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Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy.

Context: Although the long-term goal of antihypertensive therapy is to reduce adverse clinical outcomes, the only way to evaluate the efficacy of treatment in an individual is the magnitude of blood pressure (BP) reduction. ACE inhibitors and angiotensin receptor blockers (ARBs) are two drug classes that, by different mechanisms, inhibit the renin-angiotensin- aldosterone system that regulates BP. As these drugs are widely prescribed for hypertension, it is essential to determine and compare their effects on BP, heart rate and tolerability. Objectives: 1) To determine the dose-related effect of ACE inhibitors and ARBs on BP, heart rate and withdrawals due to adverse effects (WDAE), compared with placebo in the treatment of primary hypertension (SBP ≥ 140 mm Hg and/or ≥ DPB 90 mm Hg); and 2) To compare the relative effect on BP, heart rate and WDAE of a) each ACE inhibitor with other ACE inhibitors, b) each ARB with other ARBs, and c) all ACE inhibitors with all ARBs. Methods: Two systematic reviews of published, double-blind, randomized, controlled trials (RCTs) evaluating the BP lowering efficacy of fixed dose monotherapy with an ACE inhibitor or ARB compared with placebo for a duration of 3 to 12 weeks in patients with primary hypertension were conducted. Electronic databases were searched for RCTs and similar trial inclusion criteria and methods of analysis were used in both reviews. Results: Ninety two RCTs evaluated the dose-related BP lowering efficacy of 14 ACE inhibitors in 12 954 participants with a baseline BP of 157.1/101.2 mm Hg. Forty six RCTs evaluated the dose-related BP lowering efficacy of 9 ARBs in 13 451 participants with a baseline BP of 155.6/101.0 mm Hg. The best estimate of the near maximal trough BP reduction for ACE inhibitors and ARBs was -8/-5 mm Hg and -8/-5 mm Hg, respectively. ACE inhibitors and ARBs do not affect heart rate. The evidence for short-term WDAE (tolerability) was incomplete and weak and did not demonstrate a difference between the two classes of drugs. Conclusion: ACE inhibitors and ARBs are not different individually or as drug classes in BP lowering efficacy. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Angiotensin Converting Enzyme (ACE) inhibitors are one of the recommended prevention therapy for patients with acute myocardial infarction (AMI) in the clinical guidelines. Two types (tissue and non-tissue) of ACE inhibitors are available with huge cost difference but the comparative treatment benefit and risk between them are unclear. The objective of this study was to investigate the comparative treatment effectiveness and safety between tissue and non-tissue ACE inhibitors among elderly patients after AMI. This is a retrospective cohort study with intention to treatment design using Medicare service claims files from 2007 to 2009 with Medicare beneficiaries 65 years or older after the index AMI hospitalization and who survived to discharge between January 1 2008 to December 31 2008 and received ACE inhibitors (N=34,679). Risk adjustment and instrumental variable (IV) analyses were used to investigate comparative treatment effectiveness including AMI, stroke, heart failure requiring hospitalization, all-cause mortality and a composite of the endpoints during the follow-up and the comparative treatment safety - a composite of hyperkalemia and acute renal failure requiring hospitalization during the follow-up. Both the risk adjustment and IV analyses showed no significant differences between tissue and non-tissue ACE inhibitors for the investigated outcomes of the comparative treatment effectiveness and safety in the study cohort. However, subgroup analyses from the IV models showed that tissue ACE inhibitors as compared to non-tissue ACE inhibitors increased the hazard risk by approximately 30% to 60% (p < 0.05) for heart failure requiring hospitalization among the patients with heart failure and reduced hazard risk by approximately 30% to 40% (p <0.05) for AMI among patients without heart failure. In conclusion, though this study did not find significant difference between tissue and non-tissue ACE inhibitors for the comparative treatment effectiveness and safety in the study cohort, considerable comparative treatment effectiveness may exist in the subgroup of patients with and without heart failure in the elderly patients after AMI.