Leung Hok Sum. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 128-147). / Abstracts in English and Chinese. / Declaration --- p.i / Acknowledgements --- p.ii / Abbreviation --- p.iii / Abstract in English --- p.iv / Abstract in Chinese --- p.vi / Contents --- p.viii / Chapter Chapter I - --- Introduction / Chapter 1.1. --- Steroid Hormone --- p.1 / Chapter 1.2. --- Estrogen Receptors --- p.2 / Chapter 1.3. --- Selective Estrogen Receptor Modulators --- p.5 / Chapter 1.3.1. --- Tamoxifen --- p.5 / Chapter 1.3.1.1. --- Cardiovascular Effects of Tamoxifen --- p.6 / Chapter 1.3.1.2. --- Acute Vascular Effects of Tamoxifen --- p.6 / Chapter 1.3.1.3. --- Chronic Vascular Effects of Tamoxifen --- p.7 / Chapter 1.3.1.4. --- Antioxidant Effects of Tamoxifen --- p.8 / Chapter 1.3.2. --- Raloxifene --- p.8 / Chapter 1.3.2.1. --- Cardiovascular Effects of Raloxifene --- p.8 / Chapter 1.3.2.2. --- Acute Vascular Effects of Raloxifene --- p.9 / Chapter 1.3.2.3. --- Chronic Vascular Effects of Raloxifene --- p.10 / Chapter 1.3.2.4. --- Ovariectomy and Raloxifene Treatment --- p.11 / Chapter 1.4. --- Mechanism of Action of SERMs --- p.15 / Chapter 1.5. --- Effects of Functional Endothelium and Nitric Oxide --- p.18 / Chapter 1.6. --- Dihydropyridine (DHP) Calcium Channel Antagonists --- p.19 / Chapter 1.6.1. --- Development of Newer Generation of Dihydropyridines --- p.19 / Chapter 1.6.2. --- Effects of Dihydropyridines on Vascular Endothelium (I) --- p.20 / Chapter 1.6.3. --- Effects of Dihydropyridines on Vascular Endothelium (II) --- p.21 / Chapter 1.6.4. --- Effects of Dihydropyridines on Nitric Oxide Synthase (NOS) --- p.21 / Chapter 1.6.5. --- Clinical Studies of Dihydropyridines --- p.22 / Chapter 1.7. --- Vascular Ion Channels --- p.25 / Chapter 1.8. --- Objectives of The Present Study --- p.26 / Chapter Chapter II - --- Materials and Methods / Chapter 2.1. --- Tissue Preparation --- p.27 / Chapter 2.1.1. --- Preparation of The Porcine Left Circumflex Coronary Arteries --- p.27 / Chapter 2.1.2. --- Removal of Functional Endothelium --- p.27 / Chapter 2.1.3. --- Organ Bath Setup --- p.27 / Chapter 2.1.4. --- Isometric Force Measurement --- p.29 / Chapter 2.2. --- In situ Endothelial [Ca2+]i Imaging --- p.29 / Chapter 2.2.1. --- Preparation of Porcine Left Circumflex Coronary Arteries --- p.29 / Chapter 2.2.2. --- Setup For In situ Endothelial [Ca2+]i Imaging --- p.30 / Chapter 2.3. --- Electrophysiological Measurement of BKCa Current --- p.31 / Chapter 2.3.1. --- Enzymatic Dissociation of Coronary Artery Smooth Muscle Cells --- p.31 / Chapter 2.3.2. --- Electrophysiological Measurement --- p.31 / Chapter 2.4. --- DPPH Free Radical Scavenging Assay --- p.31 / Chapter 2.5. --- Solutions and Drugs --- p.32 / Chapter 2.5.1. --- "Drugs, Chemicals and Enzymes" --- p.32 / Chapter 2.5.2. --- Solutions Used in Force Measurement --- p.34 / Chapter 2.6. --- Statistical Analysis --- p.34 / Chapter Chapter III - --- Tamoxifen-Induced Endothelial Nitric Oxide-Dependent Relaxation in Porcine Coronary Arteries via Ouabain- and BaCl2-Sensitive Mechanisms / Chapter 3.1. --- Abstract --- p.35 / Chapter 3.2. --- Introduction --- p.36 / Chapter 3.3. --- Methods and Materials --- p.37 / Chapter 3.3.1. --- Vessel Preparation --- p.37 / Chapter 3.3.2. --- Isometric Force Measurement --- p.38 / Chapter 3.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.39 / Chapter 3.3.4. --- Chemicals --- p.40 / Chapter 3.3.5. --- Data Analysis --- p.40 / Chapter 3.4. --- Results --- p.41 / Chapter 3.4.1. --- Relaxant Responses --- p.41 / Chapter 3.4.2. --- Effects of Inhibitors of NO-Dependent Relaxation --- p.41 / Chapter 3.4.3. --- Effects of Putative K+ Channel Blockers and Ouabain --- p.41 / Chapter 3.4.4. --- "Effects of Ouabain, Removal of Extracellular K+ Ions and BaCI2" --- p.42 / Chapter 3.4.5. --- SNP-Induced Relaxation --- p.42 / Chapter 3.4.6. --- Effects of Actinomycin D and Cycloheximide --- p.42 / Chapter 3.4.7. --- Relaxant Effect of 17β-Estradiol --- p.43 / Chapter 3.4.8. --- Effects on