Citations

Purpose To define the maximum tolerated dose, toxicities, pharmacokinetics, and pharmacodynamics of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17DMAG). Methods 17DMAG was given intravenously over 1 hour daily for 5 days (schedule A) or daily for 3 days (schedule B) every 3 weeks. Plasma 17DMAG concentrations were measured by liquid chromatography/mass spectrometry. Heat-shock proteins (HSPs) and client proteins were evaluated at baseline and after treatment on day 1 in peripheral blood mononuclear cells (PBMCs) and in pre- and post-treatment (24 hours) biopsies done during cycle 1 at the recommended phase II dose (n = 7). Results Fifty-six patients were entered: 26 on schedule A; 30 on schedule B. The recommended phase II doses for schedules A and B were 16 mg/m2 and 25 mg/m2, respectively. Grade 3/4 toxicities included liver function test elevation (14%), pneumonitis (9%), diarrhea (4%), nausea (4%), fatigue (4%) and thrombocytopenia (4%). There were no objective responses. Four patients had stable disease. 17DMAG half-life was 24 ± 15 hours. 17DMAG area under the curve (range, 0.7 to 14.7 mg/mL × h) increased linearly with dose. The median HSP90, HSP70, and integrin-linked kinase levels were 87.5% (n = 14), 124% (n = 20), and 99.5% (n = 20) of baseline. Changes in HSPs and client proteins in tumor biopsies were not consistent between baseline and 24 hours nor did they change in the same direction as those in PBMCs collected at the time of biopsy. Conclusion The recommended phase II doses of 17DMAG (16 mg/m2 × 5 days or 25 mg/m2 × 3 days, every 3 weeks) are well tolerated and suitable for further evaluation.

ABSTRACT Introduction The presence of erectile or ejaculatory dysfunction may indicate physical problems; however, individual perceptions (e.g., sexual satisfaction) may reflect the degree of concern about these changes. Long-term data showing how changes in multiple sexual function domains track together may be useful in understanding the importance of physical declines vs. sexual satisfaction. Aim The aim of this study was to describe changes in sexual function among a population-based sample of aging men. Methods A population-based cohort study using data from the Olmsted County Study of Urinary Symptoms and Health Status among Men. Sexual function was assessed biennially from 1996 to 2004 using a previously validated questionnaire in a random sample of 2,213 men. Main Outcome Measures Changes in erectile function, libido, ejaculatory function, sexual problems, and sexual satisfaction. Results Overall, we observed declines in all of the sexual function domains, ranging from an annual decrease of 0.03 point per year for sexual satisfaction to an annual decrease of 0.23 point per year in erectile function. Moderate correlations were observed among all longitudinal changes in sexual function (range in age-adjusted rs = 0.14–0.43); however, significantly smaller correlations between changes in the functional domains and changes in sexual satisfaction and problem assessment were observed among older men (range in age-adjusted rs = 0.03–0.29). Conclusion Overall, these results demonstrate that longitudinal changes in five sexual function domains change together over time in our community-based cohort. Erectile function, ejaculatory function, and sexual drive decrease over time with greater rates of decline for older men. However, older men may be less likely to perceive these declines as a problem and be dissatisfied. These data may prove helpful to patients and clinicians in understanding and discussing changes in multiple aspects of sexual function.