In addition to the classical nuclear AR, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (IC50 = 66.3 nM), whereas it does not appear to interact with GPRC6A.The affinity of bicalutamide for the AR is relatively low as it is approximately 30 to 100 times lower than that of DHT, which is 2.5- to 10-fold as potent as an AR agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland. However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and DHT, allowing it to powerfully prevent them from binding to and activating the receptor. This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and DHT levels in the prostate gland are about 50 to 60% reduced. In women, levels of testosterone are substantially lower (20- to 40-fold) than in men, so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.Blockade of the AR by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion. This, in turn, results in an increase in circulating LH levels and activation of the gonadal production of testosterone and by extension production of estradiol.
Fluconazole is commonly used as it has been shown to have synergistic effects against naegleria when used with amphotericin in-vitro.While the use of rifampicin has been common, including in all four North American cases of survival, its continued use has been questioned. It only has variable activity in-vitro and it has strong effects on the therapeutic levels of other antimicrobials used by inducing cytochrome p450 pathways.In 2013, two successfully treated cases in the United States utilized the medication miltefosine. As of 2015, there was no data on how well miltefosine is able to reach the central nervous system. As of 2015 the U.S. CDC offered miltefosine to doctors for the treatment of free-living amoebas including naegleria. In one of the cases, a 12-year-old female, was given miltefosine and targeted temperature management to manage cerebral edema that is secondary to the infection. She survived with no neurological damage. The targeted temperature management commingled with early diagnosis and the miltefosine medication has been attributed with her survival. On the other hand, the other survivor, an 8-year-old male, was diagnosed several days after symptoms appeared and was not treated with targeted temperature management; however, he was administered the miltefosine. He suffered what is likely permanent neurological damage.In 2016, a 16-year-old boy also survived PAM. He was treated with the same protocols of the 12-year-old girl in 2013.