Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.591
Filtrar
1.
Expert Opin Pharmacother ; 20(17): 2169-2184, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31500471

RESUMO

Introduction: Antimicrobial resistance in Gram-negative pathogens is a significant threat to global health. ß-Lactams (BL) are one of the safest and most-prescribed classes of antibiotics on the market today. The acquisition of ß-lactamases, especially those which hydrolyze carbapenems, is eroding the efficacy of BLs for the treatment of serious infections. During the past decade, significant advances were made in the development of novel BL-ß-lactamase inhibitor (BLI) combinations to target ß-lactamase-mediated resistant Gram-negatives.Areas covered: The latest progress in 20 different approved, developing, and preclinical BL-BLI combinations to target serine ß-lactamases produced by Gram-negatives are reviewed based on primary literature, conference abstracts (when available), and US clinical trial searches within the last 5 years. The majority of the compounds that are discussed are being evaluated as part of a BL-BLI combination.Expert opinion: The current trajectory in BLI development is promising; however, a significant challenge resides in the selection of an appropriate BL partner as well as the development of resistance linked to the BL partner. In addition, dosing regimens for these BL-BLI combinations need to be critically evaluated. A revolution in bacterial diagnostics is essential to aid clinicians in the appropriate selection of novel BL-BLI combinations for the treatment of serious infections.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Ácidos Borônicos/química , Ácidos Borônicos/uso terapêutico , Cefalosporinas/química , Cefalosporinas/uso terapêutico , Ensaios Clínicos como Assunto , Combinação de Medicamentos , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Meropeném/química , Meropeném/uso terapêutico , Tazobactam/química , Tazobactam/uso terapêutico
2.
Chem Soc Rev ; 48(13): 3513-3536, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31157810

RESUMO

Bioconjugates are multifunctional constructs in which biomolecules like peptides, proteins, vitamins and nucleic acids are endowed with the properties of specific payloads. These constructs recently emerged as a new generation of high-precision therapeutics, with several representatives reaching the market. This success stimulated an intense search for new biocompatible synthetic methodologies to connect both components and to control the bioconjugate's function. Despite the remarkable advances made in this field, most of the technologies developed for the construction of bioconjugates were engineered to yield stable constructs that can endure complex physiological conditions. Because of this, the use of reversible covalent bonds in the synthesis of bioconjugates has been rather overlooked, notwithstanding the potential of this strategy to generate stimuli responsive constructs that may operate in areas like the selective delivery of drugs, live-cell imaging and new theranostic approaches. Boronic acids are a well-known class of reagents that have been widely used in modern synthesis for the formation of C-C and C-heteroatom bonds. Apart from this, boronic acids exhibit an exquisite reversible coordination profile that can be explored as a molecular construction tool featuring specific mechanisms to control the structure and biological properties of bioconjugates. In this review, the use of boronic acids in the construction of therapeutically useful bioconjugates will be discussed, focusing on the molecular mechanisms that allow the use of these reagents as bioconjugation warheads, as central pieces of linker structures and as functional payloads.


Assuntos
Materiais Biocompatíveis/química , Ácidos Borônicos/química , Animais , Materiais Biocompatíveis/uso terapêutico , Ácidos Borônicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Desenho de Drogas , Humanos , Nanomedicina Teranóstica
3.
J Pediatric Infect Dis Soc ; 8(3): 251-260, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30793757

RESUMO

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several ß-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Carbapenêmicos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Compostos Azabicíclicos/uso terapêutico , Aztreonam/uso terapêutico , Ácidos Borônicos/uso terapêutico , Ceftazidima/uso terapêutico , Cefalosporinas/uso terapêutico , Combinação Imipenem e Cilastatina/uso terapêutico , Combinação de Medicamentos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Meropeném/uso terapêutico , Tazobactam/uso terapêutico
4.
Artigo em Inglês | MEDLINE | ID: mdl-30323049

RESUMO

We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosa and Acinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Meropeném/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , Animais , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/isolamento & purificação
5.
Artigo em Inglês | MEDLINE | ID: mdl-30578403

RESUMO

We report a case of a 24-year-old liver transplant recipient who developed hepatic artery thrombosis and graft failure, which was complicated by subphrenic abscess and persistent Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteremia. Ceftazidime-avibactam treatment led to emergence of resistance, and alternative combination therapy failed due to persistent infection and toxicity. The infection resolved after initiation of meropenem-vaborbactam, which created a bridge to retransplantation. Treatment-emergent ceftazidime-avibactam resistance is increasingly recognized, suggesting a role for meropenem-vaborbactam.