Endothelial [Ca2+]i in Isolated Coronary Arteries With Endothelium --- p.43 / Chapter 3.5. --- Discussion --- p.53 / Chapter Chapter IV - --- Endothelium-Independent Relaxation to Raloxifene in Porcine Coronary Arteries / Chapter 4.1. --- Abstract --- p.57 / Chapter 4.2. --- Introduction --- p.58 / Chapter 4.3. --- Methods and Materials --- p.59 / Chapter 4.3.1. --- Vessel Preparation --- p.59 / Chapter 4.3.2. --- Isometric Force Measurement --- p.60 / Chapter 4.3.3. --- Electrophysiological Measurement of BKCa Current --- p.61 / Chapter 4.3.3.1. --- Enzymatic Dissociation of Coronary Artery Smooth Muscle --- p.61 / Chapter 4.3.3.2. --- Electrophysiological Measurement --- p.62 / Chapter 4.3.4. --- Chemicals --- p.63 / Chapter 4.3.5. --- Data Analysis --- p.63 / Chapter 4.4. --- Results --- p.64 / Chapter 4.4.1. --- Effect of Raloxifene on Agonist-Induced Contractions --- p.64 / Chapter 4.4.2. --- Role of Endothelium --- p.64 / Chapter 4.4.3. --- Effect of ER Antagonist --- p.65 / Chapter 4.4.4. --- Effect of Putative K+ Channel Blockers --- p.65 / Chapter 4.4.5. --- Effect of Elevated Extracellular K+ Concentrations --- p.65 / Chapter 4.4.6. --- Effects of Raloxifene on BKCa Current --- p.65 / Chapter 4.5. --- Discussion --- p.75 / Chapter Chapter V - --- Therapeutic Concentrations of Raloxifene Augment Bradykinin Mediated Nitric Oxide-Dependent Relaxation in Porcine Coronary Arteries / Chapter 5.1. --- Abstract --- p.78 / Chapter 5.2. --- Introduction --- p.79 / Chapter 5.3. --- Methods and Materials --- p.80 / Chapter 5.3.1. --- Vessel Preparation --- p.80 / Chapter 5.3.2. --- Isometric Force Measurement --- p.80 / Chapter 5.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.81 / Chapter 5.3.4. --- Free Radical Scavenging Assay --- p.82 / Chapter 5.3.5. --- Chemicals --- p.83 / Chapter 5.3.6. --- Data Analysis --- p.83 / Chapter 5.4. --- Results --- p.84 / Chapter 5.4.1. --- Relaxation to Bradykinin --- p.84 / Chapter 5.4.2. --- Effect of Raloxifene on Bradykinin-Induced Relaxation --- p.84 / Chapter 5.4.3. --- Effect of Raloxifene on Relaxation Induced by Substance P and --- p.85 / Chapter 5.4.4. --- Effect of Estrogen on Bradykinin-Induced Relaxation --- p.85 / Chapter 5.4.5. --- Effect of Raloxifene on Sodium Nitroprusside-Induced Relaxation --- p.86 / Chapter 5.4.6. --- Free Radical Scavenging Effect --- p.86 / Chapter 5.4.7. --- Raloxifene Augmentation of Bradykinin-Stimulated Endothelial [Ca2+]i --- p.86 / Chapter 5.5. --- Discussion --- p.99 / Chapter Chapter VI - --- "Cilnidipine, a Slow-Acting Ca2+ Channel Blocker, Induces Relaxation in Porcine Coronary Arteries: Role of Endothelial Nitric Oxide and [Ca2+]i" / Chapter 6.1. --- Abstract --- p.102 / Chapter 6.2. --- Introduction --- p.103 / Chapter 6.3. --- Methods and Materials --- p.104 / Chapter 6.3.1. --- Vessel Preparation --- p.104 / Chapter 6.3.2. --- Isometric Force Measurement --- p.105 / Chapter 6.3.3. --- In situ Endothelial [Ca2+]i Imaging --- p.106 / Chapter 6.3.4. --- Free Radical Scavenging Assay --- p.107 / Chapter 6.3.5. --- Chemicals --- p.108 / Chapter 6.3.6 --- Data Analysis --- p.108 / Chapter 6.4. --- Results --- p.108 / Chapter 6.4.1. --- Relaxant Responses --- p.108 / Chapter 6.4.2. --- Role of the Endothelium --- p.109 / Chapter 6.4.3. --- Effect of Inhibitors of NO-Dependent Relaxation --- p.109 / Chapter 6.4.4. --- Effect of Indomethacin and w-conotoxin --- p.110 / Chapter 6.4.5. --- Effect of Cilnidipine on Sodium Nitroprusside-Induced Relaxation --- p.110 / Chapter 6.4.6. --- Effects on Endothelial [Ca2+]i in Isolated Endothelium-Intact Coronary Arteries --- p.110 / Chapter 6.4.7. --- Free Radical Scavenging Effect --- p.110 / Chapter 6.5. --- Discussion --- p.120 / Chapter Chapter VII - --- General Summary --- p.123 / References --- p.128

Wong Chi Ming. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 182-215). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (M.S.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on March 21, 2008) Includes bibliographical references.