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A hipertensÃo arterial à uma doenÃa que afeta milhÃes de pessoas em todo o mundo e dentre seus principais fatores causadores destacam-se uma dieta pouco saudÃvel, falta de exercÃcios fÃsicos e obesidade. A inibiÃÃo da enzima conversora da angiotensina (ECA) foi identificada como um alvo terapÃutico para controlar a pressÃo arterial elevada, pois o octapeptÃdeo angiotensina II, que possui atividade vasoconstritora, terà sua atividade minimizada nos vasos sanguÃneos. Compostos encontrados na casca da castanha de caju foram separados e identificados e seu potencial de inibiÃÃo da ECA foi estudado. Observou-se que os Ãcidos anacÃrdicos possuem essa atividade, sendo o Ãcido 3-anacÃrdico o maior inibidor entre os compostos fenÃlicos extraÃdos da casca da castanha de caju. Estudos in silico sÃo realizados atualmente para predizer a biodisponibilidade oral e a capacidade de penetraÃÃo no sistema nervoso central (SNC) de uma droga. Buscou-se realizar este estudo para verificar essas propriedades nos Ãcidos anacÃrdico, assim como tambÃm, comparar com outros inibidores da ECA. Observou-se que os Ãcidos anacÃrdicos violam somente uma das cinco regras de Lipinski, e como a regra estabelece que pelo menos trÃs destes requisitos devam ser satisfeitos, conclui-se que os Ãcidos anacÃrdicos apresentam uma boa biodisponibilidade oral e penetraÃÃo no SNC. Desse modo, a busca por uma espÃcie de clone que forneÃa uma maior massa de LCC por extraÃÃo assim como uma maior quantidade de Ãcidos anacÃrdicos por quilograma de LCC se torna importante. A partir disso, verificou-se entre cinco cultivos de cajueiros anÃes (CCP-76, CCP-09, Embrapa-110, Embrapa-119 e Embrapa-109) o que poderia oferecer um LCC com maior quantidade de Ãcidos anacÃrdicos. O cajueiro identificado como CCP-76 forneceu uma maior quantidade de LCC com cerca de 30 gramas para cada 50 gramas de casca de castanha utilizada para extraÃÃo e se obteve uma concentraÃÃo de 185 gramas de Ãcidos anacÃrdico por quilograma de LCC, sendo o melhor para extraÃÃo dos alquilfenÃis, entre os estudados. Em paralelo a esses estudos, procurou-se verificar a diferenÃa de compostos existentes na raiz de Jatropha mollissima cultivada em regiÃes diferentes e verificou-se que o estresse do sertÃo cearense aumenta a sÃntese de substÃncias para a sua sobrevivÃncia, sendo a raiz a regiÃo da planta escolhida por ser rica em metabolitos secundÃrios. Assim, essas plantas podem ser utilizadas na medicina preventiva, porÃm, estudos mais profundos devem ser realizados. / Hypertension is a disease that affects millions of people around the world and among its main causative factors include an unhealthy diet, lack of physical exercise and obesity. Inhibition of angiotensin converting enzyme (ACE) has been identified as a therapeutic target for controlling high blood pressure because the octapeptide angiotensin II, which has vasoconstrictor activity, have minimized their activity in blood vessels. Compounds found in the bark of cashew nuts were separated and identified, and their potential for ACE inhibition was studied. It was observed that the anacardic acids possess this activity, being the 3-anacardic acid inhibitor best among the largest phenolic compounds extracted from the bark of cashews. In silico studies are currently performed to predict the bioavailability and the ability to penetrate the central nervous system (CNS) of a drug. We attempted to conduct this study to verify these properties in anacardic acids, as well as compare with other ACE inhibitors. It was observed that the anacardic acids infringe only one of the five rules of Lipinski, and as the rule states that at least three of these requirements must be satisfied, it is concluded that the anacardic acids exhibit good oral bioavailability and CNS penetration. Thus, the search for a cashew that provides a greater mass of LCC per extraction well as a greater amount of anacardic acid per kilogram of LCC becomes important. From this, it was found among five crops of dwarf cashew (CCP-76, CCP- 09, Embrapa-110, Embrapa-119 and Embrapa-109) which could offer a LCC with greater amount of anacardic acids. The cashew labeled CCP-76 gave a higher amount of LCC to about 30 grams per 50 grams of chestnut bark used for extraction and obtained a concentration of 185 grams per kilogram of anacardic acids LCC to be the best extraction of alkylphenols, among studied. In parallel to these studies, we sought to investigate differences existing compounds in Jatropha mollissima grown in different regions, and it was found that the stress of Cearà hinterlands increases the synthesis of substances for their survival. Thus, these plants can be used in preventive medicine, however, further study should be conducted.