Assuntos
Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Ácidos Borônicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Transplante de Fígado/efeitos adversos , Meropeném/uso terapêutico , Antibacterianos/farmacologia , Compostos Azabicíclicos/farmacologia , Proteínas da Membrana Bacteriana Externa/genética , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Ceftazidima/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Artéria Hepática/patologia , Humanos , Klebsiella pneumoniae/genética , Masculino , Testes de Sensibilidade Microbiana , Terapia de Salvação/métodos , Trombose/patologia , Adulto Jovem , beta-Lactamases/metabolismo
6.
Nursing ; 48(10): 32-43, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30192268

RESUMO

This article discusses eight drugs recently approved by the FDA, including their indications and contraindications, precautions, dosage, and nursing considerations. The article also includes summary charts on 14 recently approved antineoplastic drugs and four drugs approved for rare disorders.


Assuntos
Aprovação de Drogas , Acetatos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Combinação de Medicamentos , Fluoroquinolonas/uso terapêutico , Humanos , Meropeném , Metronidazol/análogos & derivados , Metronidazol/uso terapêutico , Nitroimidazóis/uso terapêutico , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Peptídeos/uso terapêutico , Prostaglandinas F Sintéticas/uso terapêutico , Quinazolinas/uso terapêutico , Tienamicinas/uso terapêutico , Estados Unidos , United States Food and Drug Administration
7.
Drugs ; 78(12): 1259-1270, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30128699

RESUMO

The global threat of the spread of carbapenem resistance in Enterobacteriaceae has led to the search for new antibacterials. Intravenous meropenem/vaborbactam (Vabomere™) is the first carbapenem/ß-lactamase inhibitor combination approved in the USA for use in patients with complicated urinary tract infections (cUTIs), including pyelonephritis. Vaborbactam is a potent inhibitor of class A serine carbapenemases, which, when combined with the antibacterial meropenem, restores the activity of meropenem against ß-lactamase producing Enterobacteriaceae, particularly Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae. Meropenem/vaborbactam demonstrated excellent in vitro activity against Gram-negative clinical isolates, including KPC- and extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. In the phase 3, noninferiority TANGO I trial in patients with cUTIs, intravenous meropenem/vaborbactam was noninferior to intravenous piperacillin/tazobactam for overall success (composite of clinical cure and microbial eradication; FDA primary endpoint) and microbial eradication (EMA primary endpoint). In subsequent superiority testing, meropenem/vaborbactam was superior to piperacillin/tazobactam for overall success. Meropenem/vaborbactam was generally well tolerated, with a tolerability profile generally similar to that of piperacillin/tazobactam. TANGO I did not assess the efficacy of meropenem/vaborbactam for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and meropenem/vaborbactam is currently not indicated for these patients. Available evidence indicates that meropenem/vaborbactam is a useful treatment option for patients with cUTIs.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Meropeném/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Aprovação de Drogas , Combinação de Medicamentos , Farmacorresistência Bacteriana , Enterobacteriaceae/efeitos dos fármacos , Humanos , Meropeném/farmacologia , Combinação Piperacilina e Tazobactam/farmacologia , Combinação Piperacilina e Tazobactam/uso terapêutico , Resultado do Tratamento , Estados Unidos , Infecções Urinárias/microbiologia , Infecções Urinárias/fisiopatologia , Inibidores de beta-Lactamases/farmacologia
8.
Vet Comp Oncol ; 16(4): 544-553, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29998615

