5 research outputs found
Pharmacokinetics of Intravenous Levosimendan and Its Metabolites in Subjects With Hepatic Impairment
No full textRapid Absorption of Naloxone from Eye Drops
No full textNaloxone as emergency treatment for opioid overdosing can be administered via several routes. However, the available administration methods are invasive or may be associated with incomplete or slow naloxone absorption. We evaluated pharmacokinetics and local tolerance of naloxone ocular drops in healthy beagle dogs. Naloxone administration as eye drops produced fast absorption with time to maximum plasma concentration (t(max)) achieved in 14 to 28 min, high plasma exposure (C(max) 10.3 ng/mL to 12.7 ng/mL), and good bioavailability (41% to 56%). No signs of ocular irritability were observed in the scored ocular tolerability parameters, and the reactions of dogs suggesting immediate ocular discomfort after the dosing were sporadic and short lasting. Slight and transient increase in the intraocular pressure and transient decrease in the tear production were recorded. The results suggest that eye drops may provide a fast and an effective non-invasive route for naloxone administration to reverse opioid overdosing, and clinical studies in the human are warranted
CYP11A1 inhibition as a therapeutic approach for the treatment of castration resistant prostate cancer.
No full text 340 Background: Castration-resistant prostate cancer (CRPC) is a major cause of cancer mortality worldwide. The mechanisms behind the development of resistance are complex and not fully understood; altered androgen synthesis, androgen receptor (AR) overexpression or gene amplification, and mutations have been indentified. However, tumor growth may still be responsive to therapies that can further suppress de novo intratumoral steroid synthesis upstream of CYP17A1. ODM-208 is an oral, non-steroidal and selective inhibitor of CYP11A1 enzyme that suppresses the synthesis of all steroid hormones and their precursors. Methods: The inhibition of CYP11A1 was measured in vitro by the formation of radiolabelled isocapronic acid in a human adrenal cortex cell line (H295R), and further analysing pregnenolone (Preg) and testosterone (T) formation by ELISA. The tumor growth inhibition of ODM-208 alone or in combination with prednisone (Pred) was studied in VCaP CRPC xenograft where also concentrations of main steroid hormones progesterone (P), corticosterone (CORT) and T in tumors and adrenals were analysed. In addition, plasma ACTH and LH levels were measured at the end of the xenograft study. In dogs an ACTH stimulation test was done. Toxicity studies were conducted in rats and dogs. Results: ODM-208 potently inhibits CYP11A1 and synthesis of Preg and T with nM concentrations in vitro. In the VCaP CRPC xenograft ODM-208 alone and in combination with Pred significantly inhibited tumor growth. Concentrations of T, P and CORT were significantly decreased in the adrenals, indicating strong CYP11A1 inhibition. Also, significantly decreased steroid levels in tumors was observedhe Pred combination increased plasma ACTH levels less than ODM-208 alone, whereas no difference was seen in the LH. In dogs ACTH-stimulated cortisol production was significantly inhibited after single oral dose of ODM-208. In toxicological studies ODM-208 showed expected reversible findings in target tissues, mainly related to the pharmacology. Conclusions: ODM-208 shows promising antitumor activity in preclinical CRPC models with favorable toxicological profile. Thus, ODM-208 might have potential for treating the patients with CRPC. </jats:p
Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1
No full textSupplementary Data from First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis
No full textSupplementary Data from First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesi
