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A. Definition of Phosphodiesterase Enzymes
(continued)
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PDE-5 is an enzyme found in trabecular smooth muscle. It catalyzes the degradation of cGMP, which results in an elevated cytosolic calcium concentration and smooth-muscle contraction (Fig. 2). PDE-5 inhibitors, therefore, block this biochemical pathway to promote erection. Eleven subtypes of PDEs have been described, with 30 isoenzymes mediating a variety of physiologic actions throughout the body.32 PDEs exhibit enormous functional diversity; at present, our understanding of PDE types 1 to 6 are considerably better than our understanding of PDE types 7 to 11.
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A system for inserting a pellet of alprostadil into the urethra is marketed as Muse. The system uses a prefilled applicator to deliver the pellet about an inch deep into the urethra. An erection will begin within 8 to 10 minutes and may last 30 to 60 minutes. The most common side effects are aching in the penis, testicles, and area between the penis and rectum; warmth or burning sensation in the urethra; redness from increased blood flow to the penis; and minor urethral bleeding or spotting.
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"Men can develop erectile dysfunction after sitting on a hard bicycle seat for many hours because they compress an area of the anatomy known as the perineum," explains Ken Taylor, MD, a former assistant clinical professor of family medicine at UCSD and a co-researcher in the 1999 cycling-impotence study. The perineum is the area between the anus and the scrotum.
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Q. What are the major differences between the two devices?
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NO was measured using a nitrate/nitrite assay kit (Cayman Chemical) according to the manufacturer's instructions. Results were normalized to 106 cells. Data are from triplicate wells.
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When administered in vitro, PDE5 inhibition induces apoptosis in colon carcinoma (15) and chronic lymphocytic leukemia cells (16). To determine whether similar effects could be observed in vivo, we used various transplantable mouse tumors, including CT26WT (a colon carcinoma; Fig. 1 A), the more aggressive variant C26GM (Fig. 1 B), TS/A (a mammary adenocarcinoma; Fig. 1 C), and the MCA203 fibrosarcoma (Fig. 1 D). PDE5 inhibitors were administered starting on the day of tumor challenge. Sildenafil and tadalafil significantly delayed tumor outgrowth by 50 to 70% in immune-competent mice, although all mice ultimately died (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20061104/DC1). Similar results were obtained even if sildenafil treatment was started on day 7 after tumor challenge in the CT26WT model (Fig. S2). The fact that no difference in tumor outgrowth was seen between early versus late administration of sildenafil suggests that PDE5 inhibition does not appreciably affect the early phases of tumor uptake but rather influences the later stages of tumor outgrowth. Because the addition of sildenafil to cultured CT26WT cells did not increase their apoptosis or affect their doubling time (unpublished data), we conclude that sildenafil does not have a direct antitumor effect but rather interferes in hosttumor interactions.
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