RESUMO

Osteosarcoma, a common malignancy in large dog breeds, typically metastasises from long bones to lungs and is usually fatal within 1 to 2 years of diagnosis. Better therapies are needed for canine patients and their human counterparts, a third of whom die within 5 years of diagnosis. We compared the in vitro sensitivity of canine osteosarcoma cells derived from 4 tumours to the currently used chemotherapy drugs doxorubicin and carboplatin, and 4 new anti-cancer drugs. Agents targeting histone deacetylases or PARP were ineffective. Two of the 4 cell lines were somewhat sensitive to the BH3-mimetic navitoclax. The proteasome inhibitor bortezomib potently induced caspase-dependent apoptosis, at concentrations substantially lower than levels detected in the bones and lungs of treated rodents. Co-treatment with bortezomib and either doxorubicin or carboplatin was more toxic to canine osteosarcoma cells than each agent alone. Newer proteasome inhibitors carfilzomib, ixazomib, oprozomib and delanzomib manifested similar activities to bortezomib. Human osteosarcoma cells were as sensitive to bortezomib as the canine cells, but slightly less sensitive to the newer drugs. Human osteoblasts were less sensitive to proteasome inhibition than osteosarcoma cells, but physiologically relevant concentrations were toxic. Such toxicity, if replicated in vivo, may impair bone growth and strength in adolescent human osteosarcoma patients, but may be tolerated by canine patients, which are usually diagnosed later in life. Proteasome inhibitors such as bortezomib may be useful for treating canine osteosarcoma, and ultimately may improve outcomes for human patients if their osteoblasts survive exposure in vivo, or if osteoblast toxicity can be managed.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Compostos de Anilina/uso terapêutico , Animais , Neoplasias Ósseas/veterinária , Compostos de Boro/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib/uso terapêutico , Carboplatina/uso terapêutico , Linhagem Celular Tumoral , Cães , Doxorrubicina/uso terapêutico , Glicina/análogos & derivados , Glicina/uso terapêutico , Humanos , Oligopeptídeos/uso terapêutico , Osteossarcoma/veterinária , Sulfonamidas/uso terapêutico , Treonina/análogos & derivados , Treonina/uso terapêutico
9.
Future Microbiol ; 13: 971-983, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29692218

RESUMO

Meropenem-vaborbactam is a fixed-dose combination product of a carbapenem and a cyclic boronic acid ß-lactamase inhibitor with potent in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE). The efficacy of meropenem-vaborbactam for the treatment of complicated urinary tract infections and acute pyelonephritis was demonstrated in a Phase III trial (TANGO I). Preliminary data from TANGO II, a separate Phase III study, support the efficacy of meropenem-vaborbactam for the treatment of infections caused by CRE. Overall, meropenem-vaborbactam appears to be safe and well tolerated. It has favorable toxicity, pharmacokinetic and pharmacodynamic profiles compared with other antibiotics with activity against CRE. Meropenem-vaborbactam is an important addition to the current armamentarium of antimicrobial agents with activity against K. pneumoniae carbapenemase-producing CRE.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Meropeném/uso terapêutico , Inibidores de beta-Lactamases/uso terapêutico , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Meropeném/efeitos adversos , Meropeném/farmacocinética , Meropeném/farmacologia , Resultado do Tratamento , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/efeitos adversos , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/farmacologia
10.
J Med Chem ; 61(8): 3503-3515, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29605999

RESUMO

A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.


Assuntos
Aminopterina/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Peróxido de Hidrogênio/química , Metotrexato/análogos & derivados , Metotrexato/uso terapêutico , Pró-Fármacos/uso terapêutico , Aminopterina/síntese química , Aminopterina/farmacocinética , Aminopterina/toxicidade , Animais , Antirreumáticos/síntese química , Antirreumáticos/farmacocinética , Antirreumáticos/toxicidade , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/metabolismo , Ácidos Borônicos/síntese química , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/uso terapêutico , Ácidos Borônicos/toxicidade , Colágeno Tipo II/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Células MCF-7 , Masculino , Metotrexato/farmacocinética , Metotrexato/toxicidade , Camundongos Endogâmicos DBA , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pró-Fármacos/toxicidade , Solubilidade
11.
Eur J Clin Microbiol Infect Dis ; 37(8): 1411-1419, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29675787

