RESUMO
Opioids are the first-line treatment for cancer pain. Incomplete pain relief and the high rate of adverse effects of these compounds bring a need to combine them with other drugs acting on different targets. AIMS: We here evaluate the antinociceptive interaction and adverse events of methadone combined with recombinant Phα1ß, an analgesic toxin from Phoneutria nigriventer. MAIN METHODS: Melanoma was produced by intraplantar inoculation of B16-F10 cells into the right paw. von Frey filaments measured the paw-withdrawal threshold after administration of methadone, Phα1ß, and their combination. The degree of interaction was evaluated using isobolographic analysis. Spontaneous performance and forced motor performance were assessed with the open-field and rotarod tests, respectively. Intestinal function was evaluated by the distance traveled by charcoal and opioid tolerance was induced by daily morphine injections. KEY FINDINGS: Co-administration of Phα1ß with methadone synergistically reverses the melanoma-induced mechanical hypersensitivity. No motor alterations were observed but mild alterations on intestinal function after treatment with the combination that was also capable of restoring morphine analgesia in the tail-flick test after an opioid-induced tolerance. SIGNIFICANCE: Combinatorial treatment with Phα1ß and methadone produces synergistic analgesic potentiation with potential implications to pain treatment even under opioid tolerance conditions.
Assuntos
Analgésicos/farmacologia , Dor do Câncer/tratamento farmacológico , Metadona/administração & dosagem , Manejo da Dor/métodos , Venenos de Aranha/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Comportamento Animal , Bloqueadores dos Canais de Cálcio/farmacologia , Sinergismo Farmacológico , Quimioterapia Combinada , Tolerância a Medicamentos , Trato Gastrointestinal/efeitos dos fármacos , Masculino , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias/complicações , Fatores de TempoRESUMO
The release of extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae to the environment is a public health issue worldwide. The aim of this study was to investigate the genetic background of genes encoding ESBLs in wastewater treatment plants (WWTPs) in São Paulo, southeastern Brazil. In 2009, during a local surveillance study, seven ESBL-producing Enterobacteriaceae strains were recovered from five WWTPs and screened for ESBL genes and mobile genetic elements. Multilocus sequence typing (MLST) was carried out, and wild plasmids were transformed into electrocompetent Escherichia coli. S1-PFGE technique was used to verify the presence of high molecular weight plasmids in wild-type strains and in bla ESBL-containing E. coli transformants. Strains harbored bla CTX-M-8, bla CTX-M-15, and/or bla SHV-28. Sequencing results showed that bla CTX-M-8 and bla CTX-M-15 genes were associated with IS26. MLST revealed new sequence types for E. coli (ST4401, ST4402, ST4403, and ST4445) and Klebsiella pneumoniae (ST1574), except for one K. pneumoniae from ST307 and Enterobacter cloacae from ST131. PCR and S1-PFGE results showed CTX-M-producing E. coli transformants carried heavy plasmids sizing 48.5-209 kb, which belonged to IncI1, IncF, and IncM1 incompatibility groups. This is the first report of CTX-M-8 and SHV-28 enzymes in environmental samples, and the present results demonstrate the plasmid-mediated spread of CTX-M-encoding genes through five WWTPs in São Paulo, Brazil, suggesting WWTPs are hotspots for the transfer of ESBL genes and confirming the urgent need to improve the management of sewage in order to minimize the dissemination of resistance genes to the environment.
Assuntos
Proteínas de Escherichia coli/biossíntese , Escherichia coli/genética , Patrimônio Genético , Klebsiella pneumoniae/genética , Águas Residuárias/microbiologia , beta-Lactamases/biossíntese , Técnicas de Tipagem Bacteriana , Brasil , Enterobacteriaceae/enzimologia , Enterobacteriaceae/genética , Escherichia coli/enzimologia , Klebsiella pneumoniae/enzimologia , Tipagem de Sequências Multilocus , Plasmídeos , Reação em Cadeia da Polimerase , Purificação da ÁguaAssuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli/veterinária , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Genes Bacterianos , Doenças dos Cavalos/microbiologia , Animais , Brasil , DNA Bacteriano/química , DNA Bacteriano/genética , Escherichia coli/enzimologia , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/microbiologia , Cavalos , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Análise de Sequência de DNAAssuntos
Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/isolamento & purificação , Rios/microbiologia , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Cidades , DNA Bacteriano/química , DNA Bacteriano/genética , Genótipo , Humanos , Klebsiella pneumoniae/classificação , Klebsiella pneumoniae/genética , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Tipagem de Sequências Multilocus , Plasmídeos , beta-Lactamases/genéticaRESUMO
Forty-nine typical and atypical enteropathogenic Escherichia coli (EPEC) strains belonging to different serotypes and isolated from humans, pets (cats and dogs), farm animals (bovines, sheep, and rabbits), and wild animals (monkeys) were investigated for virulence markers and clonal similarity by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The virulence markers analyzed revealed that atypical EPEC strains isolated from animals have the potential to cause diarrhea in humans. A close clonal relationship between human and animal isolates was found by MLST and PFGE. These results indicate that these animals act as atypical EPEC reservoirs and may represent sources of infection for humans. Since humans also act as a reservoir of atypical EPEC strains, the cycle of mutual infection of atypical EPEC between animals and humans, mainly pets and their owners, cannot be ruled out since the transmission dynamics between the reservoirs are not yet clearly understood.