Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling.

Exposure to mebendazole and pyrvinium during pregnancy: a Danish nationwide cohort study.

PURPOSE: Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. METHODS: From nationwide administrative registers, we identified 718,900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. RESULTS: 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8-8.7) and mebendazole (OR: 20.8, 95% CI: 17.3-24.9). CONCLUSION: 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy.

Absorption of pyrvinium pamoate.

Pyrvinium pamoate, tablets and suspension, was administered as single 350-mg doses to 12 healthy male volunteers to determine whether there had been any systemic absorption. Six subjects received tablets and 6 received suspension on the first day; on day 8, subjects received the other dose form. Up to 4 days after administration there was no evidence of drug in blood and urine by spectroflorometric assay. Metabolic studies in rats showed minute quantities of drug in the liver and plasma but not of any metabolites.