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1.
ACS Infect Dis ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38619138

RESUMO

Peptidoglycan synthesis is an underutilized drug target in Mycobacterium tuberculosis (Mtb). Diazabicyclooctanes (DBOs) are a class of broad-spectrum ß-lactamase inhibitors that also inhibit certain peptidoglycan transpeptidases that are important in mycobacterial cell wall synthesis. We evaluated the DBO durlobactam as an inhibitor of BlaC, the Mtb ß-lactamase, and multiple Mtb peptidoglycan transpeptidases (PonA1, LdtMt1, LdtMt2, LdtMt3, and LdtMt5). Timed electrospray ionization mass spectrometry (ESI-MS) captured acyl-enzyme complexes with BlaC and all transpeptidases except LdtMt5. Inhibition kinetics demonstrated durlobactam was a potent and efficient DBO inhibitor of BlaC (KI app 9.2 ± 0.9 µM, k2/K 5600 ± 560 M-1 s-1) and similar to clavulanate (KI app 3.3 ± 0.6 µM, k2/K 8400 ± 840 M-1 s-1); however, durlobactam had a lower turnover number (tn = kcat/kinact) than clavulanate (1 and 8, respectively). KI app values with durlobactam and clavulanate were similar for peptidoglycan transpeptidases, but ESI-MS captured durlobactam complexes at more time points. Molecular docking and simulation demonstrated several productive interactions of durlobactam in the active sites of BlaC, PonA1, and LdtMt2. Antibiotic susceptibility testing was conducted on 11 Mtb isolates with amoxicillin, ceftriaxone, meropenem, imipenem, clavulanate, and durlobactam. Durlobactam had a minimum inhibitory concentration (MIC) range of 0.5-16 µg/mL, similar to the ranges for meropenem (1-32 µg/mL) and imipenem (0.5-64 µg/mL). In ß-lactam + durlobactam combinations (1:1 mass/volume), MICs were lowered 4- to 64-fold for all isolates except one with meropenem-durlobactam. This work supports further exploration of novel ß-lactamase inhibitors that target BlaC and Mtb peptidoglycan transpeptidases.

2.
Antimicrob Agents Chemother ; 68(3): e0139923, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38329330

RESUMO

Non-clinical antibiotic development relies on in vitro susceptibility and infection model studies. Validating the achievement of the targeted drug concentrations is essential to avoid under-estimation of drug effects and over-estimation of resistance emergence. While certain ß-lactams (e.g., imipenem) and ß-lactamase inhibitors (BLIs; clavulanic acid) are believed to be relatively unstable, limited tangible data on their stability in commonly used in vitro media are known. We aimed to determine the thermal stability of 10 ß-lactams and 3 BLIs via LC-MS/MS in cation-adjusted Mueller Hinton broth at 25 and 36°C as well as agar at 4 and 37°C, and in water at -20, 4, and 25°C. Supplement dosing algorithms were developed to achieve broth concentrations close to their target over 24 h. During incubation in broth (pH 7.25)/agar, degradation half-lives were 16.9/21.8 h for imipenem, 20.7/31.6 h for biapenem, 29.0 h for clavulanic acid (studied in broth only), 23.1/71.6 h for cefsulodin, 40.6/57.9 h for doripenem, 46.5/64.6 h for meropenem, 50.8/97.7 h for cefepime, 61.5/99.5 h for piperacillin, and >120 h for all other compounds. Broth stability decreased at higher pH. All drugs were ≥90% stable for 72 h in agar at 4°C. Degradation half-lives in water at 25°C were >200 h for all drugs except imipenem (14.7 h, at 1,000 mg/L) and doripenem (59.5 h). One imipenem supplement dose allowed concentrations to stay within ±31% of their target concentration. This study provides comprehensive stability data on ß-lactams and BLIs in relevant in vitro media using LC-MS/MS. Future studies are warranted applying these data to antimicrobial susceptibility testing and assessing the impact of ß-lactamase-related degradation.


