RESUMO
CERTAIN-1 was a Phase 3, double-blind, randomized, parallel group study of the efficacy and safety of cefepime-taniborbactam versus meropenem in the treatment of adults with complicated urinary tract infection (cUTI), including acute pyelonephritis. We determined susceptibility of Enterobacterales and Pseudomonas aeruginosa baseline pathogens to cefepime-taniborbactam and comparators and characterized ß-lactam resistance mechanisms. Microbiologic response and clinical response were assessed in patient subsets defined by baseline pathogens that were of cefepime-, multidrug-, or carbapenem-resistant phenotype or that carried ß-lactamase genes. Among Enterobacterales baseline pathogens, 26.8%, 4.1%, and 3.0% carried genes for extended-spectrum ß-lactamases (ESBLs), AmpC, and carbapenemases, respectively. Within each treatment group, while composite success rates at Test of Cure in resistant subsets by pathogen species were similar to those by pathogen overall, composite success rates in meropenem patients were numerically lower for cefepime-resistant Escherichia coli (9/19; 47.4%) and ESBL E. coli (13/25; 52.0%) compared with E. coli overall (62/100; 62.0%). Cefepime-taniborbactam achieved composite success in 7/8 (87.5%) patients with carbapenem-resistant Enterobacterales and 8/9 (88.9%) patients with Enterobacterales with a carbapenemase gene (5 OXA-48-group; 2 KPC-3; 2 NDM-1). Cefepime-taniborbactam also achieved composite success in 8/16 (50.0%) patients and clinical success in 13/16 (81.3%) patients with P. aeruginosa; corresponding rates were 4/7 (57.1%) and 6/7 (85.7%) for meropenem. Cefepime-taniborbactam demonstrated efficacy in adult cUTI patients with cefepime-, multidrug-, and carbapenem-resistant pathogens including pathogens with ESBL, AmpC, and carbapenemase genes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03840148.
Assuntos
Antibacterianos , Cefepima , Cefalosporinas , Meropeném , Testes de Sensibilidade Microbiana , Infecções Urinárias , beta-Lactamases , Humanos , Meropeném/uso terapêutico , Meropeném/farmacologia , Cefepima/uso terapêutico , Cefepima/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , beta-Lactamases/genética , Adulto , Feminino , Masculino , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pessoa de Meia-Idade , Método Duplo-Cego , Proteínas de Bactérias/genética , Genótipo , Fenótipo , Idoso , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Resultado do Tratamento , Ácidos Borínicos , Ácidos CarboxílicosRESUMO
BACKGROUND: The currently approved method of C1 inhibitor (C1 INH) administration for patients with hereditary angioedema with C1 INH deficiency (HAE) is by intravenous injection. A C1 INH subcutaneous formulation may provide an attractive mode of administration for some patients. OBJECTIVE: To evaluate efficacy and safety of two doses of subcutaneous, plasma-derived C1 INH with the dispersing agent, recombinant human hyaluronidase (rHuPH20) to prevent angioedema attacks in patients with HAE. METHODS: A randomized, double-blind, dose-ranging, crossover study, patients 12 years of age (n = 47) with a confirmed diagnosis of HAE were randomly assigned to receive subcutaneous injections of 1000 U C1 INH with 24,000 U rHuPH20 or 2000 U C1 INH with 48,000 U rHuPH20 every 3 or 4 days for 8 weeks and then crossed-over for another 8-week period. The primary efficacy end point was the number of angioedema attacks during each treatment period. RESULTS: The study was terminated early as a precaution related to non-neutralizing antibodies to rHuPH20 in 45% of patients. The mean standard deviation number of angioedema attacks during the 8-week treatment periods were 1.58 1.59 with 1000 U C1 INH and 0.97 1.26 with 2000 U. The mean (95% confidence interval [CI]) within-patient difference (2000 U-1000 U, respectively) was 0.61 (95% CI, 1.23 to 0.01) attacks per month (p = 0.0523), and 0.56 (95% CI, 1.06 to 0.05) attacks that required acute treatment, (p = 0.0315). No deaths or other serious adverse events were reported. Injection-site reaction was the most common adverse event. CONCLUSION: Despite early termination, this study demonstrated a clinically and statistically significant difference in burden of disease, which favored 2000 U C1 INH, without associated serious adverse events.