Bluthochdruck zählt zu einer der häufigsten Zivilisationskrankheiten und ist der Hauptfaktor für die Entstehung kardiovaskulärer Erkrankungen. Das Präventionspotenzial bei Hypertonie ist sehr hoch, da lebensstilassoziierte Faktoren wie Übergewicht, hoher Kochsalz- und Alkoholkonsum oder Stress die Entstehung eines erhöhten Blutdrucks wesentlich begünstigen. Daher wird eine antihypertensive Therapie meist mit nicht-medikamentösen Maßnahmen eingeleitet. Für die Regulation des Blutdrucks ist die nähere Betrachtung des Angiotensin-Converting Enzymes (ACE) wichtig, da es eines der Schlüsselenzyme des Renin-Angiotensin-Aldosteron-Systems und des Kallikrein-Kinin-Systems darstellt. Die Möglichkeit, dass ACE-inhibierende Peptide aus Lebensmittelproteinen über die Nahrungsmittelaufnahme einen positiven physiologischen Effekt auf den Blutdruck ausüben, ist ein vielversprechender Ansatz zur Unterstützung einer nicht-medikamentösen Therapie bei Hypertonie. In der Literatur sind zahlreiche Peptide beschrieben, welche eine inhibitorische Wirkung auf das ACE in vitro besitzen. Die vorliegende Arbeit beschäftigte sich mit der Klasse der tryptophanhaltigen Dipeptide, die in der Literatur als potente, natürliche ACE-Inhibitoren beschrieben sind. Die tryptophanhaltigen Peptide wurden hinsichtlich ihrer Gewinnung, ihrer Hemmwirkung auf das Zielenzym und bezüglich ihrer Bioverfügbarkeit in vitro und in vivo untersucht.

In the exploration into new therapeutic agents for human disease, medicinal herbs offer an enormous resource due to their wide range of biologically active components. However, because of these biologically active components, medicinal herbs can also have toxic side effects. The focus of this thesis is the effect of herbal therapies, both good and bad, on chronic kidney disease (CKD) and tubulointerstitial fibrosis. Tubulointerstitial fibrosis is considered one of the defining characteristics of CKD. In Chapter 1, the literature regarding the pathogenesis of tubulointerstitial fibrosis is reviewed, beginning with the mechanisms of its development, the main structural and functional features, and the molecular mediators. The structural features include activation of resident fibroblasts and transition of tubular epithelial cells into myofibroblasts, deposition of extracellular matrix proteins, increased apoptosis of normal cells of the renal nephron and development of tubular atrophy, increased renal oxidative stress, and hypoxia of renal tissues. Molecular mediators that are explored include angiotensin II, transforming growth factor-ß1 and numerous other cytokines and growth factors. Pharmacological manipulation of these features and their molecular mediators for regression of tubulointerstitial fibrosis is then discussed. Currently, the gold standard of therapy for people with CKD is blockade of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs). Because of the complexity of the pathogenesis of renal fibrosis and the multiple mechanisms by which ACEIs and ARBs work, this portion of the thesis focuses on the qualities that additional agents should have to complement their actions. These additional agents could work by decreasing oxidative damage, by decreasing fibroblast numbers through apoptosis, through the interruption of inflammatory, fibrotic mediators, by increasing anti-inflammatory mediators or through other mechanisms. The literature review therefore continues with a discussion of the historical use of medicinal herbs in genitourinary pathologies and the known contributions that medicinal herbs can make to the treatment or development of tubulointerstitial fibrosis and CKD. From this review, a large number of herbs were identified as having traditional use in renal disorders or as being of interest, currently, to researchers of renal pathologies. However, much information is lacking regarding the mechanisms by which