Assuntos
Inibidores de beta-Lactamases , beta-Lactamas , Inibidores de beta-Lactamases/farmacologia , beta-Lactamas/farmacologia , Doripenem , Ágar , Cromatografia Líquida , Espectrometria de Massas em Tandem , Antibacterianos/farmacologia , Penicilinas , Ácido Clavulânico/farmacologia , Imipenem/farmacologia , Água , Testes de Sensibilidade Microbiana
3.
Org Lett ; 26(6): 1277-1281, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38323858

RESUMO

Fluoroformamidines are an underutilized and understudied functional group despite combining two of the most highly prized elements in drug design: nitrogen and fluorine. We report a practical and modular synthesis of fluoroformamidines via the rearrangement of in situ-generated amidoximes. High yields in just 60 s at room temperature highlight the efficiency of this protocol. Furthermore, fluoroformamidines proved to be useful intermediates in the synthesis of diverse ureas and carbamimidates.

4.
BMC Infect Dis ; 24(1): 1, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166696

RESUMO

BACKGROUND: As the population acquires immunity through vaccination and natural infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding the intrinsic severity of coronavirus disease (COVID-19) is becoming challenging. We aimed to evaluate the intrinsic severity regarding circulating variants of SARS-CoV-2 and to compare this between vaccinated and unvaccinated individuals. METHODS: With unvaccinated and initially infected confirmed cases of COVID-19, we estimated the case severity rate (CSR); case fatality rate (CFR); and mortality rate (MR), including severe/critical cases and deaths, stratified by age and compared by vaccination status according to the period regarding the variants of COVID-19 and vaccination. The overall rate was directly standardized with age. RESULTS: The age-standardized CSRs (aCSRs) of the unvaccinated group were 2.12%, 5.51%, and 0.94% in the pre-delta, delta, and omicron period, respectively, and the age-standardized CFRs (aCFRs) were 0.60%, 2.49%, and 0.63% in each period, respectively. The complete vaccination group had lower severity than the unvaccinated group over the entire period showing under 1% for the aCSR and 0.5% for the aCFR. The age-standardized MR of the unvaccinated group was 448 per million people per month people in the omicron period, which was 11 times higher than that of the vaccinated group. In terms of age groups, the CSR and CFR sharply increased with age from the 60 s and showed lower risk reduction in the 80 s when the period changed to the omicron period. CONCLUSIONS: The intrinsic severity of COVID-19 was the highest in the delta period, with over 5% for the aCSR, whereas the completely vaccinated group maintained below 1%. This implies that when the population is vaccinated, the impact of COVID-19 will be limited, even if a new mutation appears. Moreover, considering the decreasing intrinsic severity, the response to COVID-19 should prioritize older individuals at a higher risk of severe disease.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Mutação , Comportamento de Redução do Risco , Vacinação
5.
Antimicrob Agents Chemother ; 68(2): e0139323, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38169309

RESUMO

Aminoglycosides are important treatment options for serious lung infections, but modeling analyses to quantify their human lung epithelial lining fluid (ELF) penetration are lacking. We estimated the extent and rate of penetration for five aminoglycosides via population pharmacokinetics from eight published studies. The area under the curve in ELF vs plasma ranged from 50% to 100% and equilibration half-lives from 0.61 to 5.80 h, indicating extensive system hysteresis. Aminoglycoside ELF peak concentrations were blunted, but overall exposures were moderately high.


Assuntos
Aminoglicosídeos , Antibacterianos , Humanos , Antibacterianos/farmacocinética , Pulmão , Amicacina
6.
J Pharm Sci ; 113(1): 202-213, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37879409

RESUMO

Colistin is a polymyxin and peptide antibiotic that can yield rapid bacterial killing, but also leads to resistance emergence. We aimed to develop a novel experimental and Quantitative and Systems Pharmacology approach to distinguish between inducible and non-inducible resistance. Viable count profiles for the total and less susceptible populations of Pseudomonas aeruginosa ATCC 27853 from static and dynamic in vitro infection models were simultaneously modeled. We studied low and normal initial inocula to distinguish between inducible and non-inducible resistance. A novel cutoff filter approach allowed us to describe the eradication and inter-conversion of bacterial populations. At all inocula, 4.84 mg/L of colistin (sulfate) yielded ≥4 log10 killing, followed by >4 log10 regrowth. A pre-existing, less susceptible population was present at standard but not at low inocula. Formation of a non-pre-existing, less susceptible population was most pronounced at intermediate colistin (sulfate) concentrations (0.9 to 5 mg/L). Both less susceptible populations inter-converted with the susceptible population. Simultaneously modeling of the total and less susceptible populations at low and standard inocula enabled us to identify the de novo formation of an inducible, less susceptible population. Inducible resistance at intermediate colistin concentrations highlights the importance of rapidly achieving efficacious polymyxin concentrations by front-loaded dosage regimens.


