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1.
Nat Microbiol ; 9(5): 1244-1255, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38649414

RESUMO

Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Proteínas de Bactérias , Lipopolissacarídeos , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/metabolismo , Lipopolissacarídeos/metabolismo , Animais , Infecções por Acinetobacter/microbiologia , Infecções por Acinetobacter/tratamento farmacológico , Camundongos , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Transporte Biológico , Testes de Sensibilidade Microbiana , Humanos , Microscopia Crioeletrônica , Carbapenêmicos/farmacologia , Carbapenêmicos/metabolismo , Modelos Animais de Doenças , Feminino , Transportadores de Cassetes de Ligação de ATP
2.
Clin Transl Sci ; 17(2): e13732, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38593352

RESUMO

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries.


Assuntos
Citidina/análogos & derivados , Ribonucleosídeos , Ciência Translacional Biomédica , Humanos , Citidina/farmacologia , Hidroxilaminas , SARS-CoV-2
3.
J Perinatol ; 43(9): 1145-1151, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37438484

RESUMO

OBJECTIVE: To determine the adherence and safety outcomes of a 5-day antibiotic course with a "time-out" for treatment of "blood culture-negative" pneumonia in the NICU. STUDY DESIGN: Prospective surveillance of all infants diagnosed with pneumonia at 7 NICUs from 8/2020-12/2021. Safety outcomes were defined a priori by re-initiation of antibiotic therapy within 14 days after discontinuation and overall and sepsis-related mortality. RESULTS: 128 infants were diagnosed with 136 episodes of pneumonia; 88% (n = 119) were treated with 5 days of definitive antibiotic therapy. Antibiotics were restarted within 14 days in 22 (16%) of the 136 pneumonia episodes. However, only 3 (3%) of the 119 episodes of pneumonia treated for 5 days had antibiotics restarted for pneumonia. Mortality was 5% (7/128); 5 of the 7 deaths were assessed as sepsis-related. CONCLUSION: Adherence to the 5-day definitive antibiotic treatment for "culture-negative" pneumonia was high and the intervention seemed safe.


Assuntos
Pneumonia , Sepse , Recém-Nascido , Lactente , Humanos , Unidades de Terapia Intensiva Neonatal , Estudos Prospectivos , Antibacterianos/uso terapêutico , Pneumonia/tratamento farmacológico , Sepse/epidemiologia
4.
J Perinatol ; 43(6): 741-745, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36813903

RESUMO

OBJECTIVE: On 2/2019, the Neonatal Antimicrobial Stewardship Program at Nationwide Children's Hospital recommended reducing empirical antibiotic therapy for early-onset sepsis (EOS) from 48 to 24 hours with a TIME-OUT. We describe our experience with this guideline and assess its safety. METHODS: Retrospective review of newborns evaluated for possible EOS at 6 NICUs from 12/2018-7/2019. Safety endpoints were re-initiation of antibiotics within 7 days after discontinuation of the initial course, positive bacterial blood or cerebrospinal fluid culture in the 7 days after antibiotic discontinuation, and overall and sepsis-related mortality. RESULT: Among 414 newborns evaluated for EOS, 196 (47%) received a 24 hour rule-out sepsis antibiotic course while 218 (53%) were managed with a 48 hour course. The 24-hour rule-out group were less likely to have antibiotics re-initiated and did not differ in the other predefined safety endpoints. CONCLUSION: Antibiotic therapy for suspected EOS may be discontinued safely within 24 hours.


Assuntos
Unidades de Terapia Intensiva Neonatal , Sepse , Criança , Recém-Nascido , Humanos , Sepse/tratamento farmacológico , Antibacterianos/uso terapêutico , Estudos Retrospectivos
5.
Antimicrob Agents Chemother ; 66(9): e0066922, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36005813

RESUMO

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro. Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Adenosina Trifosfatases , Animais , Antibacterianos/farmacologia , DNA Girase/genética , Camundongos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Micobactérias não Tuberculosas , Pirimidinas , Pirróis
6.
CPT Pharmacometrics Syst Pharmacol ; 10(7): 658-670, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33934558

RESUMO

Uprifosbuvir is a uridine nucleoside monophosphate prodrug inhibitor of the hepatitis C virus NS5B RNA polymerase. To quantitatively elucidate key metabolic pathways, assess the link between unmeasurable effect site concentrations and viral load reduction, and evaluate the influence of intrinsic and extrinsic factors on pharmacokinetics and pharmacodynamics, a model-informed drug development (MIDD) framework was initiated at an early stage. Originally scoped as a modeling effort focused on minimal physiologically based pharmacokinetic and covariate analyses, this project turned into a collaborative effort focused on gaining a deeper understanding of the data from drug metabolism, biopharmaceutics, pharmacometrics, and clinical pharmacology perspectives. This article presents an example of the practical execution of a MIDD-based, cooperative multidisciplinary modeling approach, creating a model that grows along with the team's integrated knowledge. Insights gained from this process could be used in forming optimal collaborations between disciplines in drug development for other investigative compounds.


Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Modelos Biológicos , Uridina/análogos & derivados , Comportamento Cooperativo , Desenvolvimento de Medicamentos/métodos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/microbiologia , Humanos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Uridina/farmacologia , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores
7.
Int J Mol Sci ; 21(13)2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32635660

RESUMO

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects on renal injuries in multiple experimental animal models of kidney diseases including AKI. However, the mass production of exosomes is a challenge not only in preclinical studies with large animals but also for successful clinical applications. In this respect, tangential flow filtration (TFF) is suitable for good manufacturing practice (GMP)-compliant large-scale production of high-quality exosomes. Until now, no studies have been reported on the use of TFF, but rather ultracentrifugation has been almost exclusively used, to isolate exosomes for AKI therapeutic application in preclinical studies. Here, we demonstrated the reproducible large-scale production of exosomes derived from adipose tissue-derived MSC (ASC-exosomes) using TFF and the lifesaving effect of the ASC-exosomes in a lethal model of cisplatin-induced rat AKI. Our results suggest the possibility of large-scale stable production of ASC-exosomes without loss of function and their successful application in life-threatening diseases.


Assuntos
Injúria Renal Aguda/terapia , Tecido Adiposo/citologia , Terapia Biológica/métodos , Exossomos , Células-Tronco Mesenquimais , Injúria Renal Aguda/induzido quimicamente , Animais , Células Cultivadas , Cisplatino , Humanos , Ratos
8.
J Med Chem ; 63(21): 12156-12170, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32633947

RESUMO

Lipophilicity has a dominant effect on many parameters that determine unbound drug exposure as well as drug potency. Despite this, analysis of a large body of drug data indicates lipophilicity has no consistent directional impact on dose. This can be rationalized based on the interplay of the effects of lipophilicity on individual parameter values in pharmacokinetic equations. We believe this undermines the effectiveness of strategies that target specific ranges for drug parameters for which lipophilicity plays such a dominant role. As a result, our research organization no longer leverages the common approach of screening for low intrinsic clearance in vitro to target high unbound exposure in vivo. Instead, we advocate for approaches less biased to lipophilicity through optimization of key parameter ratios controlling dose. We believe this improves efficiency in drug discovery by enabling exploration of broad physicochemical space.


Assuntos
Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Área Sob a Curva , Proteínas Sanguíneas/química , Proteínas Sanguíneas/metabolismo , Desenho de Fármacos , Meia-Vida , Humanos , Interações Hidrofóbicas e Hidrofílicas , Preparações Farmacêuticas/química , Ligação Proteica , Curva ROC , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacocinética
9.
Toxicol Sci ; 177(1): 281-299, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559301

RESUMO

Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Preparações Farmacêuticas , Animais , Desenvolvimento de Medicamentos , Proteína 1 Associada a ECH Semelhante a Kelch , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
10.
J Perinatol ; 40(8): 1193-1201, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32433510

RESUMO

OBJECTIVE: To test the hypothesis that infants born <30 weeks' gestation supported by Seattle-PAP will have lower rates of continuous positive airway pressure (CPAP) failure than infants supported with conventional, Fisher&Paykel-CPAP (FP-CPAP). STUDY DESIGN: Randomized trial (3/2017-01/2019) at 5 NICUs. The primary outcome was CPAP failure; subgroup analyses (gestational age, receipt antenatal corticosteroids) were performed. RESULTS: A total of 232 infants were randomized. Infants in the Seattle-PAP and FP-CPAP groups had mean gestational ages of 27.0 and 27.2 weeks, respectively. We observed no differences in rates of treatment failure between Seattle-PAP (40/112, 35.7%) and FP-CPAP (38/120, 31.7%; risk difference, 4.1%; 95% CI, -8.1-16.2; P = 0.51). Subgroup analysis indicated no differences in rates of CPAP failure. We observed no differences between the two groups in frequencies of adverse events or duration of respiratory support. CONCLUSIONS: Among infants born <30 weeks' gestation, rates of CPAP failure did not differ between Seattle-PAP and FP-CPAP.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Síndrome do Desconforto Respiratório do Recém-Nascido , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Gravidez , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia
11.
Stem Cells Transl Med ; 8(12): 1265-1271, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31599497