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/administração & dosagem , Hialuronoglucosaminidase/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Idoso , Angioedemas Hereditários/diagnóstico , Criança , Proteína Inibidora do Complemento C1/efeitos adversos , Proteína Inibidora do Complemento C1/farmacocinética , Progressão da Doença , Feminino , Humanos , Hialuronoglucosaminidase/efeitos adversos , Hialuronoglucosaminidase/farmacocinética , Injeções Subcutâneas , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Human plasma-derived nanofiltered C1 esterase inhibitor (C1 INH-nf) is used to treat acute angioedema attacks in patients with hereditary angioedema (HAE), but data regarding use in children are sparse. METHODS: Patients 2 to <12 years of age, body weight ≥10 kg, with a diagnosis of HAE type I or II, were recruited for a multicenter open-label trial. Patients were recruited into 2 weight categories (10-25 kg, >25 kg). Each weight category included 2 dosing levels: C1 INH-nf (500 units [U], 1000 U) and C1 INH-nf (1000 U, 1500 U), respectively. Patients experiencing an angioedema attack were given a single intravenous dose. Primary efficacy end-point was the onset of unequivocal relief of the defining symptom within 4 h following initiation of C1 INH-nf treatment. RESULTS: Nine children were treated: 3 (10-25 kg) received 500 U; 3 (>25 kg) received 1000 U; and 3 (>25 kg) received 1500 U. The lower weight/higher dose category (10-25 kg, 1000 U) was not successfully enrolled. All patients completed the study. Most angioedema attacks (n = 5) were abdominal. All patients met the primary end-point; median time to unequivocal symptom relief was 0.5 (range: 0.25-2.5) h. Doses of C1 INH-nf ranged from 20.8 to 51.9 U/kg. CONCLUSIONS: Treatment of a single angioedema attack with C1 INH-nf doses of 500 U (in patients 10-25 kg), 1000 U, and 1500 U (in patients >25 kg) were well tolerated. Doses of C1 INH-nf <1000 U may be appropriate in some pediatric patients.
Assuntos
Angioedemas Hereditários/tratamento farmacológico , Proteína Inibidora do Complemento C1/uso terapêutico , Inativadores do Complemento/uso terapêutico , Doença Aguda , Criança , Pré-Escolar , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
IMPORTANCE: Clostridium difficile is the most common cause of health care-associated infection in US hospitals. Recurrence occurs in 25% to 30% of patients. OBJECTIVE: To determine the safety, fecal colonization, recurrence rate, and optimal dosing schedule of nontoxigenic C. difficile strain M3 (VP20621; NTCD-M3) for prevention of recurrent C. difficile infection (CDI). DESIGN, SETTING, AND PARTICIPANTS: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from June 2011 to June 2013 among 173 patients aged 18 years or older who were diagnosed as having CDI (first episode or first recurrence) and had successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe. INTERVENTIONS: Patients were randomly assigned to receive 1 of 4 treatments: oral liquid formulation of NTCD-M3, 10(4) spores/d for 7 days (n = 43), 10(7) spores/d for 7 days (n = 44), or 10(7) spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). MAIN OUTCOMES AND MEASURES: The primary outcome was safety and tolerability of NTCD-M3 within 7 days of treatment. Exploratory secondary outcomes included fecal colonization with NTCD-M3 from end of study drug through week 6 and CDI recurrence from day 1 through week 6. RESULTS: Among 168 patients who started treatment, 157 completed treatment. One or more treatment-emergent adverse events were reported in 78% of patients receiving NTCD-M3 and 86% of patients receiving placebo. Diarrhea and abdominal pain were reported in 46% and 17% of patients receiving NTCD-M3 and 60% and 33% of placebo patients, respectively. Serious treatment-emergent adverse events were reported in 7% of patients receiving placebo and 3% of all patients who received NTCD-M3. Headache was reported in 10% of patients receiving NTCD-M3 and 2% of placebo patients. Fecal colonization occurred in 69% of NTCD-M3 patients: 71% with 10(7) spores/d and 63% with 10(4) spores/d. Recurrence of CDI occurred in 13 (30%) of 43 placebo patients and 14 (11%) of 125 NTCD-M3 patients (odds ratio [OR], 0.28; 95% CI, 0.11-0.69; P = .006); the lowest recurrence was in 2 (5%) of 43 patients receiving 10(7) spores/d for 7 days (OR, 0.1; 95% CI, 0.0-0.6; P = .01 vs placebo]). Recurrence occurred in 2 (2%) of 86 patients who were colonized vs 12 (31%) of 39 patients who received NTCD-M3 and were not colonized (OR, 0.01; 95% CI, 0.00-0.05; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with CDI who clinically recovered following treatment with metronidazole or vancomycin, oral administration of spores of NTCD-M3 was well tolerated and appeared to be safe. Nontoxigenic C. difficile strain M3 colonized the gastrointestinal tract and significantly reduced CDI recurrence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01259726.
