Browsing by Subject "Medicinal Chemistry and Pharmaceutics"
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Item Androgens and Cardiovascular Disease(1998-05-01) Dickerman, Rob D.; Walter J. McConathy; Thomas Yorio; Robert GracyDickerman, Rob D., Androgens and Cardiovascular Disease Doctor of Philosophy (Biomedical Sciences), May 1998; 111 pp; 10 tables, bibliography, 197 titles. Anabolic steroids are commonly used by many muscle and strength dependent athletes due to their ability to enhance the hypertrophic effects of resistance training. The use of anabolic steroids by bodybuilders appears to carry significant health risks, most commonly reported are sudden death, myocardial infarction and cardiomyopathy. To investigate the effects of anabolic steroids on cardiovascular risks, a study was designed to analyze the effects of androgens on lipoprotein levels and structure/function of the heart. For the study on lipid-related risk, twelve competitive bodybuilders were recruited for a comprehensive analysis of serum apolipoprotein A-I, B, total cholesterol, HDL-cholesterol, LDL-cholesterol, and testosterone. Serum total cholesterol, HDL- and LDL-cholesterol, apolipoproteins A-I and Be were significantly lower in androgen-users. Consistent with previous reports, androgens were associated with decreases in HDL-cholesterol and apolipoprotein A-I. However, androgens were also associated with reduced serum total cholesterol, LDL-cholesterol and apolipoprotein B. Despite the significantly higher total cholesterol/HDL-cholesterol ratio, the low levels of serum total cholesterol levels (percentile) in the androgen-users raises questions as to whether there is increased risk for cardiovascular disease and the exact role of androgens in cardiovascular risk. To investigate the effects of anabolic steroids in pathologic concentric left ventricular hypertrophy, the effects of androgens on left ventricular size and function were analyzed. Previous investigations conducted on left ventricular size and function have yielded inconclusive results. Problems existing in each of the previous investigations were small body mass, short length of myocardial exposure time to resistance training (years of training), significantly different body mass between steroid-users and steroid-free subjects and monitoring/reporting of steroid use. These problems may have contributed to the discrepancies between studies. Therefore, we selectively recruited eight competitive heavy weight drug-free bodybuilders and eight matched competitive weight bodybuilders on self-directed regimens of anabolic steroids for examination of left ventricular size and function via echocardiography. Increases in left ventricular posterior wall (LVPW) and ventricular septal thickness (VST) were apparent in the steroid-user group (p [less than] 0.05). Ratio of echocardiographic findings to body mass index (BMI) revealed a significantly smaller left ventricular and diastolic dimension (LVDEd/BMI, p [less than] 0.05) in the steroid-user. The smaller LVDEd in steroid-users is coupled with a significantly disproportionate septal and posterior wall thickness in steroid-users. There was no direct evidence of diastolic dysfunction. Thus it appears from these studies that androgens alter lipoproteins leading to a questionable increased risk for cardiovascular disease and may potentiate concentric left ventricular hypertrophy without affecting cardiac function.Item Corticotropin-Releasing Factor and Corticosterone Modulate the Anxiogenic-Like Effects of mCPP(1998-06-01) Jenkins, Jennifer A.; Michael Forster; Robert Luedtke; Patricia GwirtzJenkins, Jennifer A., Corticotropin-Releasing Factor and Corticosterone Modulate the Anxiogenic-Like Effects of mCPP. Doctor of Philosophy (Pharmacology), June 1998, 119 pp., 2 tables, 29 figures, bibliography, 100 titles. The administration of PTZ or mCPP produces anxiety-like behavior as measured by an increase in the percentage of entries into the open arms and the time spent on the open arms of the elevated plus maze (Prunell et al., 1994). Reportedly, PTZ and mCPP substitute for each other in the drug discrimination paradigm (Wallis and Laz, 1998). It is therefore suggested that commonality exists among anxiogenic drugs as perceived by trained animals. Andrews and Stephen (1990) suggested that this overall parallelism is an indication that anxiogenic agents may possess similar properties. Therefore, the question posed is as follows: Is there a common denominator anxiety? The global hypothesis is that the core component of anxiety produced by anxiogenic agents or processes involves stimulation of the HPA axis to release CRF, ACTH and/or CORT. Long Evans rats were trained to discriminate either mCPP (1.4 mg/kg) or PTZ (16mg/kg) from saline in a two-lever choice procedure (FR10) which is food reinforced. Animals were pretreated with CRF, α-helical CRF (a CRF antagonist), two steroid synthesis inhibitors (ketoconazole, KETZ and aminoglutethimide, AMG), CORT or underwent an adrenalectomy prior to behavioral testing in order to test the hypothesis that the release of CRF and/or CORT are components of the discriminate stimulus of the mCPP and/or PTZ. Pretreatment with CRF, KETZ, AMG and an adrenalectomy facilitated mCPP level selection. However in the absence of mCPP neither drug nor adrenalectomy produced drug lever selection. In addition CORT did not alter the mCPP dose response curve. However, CORT replacement therapy returned the does response curve to baseline in adrenalectomized animals. Alpha-helical CRF did not block mCPP discrimination. Unlike mCPP-trained animals, KETZ and AMG decreased PTZ-lever selection in PTZ-trained animals. In addition, CORT enhanced and partially substituted for the discriminative stimulus of PTZ. However, adrenalectomy completely abolished drug lever selection in PTZ animals. To compare the discriminative stimulus effects of mCPP and PTZ, PTZ-trained animals were injected with cumulative doses of mCPP. mCPP-trained animals were injected with cumulative doses of PTZ. mCPP and PTZ minimally substituted for each other. The results suggested that neither CRF nor CORT are components of the discriminative stimulus of mCCP and that the role of the HPA axis in mCPP discrimination maybe be a modulator of the stress response. However, CORT is a component of the discriminative stimulus of PTZ such that CORT is necessary for drug lever selection in PTZ trained animals.Item Horse Serum High Density Lipoproteins as Drug Transporters(2004-05-01) Johnson, Shemedia; Walter McConathyJohnson, Shemedia J., Horse Serum High Density Lipoproteins (HDL) as Drug Transporters. High-density lipoproteins (HDL) are complex particles composed of specific proteins and lipids that facilitate blood and tissue cholesterol homeostasis by transporting excess peripheral cholesterol to the liver. In association with cholesterol ester transfer protein (CETP) and the enzyme, lecithin: cholesterol acyltransferase (LCAT), HDL contributes to the transport of hydrophobic lipids, including cholesterol ester and triglycerides through the blood. The studies presented here involve the evaluation of horse serum HDL as a carrier of water insoluble drugs and an improved process to isolate and purify horse serum HDL utilizing hydrophobic affinity chromatography. Dilauryl fluorescein (DLF) has been chosen as a model compound for the study of horse HDL as a drug carrier. The prepared HDL/DLF particles have similar flotation densities and size properties to native horse serum HDL. The amount of DLF incorporated into HDL is 30μg/mg protein. Various cancer cell lines internalized DLF from horse HDL/DLF particles successfully. While human plasma contains cholesterol ester transfer protein (CETP), horse plasma does not. Horse plasma/serum can be supplemented by human plasma to study the role of CETP in drug transport and the stability of the horse HDL/drug complex.Item Review of the History of Coronary Stenting, Role and Evolution of Adjunctive Pharmacotherapy and Experience with an Ongoing Drug-Eluting Stent Trial(2005-12-01) Kang, Mi Jung; Bens, Annita V.; Ratka, Anna; Oglesby, MichaelKang, Mi Jung. Review of the History of Coronary Stenting, Role and Evolution of Adjunctive Pharmacotherapy and Experience with an Ongoing Drug-Eluting Stent Trial. Master of Science (Clinical Research Management), December 2005, 116 pp., 6 tables, 12 figures, bibliography, 61 titles. The history of stent development with regard to the use of coating materials and eluting drugs, with special emphasis on mechanism of release and duration of action of drugs used in drug-eluting stents, was summarized. The general safety profile of currently used adjunctive pharmacotherapy to coronary stenting, with special emphasis on the clinical trials providing the scientific assessments of the effectiveness and safety of the regimens was reviewed. The enrollment process and the critical role of the Clinical Research Coordinator (CDC) in the process of the implementation of a clinical study with a new drug-eluting stent were described.