RESUMO

The stromal vascular fraction (SVF) is a heterogeneous population of stem/stromal cells isolated from perivascular and extracellular matrix (ECM) of adipose tissue complex (ATC). Administration of SVF holds a strong therapeutic potential for regenerative and wound healing medicine applications aimed at functional restoration of tissues damaged by injuries or chronic diseases. SVF is commonly divided into cellular stromal vascular fraction (cSVF) and tissue stromal vascular fraction (tSVF). Cellular SVF is obtained from ATC by collagenase digestion, incubation/isolation, and pelletized by centrifugation. Enzymatic disaggregation may alter the relevant biological characteristics of adipose tissue, while providing release of complex, multiattachment of cell-to-cell and cell-to-matrix, effectively eliminating the bioactive ECM and periadventitial attachments. In many countries, the isolation of cellular elements is considered as a "more than minimal" manipulation, and is most often limited to controlled clinical trials and subject to regulatory review. Several alternative, nonenzymatic methods of adipose tissue processing have been developed to obtain via minimal mechanical manipulation an autologous tSVF product intended for delivery, reducing the procedure duration, lowering production costs, decreasing regulatory burden, and shortening the translation into the clinical setting. Ideally, these procedures might allow for the integration of harvesting and processing of adipose tissue for ease of injection, in a single procedure utilizing a nonexpanded cellular product at the point of care, while permitting intraoperative autologous cellular and tissue-based therapies. Here, we review and discuss the options, advantages, and limitations of the major strategies alternative to enzymatic processing currently developed for minimal manipulation of adipose tissue. Stem Cells Translational Medicine 2019;8:1265&1271.


Assuntos
Tecido Adiposo/citologia , Separação Celular/métodos , Terapia Baseada em Transplante de Células e Tecidos/métodos , Matriz Extracelular/fisiologia , Células-Tronco/citologia , Diferenciação Celular , Humanos , Cicatrização
12.
Trials ; 20(1): 63, 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30658678

RESUMO

BACKGROUND: At birth, the majority of neonates born at <30 weeks of gestation require respiratory support to facilitate transition and ensure adequate gas exchange. Although the optimal approach to the initial respiratory management is uncertain, the American Academy of Pediatrics endorses noninvasive respiratory support with nasal continuous positive airway pressure (nCPAP) for premature neonates with respiratory insufficiency. Despite evidence for its use, nCPAP failure, requiring intubation and mechanical ventilation, is common. Recently, investigators have described a novel method to deliver bubble nCPAP, termed Seattle-PAP. While preclinical and pilot studies are encouraging regarding the potential value of Seattle-PAP, a large trial is needed to compare Seattle-PAP directly with the current standard of care for bubble nCPAP (Fisher & Paykel CPAP or FP-CPAP). METHODS/DESIGN: We designed a multicenter, non-blinded, randomized controlled trial that will enroll 230 premature infants (220/7 to 296/7 weeks of gestation). Infants will be randomized to receive Seattle-PAP or FP-CPAP. The primary outcome is respiratory failure requiring intubation and mechanical ventilation. Secondary outcomes include measures of short- and long-term respiratory morbidity and cost-effectiveness. DISCUSSION: This trial will assess whether Seattle-PAP is more efficacious and cost-effective than FP-CPAP in real-world practice among premature neonates. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03085329 . Registered on 21 March 2017.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas/métodos , Recém-Nascido Prematuro , Pulmão/fisiopatologia , Nascimento Prematuro , Respiração , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Peso ao Nascer , Pressão Positiva Contínua nas Vias Aéreas/efeitos adversos , Pressão Positiva Contínua nas Vias Aéreas/economia , Análise Custo-Benefício , Idade Gestacional , Custos de Cuidados de Saúde , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Intubação Intratraqueal , Estudos Multicêntricos como Assunto , Ohio , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Síndrome do Desconforto Respiratório do Recém-Nascido/economia , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Fatores de Tempo , Resultado do Tratamento
13.
Bioorg Med Chem Lett ; 27(4): 1094-1098, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28089699

RESUMO

The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human ß3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR studies directed towards maintaining well established ß3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Piperazinas/farmacologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/química , Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Humanos , Piperazinas/química , Piperazinas/uso terapêutico , Relação Estrutura-Atividade
14.
ACS Med Chem Lett ; 7(12): 1173-1178, 2016 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-27994759

RESUMO

A new class of hepatitis C NS3/4A inhibitors was identified by introducing a novel spirocyclic proline-P2 surrogate onto the P2-P4 macrocyclic core of MK-5172 (grazoprevir). The potency profile of new analogues showed excellent pan-genotypic activity for most compounds. The potency evaluation included the most difficult genotype 3a (EC50 values ≤10 nM) and other key genotype 1b mutants. Molecular modeling was used to design new target compounds and rationalize our results. A synthetic approach based on the Julia-Kocienski olefination and macrolactamization to assemble the P2-P4 macrocyclic core containing the novel spirocyclic proline-P2 moiety is presented as well.