RESUMO

Meropenem-vaborbactam is a carbapenem and ß-lactamase inhibitor combination that is newly indicated for the treatment of complicated urinary tract infections (cUTI), including adult pyelonephritis. Vaborbactam was developed due to emergence of carbapenem-resistant strains of Enterobacteriaceae. In a phase I trial, patients that received meropenem-vaborbactam 2-2 g intravenously over 3 h every 8 h, Cmax was 58.2 ± 10.8 µg/mL for meropenem and 59.0 ± 8.4 µg/mL for vaborbactam. AUC0-8 was 186 ± 33.6 µg â€¢ h/mL for meropenem and 204 ± 34.6 µg â€¢ h/mL for vaborbactam. Vss = 16.3 ± 2.6 L for meropenem and 17.6 ± 2.6 L for vaborbactam. Protein binding for vaborbactam averaged 33% in humans. Plasma clearance ranged from 10.42 ± 1.85 to 14.77 ± 2.84 L/h. One phase III trial evaluated efficacy for meropenem-vaborbactam 2-2 g intravenously every 8 h versus piperacillin-tazobactam 4-0.5 g intravenously every 8 h in complicated UTI. It found non-inferiority and statistical superiority for meropenem in overall success at the end of treatment primary end point. In another phase III trial evaluating efficacy in carbapenem-resistant Enterobacteriaceae (CRE) infections, meropenem-vaborbactam 2-2 g intravenously every 8 h was associated with decreased 28-day mortality and increased clinical cure compared with a best available therapy group.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Tienamicinas/uso terapêutico , Animais , Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/fisiologia , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Ensaios Clínicos como Assunto , Infecções por Enterobacteriaceae/diagnóstico , Humanos , Meropeném , Testes de Sensibilidade Microbiana , Tienamicinas/farmacologia , Distribuição Tecidual , Resultado do Tratamento , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico
13.
Ann Pharmacother ; 52(8): 769-779, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29514462

RESUMO

OBJECTIVE: To review the pharmacology, spectrum of activity, pharmacokinetics, pharmacodynamics, safety, efficacy, administration, and considerations for clinical use of meropenem/vaborbactam (M/V). DATA SOURCES: A literature search using PubMed and clinicaltrials.gov (June 2013 to December 2017) was conducted using the search terms meropenem, vaborbactam, RPX7009, biapenem, RPX2003, and carbavance. References from relevant articles and conference abstracts were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical, phase I studies, and phase III studies written in the English language were evaluated. DATA SYNTHESIS: M/V is a novel carbapenem/ß-lactamase inhibitor antimicrobial with in vitro activity against nearly 99% of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae. M/V is approved for the treatment of adults with complicated urinary tract infections (cUTIs), including pyelonephritis. In a phase III cUTI trial (TANGO I), 98.4% of patients treated with M/V experienced overall clinical success compared with 94% of patients treated with piperacillin/tazobactam (95% CI = 0.7 to 9.1). When compared with best available therapy for carbapenem-resistant Enterobacteriaceae (CRE) infections in TANGO II, patients receiving M/V were more likely to achieve clinical cure at both the end of therapy (64.3% vs 33.3%, P = 0.04) as well as at the test of cure (57.1% vs 26.7%, P = 0.04). The most common adverse effects associated with M/V were headache, infusion-site reactions, and diarrhea. CONCLUSION: M/V has a valuable role in the treatment of CRE and should be used judiciously to preserve its use for resistant infections.


Assuntos
Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Ácidos Borônicos/uso terapêutico , Meropeném/uso terapêutico , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ácidos Borônicos/química , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/farmacologia , Humanos , Meropeném/química , Meropeném/farmacocinética , Meropeném/farmacologia
14.
Pharmacotherapy ; 38(4): 444-461, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29427523

RESUMO

Vaborbactam (VAB; formerly RPX7009) is a novel beta-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta-lactamases. It has been co-formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug-resistant nonfermenting gram-negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa. The purpose of this article is to review existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress in clinical trials of meropenem and VAB (MV). Phase 1 studies have demonstrated single and multiple doses of VAB up to 2000 mg, alone or in combination with meropenem 2000 mg administered as a prolonged infusion over 3 hours, are well tolerated with an adverse effect profile similar to that of meropenem monotherapy. The available data suggest preexisting resistance among KPC-producing isolates is rare. Strains with elevated MICs have been characterized by multiple resistance determinants including porin defects, increased drug efflux, and increased blaKPC expression. It remains uncertain whether multifactorial resistance will emerge during MV treatment and with more widespread use. Early data are positive for complicated urinary tract infections and MV compared with best available therapy in patients with serious carbapenem-resistant Enterobacteriaciae (CRE) infections. As clinicians contemplate how to incorporate MV into CRE treatment strategies, it will be important to track and understand resistance, discern the role, if any, of combination therapy in enhancing efficacy and/or preserving activity, and define the specific therapeutic niche of MV among the expanding anti-CRE armamentarium.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Meropeném/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Área Sob a Curva , Proteínas de Bactérias , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/farmacologia , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Farmacorresistência Bacteriana , Infecções por Klebsiella/tratamento farmacológico , Meropeném/administração & dosagem , Meropeném/farmacologia , Taxa de Depuração Metabólica , Testes de Sensibilidade Microbiana , Porinas , Infecções Urinárias/tratamento farmacológico , beta-Lactamases
15.
Artigo em Inglês | MEDLINE | ID: mdl-29038270