Assuntos
Colistina , Infecções por Pseudomonas , Humanos , Colistina/farmacologia , Pseudomonas aeruginosa , Farmacologia em Rede , Antibacterianos , Infecções por Pseudomonas/tratamento farmacológico , Sulfatos , Testes de Sensibilidade Microbiana
7.
RSC Adv ; 13(43): 30129-30132, 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37842679

RESUMO

Herein, we report a modified Beckmann rearrangement using sulfone iminium fluoride (SIF) reagents to rapidly synthesize imidoyl fluoride intermediates. Subsequently, amidine and imidate products can be formed following the introduction of amine and alcohol nucleophiles, respectively. Overall, approximately 50 amidine and imidate products have been isolated in high yields utilizing mild conditions.

8.
J Korean Med Sci ; 38(27): e214, 2023 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-37431542

RESUMO

BACKGROUND: We aimed to analyze the risk factors for sudden death after diagnosis of coronavirus disease 2019 (COVID-19) in South Korea and to provide evidence for informing prevention and control interventions for patients at risk of sudden death. METHODS: We included 30,302 COVID-19 related deaths registered in the patient management information system (Central Disease Control Headquarters) between January 1, 2021, and December 15, 2022. We collected their epidemiological data recorded by the reporting city, province, or country. We performed multivariate logistic regression analysis to identify risk factors for sudden death after diagnosis of COVID-19. RESULTS: Among the 30,302 deaths, there were 7,258 (24.0%) and 23,044 (76.0%) sudden and non-sudden deaths, respectively. Sudden death means a person who died within 2 days of diagnosis and who did not receive inpatient treatment. Underlying condition, vaccination status, and place of death were significantly associated with the survival period in all age groups. Moreover, region, sex, and prescription were significantly associated with the survival period only in certain age groups. However, reinfection was not significantly associated with the survival period in any age group. CONCLUSION: To our knowledge, this is the first study on the risk factors for sudden death after a diagnosis of COVID-19, which included age, underlying condition, vaccination status, and place of death. Additionally, individuals aged < 60 years without an underlying condition were at high risk for sudden death. However, this group has relatively low interest in health, as can be seen from the high non-vaccination rate (16.1% of the general population vs. 61.6% of the corresponding group). Therefore, there is a possibility for the presence of an uncontrolled underlying disease in this population. In addition, many sudden deaths occurred due to delayed hospital visits to continue economic activities even after the onset of COVID-19 symptoms (7 days overall vs. 10 days average for the group). In conclusion, 'continued interest in health' is a key factor in avoiding sudden death in the economically active group (under 60 years of age).


Assuntos
COVID-19 , Humanos , Pessoa de Meia-Idade , COVID-19/epidemiologia , República da Coreia/epidemiologia , Fatores de Risco , Morte Súbita/epidemiologia , Morte Súbita/etiologia , Hospitalização , Teste para COVID-19
9.
Osong Public Health Res Perspect ; 14(2): 89-99, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37183329

RESUMO

OBJECTIVES: This study aimed to classify coronavirus disease 2019 (COVID-19)-related deaths according to whether COVID-19 was listed as the cause of death, and to investigate the differences in demographic characteristics and risk factors for COVID-19 death classifications. METHODS: A total of 5,625 deaths in South Korea among patients with confirmed COVID-19 from January 20, 2020 to December 31, 2021 were selected. Excluding false reports and unnatural deaths, 5,597 deaths were analyzed. Based on death report data, deaths were classified according to whether the cause of death was listed as COVID-19 (CD) or not (NCD). The epidemiological characteristics and causes of deaths were investigated using descriptive, univariate, and multivariate statistical analyses. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to analyze the risk factors. RESULTS: The case fatality ratio was 0.89% and increased with age. Additionally, 96.4% of the subjects had an underlying disease, and 53.4% died in winter. The proportion of NCDs was 9.3%, of whom 19.1% died at home and 39.0% were confirmed to have COVID-19 after death. Malignant neoplasms (102/416 vs. 637/4,442; OR, 1.71; 95% CI, 1.36-2.16; p<0.001) were significantly associated with NCD. CONCLUSION: This is the first study to analyze risk factors by cause of death using COVID-19 death report data in South Korea. These results are expected to be used as evidence for establishing a death monitoring system that can collect timely information in a new infectious disease pandemic.

