RESUMO
We previously reported that ciprofloxacin (CIP) free lung interstitial concentrations are decreased by biofilm-forming Pseudomonas aeruginosa pulmonary chronic (14 d) infection. To get a better understanding on the influence of infection on CIP lung distribution, in the present study free lung interstitial fluid and epithelial lining fluid (ELF) concentrations were determined by microdialysis in biofilm-forming P. aeruginosa acutely (2 d) and chronically infected (14 d) Wistar rats following CIP 20 mg/kg i.v. bolus dosing. A popPK model was developed, using NONMEM® (version 7.4.3) with FOCE+I, with plasma data described as a three-compartment model with first-order elimination. For lung data inclusion, the model was expanded to four compartments and ELF concentrations were described as a fraction of lung levels estimated as a distribution factor (ƒD). Acute infection had a minor impact on plasma and lung CIP distribution and both infection stages did not alter ELF drug penetration. Probability of target attainment of ƒAUC0-24/MIC ≥ 90 using 20 mg q8h, equivalent to 400 mg q8h in humans, showed that CIP free concentrations in plasma are adequate to successfully treat lung infections. However, lung and ELF free interstitial concentrations might be insufficient to result in efficacious treatment of biofilm-forming P. aeruginosa chronic infection. However, lung and ELF free interstitial concentrations might be insufficient to result in efficacious treatment of biofilm-forming P. aeruginosa chronic infection.
Assuntos
Ciprofloxacina , Infecções por Pseudomonas , Humanos , Ratos , Animais , Antibacterianos , Pseudomonas aeruginosa , Infecção Persistente , Ratos Wistar , Infecções por Pseudomonas/tratamento farmacológico , Pulmão , Biofilmes , Testes de Sensibilidade MicrobianaRESUMO
Fungal biofilms, such as Candida albicans biofilms, are capable of surviving in hostile environments owing to their remarkable ability to adhere to surfaces and their tolerance to chemical interventions. Currently, therapeutic treatment options are few, making these biofilm-based infections problematic particularly due to their great tolerance to conventional antimicrobial drugs, thus causing serious health and economic problems. Therefore, the development of new drugs and antibiofilm specific therapies for the prevention and treatment of antifungal to eradicate biofilms are needed. This study was aimed at carrying out a patent review analysis to identify the innovation trends, and to explore the latest antifungal drugs and the specific therapeutic strategies available for the treatment of fungal biofilms. The present patent review was carried out using the Espacenet database, using the key words "biofilm and antifungal," from 2002 to December 2019. Through this review, it was possible to identify that most of the patent contents refer to new synthetic drugs derived from natural products and associations thereof with existing antifungal drugs. Methods and biomaterials for the treatment and prevention of fungal biofilms, mainly for C. albicans biofilms, which is the most isolated and studied fungal species, were also disclosed. The lack of scientific and technical information on the biofilm eradication subject is remarkable and further confirmed by the small number of patents identified in this survey.
Assuntos
Anti-Infecciosos , Preparações Farmacêuticas , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biofilmes , Candida albicansRESUMO
PURPOSE: This study aimed to determine free etoposide (ETO) concentrations in two regions of Walker-256 (W256) solid tumor using microdialysis and to establish a population pharmacokinetic (popPK) model to describe simultaneously free tumor and total plasma concentrations. METHODS: W256 tumor-bearing Wistar rats received ETO 10 or 20 mg/kg i.v. bolus. Free ETO concentrations were sampled from central and peripheral regions of the tumor via CMA/20 probes for up to 7 h, whereas blood samples were collected via carotid artery cannulation. Total plasma and free tumor concentration-time profiles were analyzed by non-compartmental approach using WinNonlin® v. 5.3. PopPK modeling was conducted using MONOLIX v.4.3.3. RESULTS: ETO penetration was higher in the periphery (61 ± 15% and 61 ± 29%) than in tumor center (34 ± 6% and 28 ± 11%) following 10 and 20 mg/kg doses, respectively (ANOVA, α = 0.05). A 4-compartment model fitted ETO concentration-time profiles in all sampling compartments. CONCLUSIONS: The popPK model allowed the simultaneous fitting of plasma and tumor concentrations and a better understanding of ETO distribution in solid tumors. ETO plasma concentrations are not a good surrogate for tumoral exposure, emphasizing the importance of knowing intratumoral concentrations to predict drug response.
Assuntos
Etoposídeo/farmacocinética , Neoplasias/sangue , Animais , Etoposídeo/sangue , Etoposídeo/farmacologia , Masculino , Microdiálise/métodos , Neoplasias/tratamento farmacológico , Ratos , Ratos Wistar , Distribuição Tecidual/fisiologiaRESUMO
Chronic bacterial prostatitis treatment consists of broad-spectrum antibiotic therapy for long periods of time. Drug penetration into the prostate makes the treatment a challenged. Ciprofloxacin is one of the most prescribed drugs for this treatment. A liquid chromatography with fluorescence detection method was developed and validated for determining ciprofloxacin concentrations in two different matrices: plasma and prostate microdialysate. Ciprofloxacin was separated on a C18 column eluted with a mobile phase constituted of a mixture of 0.4% aqueous triethylamine:methanol:acetonitrile (75:15:10, v/v/v) and 0.4% aqueous triethylamine:acetonitrile (88:12, v/v) for microdialysate and plasma samples, respectively. Linearity was obtained over a concentration range of 5-1000 ng/mL (microdialysate) and 10-2000 ng/mL (plasma), with coefficients of determination ≥0.9956. Precision was determined from the analysis of six quality control samples and showed RSD values <11.1 and 7.4% for intra and inter-assay precision, respectively. The accuracy ranged from 85.6 to 114.3%. The method was applied to a preliminary pharmacokinetic study to investigate ciprofloxacin concentrations in prostate, sampled by microdialysis, and plasma after a 7 mg/kg intravenous dose to Wistar rats. The method showed high sensitivity using only protein precipitation as plasma sample clean-up and was successfully applied to investigate ciprofloxacin prostate penetration.