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Hormonal Regulation in the Treatment of Fibroids
Published in John C. Petrozza, Uterine Fibroids, 2020
Victoria Fitz, Steven L. Young
Telapristone was shown in in vitro studies to induce apoptosis and inhibit proliferation in uterine leiomyoma cells [40]. Clinical trials in women with fibroids were initiated but discontinued owing to concerns for liver toxicity in 2009. Development has since restarted with lower doses of the medication [37]. Vilaprisan is another SPRM which is currently being investigated with Phase III trials.
Medical Options for Uterine Fibroids in the Context of Reproduction
Published in Botros R.M.B. Rizk, Yakoub Khalaf, Mostafa A. Borahay, Fibroids and Reproduction, 2020
Hoda Elkafas, Mona Al Helou, Qiwei Yang, Ayman Al-Hendy
Asoprisnil was first shown to repress uterine bleeding through a dual mechanism that includes a direct effect on the endometrium and inhibition of ovulation. However, it reduces bleeding at doses that did not inhibit ovulation, which means that the endometrial effects are the primary mechanism of bleeding suppression. The rapid effect on bleeding versus a gradual decrease in fibroid mass shows that the effect of PRMs on bleeding is independent of its effects on uterine fibroids [38,39]. Asoprisnil overcomes uterine bleeding in a dose-dependent way, and the reduced bleeding listed in 28%, 64%, and 83% of cases at 5, 10, and 25 mg/day, respectively, and diminished fibroid size by up to 36% at 25 mg/day, probably by minimizing uterine artery blood flow. Recently, follow-up studies have raised concerns about asoprisnil, because its primary function is as a progesterone antagonist, and it does not have an estrogenic effect in the endometrium [38]. Furthermore, clinical trials of telapristone acetate were suspended due to liver toxicity; however, trials have recently continued using lower doses of telapristone acetate [56]. At the molecular level, it works by the following mechanisms: inhibition of collagen synthesis that leads to apoptosis in uterine fibroids but does not affect normal myometrium [57]; reduction of the expression of antiapoptotic Bcl-2; increase in caspase-3; and attenuation of VEGF and proliferating cell nuclear antigen (PCNA) [58]. A multicenter, randomized placebo controlled trial found that after 12 weeks treatment with Asoprinil showed significant reduction in uterine bleeding, reduction in fibroid sizes with minimum hypoestrogenic side effect. Unluckily, recently due to the failing phase III clinical trial in 2008, it has not been taken more in clinical trials, due to unsafe changes in the endometrial lining of the uterus. Telapristone acetate (CDB4124), marked under the name of Proellex, has been tested as a treatment for symptoms linked to endometriosis and fibroid [59]. It showed encouraging findings in preliminary studies, successfully causing apoptosis in fibroid cells without affecting normal adjacent myometrium [59]. Researchers were expecting that telapristone could potentially become a long-term treatment. However, phase III studies were halted because of significant increases in liver enzymes [60]. Recently, there is a continuing phase II clinical trial that began in 2014 aiming to evaluate both safety and efficiency of lower oral as well as vaginal doses of telapristone acetate [64].
Potential synergism between ulipristal acetate and vitamin D3 in uterine fibroid pharmacotherapy – 2 case studies
Published in Gynecological Endocrinology, 2019
Michał Ciebiera, Błażej Męczekalski, Krzysztof Łukaszuk, Grzegorz Jakiel
What about a similar effect of UPA on UF cells? Recent data showed that TGF-β3 concentrations in the serum and UF tissue are significantly lower in patients treated with the use of UPA [41]. According to Courtoy et al., MMPs are also UPA-dependent [42]. Xu et al. found that UPA inhibited the proliferation of UF cells by down-regulating PCNA expression and inducing apoptosis by up-regulating cleaved caspase-3 as well as poly (ADP-ribose) polymerase (PARP) expression and down-regulating Bcl-2 protein [43]. Another SPRM, telapristone, that shares similar pathways, was proved to significantly decrease levels of the proliferation marker PCNA and the protein Bcl-2 [44]. However, according to Courtoy et al. significant modification was found as regards the expression of Bcl-2 protein in women not treated and treated with the use of UPA [45].
Successes and failures of uterine leiomyoma drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Mohamed Ali, Zunir Tayyeb Chaudhry, Ayman Al-Hendy
Telapristone acetate (CDB4124), branded under the name of Proellex, is a newer SPRM undergoing trials for UFs and endometriosis [49]. It showed promising results in preliminary studies, successfully inducing apoptosis in fibroid cells while leaving normal adjacent myometrium unaltered [49]. Investigators were hopeful that telapristone could potentially become a chronic therapy for long-term symptom control. Unfortunately, multiple large studies, including a phase III trial, were prematurely terminated owing to concerns for safety while testing telapristone in symptomatic fibroids [50]. At present time, there is an ongoing phase II clinical trial started on 2014 aiming to evaluate both safety and efficacy of lower oral as well as vaginal doses of Telapristone acetate [51]. Vilaprisan, a novel SPRM that recently passed a 12 week phase I clinical trial successfully, in which most of the women who took the medication at daily dose of 1–5 mg reported absence of menstrual bleeding. These results supported the initiation of advanced clinical trials to evaluate vilaprisan in women with symptomatic UFs [52].
Emerging treatment options for uterine fibroids
Published in Expert Opinion on Emerging Drugs, 2018
Jacques Donnez, Pablo Arriagada, Olivier Donnez, Marie-Madeleine Dolmans
In the SPRM class, vilaprisan (BAY-1002670) has so far undergone three phase I and two phase II trials (ASTEROID I and II programs) comparing multiple doses of vilaprisan with a placebo and/or UPA, while ongoing investigations include one phase I (hepatic impairment, requested by the US Food and Drug Administration [FDA]) and two phase III trials (ASTEROID III and IV). Telapristone acetate (Proellex®, Repros Therapeutics, CDB-4124) is another SPRM intended for the treatment of uterine fibroids and endometriosis, and exists in both oral and vaginal formulations. Telapristone acetate started development in the late 1990s and reached phase III, evaluating a daily dose of 50 mg. However, four phase III trials were subsequently terminated due to safety concerns (dose-related increases in liver enzymes) and the 50 mg dose program was discontinued. In 2012, the development program was resumed using lower doses (6 and 12 mg), including an additional trial extension with a 12 mg dose initiated in 2016. Early in 2017, Repros announced that the FDA would continue to maintain a partial clinical hold on Proellex for the treatment of uterine fibroids due to possible adverse effects on the liver.