the hypothesised benefits occur, making it impossible to assess which herb(s) may offer valuable additive support or alternative treatments to the therapies currently given to people with CKD. Furthermore, there is a lack of information regarding toxicity of these herbs; many herbs have never been assessed in cell culture or in animal toxicity studies. It was apparent that preliminary in vitro work was necessary before in vivo pharmacological work could be undertaken. This thesis, therefore, aimed to test the following hypotheses: (1) That medicinal herbs used currently for treatment of renal dysfunction have high anti-oxidant properties that can be further enhanced by specific extraction processes; (2) That the in vitro testing of selected extracts from medicinal herbs, identified in (1), will reveal some anti-oxidant benefits or indications of toxicity that need careful analysis in animal studies; (3) That careful in vivo testing of specific toxic medicinal herbs identified in these leadup studies will define specific pathological processes that predict an outcome of CKD; and (4) That careful in vivo testing of selected medicinal herbs, used in conjunction with more conventional medicines for CKD, will show an additive benefit when used to ameliorate development of CKD induced using an established animal model. The subsequent laboratory work was designed to test the validity of these hypotheses and the results are then presented in Chapters that each comprise a publication. The aim of Chapter 2 was to present a systematic analysis of the oxidant properties of 55 medicinal herbs that have been used traditionally to treat kidney and urinary disorders or have been of recent interest to researchers of renal disorders. Since different extraction processes yield different constituents, each of the herbs was sequentially extracted with three solvents of decreasing polarity. An assay was performed on each of the fractions to determine the oxygen radical absorbance capacity. The aim of Chapter 3 was to test the benefit or otherwise of each of the three extracts of the chosen herbs using an in vitro cell study. Each extract was tested for potential toxic, apoptotic, mutagenic and antioxidant activity on normal mammalian renal tubular epithelial cells (NRK-52E). The effect of the extracts on renal fibroblasts (NRK-49F) was also analysed. Several specific hypotheses arose from the combination of the systematic analyses and the literature review regarding benefits and toxicities of a number of the extracts. The subsequent in vivo work was designed to test the validity of two of these hypotheses. The aim of Chapter 4 was to test the hypotheses developed from the results of the previous Chapter. The herb Dioscorea villosa had demonstrated extreme cytotoxicity to mammalian renal epithelial cells and had caused transdifferentiation of epithelial cells into fibroblasts. An in vivo rodent model was used to test chronic dosage with this herb and its toxicity and predisposition for induction of CKD verified. The aim of Chapter 5 was to determine whether a herbal preparation (Angelica sinensis and Astragalus membranaceus) that had some support from the literature and the results from Chapters 2 and 3, could complement the actions of ACEIs in a rodent model of renal fibrosis (unilateral ureteral obstruction). The combination of herbal medicines and the ACEI was significantly more effective than the ACEI alone in ameliorating several characteristics of CKD development. To conclude the thesis, Chapter 6 provides an overview discussion of the results and a critical analysis of the methods used. Further, Chapter 6 looks towards future experiments that are planned to further resolve issues of concern about effects on renal health from use of medicinal herbs. .

Thesis (M.Pharm. (Pharmacy Practice))---North-West University, Potchefstroom Campus, 2008.