Trilostane and epostane are synthetic steroids which inhibit the 3beta-hydroxysteroid dehydrogenase enzyme. This enzyme is part of a system which catalyses an essential step in the synthesis of biologically active steroids. In animals and man trilostane preferentially inhibits adrenal steroid synthesis whilst epostane inhibits placental/ovarian steroid synthesis. The synthesis of radiolabelled trilostane and epostane are described. Stability investigations showed these radiolabelled compounds to be susceptible to degradation, although trilostane less so than epostane. Careful handling procedures were essential for metabolism studies. Animal studies showed no difference in the overall excretion and distribution of radioactivity for [[14]Cl-trilostane and [[14]C]-epostane. However the site specific localisation of active components within adrenals and ovaries reflected the in vivo organ selectivity observed for these compounds. In man a major plasma metabolite of trilostane was shown to be 17-ketotrilostane which is intrinsically twice as active as parent compound with regard to 3beta-hydroxysteroid dehydrogenase inhibition. A specific, sensitive and accurate HPLC assay was developed which enabled the measurement of trilostane and 17-ketotrilostane in plasma. Plasma concentrations of 17-ketotrilostane in male volunteers were approximately three-fold higher than trilostane, and consequently this metabolite may be an important contributor to the clinical efficacy of this drug. Micronisation of both trilostane and epostane was shown to be appropriate in order to maximise the oral systemic availability of these compounds. However even with micronised formulations considerable inter-and intra-subject variability was noted. For trilostane, variability in absorption, coupled with individual differences in the metabolism to the more active 17-ketotrilostane, may in part account for the variable efficacy encountered in clinical trials.

Malaria is a devastating global health issue that affects approximately 200 million people yearly and over half a million deaths are caused by this parasitic protozoan disease. Most commercially available drugs only target the blood stage form of the parasite, but the only way to ensure proper elimination is to treat the exoerythrocytic stages of the parasite development cycle. There is a demand for the discovery of new liver stage antimalarial compounds as there are only two current FDA approved drugs for the treatment of liver stage parasites, one of which fails to eliminate dormant forms and the other inducing hemolytic anemia in patients with G6PD deficiency. In efforts to address the dire need for liver stage drugs, we developed a high-throughput liver stage drug-screening assay to identify liver stage active compounds from a wide variety of chemical libraries with known blood stage activity. The liver stage screen led us to further investigate an old, abandoned compound known as menoctone. Menoctone was developed as a liver stage active antimalarial, however, the development of more potent compounds led to the abandonment of further menoctone research. Our research demonstrated that resistant parasites can transmit mutations through mosquitoes, which was previously believed to not be possible. Furthermore, we studied a novel genetic marker that may indicate potential resistance against malaria parasite infection and the cytotoxic effects associated with the disease. Future experiments aim to identify and advance our methods for the elimination of Plasmodium exoerythrocytic parasites.

No description available.