Thesis (Ph. D.)--University of Wisconsin--Madison, 1915. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (p. 52-60).

Memoria de Título para optar al título de Química Farmacéutica / Los extractos herbales deben ser evaluados en cuanto a eficacia y seguridad. Estudios de toxicidad aguda in vivo deben considerar los diferentes mecanismos por los cuales los principios activos pueden producir toxicidad. Por consiguiente, se desarrolló una metodología para examinar parámetros generales relacionados con la respuesta de toxicidad aguda. Para ello se utilizaron ratas Sprague-Dawley machos las cuales fueron tratadas con dos dosis de Saw Palmetto, Serenoa repens W. Bartram HiPower® (la dosis recomendada para humanos y una dosis 10 veces mayor) durante 10 días. Se evaluaron los parámetros generales homeostáticos (hemograma y perfil bioquímico), así como características morfológicas de tejidos involucrados en la respuesta a xenobióticos (hígado, timo, bazo y ganglios linfáticos). Todos los parámetros analizados no fueron significativamente diferentes en el grupo control como en los tratados con ambas dosis de Saw Palmetto, HiPower®, sugiriendo que este preparado comercial presenta un buen perfil de seguridad durante el periodo de tratamiento evaluado. La diferencia en las dosis utilizadas fue un orden de magnitud y a pesar de ello, no se observaron alteraciones en los parámetros medidos. El protocolo utilizado en este estudio podría ser utilizado para ensayar la toxicidad aguda in vivo de diferentes extractos herbales. / Herbal extracts must be evaluated for their efficacy and safety. In vivo acute toxicity studies must consider the different mechanisms by which active compounds may elicit toxicological outcomes. Thus, a methodology to test general parameters related to acute toxicity responses in a murine model was developed, using a Saw Palmetto, Serenoa repens W. Bartram extract (HiPower®): adult male Sprague-Dawley rats were treated orally with two doses of Saw Palmetto (the recommended dose for humans and a dose 10-fold higher) for 10 days, to examine general homeostatic parameters (hemogram and clinical chemistry) as well as morphological features of tissues involved in the response to xenobiotics (liver, timus, spleen, and lymphatic ganglia). All the parameters assayed did not undergo significant changes during treatment, suggesting that the commercial extract of Saw Palmetto HiPower® displays a good safety profile for the period tested. The doses assayed spanned over one order of magnitude in the drug concentration and we did not observe differences in the parameters assayed. This method may be adopted for testing the in vivo acute toxicity of any herbal extracts

published_or_final_version / abstract / toc / Biochemistry / Master / Master of Philosophy

Doctor of Philosophy / Department of Human Nutrition / Brian L. Lindshield / The growth-inhibitory effect of saw palmetto supplements (SPS) with high long-chain fatty acids (FA)-low phytosterols (HLLP), high long-chain FA-high phytosterols (HLHP), and high medium-chain FA-low phytosterols (HMLP) was determined using androgen-sensitive LNCaP prostate cancer (PCa) cells and Syrian hamster flank organs. In vitro, all three SPS at high concentrations significantly decreased dihydrotestosterone-stimulated LNCaP cell number. HMLP and HLLP at high concentrations significantly decreased, but HLHP which significantly increased testosterone-stimulated LNCaP cell number. In Syrian hamsters, all three SPS treatments caused notable, but nonsignificant reduction in the difference between the left and right flank organ growth in the testosterone-, but not dihydrotestosterone-treated SPS groups. Results suggest SPS might be a mild 5-alpha-reductase (5-alpha-R) inhibitor. The pharmaceuticals finasteride inhibits 5-alpha-R2, and dutasteride inhibits 5-alpha-R1 and 5-alpha-R2 isoenzymes. Because finasteride inhibits only 5-alpha-R2, we hypothesized that it would not be as efficacious in preventing PCa development and/or progression in TRAMP mice as dutasteride. Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to control, pre- and post- finasteride and dutasteride diet groups that began at 6 and 12 weeks of age, respectively, and terminated at 20 weeks of age. Pre and post groups received drugs before and after mice were expected to develop PCa, respectively. Post-Dutasteride treatment was significantly more effective than Pre-Dutasteride; and dutasteride treatments significantly more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia progression and PCa development. The finasteride groups and the Pre-Dutasteride group had significantly increased incidence of poorly differentiated PCa versus control. Androgen receptor and Ki-67 protein, DNA fragmentation from apoptosis, 5-alpha-R1 and 5-alpha-R2 mRNA levels were determined in mice with genitourinary weight less than 1 gram and greater than 1 gram to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and Post-Dutasteride’s efficacy. Results suggest the difference in genitourinary weights is influenced more by proliferation, rather than androgen receptor and apoptosis in tumor. Mice age may not be significantly important in regulating proliferation, androgen receptor and apoptosis to promote tumor growth. In conclusion, the results with 5-alpha-reductase inhibitors may support the therapeutic use of dutasteride, but not finasteride, or saw palmetto supplements.