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Prevention and treatment of benign prostatic hyperplasia using lonidamine and lonidamine analogs

a technology of prostatic hyperplasia and lonidamine, which is applied in the direction of instruments, drug compositions, biocide, etc., can solve the problems of increased occurrence of high-grade prostate cancer, limited therapy, and loss of libido and muscle mass in males

Inactive Publication Date: 2005-12-08
THRESHOLD PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] The invention provides methods and compositions for treating BPH in a human subject by administration of lonidamine or a lonidamine analog to the subject. Pharmaceutical compositions useful for treatment of BPH, including sustained release formulations, are also provided. In one embodiment, the formulation is orally administered and permits once-a-day dosing of a therapeutically effective dose of the compound.

Problems solved by technology

Use of drugs in this class can cause a loss of libido and loss of muscle mass and tone in males and is associated with an increased occurrence of high grade prostate cancer.
In addition, this therapy is limited by the very long delay (months) between first administering the drug and significant reduction in prostate size in the patient.
While this class of drugs reduces symptoms more rapidly than the first, it does not reduce the size of the prostate or prevent it from growing larger, which can lead to eventual surgical intervention.

Method used

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  • Prevention and treatment of benign prostatic hyperplasia using lonidamine and lonidamine analogs
  • Prevention and treatment of benign prostatic hyperplasia using lonidamine and lonidamine analogs
  • Prevention and treatment of benign prostatic hyperplasia using lonidamine and lonidamine analogs

Examples

Experimental program
Comparison scheme
Effect test

example 1

Clinical Trial

[0124] A Phase II randomized dose comparison study of lonidamine administration for the treatment of symptomatic benign prostatic hyperplasia is conducted. Patients are males 50 to 80 years of age with BPH confirmed by ultrasonography, a serum PSA >2, and no evidence of prostate cancer. Lonidamine (150 mg tablet; Doridamina formulation) is administered 150 mg p.o. TID (intermediate dosage) or QD (low dosage) 8 weeks. Patients receiving TID dosing take the compound 5 days on and 2 days off to aid compliance with the protocol.

[0125] Patients are assessed at baseline, day 30 and day 60 for prostate volume by ultrasonography, urine flow, AUASI score, PSA, adverse events, and serum chemistry to determine whether one of the two doses provides significantly greater benefit than the other dose and to measure the reduction in prostate size achieved by the therapy.

example 2

Lonidamine Reduces Expression of HIF-1α in Prostate Cells

[0126] This example shows the effects of lonidamine treatment on HIF-1α expression in two cell lines derived from metastatic lesions of human prostate cancers. LNCaP is a citrate-producing cell (ATTC No. CRL-1740) while PC3 is citrate oxidizing cell (ATTC No. CRL-1435). See Franklin et al; 1995. Cells may be obtained from the American Type Culture Collection (ATCC), P.O.Box 1549, Manassas, Va. 20108 USA.

[0127] As shown in FIGS. 2 and 3, lonidamine treatment reduced the level of HIF-1α protein detected in nuclear (NE) and whole-cell extract (WCE) preparations. The inhibition was dose-dependent, and observed under normoxic (PC3 cells only) and hypoxic conditions (LNCaP cells and PC3 cells). The lonidamine effect was specific to the HIF-1α subunit under the conditions tested and, except at 800 μM concentration, had no detectable inhibition under the conditions tested on the protein levels of actin, caspase 3, NF-κB, or IκBa. Lo...

example 3

Lonidamine Induces Apoptosis in Citrate-Producing Cells

[0130] To determine whether apoptosis occurs in cells treated with lonidamine, the effect of lonidamine on cells producing citrate (LNCaP) and cells oxidizing citrate (PC3) was assessed. As shown in FIG. 4, lonidamine induced activation of caspase 3 in citrate-producing cells (LNCaP) to a much greater extent than in citrate-oxidizing cells (PC3). The activation of caspase3 is a time-dependent process (FIG. 5).

[0131] The effect of lonidamine was also examined in primary cultures of prostate epithelial cells (which accumulate citrate) or prostate stromal cells (which do not accumulate citrate). As shown in FIG. 6, lonidamine induced apoptosis only in prostate epithelial cells in a dose-dependent manner. In contrast, induction of apoptosis was not observed in prostate stromal cells after treatment with lonidamine.

Methods:

[0132] Immunoblotting: Immunoblotting was carried out as described in Example 2. To detect the expression o...

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Abstract

A method for treatment or prophylaxis of benign prostatic hyperplasia by administration of lonidamine or a lonidamine analog is provided. Also provided are unit dosage forms of lonidamine or an analog, useful for such treatment and prophylaxis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 759,337 (filed Jan. 16, 2004) which claimed the benefit of U.S. provisional application Nos. 60 / 496,163 (filed 18 Aug. 2003), 60 / 488,265 (filed Jul. 18, 2003); 60 / 472,907 (filed 22 May 2003), 60 / 460,012 (filed 2 Apr. 2003), 60 / 458,846 (filed 28 Mar. 2003), 60 / 458,665 (filed 28 Mar. 2003), 60 / 458,663 (filed 28 Mar. 2003), 60 / 442,344 (filed 23 Jan. 2003), and 60 / 441,110 (filed 17 Jan. 2003). Each of the aforementioned applications is incorporated herein by reference in its entirety for all purposes.FIELD OF THE INVENTION [0002] The invention relates to treatment and prevention of benign prostatic hyperplasia, and has application in the field of medicine and related fields, including chemistry, medicinal chemistry, and molecular biology. BACKGROUND OF THE INVENTION [0003] Benign Prostatic Hyperplasia (BPH), a disease in which prostate epithelial cells grow abnormally...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61P13/08A61KA61K31/70G01N33/567A61K31/416C12Q1/06A61K31/415A61K9/22
CPCA61K31/416A61K31/70G01N2800/342A61P13/08A61K31/415
Inventor TIDMARSH, GEORGE
Owner THRESHOLD PHARM INC
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