Health and Prostate

Overview

Chlormadinone acetate (Teikoku’s Prostal/Prostal L) is the only gonadotropin modulator available for treating benign prostatic hyperplasia. It is used only in Japan, where finasteride and dutasteride are not approved. Potentially serious side effects (e.g., diarrhea, sexual dysfunction, liver toxicity) make agents in this class less desirable than less-toxic therapies, such as the 5-ARIs. However, new agents in development may offer effective therapeutic relief and an improved side-effect profile. Because of their mechanism of action, these agents could have a greater effect on disease symptoms and progression.

Mechanism Of Action

Current understanding of the etiology of benign prostatic hyperplasia has established hormonal changes as a major contributor to the enlargement of prostate tissue around the urethra. The control of androgen production in the testes is directly mediated by hypothalamic/pituitary hormones. Gonadotropin-releasing hormone (Gonadotropin-releasing hormone), also known as luteinizing hormone-releasing hormone (luteinizing hormone-releasing hormone), is secreted by neurons in the hypothalamus; it subsequently stimulates the release of both luteinizing hormone (luteinizing hormone) and follicle-stimulating hormones (follicle-stimulating hormone) in the anterior pituitary. In the testes, luteinizing hormone interacts with specific cell-surface receptors in the plasma membrane of Leydig cells, activating the biochemical steps that lead to the synthesis of testosterone.

Cetrorelix

ML-04

Milkhaus Laboratory has ML-04 (HP-4), a patented oral form of human chorionic gonadotropin (hCG), in U.S. Phase II trials as a potential therapeutic for benign prostatic hyperplasia. ML-04 is also in Phase II trials for chronic prostatitis and myelodysplastic syndrome (MDS).

In benign prostatic hyperplasia, prostate cells have lost their capacity to be normally regulated, which results in hyperplasia and failure of programmed cell death (apoptosis). Prostatic cells express hCG receptors, and researchers hypothesize that hCG used therapeutically might restore normal cell regulatory controls in benign prostatic hyperplasia tissue, thus blocking or reversing the disease process.

The results of a multicenter, double-blind, placebo-controlled Phase Ha trial of ML-04 in patients with moderate to severe benign prostatic hyperplasia were reported in 1998. In the 100-patient trial, the difference in symptom relief between ML-04 and placebo as measured by the AUASI score was statistically significant: over a 16-week period, the average change from baseline was — 3.29 for the placebo group and — 6.79 for the ML-04 group. ML-04 reportedly improved sexual function and was safe.

The company is continuing to evaluate ML-04 in a Phase lib trial with more patients, longer treatment duration, and a broader dose range. In April 2003, enrollment was complete, with a total of 546 patients in 11 centers worldwide. The effectiveness of the drug will be measured by symptom relief as assessed by changes in the AUASI score. Final results have yet to be announced.