Thesis (M.S.)--University of North Carolina Wilmington, 2007. / Includes bibliographical references (Leaves: 110-116)

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

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Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-29T19:53:36Z No. of bitstreams: 1 rafaelmoraespinto.pdf: 447765 bytes, checksum: b928e9b6d5d9c3600bc07d8048d510f2 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-30T11:25:48Z (GMT) No. of bitstreams: 1 rafaelmoraespinto.pdf: 447765 bytes, checksum: b928e9b6d5d9c3600bc07d8048d510f2 (MD5) / Made available in DSpace on 2017-03-30T11:25:48Z (GMT). No. of bitstreams: 1 rafaelmoraespinto.pdf: 447765 bytes, checksum: b928e9b6d5d9c3600bc07d8048d510f2 (MD5) Previous issue date: 2009-08-10 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / O uso de terapia hormonal na menopausa não está isento de riscos sendo relatados eventos adversos como embolia pulmonar e câncer após seu uso. Nestes casos, os fitoestrogênios, compostos estrogênicos presentes nas plantas, podem ser utilizados como alternativa ao tratamento hormonal, já existindo comprovação da eficácia e segurança em seu uso. O extrato de Ginkgo biloba, um dos fitoterápicos mais consumidos no mundo, utilizado para o tratamento de distúrbios circulatórios e neurológicos, produziu efeito estrogênico in vitro em células tumorais MCF7 e promoveu alteração do epitélio vaginal de camundongos, aventando a possibilidade do seu uso como um fitoestrogênio. Porém, ainda não existem estudos conclusivos in vivo indicando o efeito estrogênico do extrato, sendo este o objetivo do presente trabalho. Neste experimento, foram utilizadas 70 ratas Wistar, pré-púberes, com 22 dias de idade. As ratas foram pesadas e distribuídas aleatoriamente em sete grupos com 10 animais em cada. O grupo controle negativo recebeu 0,4mL de água destilada via intragástrica. O grupo controle positivo recebeu 1µg/Kg de 17α-estradiol em 0,3mL de óleo mineral, via subcutânea. Os grupos tratados receberam extrato de Ginkgo biloba nas doses de 4, 40, 100, 500 e 1000mg/Kg/dia, administrado em 0,4mL de solução aquosa via intragástrica. A administração das soluções ocorreu uma vez ao dia por três dias. Após 24 horas do último dia de tratamento foi analisada a presença de abertura vaginal e os animais foram eutanasiados para remoção do trato reprodutor. O útero foi separado da vagina e dos ovários e então pesado. Análise histomorfométrica dos cornos uterinos e vagina (espessura da mucosa vaginal e do epitélio superficial uterino) foi realizada. A análise estatística dos dados obtidos foi feita pelo teste ANOVA seguido de teste post-hoc de Tukey ou Dunnett T3 com nível de significância de α = 0,05. O tratamento com Ginkgo biloba não alterou o peso corporal nem o peso uterino. A espessura da mucosa vaginal foi menor nos animais que receberam 1000mg/Kg do extrato. Nos animais tratados com 4, 40, 100 e 500mg/Kg de G. biloba observou-se aumento da espessura do epitélio superficial uterino. Podemos concluir que o extrato de Ginkgo biloba estudado apresentou indícios de efeito estrogênico quando administrado a ratas Wistar nas doses de 4, 40, 100 e 500mg/Kg e efeito antiestrogênico na dose de 1000mg/Kg. / The use of hormonal therapy in menopause is not absent of risks being related to adverse effects such as pulmonary embolism and cancer due to its use. In these cases, phytoestrogens, the estrogenic compounds present in plants, can be used as an alternative to the hormonal treatment. There is already proof of efficacy and safety in their use. Ginkgo biloba extract, one of the most consumed phytotherapics in the world, used to the treatment of circulatory and neurologic disturbs, produced estrogenic effect in vitro in MCF7 tumoral cells and promoted alteration in the vaginal epithelium of mice, suggesting a possibility of being used as a phytoestrogen. However, there are not conclusive studies in vivo indicating the estrogenic effect of any Ginkgo biloba extract, being this the objective