Effects of physical exercise combined with captopril or losartan on left ventricular hypertrophy of hypertensive rats.

Background: Left ventricular hypertrophy (LVH) is an endpoint of hypertensive cardiac alterations. Renin-angiotensin-aldosterone system (RAAS) blockers are among the most effective on LVH regression. Physical exercise combined to antihypertensive drug contributes to arterial pressure (AP) control and LVH prevention. We evaluated the effects of physical exercise combined to captopril or losartan during eight weeks for spontaneously hypertensive rats (SHR) on some cardiac parameters.Methods: SHR (n=5-6 per group) were sedentary or trained 5 days a week in treadmill during 8 weeks; and they were treated with daily oral captopril (12.5, 25, or 50mg/kg), losartan (2.5, 5, or 10mg/kg), or vehicle. At the end, it was obtained systolic AP (SAP), electrocardiogram (ECG), and hearts metalloproteinase 2 (MMP-2) activity and histology.Results: Captopril 25 and 50 mg/kg, and losartan 10 mg/kg lowered SAP of sedentary and trained SHR. Losartan 5 mg/kg combined with physical exercise also lowered SAP. Combined with exercise, captopril 50 mg/kg lowered 13.6% of QT interval, 14.2% of QTc interval, and 22.8% of Tpeak-Tend compared to sedentary SHR. Losartan 5 and 10mg/kg lowered QT interval of sedentary and trained SHR. Losartan 2.5, 5 and 10mg/kg combined with physical exercise lowered respectively 25.4%, 24.8%, and 31.8% of MMP-2 activity. Losartan (10mg/kg) combined with exercise reduced cardiomyocyte diameter.Conclusion: These data support the hypothesis of physical exercise combined with RAAS blockers could improve the benefits on hypertensive LVH treatment.

Reduced cardiotoxicity and increased oral efficacy of artemether polymeric nanocapsules in Plasmodium berghei-infected mice.

Artemether (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 ATM-NC 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. ATM-NC (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.

Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo.

Artemether (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.

Caspofungin Effects on Electrocardiogram of Mice: An Evaluation of Cardiac Safety.

Caspofungin is an echinocandin, exhibiting efficacy against most Candida species invasive infection. Its cardiotoxicity was reported in isolated rat heart and ventricular myocytes, but in vivo and clinical studies are insufficient. Our objective was to evaluate caspofungin in vivo cardiac effects using an efficacious 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 effects 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 significantly in infected mice treated with caspofungin 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 effect. Caspofungin induced increase of PR and an additional increase of QRS after 24 h of a single dose in infected mice. No significant alterations occurred in ECG intervals and HRV parameters of uninfected mice, after caspofungin treatment. Caspofungin showed in vivo cardiac relative safety maintaining its antifungal efficacy against C. albicans.

Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.

The 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-epsilon-caprolactone nanocapsules (NC). The acute lethal dose (LD(100)) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD(50) was 154 mg/kg. In contrast, the LD(100) for Hf-NC was 300 mg/kg with a longer mean time to death than Hf.HCl. The calculated LD(50) 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 (P<0.001) 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.

Prolonged cardioprotective effect of pyridostigmine encapsulated in liposomes.

AIMS: The purpose of the present work was to investigate the ability of pyridostigmine encapsulated in long-circulating 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 1.0mg/kg doses, and sympathetic stimulation was conducted by administration of 1 or 3 microg of noradrenaline (NA) after 1, 2, 4 or 6h. 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 microg). 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 0.3mg/kg (6.8% after 3.0 microg of NA) and was no longer observed after 2h of the treatment. On the other hand, the maximum effect of pyridostigmine in liposomal formulation preventing QT interval increase was observed 2h after treatment (9.7% after 3.0 microg of NA) and was still present until 6h when 1mg/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.

Síntese de sinais de variabilidade da freqüência cardíaca baseada em modelagem não-linear / Heart rate variability synthesis based on nonlinear modelling

A análise de sinais por meio de índice não-lineares normalmente requer séries de dados estacionários e com um grande número de amostras. Tais requisitos não são facilmente obtidos no caso de sinais biológicos, como a variabilidade da freqüênci cardíaca (VFC). Uma possível maneira de se contornar tais dificuldades seria por meio da geração de um sinal que apresentasse as características dinâmicas do sinal real e que fosse estacionário por construção. Este trabalho apresenta uma técnica de síntese de sinais estacionários, com características semelhantes às de sinais de VFC, baseada na geração de séries de longa duração por meio de modelos NARMAX (Nonlinear AutoRegressive Moving Average with eXogenous inputs). Foram usadas duas representações: polinomial e neural. Um sinal de entrada foi construído considerando informações espectrais do sinal de VFC original. Índices lineares e não-lineares foram utilizados para validar as séries sintéticas, e verificar se essas séries apresentam características, principalmente dinâmicas, próximas daquelas apresentadas pelas séries VFC. Os resultados mostraram que os índices estatísticos do dominio do tempo para as séries sintéticas ficaram distantes dos resultados das séries reais, no caso de séries longas. Os resultados referentes à entropia aproximada se mostraram próximos entre sintéticos e reais, principalmente para as séries geradas por modelos neurais. O índice alfa 1 do método Detrended Fluctuation Analysis (DFA) para as séries sintéticas mostrou-se próximo daqueles apresentados pelas séries reais.