10.
J Korean Med Sci ; 38(3): e21, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647219

RESUMO

As of September 3, 2022, 5,388,338 coronavirus disease 2019 (COVID-19) cases and 46 deaths (3 in 2021 and 43 in 2022) were reported in children ≤ 18 years in Korea. Cumulative confirmed cases accounted for 67.3% of the population aged ≤ 18 years and case fatality rate was 0.85/100,000. Among 46 fatal cases, 58.7% were male and median age was 7 years. Underlying diseases were present in 47.8%; neurologic diseases (63.6%) and malignancy (13.6%) most common. Only four had history of COVID-19 immunization. COVID-19 associated deaths occurred at median 2 days from diagnosis (range: -1 to 21). Among COVID-19 deaths, 41.3% occurred before admission; 2 before hospital arrival and 17 in the emergency department. Among children whose cause was documented, myocarditis, respiratory and multiorgan failure were most common. COVID-19 associated death was seen early after diagnosis in children and public health policies to provide access to medical care for children with COVID-19 are essential during the pandemic.


Assuntos
COVID-19 , Criança , Masculino , Humanos , Feminino , SARS-CoV-2 , Hospitalização , República da Coreia/epidemiologia
11.
Target Oncol ; 18(1): 147-158, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36515782

RESUMO

BACKGROUND: There is limited evidence regarding immune-related adverse events (irAEs) in Asian cancer patients treated with antibodies directed against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1). OBJECTIVE: This study aimed to investigate the clinical patterns and prognostic significance of grade 1-2 and grade ≥ 3 irAEs by PD-1/PD-L1 inhibitors in cancer patients using real-world clinical data. PATIENTS AND METHODS: We conducted a retrospective study of cancer patients who received pembrolizumab, nivolumab, or atezolizumab at a tertiary hospital in South Korea. Incidence, time to onset, and grade 1-2 and grade ≥ 3 irAE risk factors were analyzed from medical records. The association of irAE severity with progression-free survival (PFS) and prognostic factors for PFS were evaluated. RESULTS: Among a total of 431 patients, irAEs occurred in 45.2%, and 9.5% were grade ≥ 3 irAEs. There were no significant differences in the median time to onset based on severity. Risk factors for the development of grade ≥ 3 irAEs were the presence of autoimmune disorders or diabetes mellitus. The median PFS was significantly different at 13.20, 9.00 and 4.17 months for the grade 1-2, grade ≥ 3, and no irAE groups, respectively. An increase in administration cycles was associated with a reduced risk of progression in patients with grade 1-2 and grade ≥ 3 irAEs. CONCLUSIONS: The development of grade ≥ 3 irAEs was affected by comorbidities and associated with improved PFS compared with those without irAEs. Our findings identified the real-world epidemiology, risk factors, and prognostic significance of irAEs, which may guide treatment decisions of PD-1/PD-L1 inhibitors.


Assuntos
Antineoplásicos Imunológicos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Neoplasias , Humanos , Antineoplásicos Imunológicos/efeitos adversos , Análise de Dados , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos
12.
Clin Infect Dis ; 75(Suppl 3): S379-S391, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-36251546

RESUMO

BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.


