Magister Scientiae (Medical Bioscience) - MSc(MBS) / Cardiovascular disease is a major health problem and remains the number one cause of death worldwide. For centuries, medicinal plants have been used in different cultures as medicines for the treatment and control of various diseases. Olea africana, also known as the wild olive, is amongst the herbal plants used by people to treat many ailments.Recently, scientific studies on the hypotensive, vasodilatory and antidysarrhythmic effects of O. africana have been reported. Triterpenoids isolated from the O. africana leaves, for example, have antioxidant properties. The aqueous extract from the leaves of O. africana also have angiotensin-converting enzyme (ACE) inhibitory effects. ACE inhibitors and antioxidants protect the heart against ischemic-reperfusion injury. The serine / threonine protein kinase B (PKB) also known as Akt is activated downstream of phosphoinositide 3- (PI-3) kinase (PI-3-Kinase) and is involved in cardioprotection against ischemia-reperfusion injury. Angiotensin II (AII) decreases the intrinsic PI-3-kinase activity. In this study, we hypothesized that ACE inhibitors increase PI-3-kinase activity and thus activates PKB. The aims of this study were: 1) to determine whether treatment with the crude aqueous extract of leaves of O. africana protect the heart against ischemic-reperfusion injury and 2) if so, to determine whether the protection is mediated via the PKB signaling mechanism. Hearts isolated from male Wistar rats were perfused with different concentrations of the plant extract. In one set of experiments, male Wistar rats were treated with the plant extract (1000 mg/kg/day) for 5 weeks for the evaluation of cardiac function before and after ischemia. At the end of the experiments, hearts were freeze-clamped and kept for PKB / Akt determination. In another set of experiments, we determined the effect of O. africana extract (1000 mg/kg/day) or captopril (50 mg/kg/day) on infarct size. Rats fed jelly served as controls for captopril. In a subset of experiments, hearts were frozen immediately after treatment with O. africana extract (1000 mg/kg/day) or captopril (50mg/kg/day) and PKB were determined.Perfusion with the plant extract significantly decreased coronary flow (p<0.05). The heart function was decreased as evidenced by observed decreases in the force of contraction and heart rate, although these were not measured. Chronic treatment with the crude aqueous plant extract had no effect on cardiac function before ischemia, functional recovery (% left ventricular developed pressure and % rate pressure product) and PKB /Akt phosphorylation (p>0.05). Both the aqueous extract of O. africana leaves and captopril had no effect on infarct size compared to the control group (p>0.05). Captopril,however, improved the recovery of the left ventricular developed pressure. Non-perfused hearts isolated from rats treated with O. africana extract and captopril did not show any response to both captopril and the O. africana extract treatment as measured by PKB /Akt phosphorylation. The results of the present study suggest that the crude aqueous extract of O. africana is not cardioprotective against ischemia-reperfusion injury in this system of the isolated perfused rat heart.