RESUMO

The recently approved combination of meropenem and vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine pyelonephritis model. The data indicate that the combination of meropenem and vaborbactam significantly increased bacterial killing compared to that with the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Proteínas de Bactérias/metabolismo , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Klebsiella pneumoniae/isolamento & purificação , Klebsiella pneumoniae/metabolismo , Camundongos , Testes de Sensibilidade Microbiana , Pielonefrite/microbiologia , Infecções Urinárias/microbiologia , beta-Lactamases/metabolismo
16.
Mini Rev Med Chem ; 18(8): 672-683, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-27484624

RESUMO

Lipases are enzymes that catalyse the hydrolysis of ester bonds of triglycerides ranging among biocatalysts of considerable physiological significance and industrial potential. Better understanding of the catalytic functions and achieving the possibility to control the biocatalysis process, in particular exploring some activators and inhibitors of lipases, seems to be crucial in the context of novel applications. The lipase activity is a function of interfacial composition: the enzyme can be there activated as well as denaturated or deactivated and the interface is an appropriate site for modulating lipolysis. Lipase inhibitor, interacts directly with the enzyme and inhibits lipase action. Alternatively, some compounds can postpone the lipolytic reaction via adsorption to the interphase or to the substrate molecules. The aim of this review is to summarise the current knowledge concerning human, animal and microbial lipase inhibitors, which were grouped into two categories: synthetic lipase inhibitors (including phosphonates, boronic acids and fats analogues) and natural compounds (including ß-lactones and some botanical foodstuffs - plant extracts and plant metabolites, mainly polyphenols and saponins as well as peptides and some dietary fibers). The topics discussed include also inhibition issues from the viewpoint of obesity treatment. Among natural compounds able to inhibit lipase activity are ß- lactones including orlistat. Orlistat is the only registered drug for obesity treatment in many countries and lipases are essential enzymes for lipid absorption - thus fat absorption or obesity can be controlled by lipase inhibition, especially pancreatic lipase which is responsible for the hydrolysis of over 80% of total dietary fats. Its effectiveness in obesity treatment was also described.


Assuntos
Inibidores Enzimáticos/síntese química , Lipase/antagonistas & inibidores , Animais , Ácidos Borônicos/química , Ácidos Borônicos/metabolismo , Ácidos Borônicos/uso terapêutico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Ácidos Graxos/uso terapêutico , Humanos , Lactonas/química , Lactonas/metabolismo , Lactonas/uso terapêutico , Lipase/metabolismo , Obesidade/tratamento farmacológico , Obesidade/patologia , Organofosfonatos/química , Organofosfonatos/metabolismo , Organofosfonatos/uso terapêutico , Orlistate , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico , Tensoativos/química , Tensoativos/metabolismo
17.
Artigo em Inglês | MEDLINE | ID: mdl-29109160

RESUMO

Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Antibacterianos/farmacocinética , Proteínas de Bactérias/metabolismo , Ácidos Borônicos/farmacocinética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Humanos , Meropeném/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/patologia , Infecções dos Tecidos Moles/microbiologia , Coxa da Perna/microbiologia , Coxa da Perna/patologia , Inibidores de beta-Lactamases/farmacocinética , beta-Lactamases/metabolismo
18.
Curr Mol Med ; 17(5): 341-349, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29210650

RESUMO

Carcinoma-associated fibroblasts (CAFs) are activated fibroblasts during development of several cancer types, and therefore emerge as an attractive therapeutic target for cancer therapy. Drugs such as PT-100 and sibrotuzumab that block the functions of CAFs have already been in clinical trials. However, these drugs exhibit limited efficacy in patients, partially due to the fact that currently used biomarkers for determining efficacy are not CAF-specific. Furthermore, depletion of CAFs may promote carcinogenesis and accelerate cancer progression by inducing immunosuppression and hypoxia, leading to reduced survival. Accumulating evidence demonstrates that restoring the expression of key microRNA induces the functional conversion of CAFs into normal fibroblasts by targeting different signaling pathways and metabolic mechanisms. Therefore, reprograming CAFs into normal fibroblasts by altering specific expression of microRNAs, rather than targeted ablation, may be an effective, novel strategy for cancer treatment. This review focuses on specific microRNAs involved in the transformation of CAFs as well as their multiple roles during tumorigenesis and chemo-resistance.