Assuntos
Antraz , Anti-Infecciosos , Bacillus anthracis , Combinação Amoxicilina e Clavulanato de Potássio/uso terapêutico , Animais , Antraz/tratamento farmacológico , Antraz/prevenção & controle , Antibacterianos/farmacologia , Anti-Infecciosos/uso terapêutico , Combinação Imipenem e Cilastatina/farmacologia , Combinação Imipenem e Cilastatina/uso terapêutico , Ciprofloxacina/uso terapêutico , Doxiciclina/uso terapêutico , Glicopeptídeos/farmacologia , Glicopeptídeos/uso terapêutico , Humanos , Levofloxacino/uso terapêutico , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Modelos Animais , Tetraciclinas/uso terapêutico , Estados Unidos , beta-Lactamas/uso terapêutico
13.
Artigo em Inglês | MEDLINE | ID: mdl-33924094

RESUMO

Inappropriate polypharmacy is likely in older adults with chronic kidney disease (CKD) owing to the considerable burden of comorbidities. We aimed to describe the impact of pharmacist-led geriatric medication management service (MMS) on the quality of medication use. This retrospective descriptive study included 95 patients who received geriatric MMS in an ambulatory care clinic in a single tertiary-care teaching hospital from May 2019 to December 2019. The average age of the patients was 74.9 ± 7.3 years; 40% of them had CKD Stage 4 or 5. Medication use quality was assessed in 87 patients. After providing MMS, the total number of medications and potentially inappropriate medications (PIMs) decreased from 13.5 ± 4.3 to 10.9 ± 3.8 and 1.6 ± 1.4 to 1.0 ± 1.2 (both p < 0.001), respectively. Furthermore, the number of patients who received three or more central nervous system-active drugs and strong anticholinergic drugs decreased. Among the 354 drug-related problems identified, "missing patient documentation" was the most common, followed by "adverse effect" and "drug not indicated." The most frequent intervention was "therapy stopped". In conclusion, polypharmacy and PIMs were prevalent in older adults with CKD; pharmacist-led geriatric MMS improved the quality of medication use in this population.


Assuntos
Polimedicação , Insuficiência Renal Crônica , Idoso , Idoso de 80 Anos ou mais , Humanos , Prescrição Inadequada , Conduta do Tratamento Medicamentoso , Farmacêuticos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos
14.
Clin Pharmacol Ther ; 109(4): 1000-1020, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33576025

RESUMO

Multidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed the adoption of new technologies. It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy. Although drug development has relied on minimal inhibitory concentration testing and established in vitro and mouse infection models, the limited understanding of outer membrane permeability in Gram-negative bacteria presents major challenges. Our team has developed a platform using the latest technologies to characterize target site penetration and receptor binding in intact bacteria that inform translational modeling and guide new discovery. Enhanced assays can quantify the outer membrane permeability of ß-lactam antibiotics and ß-lactamase inhibitors using multiplex liquid chromatography tandem mass spectrometry. While ß-lactam antibiotics are known to bind to multiple different penicillin-binding proteins (PBPs), their binding profiles are almost always studied in lysed bacteria. Novel assays for PBP binding in the periplasm of intact bacteria were developed and proteins identified via proteomics. To characterize bacterial morphology changes in response to PBP binding, high-throughput flow cytometry and time-lapse confocal microscopy with fluorescent probes provide unprecedented mechanistic insights. Moreover, novel assays to quantify cytosolic receptor binding and intracellular drug concentrations inform target site occupancy. These mechanistic data are integrated by quantitative and systems pharmacology modeling to maximize bacterial killing and minimize resistance in in vitro and mouse infection models. This translational approach holds promise to identify antibiotic combination dosing strategies for patients with serious infections.


Assuntos
Técnicas Bacteriológicas/métodos , Descoberta de Drogas/métodos , Farmacorresistência Bacteriana Múltipla/fisiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/fisiologia , Animais , Membrana Celular/fisiologia , Modelos Animais de Doenças , Humanos , Modelos Teóricos , Proteínas de Ligação às Penicilinas/fisiologia , beta-Lactamas/farmacologia
15.
Psychoneuroendocrinology ; 124: 105063, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33249332

RESUMO

Previous research indicates that circulating concentrations of cortisol increase during interactions with opposite-sex others in the presence of mating cues. However, it remains unknown whether this phenomenon extends to work-related tasks in which explicit mating cues are absent. In a series of two studies, we assessed women's and men's salivary cortisol concentrations before and after completing a cooperative brainstorming (Study 1) and competitive negotiation (Study 2) task wherein they worked with same- or opposite-sex partners. Both studies revealed significant participant sex by partner sex interactions. Specifically, male participants demonstrated significantly larger increases in salivary cortisol concentrations when working alongside opposite-sex as opposed to same-sex partners on a cooperative task. In contrast, female participants demonstrated significantly larger increases in salivary cortisol concentrations when working with opposite-sex as opposed to same-sex partners on a competitive task. Opposite-sex teams also produced fewer novel ideas relative to same-sex teams on the cooperative brainstorming task; however, differences in cortisol did not account for this effect. Our research extends previous research demonstrating elevated cortisol during opposite-sex interactions in the presence of explicit mating cues to a work-related context that is divorced from mating cues.


