DEFAR - Artigos publicados em periódicos
URI permanente para esta coleçãohttp://www.hml.repositorio.ufop.br/handle/123456789/531
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Item Polyester nanocapsules for intravenous delivery of artemether : formulation development, antimalarial efficacy, and cardioprotective effects in vivo.(2022) Diniz, Alessandra Teixeira Vidal; Guimarães, Homero Nogueira; Garcia, Giani Martins; Braga, Érika Martins; Richard, Sylvain; Guimarães, Andrea Grabe; Mosqueira, Vanessa Carla FurtadoArtemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(D,L-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-block-poly(D,L-lactide) (PEG5kDa- PLA45kDa) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0–4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the “Four-day test” protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with P. berghei or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy.Item Caspofungin effects on electrocardiogram of mice : an evaluation of cardiac safety.(2021) Paula, Danielle Cristiane Correa de; Leite, Elaine Amaral; Araújo, Carolina Morais; Branquinho, Renata Tupinambá; Guimarães, Homero Nogueira; Guimarães, Andrea GrabeCaspofungin is an echinocandin, exhibiting efcacy against most Candida species invasive infection. Its cardiotoxicity was reported in isolated rat heart and ventricular myocytes, but in vivo and clinical studies are insufcient. Our objective was to evaluate caspofungin in vivo cardiac efects using an efcacious dose against Candida albicans. Female Swiss mice were infected with C. albicans, and treated with caspofungin, 5 or 10 mg/kg, intraperitoneal along 5 days. Survival rate and colony forming units (CFU) into vital organs were determined. For cardiac efects study, mice were treated with caspofungin 10 mg/ kg, and electrocardiogram (ECG) signal was obtained on C. albicans-infected mice, single dose-treated, and uninfected mice treated along 5 days, both groups to measure ECG intervals. Besides, ECG was also obtained by telemetry on uninfected mice to evaluate heart rate variability (HRV) parameters. The MIC for caspofungin on the wild-type C. albicans SC5314 strain was 0.3 μg/ml, indicating the susceptible. Survival rate increased signifcantly in infected mice treated with caspo fungin compared to mice treated with vehicle. None of the survived infected mice presented positive CFU after treatment with 10 mg/kg. C. albicans infection induced prolongation of QRS, QT, and QTc intervals; caspofungin did not alter this efect. Caspofungin induced increase of PR and an additional increase of QRS after 24 h of a single dose in infected mice. No signifcant alterations occurred in ECG intervals and HRV parameters of uninfected mice, after caspofungin treatment. Caspofungin showed in vivo cardiac relative safety maintaining its antifungal efcacy against C. albicans.Item Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice.(2018) Souza, Ana Carolina Moreira; Mosqueira, Vanessa Carla Furtado; Silveira, Ana Paula Amariz; Antunes, Lidiane Rodrigues; Richard, Sylvain; Guimarães, Homero Nogueira; Guimarães, Andrea GrabeArtemether (ATM) cardiotoxicity, its short half-life and low oral bioavailability are the major limiting factors for its use to treat malaria. The purposes of this work were to study free-ATM and ATM-loaded poly-ε-caprolactone nanocapules (ATM-NC) cardiotoxicity and oral efficacy on Plasmodium berghei-infected mice. ATM-NC was obtained by interfacial polymer deposition and ATM was associated with polymeric NC oily core. For cardiotoxicity evaluation, male black C57BL6 uninfected or P. berghei-infected mice received, by oral route twice daily/4 days, vehicle (sorbitol/carboxymethylcellulose), blank-NC, free-ATM or ATMNC at doses 40, 80 or 120 mg kg−1 . Electrocardiogram (ECG) lead II signal was obtained before and after treatment. For ATM efficacy evaluation, female P. berghei-infected mice were treated the same way. ATM-NC improved antimalarial in vivo efficacy and reduced mice mortality. Free-ATM induced significantly QT and QTc intervals prolongation. ATMNC (120 mg kg−1 ) given to uninfected mice reduced QT and QTc intervals prolongation 34 and 30%, respectively, compared with free-ATM. ATM-NC given to infected mice also reduced QT and QTc intervals prolongation, 28 and 27%, respectively. For the first time, the study showed a nanocarrier reducing cardiotoxicity of ATM given by oral route and it was more effective against P. berghei than free-ATM as monotherapy.