of this work. In this experiment seventy 22 day-old impuberal Wistar rats were used. The rats were weighed and randomly distributed into seven groups with ten animals each. The negative control group received 0.4mL of distilled water, by gavage. The positive control group received 1 µg/Kg of 17α-estradiol in 0.3mL of mineral oil, by subcutaneous injection. The treated groups received Ginkgo biloba extract in doses of 4, 40, 100, 500 and 1000mg/Kg/day, administered in 0.4mL of aqueous solution, by gavage. The administration of the solutions occurred once a day during three days. After 24 hours from the last day of treatment the presence of vaginal opening was analyzed and the animals were euthanized to remove the reproductive tract. The uterus was separated from the vagina and from the ovaries and then weighted. The uterine horns and the vagina were fixed to histomorphometric analysis and vaginal mucosa and uterine superficial epithelium thickness were measured. Statistical comparisons were made, using ANOVA, followed by post hoc Tukey or Dunnett T3. The level of significance of tests was α = 0.05. The Ginkgo biloba treatment did not alter the body weight neither the uterine weight. The vaginal mucosa thickness was thinner in the animals that received 1000mg/Kg of the extract. In the animals treated with 4, 40, 100 and 500mg/Kg of Ginkgo biloba it was observed that the uterine superficial epithelium was thicker. We conclude that the Ginkgo biloba extract studied showed indications of an estrogenic effect when administered to Wistar rats with doses of 4, 40, 100 and 500mg/Kg and an anti-estrogenic effect with a dose of 1000mg/Kg.

Indiana University-Purdue University Indianapolis (IUPUI) / Breast cancer remains the most prevalent malignancy diagnosed in women. More than two thirds of all diagnosed breast cancers are estrogen receptor (ER)-positive and are dependent on estrogen signaling. Drugs for the treatment of ER-positive breast cancer can be divided into three classes: selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs) and aromatase inhibitors (AIs). However, the efficacy and safety of SERMs, SERDs and AIs are compromised by side effects or tumor resistance. One possible way of improving treatment efficacy and safety profiles is to develop agents with dual aromatase inhibitory and ER modulatory activity. Over the past 30 years, tamoxifen, a SERM, has become the most widely used drug for the adjuvant treatment of breast cancer. The metabolism of tamoxifen has a complex profile involving both active and inactive metabolites, among which endoxifen, 4-hydroxytamoxifen (4-HT) and norendoxifen (Nor) have been shown to have ER modulatory activity. Previous studies have also shown that norendoxifen is a potent AI in vitro. These preliminary studies support the utilization of tamoxifen metabolites as lead compounds for the development of dual AI/SERM(D) agents. Hydroxynorendoxifen (Hdn) was identified as a novel tamoxifen metabolite, with an average plasma concentration of 0.82 nM. Nor and Hdn were potent and relatively selective AIs, with Kis of 70 nM and 20 nM, respectively. Nor and Hdn have high binding affinity for ER-α and ER-β, with EC50 values less than 35 nM. Nor and Hdn can inhibit breast cancer cell proliferation with high potency, with IG50s of 25 nM and 9 nM, respectively. Nor and Hdn can suppress progesterone receptor (PGR) mRNA expression level by reducing it by 68% and 86%. Moreover, a series of Nor analogues were shown to have both potent aromatase inhibitory activity and high ERs binding affinity. Results from this dissertation will contribute to three aspects: 1) the identification of Hdn as a tamoxifen metabolite illustrated a more comprehensive metabolism profile of tamoxifen; 2) the data suggest Nor and Hdn possess dual aromatase inhibitory and ER antagonistic activity; 3) a series of Nor analogues were characterized as lead compounds for the development of dual AI/SERM(D) agents.

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