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Preclinical and clinical development of new progesterone receptor antagonists with high receptor specificity for breast cancer treatment
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
J. Hoffmann, H. Hess-Stumpp, R. B. Lichtner, U. Fuhrmann, G. Siemeister, M. R. Schneider
In intact control animals, progressive tumor growth was observed, whereas ovariectomy caused a complete tumor regression in 90% of the animals. A dose of 0.5 mg/kg of the progesterone antagonist ZK 230211 administered subcutaneously led to an inhibition of tumor growth, although this was not statistically significant. A maximal statistically significant growth inhibition was achieved with doses ≥ 2 mg/kg (Figure 4). In the group treated with 2 mg/kg, 50% of the animals showed complete tumor regression. Higher doses of ZK 230211 (5 and 10 mg/kg) resulted in tumor growth inhibition comparable to that with the dose of 2 mg/kg. Onapristone, a pure progesterone receptor antagonist, also showed a growth-inhibitory effect, but with no statistical significance at the dose used (5 mg/kg). Taken together, in the DMBA-induced mammary tumor model in the rat, ZK 230211 completely suppressed tumor growth in intact animals. At equal doses, the newer investigational drug ZK 230211 was distinctly more potent than onapristone.
Medical management of endometriosis
Published in Seema Chopra, Endometriosis, 2020
Mifepristone (RU486): Its use, apart from medical abortions, is also studied in the management of pain associated with endometriosis. Small trials have shown that both mifepristone in a dose of 50 mg and onapristone demonstrated significant reduction in visible disease and clinical symptoms [36,37]. On the other hand, mifepristone 5 mg/day resulted in pain improvement but no regression of endometriotic implants [38]. They modulate the action of progesterone on eutopic and ectopic epithelium. Mifepristone subdermal implants are the alternative effective option for endometriosis [39]. More randomized trials are needed to confirm the utility of mifepristone in women with endometriosis.
Pharmacokinetics, toxicological and clinical aspects of ulipristal acetate: insights into the mechanisms implicated in the hepatic toxicity
Published in Drug Metabolism Reviews, 2021
In conclusion, the prescription of UPA should involve careful surveillance and monitorization of liver function. In order to exclude patients that would be potentially more vulnerable to hepatic toxicity with the treatment with UPA, the PRAC recommend amendments to the product information of UPA to clarify raised points. If we look at the DILI Network likelihood scores, UPA could be described as Category C: ‘the drug is probably linked to idiosyncratic liver injury, but has been reported uncommonly and no characteristic signature has been identified; the number of identified cases is less than 12 without significant case series’ (National Institute of Diabetes and Digestive and Kidney Diseases 2012). Further in vitro studies are needed to clarify the mechanistic basis of UPA as a cause of DILI (Gatti et al. 2020). Moreover, the in vivo metabolism data in humans is really very limited and additional studies are required, specially focused on the consequences of genetic polymorphisms, which were not yet clearly evaluated. As demonstrated for onapristone, another antiprogestin, extended-release formulations, by reducing drug exposure, may predispose to a lower risk of hepatotoxicity (Lewis et al. 2020). This review also highlights that the diagnosis of DILI requires a high degree of awareness of the condition and the careful exclusion of alternative etiologies of liver disease.
Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer
Published in Expert Opinion on Investigational Drugs, 2019
Nirmish Singla, Rashed A. Ghandour, Ganesh V. Raj
Onapristone (AR-18, ZK-98299, or ZK-299) is a synthetic steroidal antagonist of the progesterone receptor that was initially described in 1984 and subsequently investigated in breast cancer and as a contraceptive, but discontinued in the 1990s due to hepatic dysfunction [68,69]. Onapristone resurfaced as an investigational treatment for prostate cancer over the last few years. In multi-institution, open-label, phase I/II trial of extended-release onapristone alone or in combination with abiraterone in 36 CRPC patients progressing after enzalutamide/abiraterone (NCT02049190) [70], onapristone appeared to be safe without dose-limiting toxicities, significant liver function abnormalities, or grade 3/4 adverse events. While patients treated with single-agent onapristone did not exhibit significant PSA declines or improved radiographic progression-free survival (rPFS), those on combination onapristone and abiraterone had improved rPFS.
Drug design strategies for Cushing’s syndrome
Published in Expert Opinion on Drug Discovery, 2019
S. A. Usanov, A. V. Kliuchenovich, N. V. Strushkevich
Since the discovery and first clinical use of RU-486, there have been numerous attempts to replace it with more selective compounds in order to achieve pure antiglucocorticoid activity and which excludes any off-label activity, such as the former’s antiprogestagenic activity. For example, with onapristone (ZK-299) (Figure 4, 16), a synthetic and steroidal drug, the drug demonstrated antiprogestagenic effects most common with the results of such attempts. Notably, onapristone showed an efficacy in treating of primary breast cancer [56] but yet it has never been marketed.