Background: Diabetes mellitus is a chronic disease that manifests as an increased level of glucose in the blood. According to the World Health Organization (WHO), 347 million people have diabetes worldwide. In year 2004, 3.4 million people died from the consequences of high blood glucose. In the Swedish population the prevalence of diabetes is estimated to 3-4 %, out of which 85-90% are Type 2. Among senior citizens a prevalence of diabetes is seen in Sweden up to 14 - 15%. Diabetes is increasing globally, particularly in developing countries, which is probably a consequence of the increased prevalence of overweight and obesity combined with low physical activity. Angiotensin converting enzyme (ACE) inhibitors are the first-line therapy in the treatment of high blood pressure among diabetics and patients suffering from congestive heart failure. The action of these inhibitors results in a decreased formation of angiotensin 2, an endogenous hormone peptide that raises the blood pressure by contracting the blood vessels. ACE inhibitors are also beneficial in the treatment of patients with renal insufficiency.Objective: The aim of this project was, with the help of published clinical trials and meta-analysis, to examine the effect of ACE inhibitors on cardiovascular diseases and mortality in type 2 diabetic and diabetic in hypertensive patients.Results: Appraisals of clinical trials within the frame of this project revealed thatACE inhibitor in patients with diabetes reduces:- Myocardial infarction (NNT = 37 during 4.5 years),- Development of stroke (NNT = 32 during 2.8 years),- Cardiovascular events (NNT = 29 during 4.5 years),- Total mortality (NNT = 20 during 2.8 years).- Left ventricular dysfunction (NNT = 6 during 3.4 years)- Complications that usually occur in association with diabetes such as nephropathy (NNT = 83 during 5 years).Conclusion: ACE inhibitors are considered well-established and safe drugs. Despite that, only 38% of the patients with diabetic in Sweden are prescribed ACE inhibitors or angiotensin II antagonists. Due to the high efficacy of ACE-inhibitors among patients with diabetes (i.e. treating 15 high-risk diabetic patients with ACE-inhibitors for a median of 4.5 years prevents one incidence of myocardial infarction, stroke, or cardiovascular mortality) measures ought to be taken in favour of a more widespread use of ACE-inhibitors among patients with diabetes. This will result not only in medical benefits, but also in reducing cost of caring for the elderly diabetics in the community. For most diabetic patients it is very cost effective to prescribe an ACE-inhibitor therapy.

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is abundantly expressed in many organs. With respect to the role of circulating ACE2 and its receptor expression in the pathogenesis of the SARS-CoV-2 infection, it is still debated whether diseases such as hypertension or pharmacotherapies, including ACE inhibitors and angiotensin receptor blockers that affect ACE2 receptor expression, may modulate the severity and outcome of the coronavirus disease 2019 (COVID-19). We therefore tested the hypothesis that treatment with the ACE inhibitor Ramipril affects organ-specific ACE2 receptor mRNA and protein expression as well as the serum metabolome in BioBreeding (BB) rats. Twelve male BioBreeding rats were randomly divided into a Ramipril (10 mg/kg body weight) treatment group or a control group (N = 12; n = 6 per group) over a period of seven days. Ramipril treatment resulted in the reduction of acylcarnitines (C3–C6) out of 64 metabolites. Among the different organs studied, only in the lungs did Ramipril treatment significantly increase both Ace2 mRNA and ACE2 receptor membrane protein levels. Increased ACE2 receptor lung expression after Ramipril treatment was not associated with differences in ACE2 serum concentrations between experimental groups. Our data provide experimental in vivo evidence that the ACE inhibitor Ramipril selectively increases pulmonary ACE2 receptor mRNA and protein levels and reduces acylcarnitines.

No / Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.

