prescribed for children aged 0-9 years, adult women, and patients living in western Japan. CONCLUSIONS: Antibiotic prescription rates are high in Japan. Acute respiratory or gastrointestinal infections, which received the majority of the antibiotics generally not indicated, should be the main targets of antimicrobial stewardship intervention.


Assuntos
Antibacterianos/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Prescrições de Medicamentos/estatística & dados numéricos , Adolescente , Adulto , Idoso , Gestão de Antimicrobianos , Cefalosporinas/uso terapêutico , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Recém-Nascido , Seguro Saúde , Japão/epidemiologia , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Faringite/tratamento farmacológico , Quinolonas/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Sinusite/tratamento farmacológico , Adulto Jovem
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