Combined treatment with olmesartan medoxomil and amlodipine besylate attenuates atherosclerotic lesion progression in a model of advanced atherosclerosis.

INTRODUCTION: Besides their blood pressure-lowering effects, olmesartan medoxomil and amlodipine besylate exhibit additional anti-inflammatory mechanisms in atherosclerosic disease. Most of the studies investigating the effects of atherosclerosis focused on early atherosclerotic lesions, whereas lesions in human disease, at the time when medical treatment is started, are already well established. Therefore, we set up a model of advanced atherosclerosis and investigated the effects of olmesartan medoxomil, amlodipine besylate, and the combination of both on atherosclerotic lesion size and lesion composition. MATERIALS AND METHODS: Olmesartan medoxomil (1 mg/kg/day), amlodipine besylate (1.5 mg/kg/day), and the combination of both was added to chow and was fed to apolipoprotein E-deficient (ApoE(-/-)) mice at 25 weeks of age. Mice were sacrificed after 25 weeks of drug administration and perfused with formalin. Innominate arteries were dissected out and paraffin embedded. Serial sections were generated, and lesion sizes and their composition - such as minimal thickness of the fibrous cap, size of the necrotic core, and presence of calcification - were analyzed. Electrophoretic mobility shift assays were used to detect DNA-binding activity of the transcription factor nuclear factor-kappa B (NF-κB) in aortic tissue. RESULTS: Treatment with the combination of olmesartan medoxomil and amlodipine besylate led to a significant reduction in atherosclerotic lesion size in ApoE(-/-) mice (olmesartan medoxomil/amlodipine besylate: 122,277±6,795 µm(2), number [n]=14; versus control: 177,502±10,814 µm(2), n=9; P<0.001). Treatment with amlodipine besylate (n=5) alone did not reach significance. However, a trend toward a decrease in lesion size in the amlodipine besylate-treated animals could be observed. In the histological analysis of atherosclerotic lesion composition, significantly thicker fibrous caps were found in treatment with amlodipine besylate (amlodipine: 5.12±0.26 µm, n=6; versus control: 3.98±0.18 µm, n=10; P<0.01). Furthermore, all sections revealed morphological signs of calcification, but no difference could be detected. Treatment with the combination of olmesartan medoxomil and amlodipine besylate showed no effect on lesion composition. Electrophoretic mobility shift assays of nuclear extracts demonstrated reduced activity of the transcription factor NF-κB when treated with olmesartan medoxomil, amlodipine besylate, or their combination, as compared to controls. CONCLUSION: Combined treatment with olmesartan medoxomil and amlodipine besylate attenuated atherosclerotic lesion progression, possibly due to anti-inflammatory mechanisms. Our data support the hypothesis that even in advanced atherosclerosis anti-inflammatory treatment, using angiotensin II type 1 receptor blockers and calcium channel antagonists of the dihydropyridine type can attenuate atherosclerotic lesion progression.

The effect of dissolution medium, rotation speed and compaction pressure on the intrinsic dissolution rate of amlodipine besylate, using the rotating disk method

The aim of this study was to evaluate the effect of dissolution medium, rotation speed and compaction pressure on the intrinsic dissolution rate (IDR) of the antihypertensive drug amlodipine besylate, using the rotating disk method. Accordingly, a fractional factorial design (33-1) was used, employing dissolution media (water, phosphate buffer pH 6.8 and HCl 0.1 M), rotation speed (50, 75 and 100 rpm), and compaction pressure (1000, 1500 and 2000 psi) as independent variables. The assays were randomized and statistically compared using the Statistica(r) 11 software program. Significance testing (ANOVA) indicated that the dissolution medium had a considerable impact on the IDR of amlodipine besylate. Analysis of the linear and quadratic components of the variables led to the proposition of a mathematical model that describes the IDR as a function of the parameters studied. Conversely, the levels of compaction pressure and rotation speed employed during experimental planning were less relevant, especially when the assay was conducted in the HCl 0.1 M medium.

A finalidade do presente trabalho foi avaliar o efeito do meio de dissolução, velocidade de rotação e pressão de compactação na velocidade de dissolução intrínseca (VDI) do fármaco anti-hipertensivo besilato de anlodipino, usando o método do disco rotativo. Dessa forma, foi utilizado um planejamento experimental do tipo fatorial facionado (33-1) utilizando como variáveis independentes o meio de dissolução (água, HCl 0,1M e tampão fosfato pH 6,8), velocidade de rotação (50, 75 e 100 rpm) e pressão de compactação do fármaco (1000, 1500 e 2000 psi). Os ensaios foram randomizados e comparados estatisticamente pelo software Statistica(r) 11. A análise de variância (ANOVA) indicou que o meio de dissolução exerce considerável impacto na VDI do besilato de anlodipino. A análise das variáveis em seus componentes lineares e quadráticos permitiu a proposição de um modelo matemático que descreve a VDI em função dos parâmetros estudados. Por outro lado, os níveis de pressão de compactação e velocidade de rotação empregados exercem efeito menos relevantes, especialmente quando o ensaio é conduzido em HCl 0,1 M.