Organic nitrates, such as nitroglycerine (NTG), are widely used for their potent vasodilator capacity in the management of coronary artery disease and heart failure. Unfortunately, their beneficial effect is rapidly lost due to the development of nitrate tolerance, which is translated by an impaired vasorelaxation to NTG and an increased oxidative stress production. Although the mechanisms of the development of nitrate tolerance are still not fully elucidated, much interest has been focused in treating nitrate-receiving patients together with other drugs in order to overcome the development of nitrate tolerance. The Nitric Oxide generating enzyme, eNOS, and the superoxide anion generating enzyme, NAD(P)H oxidase, have been suggested to play a role in the development of nitrate tolerance. The aim of this study was to analyse the underlying mechanism by which ramipril, an ACE inhibitor and rosuvastatin, a new molecule of the statin class, are able to protect against the development of nitrate tolerance in the aortas isolated from rats, wild-type (wt) and eNOS-/- mice. <p>These results show that ramipril as well as rosuvastatin are able to protect against the development of nitrate tolerance in the wt and eNOS-/- mice aortas suggesting that eNOS is not necessary for their protective effect. The aortas from nitrate tolerant rats and mice showed a significant increase in the NAD(P)H oxidase activation compared to the aortas from the control and from the co-treated ramipril+NTG or rosuvastatin+NTG animals. In line with these findings were the results obtained by RT-PCR analysis: the mRNA expression of the different subunits of the NAD(P)H oxidase, such as gp91phox, p22phox, were significantly decreased after rosuvastatin or ramipril treatment in wt and eNOS-/- mice aortas. Apocynin, the NAD(P)H oxidase inhibitor was also able to inhibit the development of nitrate tolerance in the rat and mouse aortas. <p>In conclusion, these results suggest that rosuvastatin and ramipril are able to protect against the development of nitrate tolerance by counteracting the nitrate-induced oxidative stress. The mechanism of protection involves a direct interaction with the NAD(P)H oxidase pathway and seems to be completely independent of the eNOS pathway. <p> / Doctorat en sciences pharmaceutiques / info:eu-repo/semantics/nonPublished

La prévention des maladies cardiovasculaires constitue actuellement une approche capitale dans la diminution de la mortalité au sein de nos pays industrialisés. Tous les facteurs de risques étant associés à une dysfonction endothéliale, nous nous sommes intéressés à deux classes de médicaments dont l’action bénéfique se situe, du moins en partie, au niveau de l’endothélium vasculaire :les inhibiteurs de l’enzyme de conversion de l’angiotensine (IECA) et les inhibiteurs de l’hydroxy-3-méthyl-3-glutaryl-Coenzyme A (HMG-CoA) réductase (statines).<p> Le présent travail contribue à l’étude in vitro des effets protecteurs vasculaires de l’administration chronique, chez le rat, de deux statines (la pravastatine et l’atorvastatine) vis-à-vis de la toxicité aiguë des LDL humaines oxydées et vis-à-vis de la tolérance à la nitroglycérine. Une comparaison est menée par rapport au ramipril dans ces deux modèles expérimentaux.<p>Les effets de ces médicaments se manifestent au niveau vasculaire par une amélioration de la disponibilité du NO. Toutefois, dans nos modèles, des mécanismes singulièrement différents ont été identifiés entre les agents étudiés :alors que le ramipril engendre une augmentation de l’expression de la eNOS, enzyme synthétisant le NO, les statines permettent une meilleure disponibilité de ce radical par un mécanisme post-traductionnel. Outre cette action, elles semblent agir directement sur des enzymes oxydatives comme les NAD(P)H oxydases.<p>Une action antioxydante des statines pourrait expliquer tous les effets observés, ce qui n’est pas le cas pour le ramipril. Vu que le stress oxydatif intervient dans tous les facteurs de risques cardiovasculaires, diverses perspectives cliniques sont envisagées afin d’améliorer l’approche thérapeutique de la maladie athéroscléreuse.<p> / Doctorat en sciences pharmaceutiques / info:eu-repo/semantics/nonPublished