Orientador: Gilberto de Nucci / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T17:06:06Z (GMT). No. of bitstreams: 1 Okuyama_CristinaEunice_D.pdf: 791888 bytes, checksum: 44bf756719cf0cdc26ab70b220532e28 (MD5) Previous issue date: 2006 / Resumo: Compostos farmacológicos que liberam óxido nítrico (NO) têm sido utilizados para avaliar o amplo papel do NO na fisiopatologia e terapêutica de diversas doenças. Estudos demonstram que a deficiência de NO está envolvida com a gênese e evolução de diversos estágios de doenças como, por exemplo, a hipertensão. Deste modo, a adição de uma molécula de NO em drogas previamente estudadas vem sendo praticada por diversos pesquisadores na última década. Estes pesquisadores buscam associar as propriedades farmacológicas de cada droga com as atividades proporcionadas pelo NO exógeno. No presente trabalho, comparamos a farmacocinética e a farmacodinâmica do enalapril com as de um nitro-derivado do enalapril (NCX899), em Beagles machos não anestesiados. Os efeitos do enalapril e NCX899 na hipertensão arterial, bradicardia e vasoconstrição periférica induzida pela inibição aguda da síntese de NO em cães anestesiados também foram investigados. Na avaliação farmacocinética, os cães receberam NCX899 (4 µmol/Kg) ou Enalapril (4 µmol/Kg) pela via intravenosa. Em seguida, as concentrações plasmáticas dos analitos e metabólitos foram quantificadas pelo método de cromatografia líquida de alta eficiência, acoplada à espectrometria de massa (LCMS- MS). No grupo NCX899, a área sob a curva (ASC0-24h) foi 29,18 ± 4,72, 229,37 ± 51,32 e 5159,23 ± 514,88 µgh/l para os analitos nitro-enalapril, enalapril e enalaprilato, respectivamente. No grupo Enalapril, a ASC0-24h foi de 704,53 ± 158,86 e 4149,27 ± 847,30 µgh/l para os analitos enalapril e enalaprilato, respectivamente. As análises estatísticas entre os grupos demonstraram uma diferença significativa para o analito enalapril, mas não para o analito enalaprilato, o metabólito ativo. Entretanto, o NCX899 e o Enalapril foram efetivos de maneira semelhante na inibição da atividade da enzima conversora de angiotensina sérica. Em cães anestesiados, a administração intravenosa do inibidor da síntese de NO, o N?-nitro-L-arginina metil éster (L-NAME; 0,1-10 mg/kg), elevou significativamente a pressão arterial e causou bradicardia. O composto NCX899 atenuou significativamente a hipertensão arterial, bradicardia e vasoconstrição periférica, enquanto o Enalapril não apresentou efeito significativo. Além disso, nossos estudos também demonstraram que o NCX899 pode atuar não só como anti-hipertensivo, mas também auxiliar na inibição da agregação plaquetária. Assim, concluímos que o nitro-derivado do enalapril (NCX899) apresenta uma relação farmacocinética/farmacodinâmica similar ao composto enalapril. No entanto, ao contrário do Enalapril, o NCX899 apresenta um efeito protetor nas alterações cardiovasculares induzidas pela inibição aguda de NO / Abstract: Pharmacological compounds that release nitric oxide (NO) have been useful tools for evaluating the broad role of NO in physiopathology and therapeutics of several diseases. Studies show that lack of NO can cause several diseases such as hypertension. Thus, the addition of a NO molecule in drugs previously studied has been reported by some researchers in the last decade. They look for the combination of the pharmacologic properties of each drug, plus exogenous NO properties. This work has compared the pharmacokinetics and pharmacodynamics of enalapril and a NO-releasing enalapril molecule (NCX899) in conscious male Beagles. The effects of both enalapril and NCX899 in the arterial hypertension, bradycardia and peripheral vasoconstriction induced by acute NO inhibition in anesthetized dogs have also been investigated. In the pharmacokinetic evaluation, dogs received either NCX899 (4 µmol/Kg) or Enalapril (4 µmol/Kg) intravenously. Later, the plasma concentrations of the analytes and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). In the NCX899 group, the area under time-course curve (AUC0-24h) was 29.18 ± 4.72, 229.37 ± 51.32 and 5159.23 ± 514.88 µgh/l for the nitro-enalapril, enalapril and enalaprilat analytes, respectively. In the Enalapril group, the AUC0-24h was 704.53 ± 158.86 and 4149.27 ± 847.30 µgh/l for the enalapril and enalaprilat analytes, respectively. The statistical analysis between both groups showed a significant difference for the enalapril analyte, but not for enalaprilat, the active metabolite. Moreover, NCX899 and Enalapril were equally effective on inhibiting the activity of serum angiotensin-converting enzyme. In anesthetized dogs, intravenous administration of the NO synthase (NOS) inhibitor N?-nitro-L-arginine methyl ester (L-NAME; 0.1-10 mg/kg) significantly elevated arterial blood pressure with concomitant bradycardia. The compound NCX899 significantly attenuated arterial hypertension, bradycardia and peripheral vasoconstriction, whereas Enalapril had no significant effect. In addition, our work showed that NCX899 also has properties of inhibiting the activity of platelets aggregation. In conclusion, our results showed that the NO-releasing derivative of enalapril NCX899 presents a pharmacokinetic / pharmacodynamic relationship similar to the enalapril compound. Moreover, different from Enalapril, NCX899 presented protective effect in the cardiovascular alterations induced by acute NOS inhibition / Doutorado / Doutor em Farmacologia

Background: Amiodarone (AM) is a widely used anti-arrhythmic medication. Its utility is, however, limited by adverse side effects. The mechanism of amiodarone-induced toxicity (APT) in the lungs is attributed primarily to stimulation of the angiotensin enzyme system leading to lung cell apoptosis and cell death. This mechanism has been demonstrated by in vitro and in vivo experimental animal studies. To date, however, no in vivo human studies have confirmed this mechanism for APT. Purpose: This study was undertaken to determine whether angiotensin converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) offer a protective effect against APT in humans. Demonstration of a protective effect of an ACE-I or ARB would suggest that stimulation of the angiotensin enzyme system may be a key process in APT. Design: An 8-year retrospective analysis of all patients on AM therapy at the James H. Quillen Veterans Affairs Medical Center was undertaken. Results: A total of 1000 patients on AM were identified. One-hundred-and-seventeen were excluded from the study. Five-hundred-and-twenty-four patients were simultaneously on an ACE-I or ARB. The remaining 359 patients were not. Pulmonary toxicity attributed to AM was identified in five and 14 patients with and without concomitant ACE-I or ARB therapy, respectively. The APT rate for the entire patient sample was 2.2%. APT occurred in 1% of patients on an ACE-I or ARB and in 3.9% of patients not taking an ACE-I or ARB. This observed difference in percentage of APT was statistically significant. Conclusion: The concomitant use of ACE-I or ARB in patients taking AM appears to offer a protective effect against APT. This observation suggests that the stimulation of the angiotensin enzyme system may play an important role in APT in humans.

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Angioedema is a localized, non-pitting, non-dependent, submucosal, and subcutaneous swelling resulting from the extravasation of fluid into the interstitium due to the increased production of plasma kinins and histamine. It can present with urticaria or anaphylaxis and is usually associated with angiotensin-converting enzyme inhibitors (ACEis), complement deficiencies, or the side effects of tissue plasminogen activator (tPA). Orolingual angioedema following tPA for acute ischemic stroke is a transient, self-resolving hemifacial swelling contralateral to neurological deficits that can rarely progress to the airway, compromising it and leading to a life-threatening situation if not managed promptly.

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.

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Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request