RESUMO
GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae and Haemophilus influenzae (mouse lung model) and with Staphylococcus aureus (rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivo efficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniae and S. aureus isolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae (R(2), 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus (R(2), 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10 reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniae isolates (R(2), 0.62) and 7.2 and 13.0 for five H. influenzae isolates (R(2), 0.93). The data showed that for eight S. aureus isolates, fAUC correlated better with efficacy than fAUC/MIC (R(2), 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 µg/ml). Median fAUCs of 2.1 and 6.3 µg · h/ml were associated with stasis and 1-log10 reductions, respectively, for S. aureus.
Assuntos
Antibacterianos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Inibidores Enzimáticos/farmacocinética , Infecções por Haemophilus/tratamento farmacológico , Ácidos Hidroxâmicos/farmacocinética , Pneumonia Pneumocócica/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Antibacterianos/sangue , Antibacterianos/farmacologia , Área Sob a Curva , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacologia , Infecções por Haemophilus/sangue , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Haemophilus influenzae/crescimento & desenvolvimento , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Masculino , Camundongos , Testes de Sensibilidade Microbiana , Pneumonia Pneumocócica/sangue , Pneumonia Pneumocócica/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/enzimologia , Streptococcus pneumoniae/crescimento & desenvolvimentoRESUMO
OBJECTIVE: To assess two zona drilling methods in terms of blastocyst development rates using sister embryos. DESIGN: Prospective, randomized study. Sister embryos of 14 patients were randomly assigned on day 3 to acidified Tyrode's zona drilling or to laser zona drilling. After biopsy, subsequent embryo culture until the blastocyst stage (day 5) was performed. SETTING: Private fertility center. PATIENT(S): Patients undergoing IVF-preimplantation genetic diagnosis. INTERVENTION(S): Embryo biopsy using either laser-assisted hatching or acidified Tyrode's hatching on sibling embryos and subsequent blastocyst development evaluation. MAIN OUTCOME MEASURE(S): Evaluation of blastocyst development in terms of degree of expansion and cell number in the inner cell mass and trophectoderm. RESULT(S): Blastocyst development rates (and blastocyst quality) were similarly high in both the acidified Tyrode's hatching group and the laser-assisted hatching group. CONCLUSION(S): Laser hatching does not impair embryonic development to the blastocyst stage, demonstrating that laser-assisted hatching is a suitable alternative to the use of acidified Tyrode's solution for zona drilling.
Assuntos
Blastocisto/fisiologia , Soluções Isotônicas/uso terapêutico , Lasers , Técnicas de Reprodução Assistida , Zona Pelúcida/efeitos dos fármacos , Zona Pelúcida/efeitos da radiação , Adulto , Blastocisto/citologia , Blastocisto/efeitos dos fármacos , Blastocisto/efeitos da radiação , Técnicas de Cultura Embrionária , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos da radiação , Feminino , Fertilização in vitro , Humanos , Concentração de Íons de Hidrogênio , Soluções Isotônicas/química , Gravidez , Taxa de Gravidez , Diagnóstico Pré-Implantação , Estudos ProspectivosRESUMO
The objective of the present study was to compare a traditionally used bovine-derived hyaluronidase (Hyase) with the newly developed recombinant human-derived enzyme product (Cumulase) in intracytoplasmic sperm injection (ICSI) procedures using a sibling oocyte model in a prospective randomized design. The results of the study demonstrate that Cumulase is safe and effective in an ICSI treatment program and can provide comparable if not improved parameters, including fertilization and embryo developmental rates.