Orientador: Gilberto de Nucci / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T09:06:01Z (GMT). No. of bitstreams: 1 Sanfelice_AndreTassoDantas_M.pdf: 2681697 bytes, checksum: 0b507c57048f3b18ee152ffbbe878963 (MD5) Previous issue date: 2005 / Resumo: Objetivo: Avaliar a bioequivalência de uma formulação de ramipril 5 mg (formulação teste de ramipril dos laboratórios Biossintética Ltda. e a formulação de referência padrão Triatec@ da Aventis Pharma) em vinte e seis voluntários de ambos os sexos. Método: O estudo foi conduzido usando um estudo aberto, randomizado, cruzado de duas fases com um intervalo de washout de 2 semanas. As amostras de plasma foram obtidas sobre um período de 36 horas. As concentrações plasmáticas de ramipril e ramiprilato foram analisadas por cromatografia líquida acoplada à espectrometria de massa (LC-MS-MS), com modo de ionização electrospray positivo usando o monitoramento de múltiplas reações (MRM). Das curvas de concentração plasmática versus o tempo para ramipril e ramiprilato, os seguintes parâmetros farmacocinéticos foram obtidos: ASCo-36h ASCIast, ASC(}...infe Cmax. Resultados: O limite de quantificação foi 0.2 ng.mL-1 e 1.0 ng.mL-1 para ramipril e ramiprilato, respectivamente. A média geométrica e a respectivo intervalo de confiança de 90% para RamipriIJTriatec@ e Ramiprilatol Triatec@ foram respectivamente: 104.69".10 (90% IC= 93.210/0-117.59%) para Cmax" 102.49% (90% IC= 92.76%-113.24%) para ASClast" 102.97% (90% IC= 93.21%-113.74%) para ASCO-36h" 103.60% (90% IC= 93.56%-114.73%) para ASCinf;, 108.48% (90% IC= 98.86%-119.03%) para Cmax, 105.88% (90% IC= 101.55%-110.39%) para ASClast,105.81% (90% IC= 101.53%-110.27%) para ASCo.36h, 97.30% (90% IC= 90.17%-104.99%) para ASCinf. Conclusão: Desde que o IC de 90% para ASCtast, ASCO-36h, ASCO-inf e Cmax apresentou-se dentro do intervalo de 80-125% proposto pelo FDA (US), foi concluído que a formulação ramipril elaborada pelo laboratório Biosintética Ltda é bioequivalente para a formulação Triatec@ para taxa e velocidade de absorção / Abstract: Objective: To assess the bioequivalence of one ramipril 5 mg tablet formulation (ramipril test formulation from Laboratórios Biosintética Ltda and Triatec$ from Aventis Pharma standard reference formulation) in 26 healthy volunteers ofboth sexes. Methods: The study was conducted using an open, randomized, two-period crossover design with a 2-week washout interval. Plasma samples were obtained over a 36 h period. Plasma ramipril and ramiprilat concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the ramipril and ramiprilat plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: ASCO-36h ASClast, ASCo-infand Cmax. Results: The limit of quantification was 0.2 ng.mL-1 and 1.0 ng.mL-1 for ramipril and ramiprilat, respectively. The geometric mean and respective 90% confidence interval (CI) RamipriVTriatec@ and Ramiprilat/ Triatec@ percent ratios were respectively: 104.69% (90% CI= 93.21%-117.59%) for Crnax,1O2.49% (90% CI= 92.76%-113.24%) for ASCIast,1O2.97% (90% CI= 93.21%-113.74%) for ASCo-36h,103.60% (90% CI= 93.56%-114.73%) for ASCnf)08.48% (9001Ó CI= 98.86%-119.03%) for Crnax,1O5.88% (90% CI= 101.55%-110.39%) for ASClast,105.81% (90% CI= 101.53%-110.27%) for ASCO-36h, 97.30% (9001Ó CI= 90.17%-104.99%) for ASCinf. Conclusion: Since the 90% CI for ASClast, ASCO-36h, ASCO-inf and Cmax ratios were within the 80-125% interval proposed by the US FDA, it was concluded that ramipril formulation elaborated by Laboratórios Biosintética Ltda is bioequivalent to Triatec@ formulation for both the rate and the extent of absorption / Mestrado / Clinica Medica / Mestre em Clinica Medica