Assuntos
Clostridioides difficile , Enterocolite Pseudomembranosa/prevenção & controle , Prevenção Secundária/métodos , Esporos Bacterianos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Diarreia/etiologia , Método Duplo-Cego , Enterocolite Pseudomembranosa/complicações , Enterocolite Pseudomembranosa/tratamento farmacológico , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Lacrimal gland (LG) stem cell-based therapy is a promising strategy for lacrimal gland diseases. However, the lack of a reliable, serum-free culture method to obtain a sufficient number of LG stem cells (LGSCs) is one obstacle for further research and application. The three-dimensional (3D), serum-free culture method for adult mouse LGSCs is well established and shown here. The LGSCs could be continuously passaged and induced to differentiate to acinar or ductal-like cells. For the LGSC primary culture, the LGs from 6-8-week-old mice were digested with dispase, collagenase I, and trypsin-EDTA. A total of 1 × 104 single cells were seeded into 80 µL of matrix gel-lacrimal gland stem cell medium (LGSCM) matrix in each well of a 24-well plate, precoated with 20 µL of matrix gel-LGSCM matrix. The mix was solidified after incubation for 20 min at 37 °C, and 600 µL of LGSCM added. For LGSC maintenance, LGSCs cultured for 7 days were disaggregated into single cells by dispase and trypsin-EDTA. The single cells were implanted and cultured according to the method used in the LGSC primary culture. LGSCs could be passaged over 40 times and continuously express stem/progenitor cell markers Krt14, Krt5, P63, and nestin. LGSCs cultured in LGSCM have self-renewal capacity and can differentiate into acinar or ductal-like cells in vitro and in vivo.
Assuntos
Aparelho Lacrimal , Animais , Células Cultivadas , Ácido Edético , Camundongos , Células-Tronco , TripsinaRESUMO
A substantial number of individuals with type 2 diabetes mellitus (T2DM) demonstrate a predominance of small dense low-density lipoprotein (sdLDL), which is associated with an increased risk of cardiovascular disease (CVD). In some cases, sdLDL persists after treatment with a statin to reduce levels of LDL. The effect of the addition of a thiazolidinedione, rosiglitazone (RSG) (4 mg/day or 8 mg/day) to statin therapy on LDL phenotype and C reactive protein (CRP) levels was investigated in a 12- week, placebo-controlled study of 72 T2DM patients who were well controlled and on a statin, but who had persistently predominant sdLDL. Addition of RSG 8 mg to statin therapy significantly increased LDL buoyancy (relative flotation +0.014, p = 0.003) and LDL particle size (+4.2A, p = 0.001) from baseline and relative to the change with placebo (+0.014 and +3.8A; p = 0.03 and p = 0.04, respectively), and was associated with a non-significant decrease in sdLDL. RSG 8 mg moderately, but significantly, increased total cholesterol (by 12.2%, p = 0.004), LDL-cholesterol (11.2%, p = 0.02) and intermediate-density lipoprotein (IDL)-cholesterol from baseline but did not increase total or LDL apolipoprotein B. RSG 4 mg and 8 mg significantly reduced CRP compared with placebo (-44.9% and -48.0%; p = 0.008 and p = 0.004, respectively), and significantly reduced insulin resistance and fasting plasma glucose from baseline. Addition of RSG to statin therapy may further reduce cardiovascular risk by improving the LDL phenotype, as well as reducing insulin resistance and CRP levels. However, the increase in IDL may be proatherogenic and must be considered when assessing the benefits of rosiglitazone.
