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Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
NNC55-0396 (Ki = 2.8 nM) and Ro40-5966 (Ki = 4.5 nM), two novel calcium channel blocker of mibefradil analogs, have a three- to fourfold greater inhibitory activity toward recombinant CYP2D6 than mibefradil (Ki = 12.7 nM) (Figure 4.12) (Bui et al. 2008). Temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 with Ki of 1.5 and 5 μM, respectively (Boni et al. 2009b). Temsirolimus does not alter the pharmacokinetics of desipramine in vivo (Boni et al. 2009b). Temsirolimus is a novel inhibitor of mammalian target of rapamycin, which has been approved for treatment of renal cell carcinoma. Mirodenafil, a novel PDE5 inhibitor, inhibits CYP2D6 with an IC50 of 77 μM (Lee et al. 2008).
Phosphodiesterase 5 inhibitors: preclinical and early-phase breakthroughs for impotence treatments
Published in Expert Opinion on Investigational Drugs, 2023
Zachary Melchiode, Tivoli Nguyen, Omar Dawood, Graham A. Bobo, Wayne J.G. Hellstrom
Mirodenafil has demonstrated safety and efficacy in treating ED in patients with comorbidities and in combination with other medications. In a phase III study conducted by Park et al., on-demand treatment with 100 mg mirodenafil, compared to placebo, led to significant improvements in IIEF-EFD (9.3 vs 1.4), IIEF Q3 (1.7 vs 0.4), and IIEF Q4 (1.7 vs 0.3) scores, with mild and spontaneously resolving adverse effects [30]. In a prospective, multicenter, open-label study, Bang et al. also reported that daily use of 50 mg mirodenafil was safe and effective in patients on alpha-blocker therapy for BPH-LUTS after 8 weeks of treatment [29]. They observed that the total IPSS score decreased from an average of 23.7 to 13.7, Qmax increased from an average of 12.82 to 16.80, and PVR decreased from an average of 42.60 to 24.67 after 8 weeks of treatment. Paick et al. demonstrated that 100 mg mirodenafil was effective in treating ED in Korean men taking at least one antihypertensive medication, without causing any serious adverse effects [30]. Furthermore, all treatment-related adverse effects resolved spontaneously without discontinuation of treatment. In this study, the mirodenafil group, in comparison to the placebo group, had more significant increased scores in IIEF-EFD (9.35 ± 6.86 vs 2.66 ± 6.44), IIEF Q3 (1.37 ± 1.66 vs 0.31 ± 1.64), SEP Q2 (30.18 ± 37.45% vs 6.50 ± 43.20%), and SEP Q3 (55.30 ± 40.44 vs 16.48 ± 36.05%) as well as increased positive responses to the GAQ (84.31% vs 26.00%). After the 12-week treatment period, 40.7% of the mirodenafil group achieved normal EF, as measured by an IIEF-EFD score higher than 26, compared to only 7.5% of the placebo group [30].
Pharmacotherapy for erectile dysfunction in diabetic males
Published in Expert Opinion on Pharmacotherapy, 2018
Another drug, mirodenafil, is a second generation PDE5-I that has high affinity and selectivity for the PDE5 enzyme compared to conventional PDE5-Is with better efficacy. Similar to other PDE5-Is, mirodenafil has mild-to-moderate side effects (53.7%) including flushing (6.7–24.1%) and headache (1.8–14.8%) [41]. An interesting study aimed to evaluate the efficacy, safety, and tolerability of mirodenafil in the treatment of ED in Korean men with DM. This study showed that the mirodenafil group showed significantly improved sex life and partner relationship compared to placebo group. Most treatment-associated adverse effects (AEs) were mild and were resolved spontaneously [42].
Sexual function in Chinese women with different clinical phenotypes of polycystic ovary syndrome
Published in Gynecological Endocrinology, 2023
Xuanxuan Tian, Xiangyan Ruan, Juan Du, Jiaojiao Cheng, Rui Ju, Alfred O. Mueck
Multivariate linear regression analysis demonstrated that Bio-T and WC were risk factors for FSD, and we also observed significantly higher levels of Bio-T and WC in the ‘classical phenotype’ of PCOS. The association between levels androgen and sexual function remain inconsistent. Ercan et al. [40] reported a significant negative correlation between the scores of total FSFI and total testosterone and free testosterone. Veras et al. [41] reported a negative collection between sexual function and total testosterone levels and DHEAS. However, Mansson et al. and Stovall et al. [11, 42] showed an inverse relationship. Maseroli et al. [43] reported a moderate association between total T and a better sexual desire/global sexual function, although weak. Similar results on desire were obtained for free testosterone and FAI. Rellini et al. [44] reported clinical signs of hyperandrogenism are associated with sexual clues driving desire for sex more than biochemical parameters of hyperandrogenism. The real mechanism of androgen on sexuality is complicated. Paick et al. [45] reported ‘Mirodenafil’, in doses of 50 or 100 mg, significantly improved erectile function, inferring androgens may play a role in genital vascularization. Whilst some patients with hypoactive sexual desire disorder (HSDD) can be treated with testosterone, an explanation for this obvious paradox may be that PCOS women with higher bio-T tend to have a negative self-image, obesity and psychosocial and emotional disorders [40]. A large WC puts women at a higher risk of cardiometabolic diseases that in turn are linked with impaired sexual activity and type 2 diabetes, as frequently seen in ‘classical phenotype’ PCOS women [20–22, 46], and also a higher risk of endocrine hormone disorders associated with FSD [22].