15.
J Med Chem ; 59(24): 11039-11049, 2016 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-28002958

RESUMO

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.


Assuntos
Anemia/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridazinas/farmacologia , Pirimidinas/farmacologia , Administração Oral , Anemia/enzimologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
16.
Pediatrics ; 137(5)2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27244778

RESUMO

OBJECTIVE: To reduce the incidence of necrotizing enterocolitis (NEC) among very low birth weight (VLBW) infants admitted to 8 intensive care nurseries from a 2010 baseline of 8.0% to <4.0% by 2012 and sustain for 6 months using quality improvement (QI) methodology. METHODS: A multidisciplinary NEC QI team used the Vermont Oxford Network definition of NEC and the Institute for Healthcare Improvement model. The specific aims were evidenced based and included (1) standardized early human milk feedings, (2) conservative feeding guidelines during blood transfusions and indomethacin treatment, and (3) restriction of ranitidine use in VLBW infants. Inclusion criteria included VLBW infants admitted within the study period without NEC. Exclusion criteria included established NEC or spontaneous intestinal perforation unrelated to NEC. The incidence of NEC and NEC-related surgery were tracked using statistical process control methodology. RESULTS: The baseline NEC rate in 2010 was 8% (27 NEC cases in 335 VLBW infants). After initiation of early human-milk feeding and conservative feeds during blood transfusions guidelines in November 2011, only 3.1% (19 of 606 VLBW infants) had developed NEC through December 2013 (P = .001). Special cause variation was noted in June 2012 establishing a new centerline at 3.1%. NEC-related mortality decreased from a 2010 baseline mean of 2.7% to a new baseline mean of 0.9% from January 2011 to December 2013. CONCLUSIONS: Implementation of QI initiatives decreased the NEC rate from 8.0% to <4.0%. Early human milk feedings and conservative feeding during blood transfusion policies appear to have significant impact on NEC reduction.


Assuntos
Enterocolite Necrosante/prevenção & controle , Doenças do Prematuro/prevenção & controle , Recém-Nascido de muito Baixo Peso , Leite Humano , Melhoria de Qualidade , Anti-Inflamatórios não Esteroides/uso terapêutico , Transfusão de Sangue , Enterocolite Necrosante/epidemiologia , Enterocolite Necrosante/mortalidade , Humanos , Incidência , Indometacina/uso terapêutico , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/mortalidade , Guias de Prática Clínica como Assunto , Ranitidina/uso terapêutico
17.
ACS Med Chem Lett ; 7(1): 111-6, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26819676

RESUMO

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

18.
Bioorg Med Chem Lett ; 26(1): 55-9, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26590100

RESUMO

The paper will describe the synthesis and SAR studies that led to the discovery of benzamide (reverse amide) as potent and selective human ß3-adrenergic receptor agonist. Based on conformationally restricted pyrrolidine scaffold we discovered earlier, pyrrolidine benzoic acid intermediate 22 was synthesized. From library synthesis and further optimization efforts, several structurally diverse reverse amides such as 24c and 24i were found to have excellent human ß3-adrenergic potency and good selectivity over the ß1 and ß2 receptors. In addition to human ß1, ß2, ß3 and hERG data, PK of selected compounds will be described.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Benzamidas/farmacologia , Descoberta de Drogas , Receptores Adrenérgicos beta 3/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/síntese química , Agonistas de Receptores Adrenérgicos beta 3/química , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
19.
J Med Chem ; 59(2): 609-23, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26709102

RESUMO

The discovery of vibegron, a potent and selective human ß3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical ß3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived ß3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/uso terapêutico , Pirimidinonas/uso terapêutico , Pirrolidinas/uso terapêutico , Bexiga Urinária Hiperativa/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 3/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/toxicidade , Animais , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Feminino , Humanos , Lipidoses/induzido quimicamente , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Pirimidinonas/farmacocinética , Pirimidinonas/toxicidade , Pirrolidinas/farmacocinética , Pirrolidinas/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Micção/efeitos dos fármacos , Difração de Raios X
20.
J Org Chem ; 80(18): 9292-6, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26302268

RESUMO

Bromination reactions of substituted and ring fused phenols were studied by both experiment (t-BuNH-Br) and computation (density functional theory). The outcomes support each other, indicating a clear and predictable regioselective preference among 3,4-bis-alkylated and 3,4-ring-fused phenols.

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