Assuntos
Hidrocortisona , Parceiros Sexuais , Sinais (Psicologia) , Feminino , Humanos , Masculino , Homens
16.
Artigo em Inglês | MEDLINE | ID: mdl-33106266

RESUMO

Mycobacterium abscessus causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of M. abscessus infections, and the multitude of combinations that have been used clinically have had low success rates and high rates of toxicities. With ß-lactam antibiotics being safe, double ß-lactam and ß-lactam/ß-lactamase inhibitor combinations are of interest for improving the treatment of M. abscessus infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different ß-lactams in M. abscessus We determined the preferred PBP targets of 13 ß-lactams and 2 ß-lactamase inhibitors in two M. abscessus strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the ß-lactam concentrations that half-maximally inhibited Bocillin binding (50% inhibitory concentrations [IC50s]). Principal component analysis identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016 to 0.5 mg/liter) (cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031 to 1 mg/liter) (ceftriaxone and cefotaxime) or intermediate (0.35 to 16 mg/liter) (ceftazidime and cefoxitin) concentrations. Sulbactam, aztreonam, carumonam, mecillinam, and avibactam (cluster 3) inactivated the same PBPs as cephalosporins but required higher concentrations. Other penicillins (cluster 4) specifically targeted PbpA at 2 to 16 mg/liter. Carbapenems, ceftriaxone, and cefotaxime were the most promising ß-lactams since they inactivated most or all PBPs at clinically relevant concentrations. These first PBP occupancy patterns in M. abscessus provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with ß-lactams.


Assuntos
Mycobacterium abscessus , Inibidores de beta-Lactamases , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Proteínas de Ligação às Penicilinas/genética , Penicilinas , Inibidores de beta-Lactamases/farmacologia , beta-Lactamas/farmacologia
17.
Pharmaceutics ; 11(7)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295857

RESUMO

Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.

18.
J Nanosci Nanotechnol ; 14(3): 2274-9, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24745223

RESUMO

The electrical resistance behavior of graphene was studied under oxidizing and reducing gas exposure. The graphene surface was modified via oxyfluorination to obtain a specific surface area and oxygen functional groups. Fluorine radicals provided improved pore structure and introduction of an oxygen functional group. A high-performance gas sensor was obtained based on enlarged target gas adsorption sites and an enhanced electron charge transfer between the target gas and carbon surface via improved pore structure and the introduction of oxygen functional groups, respectively.


Assuntos
Monitoramento Ambiental/instrumentação , Monitoramento Ambiental/métodos , Grafite/química , Oxigênio/química , Adsorção , Poluentes Atmosféricos/análise , Carbono/química , Elétrons , Flúor/química , Gases , Microscopia Eletrônica de Transmissão , Porosidade , Propriedades de Superfície , Fatores de Tempo
19.
J Phys Chem B ; 109(13): 6204-9, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-16851686

RESUMO

Unique starlike CdS particles were prepared from the lyotropic triblock copolymer solution system. The starlike CdS consists of a spherical core and dozens of the attached conical nanolobes. From the comparative studies with the spherical and rod-shaped CdS nanoparticles, the unique photophysical property is presented for the starlike CdS particle. The experimental results suggest that the photogenerated charge carriers at the tip-edge region of the conical nanolobe in the starlike CdS system diffuse into the thicker inner part including the core region, which is possibly due to the decreasing excited state potential gradient from the tip edge to the thicker inner part. This type of charge carrier diffusion dynamics from the surrounding to the thicker inner part in this anisotropic morphology of the starlike CdS semiconductor closely resembles the energy transfer dynamics in the organic dendrimers.

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