Assuntos
Ácidos Borônicos/uso terapêutico , Carcinoma , Reprogramação Celular/efeitos dos fármacos , Dipeptídeos/uso terapêutico , Fibroblastos , MicroRNAs/metabolismo , RNA Neoplásico/metabolismo , Animais , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos
19.
Int Immunopharmacol ; 50: 48-54, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28628770

RESUMO

Triggered by the successful administration of the proteasome inhibitor bortezomib in kidney transplant recipients with acute or chronic antibody-mediated rejection, we evaluated the effect of the proteasome inhibitor CEP-18770 and of the selective immunoproteasome inhibitor ONX-0914 on cellular and humoral alloimmunity. Cellular alloimmunity was assessed by cell proliferation in a two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method, where humoral alloimmunity was induced in one-way MLR. The de novo production of alloantibodies was measured with an antibody-mediated complement-dependent cytotoxicity assay, in which supernatants from the above MLRs were used against resting PBMC similar to the stimulator cells of the forementioned MLRs. In two-way MLRs ONX-0914 inhibited cell proliferation more than CEP-18770. In one-way MLRs CEP-18770 and ONX-0194 decreased alloantibody production to the same extent. Inhibition of the immunoproteasome is superior to inhibition of the proteasome in suppressing cellular alloimmunity, and equally effective as regards to humoral alloimmunity. Considering the selective expression of the immunoproteasome in immune cells and the expected restrictive toxicity of its inhibitors, these results render immunoproteasome an excellent target for the development of new immunosuppressive medications in the field of transplantation.


Assuntos
Ácidos Borônicos/uso terapêutico , Bortezomib/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Transplante de Rim , Leucócitos Mononucleares/efeitos dos fármacos , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Treonina/análogos & derivados , Citotoxicidade Celular Dependente de Anticorpos , Proliferação de Células , Células Cultivadas , Histocompatibilidade , Humanos , Imunidade Celular , Imunidade Humoral , Imunossupressão , Isoanticorpos/metabolismo , Leucócitos Mononucleares/imunologia , Teste de Cultura Mista de Linfócitos , Treonina/uso terapêutico
20.
Biomaterials ; 134: 143-153, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28460336

RESUMO

Early diagnosis of metastatic cancers could greatly limit the number of cancer-associated deaths. Aberrant surface expression of sialic acid (hypersialylation) on tumors correlating with metastatic incidence and its involvement in tumorigenesis and progression is widely reported; hence detection of hypersialylated tumors may be an effective strategy to identify metastatic cancers. We herein report on the application of phenylboronic acid-installed PEGylated gold nanoparticles coupled with Toluidine blue O (T/BA-GNPs) as SERS probes to target surface sialic acid (N-acetylneuraminic acid, Neu5Ac). Strong SERS signals from metastatic cancer cell lines (breast cancer; MDA-MB231 and colon cancer; Colon-26) were observed, contrary to non-metastatic MCF-7 cells (breast cancer). The detected SERS signals from various cancer cell lines correlated with their reported metastatic potential, implying that our T/BA-GNP based SERS system was capable of distinguishing the metastaticity of cells based on the surface Neu5Ac density. T/BA-GNP based SERS system could also significantly differentiate between hypersialylated tumor tissues and healthy tissues with high SERS signal to noise ratio, due to plasmon coupling between the specifically aggregated functionalized GNPs. Furthermore, we also confirmed reduction in SERS signals from MDA-MB231 surface upon treatment with our original reactive oxygen species (ROS)-scavenging polymeric micelle, nitroxide-radical containing nanoparticles (RNPs). The ROS-mediated abrogation of sialylation by impairing the activation of NF-κB-sialyltransferase signaling cascade upon RNP treatment was confirmed by expression studies and the T/BA-GNPs based SERS system. The aforementioned findings thus, establish T/BA-GNPs based SERS as a potential cytodiagnostic system to detect hypersialylated metastatic tumors and RNPs as anti-metastatic cancer drug candidates.


Assuntos
Ácidos Borônicos/uso terapêutico , Ácido N-Acetilneuramínico/metabolismo , Análise Espectral Raman/métodos , Animais , Western Blotting , Ácidos Borônicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cromatografia em Gel , Ouro/química , Humanos , Células MCF-7 , Nanopartículas Metálicas/química , Camundongos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA