The potential value of 5-androstenediol in countering acute radiation syndrome.

Moderate-to-high doses of ionizing irradiation can lead to potentially life-threatening morbidities and increase mortality risk. In preclinical testing, 5-androstenediol has been shown to be effective in protecting against hematopoietic acute radiation syndrome. This agent is important for innate immunity, serves to modulate cell cycle progression, reduces radiation-induced apoptosis, and regulates DNA repair. The drug has been evaluated clinically for its pharmacokinetics and safety. The United States Food and Drug Administration granted investigational new drug status to its injectable depot formulation (NEUMUNE). Its safety and efficacy profiles make it an attractive candidate for further development as a radiation countermeasure.

Preliminary clinical findings on NEUMUNE as a potential treatment for acute radiation syndrome.

5-androstenediol (5-AED) has been advanced as a possible countermeasure for treating the haematological component of acute radiation syndrome (ARS). It has been used in animal models to stimulate both innate and adaptive immunity and treat infection and radiation-induced immune suppression. We here report on the safety, tolerability and haematologic activity of 5-AED in four double-blinded, randomized, placebo-controlled studies on healthy adults including elderly subjects. A 5-AED injectable suspension formulation (NEUMUNE) or placebo was administered intramuscularly as either a single injection, or once daily for five consecutive days at doses of 50, 100, 200 or 400 mg. Subjects (n = 129) were randomized to receive NEUMUNE (n = 95) or the placebo (n = 34). NEUMUNE was generally well-tolerated; the most frequent adverse events were local injection site reactions (n = 104, 81%) that were transient, dose-volume dependent, mild to moderate in severity, and that resolved over the course of the study. Blood chemistries revealed a transient increase (up to 28%) in creatine phosphokinase and C-reactive protein levels consistent with intramuscular injection and injection site irritation. The blood concentration profile of 5-AED is consistent with a depot formulation that increases in disproportionate increments following each dose. NEUMUNE significantly increased circulating neutrophils (p < 0.001) and platelets (p < 0.001) in the peripheral blood of adult and elderly subjects. A dose-response relationship was identified. Findings suggest that parenteral administration of 5-AED in aqueous suspension may be a safe and effective means to stimulate innate immunity and alleviate neutropenia and thrombocytopenia associated with ARS.

Administration of 5-androstenediol to mice: pharmacokinetics and cytokine gene expression.

The development of an effective pharmacological countermeasure is needed to reduce the morbidity and mortality in military and civilian populations associated with possible exposure to ionizing radiation. Previous studies in mice have shown that a single subcutaneous (sc) injection of the natural steroid androst-5-ene-3beta,17beta-diol (5-androstenediol, 5-AED), 24-48 h prior to a lethal dose of whole-body (60)Co gamma radiation, stimulated hematopoiesis and enhanced survival. These effects are consistent with our previous observation of 5-AED-induced elevations in circulating G-CSF in normal and irradiated mice. The purpose of this study was to obtain data on the pharmacokinetics of 5-AED after sc and buccal administration to mice, and to determine whether cytokine genes are induced by sc 5-AED in hematopoietic tissues (bone marrow, spleen). We studied effects on serum cytokines and chemokines, and also analyzed the pharmacokinetics of 5-AED after sc administration and compared it with buccal delivery. 5-AED was administered 24 h before irradiation or sham-irradiation. Cytokine mRNAs were quantified by quantitative real-time PCR (QRT-PCR), and cytokine levels in serum by multiplex Luminex. 5-AED administration was associated with elevation of message for GM-CSF, IL-2, IL-3, IL-6, and IL-10 in spleen, and GM-CSF and IL-2 in bone marrow. Irradiation enhanced G-CSF, GM-CSF, IFN-gamma, TPO, IL-2, IL-3, IL-6, IL-10, and IL-12 in spleen, and GM-CSF, IFN-gamma, TPO, IL-3, and IL-10 in bone marrow. Serum levels of G-CSF were significantly elevated in 5-AED-treated mice 4 h after irradiation or sham-irradiation. Serum macrophage inflammatory protein-1gamma (MIP-1gamma) was significantly elevated 4 h after irradiation in 5-AED-treated mice. Plasma 5-AED peaked 2 h after sc injection (30 mg/kg), and remained significantly above control after 4 days, but not 8 days. The time course of plasma 5-AED after buccal delivery (60 mg/kg) was similar, but levels were significantly lower compared to sc delivery. Plasma 5-AED 24 h after administration was not significantly different between sc and buccal delivery. However, in contrast to many studies showing enhanced survival after sc administration of 5-AED, we found no effect on survival of buccal 5-AED. The results suggest that radioprotection is not dependent on the 5-AED concentration at the time of irradiation, but rather on events triggered during the first few hours after administration. The current results suggest that further studies are warranted to directly test the roles of cytokines in the radioprotective effects of 5-AED.

Over-the-counter delta5 anabolic steroids 5-androsen-3,17-dione; 5-androsten-3beta, 17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione: excretion studies in men.

Studies of urinary steroids were performed in males after oral administration of 5-androsten-3,17-dione; 5-androsten-3beta,17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone amplify most endogenous steroids, but to a lesser extent than their delta4 analogues do. Especially affected are androsterone, etiocholanolone, dehydroandrosterone, dehydroepiandrosterone, and isomeric 5-androstendiols. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone elevate the urinary testosterone to epitestosterone (T/E) ratio by a factor of 2-3 a few hours after administration. This may cause a positive T/E test (> 6) for individuals with normal T/E ratios higher than 2. Most of the steroids return to their original concentrations in less than 24 h. Etiocholanolone and 5beta-androstan-3alpha,17beta-diol remain elevated for several days. A reduced androsterone to etiocholanolone (A/E) ratio may be an indication of delta5 steroids abuse. 19-Nor-5-androsten-3,17-dione has a similar effect, except that all metabolites in urine are 19-nor exogenous steroids. Identification criteria for 19-nor-5-androsten-3,17-dione may be the same as nandrolone, that is, detection of 19-norandrosterone and 19-noretiocholanolone. Specific abundant metabolites of 19-nor-5-androsten-3,17-dione are 19-nordehydroandrosterone and 19-nordehydroepiandrosterone. In the later stages of excretion, higher concentration of 1 9-noreticholanolone relative to 19-norandrosterone specifically indicates administration of 19-nor delta5 steroids.