Assuntos
Proteína C-Reativa/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Lipoproteínas LDL/efeitos dos fármacos , Tiazolidinedionas/uso terapêutico , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Lipoproteínas LDL/sangue , Lipoproteínas LDL/química , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Inibidor 1 de Ativador de Plasminogênio/sangue , Rosiglitazona , Tiazolidinedionas/farmacologia , Resultado do TratamentoRESUMO
BACKGROUND: Markers of systemic inflammation (eg, C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be "nontraditional" risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future myocardial infarction or unstable angina. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. The purpose of this analysis was to determine whether rosiglitazone alters serum concentrations of CRP, IL-6, MMP-9, and white blood cell count (WBC) and to examine the relationship of these effects with demographic and disease variables. METHODS AND RESULTS: CRP, IL-6, MMP-9, and WBC were analyzed from stored frozen serum samples obtained from patients with type 2 diabetes who completed a 26-week randomized, double-blind, placebo-controlled study. After 26 weeks of rosiglitazone treatment, the percentage reductions in mean CRP, MMP-9, and WBC levels were statistically significant compared with baseline and placebo (P<0.01). The percentage reduction in mean IL-6 was small and similar in the rosiglitazone and placebo groups. The change in each inflammatory marker from baseline to week 26 was significantly correlated (P<0.05) with each of the other markers, as well as with the homeostasis model assessment estimate of insulin resistance. CONCLUSIONS: Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazóis/uso terapêutico , Tiazolidinedionas , Fatores de Transcrição/agonistas , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/análise , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Método Duplo-Cego , Feminino , Humanos , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Fatores de Risco , RosiglitazonaRESUMO
OBJECTIVE: To compare the metabolic effects of rosiglitazone, an antidiabetic agent of the thiazolidinedione class, in patients with type 2 diabetes with fair to moderate glycaemic control (glycosylated haemoglobin (HbA(lc)) < 9%) and poor glycaemic control (HbA(lc) > or = 9%). RESEARCH DESIGN AND METHODS: Data were pooled from two 26-week, randomised, placebo-controlled, double-blind studies of rosiglitazone (4 and 8 mg/day). RESULTS: After 26 weeks of treatment, HbA(lc) was significantly reduced (p < 0.05) compared with baseline and placebo in patients taking rosiglitazone 8 mg/day for both HbA(lc) stratifications, with greater reductions in patients with baseline HbA(lc) > or = 9%. After 26 weeks of treatment, reductions in fasting plasma glucose (FPG) were significant (p < 0.05) compared with baseline and placebo in both rosiglitazone treatment groups for both HbA(lc) stratifications, with greater reductions in the group with poor glycaemic control. Rosiglitazone significantly improved insulin sensitivity (p < 0.05) compared with baseline in patients with baseline HbA(lc) < 9%. Rosiglitazone significantly improved beta-cell function (p < 0.05) compared with baseline with more improvement in the group with baseline HbA(lc) > or = 9%. These improvements were statistically significant compared with placebo, regardless of HbA(lc) stratification. CONCLUSION: Rosiglitazone significantly improved HbA(lc) and FPG levels in patients with type 2 diabetes, with the greatest improvements observed in patients with baseline HbA(lc) levels > or =9%.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Hipoglicemiantes/farmacologia , Tiazóis/farmacologia , Tiazolidinedionas , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Humanos , Hipoglicemiantes/uso terapêutico , Pessoa de Meia-Idade , Rosiglitazona , Tiazóis/uso terapêuticoRESUMO
BACKGROUND: Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. METHODS: In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645. FINDINGS: Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0.95), but not when measured by plasma cytomegalovirus DNA PCR (27.8%vs 30.4%; OR 0·88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6%vs 37.4%; OR 0.73, 0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). INTERPRETATION: Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. FUNDING: ViroPharma Incorporated.
Assuntos
Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Quimioprevenção/métodos , Infecções por Citomegalovirus/prevenção & controle , Placebos/administração & dosagem , Ribonucleosídeos/administração & dosagem , Transplante de Células-Tronco , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Canadá , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ribonucleosídeos/efeitos adversos , Transplante , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
The effect of the insulin sensitizer rosiglitazone (RSG) on biological markers of endothelial dysfunction in subjects with type 2 diabetes mellitus (T2DM) was investigated in a 12-week, multi-center, randomized, double-blind study. One hundred and thirty-six subjects aged 40-70 years, with FPG > or = 7.0 and < or = 15.0 mmol/l, previously treated with a single oral anti-diabetic agent or diet/exercise, were randomized to RSG 8 mg/day (n=65) or placebo (PBO, n=71). Results revealed that RSG significantly reduced soluble (s)E-selectin by -10.9% (P=0.004) compared with PBO, but did not significantly alter soluble vascular cell adhesion molecule-1 (+0.6%, P=NS). Compared with PBO, RSG also significantly reduced plasminogen activator inhibitor-1 (-36.9%, P<0.001), tissue plasminogen activator antigen (-22.7%, P<0.001), FPG (-2.8 mmol/l, P<0.001), fasting fructosamine (-42.0 mg/dl, P<0.001). Post-prandial AUC(0-4h) for free fatty acids (FFAs) reduced by -6.5 mg/dl*h from baseline (P=0.03), a change that positively and significantly correlated with changes in sE-selectin (r=0.22, P=0.05). The incidence of adverse events was similar in the two groups (RSG: 35.4%; PBO: 40.8%); the majority mild or moderate. These data support the hypothesis that, in patients with T2DM, rosiglitazone has beneficial effects on biological markers of endothelial dysfunction. Improvements in insulin sensitivity and decreases in FFAs may play a role in these effects.