DEFAR - Departamento de Farmácia
URI permanente desta comunidadehttp://www.hml.repositorio.ufop.br/handle/123456789/530
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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 Spironolactone and eplerenone are cardioprotective during early phase of ischemia in rats submitted to acute coronary occlusion.(2022) Amancio, Gabriela de Cássia Sousa; Hermidorff, Milla Marques; Alvarenga, Ana Cláudia; Lima, Wanderson Geraldo de; Guimarães, Homero Nogueira; Rodrigues, Henrique Resende; Silva, Emília Calil; Assis, Leonardo Vinícius Monteiro de; Guimarães, Andrea Grabe; Isoldi, Mauro CésarIntroduction: Mineralocorticoid receptor antagonists (MRAs) are effective in reducing left ventricle remodeling and sudden death after acute myocardial infarction (AMI). Objectives: MRAs in vitro display cardioprotective effects, independent of MR; however, it is unknown whether the rapid effects of MRAs are cardioprotective in vivo. This study evaluated the acute effects of spironolactone and eplerenone in the first minutes of AMI. Methods: Wistar Rats, submitted or not to bilateral adrenalectomy, were treated orally with spironolactone (20 mg/kg) or eplerenone (10 mg/kg), and submitted to the left coronary ligation, under anesthesia. Electrocardiogram (ECG) recordings were obtained to evaluate ST-T segment, QT, and QTc intervals. Arterial pressure was also measured before (baseline) and after coronary ligation. Results: Spironolactone or eplerenone given, one hour before coronary ligation, prevented ST- T segment elevation in adrenalectomized and non-adrenalectomized. QT interval analysis showed that MRAs prevented its prolongation after coronary ligation. QT and QTc intervals remained similar to baseline and were smaller than the values displayed by the non-treated group. Animals treated with spironolactone, regardless of adrenalectomy, showed a 3-fold reduced mortality rates compared to the control group. Conclusion: MRAs display acute cardioprotective effects in early phase of AMI, which are independent of aldosterone.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.Item Antinociceptive and anti-inflammatory activities of ethanolic extracts of Lychnophora species.(2008) Guzzo, Luciana Souza; Guimarães, Dênia Antunes Saúde; Silva, Adriana Carneiro; Lombardi, Júlio Antônio; Guimarães, Homero Nogueira; Guimarães, Andrea GrabeExtracts from Lychnophora species are traditionally used in Brazil as anti-inflammatory, and to treat bruise, pain and rheumatism. The ethanolic extract of aerial parts of five species of Lychnophoras and one specie of Lychnophoriopsis were examined for the antinociceptive (hot-plate and writhing tests) and anti-inflammatory (carrageenan-induced paw oedema test) activity in mice, by oral and topical routes, respectively. In the hot-plate test, the Lychnophora pinaster (0.75 g/kg) and Lychnophora ericoides (1.50 g/kg) extracts significantly increased the time for licking of the paws. The species Lychnophora passerina, Lychnophoriopsis candelabrum and Lychnophora pinaster, using the dose of 0.75 g/kg, and Lychnophora ericoides and Lychnophora trichocarpha in both doses evaluated (0.75 and 1.50 g/kg) significantly reduced the number of writhes induced by acetic acid. The administration of Lychnophora pinaster and Lychnophora trichocarpha ointments, in both concentrations evaluated (5 and 10%, w/w), and Lychnophora passerina and Lychnophoriopsis candelabrum, in the concentration of 10%, significantly reduced the paw oedema measured 3 h after carrageenan administration, suggesting, for the first time, an anti-inflammatory activity upon topical administration of these species. The present work comparatively demonstrated the antinociceptive and anti-inflammatory activities of some Brazilian Lychnophoras.Item Reduced cardiovascular alterations of tartar emetic administered in long-circulating liposomes in rats.(2010) Maciel, Naira Rezende; Reis, Priscila Gomes dos; Kato, Kelly Cristina; Vidal, Alessandra Teixeira; Guimarães, Homero Nogueira; Frezard, Frederic Jean Georges; Barcellos, Neila Marcia Silva; Guimarães, Andrea GrabeTrivalent antimonial drugs, including tartar emetic (TA), are known to induce important cardiotoxicity observed by electrocardiographic abnormalities. Liposome encapsulation was found to reduce the overall acute toxicity of TA. The present work investigated the cardiovascular parameters alterations of rats submitted to the treatment with free and encapsulated TA in long-circulating liposomes. Liposomes were made using lipids DSPC, DSPE-PEG and cholesterol. The cardiovascular signals, electrocardiogram (ECG) and arterial blood pressure (AP), were recorded from anaesthetized Wistar rats after intravenous (IV) administration of a single specially high dose (17 mg/kg) of TA in liposomes and in free form. The IV administration of TA solution caused significant increase of QT interval of ECG and significant reduction of AP when compared to the control group. These alterations were not observed when liposomes TA were administered and the profile of ECG and AP data was quite similar to the control groups. In conclusion, a liposomal formulation of TA showed a reduced cardiotoxic profile for TA when compared to the free form.Item Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.(2007) Leite, Elaine Amaral; Guimarães, Andrea Grabe; Guimarães, Homero Nogueira; Coelho, George Luiz Lins Machado; Barratt, Gillian; Mosqueira, Vanessa Carla FurtadoThe main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-ε-caprolactone nanocapsules (NC). The acute lethal dose (LD100) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD50 was 154 mg/kg. In contrast, the LD100 for Hf-NC was 300 mg/ kg with a longer mean time to death than Hf.HCl. The calculated LD50 was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (Pb0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.Item Prolonged cardioprotective effect of pyridostigmine encapsulated in liposomes.(2010) Vidal, Alessandra Teixeira; Guimarães, Homero Nogueira; Paula, Danielle Cristiane Correa de; Frezard, Frederic Jean Georges; Barcellos, Neila Marcia Silva; Guimarães, Andrea GrabeAims: The purpose of the present work was to investigate the ability of pyridostigmine encapsulated in longcirculating liposomes, to protect against ECG(electrocardiogram) alterations induced by sympathetic stimulation in rats. Main methods: The encapsulation of pyridostigmine was carried out by freeze–thaw and extrusion. Blood pressure and ECG (limb lead II) were monitored in anaesthetized male Wistar rats. The formulation containing pyridostigmine was intravenously administrated in 0.1, 0.3 and 1.0 mg/kg doses, and sympathetic stimulation was conducted by administration of 1 or 3 μg of noradrenaline (NA) after 1, 2, 4 or 6 h. The obtained cardiovascular parameters were compared to animals that received intravenous injection of pyridostigmine in free form or saline. Key findings: After saline, NA induced a significant increase in QT interval (22.3% after 3.0 μg). Previous administration of free pyridostigmine significantly prevented the increase of QT interval after sympathetic stimulation and the most prominent effect was observed after 1h for the dose of 0.3 mg/kg (6.8% after 3.0 μg of NA) and was no longer observed after 2 h of the treatment. On the other hand, the maximum effect of pyridostigmine in liposomal formulation preventing QT interval increasewas observed 2 h after treatment (9.7% after 3.0 μg of NA) and was still present until 6 h when 1 mg/kg was previous administrated. Significance: The results of the present study, beyond to confirm the cardioprotective action of pyridostigmine, suggest that liposomal pyridostigmine may be a potential therapeutic alternative to prevent cardiovascular disturbances resulting from sympathetic hyperactivity.