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Dopamine and Tumorigenesis in Reproductive Tissues
Published in Nira Ben-Jonathan, Dopamine, 2020
The blockade of cGMP breakdown by PDE inhibitors also has beneficial effects on prostate cancer [96]. PDE5 and PDE11 were the most prominent PDEs in DU145 and PC-3 cells, representing 90% of the total cGMP-specific PDE activity. Treatment of DU145 cells with a PDE inhibitor reduced hypoxia-associated acquisition of resistance to doxorubicin, and attenuated the growth of human prostate cancer xenografts in mice. The authors concluded that these data offer a rationale for future therapeutic applications of PDE inhibitors in men with prostate cancer.
Erectile dysfunction and Peyronie’s disease
Published in J Kellogg Parsons, E James Wright, The Brady Urology Manual, 2019
Trinity J Bivalacqua, Mohamad E Allaf
Side effects: Common adverse events for all PDE5 inhibitors include headache, flushing, rhinitis, and dyspepsiaSildenafil – visual disturbances related to inhibition of PDE6Tadalafil – myalgia and back pain thought to be associated with inhibition of PDE11.
Absorption, distribution, metabolism, and excretion of [14C]TPN729 after oral administration to rats
Published in Xenobiotica, 2022
Huan Cheng, Jinghua Yu, Chen Yang, Ning Zhang, Zhen Fan, Xiaojuan Zhang, Junchen Wang, Zhen Wang, Da-fang Zhong, Ji-Xiang He, Shu Yan, Xingxing Diao
These adverse effects were attributed to the diversity of PDE enzymes and the selectivity of the PDE5 inhibitors for PDE5 (Wang et al. 2013; Zhu et al. 2016). PDE enzymes comprise 11 different families and PDE5 was shown to be the most important type in the penis (McCullough 2002). Due to the similarity of PDE isoforms, PDE5 inhibitors can also act on other isoforms, such as PDE1, PDE6, and PDE11, resulting in some adverse effects (Scaglione et al. 2017). Sildenafil was reported to cause visual disturbances through inhibition of the photoreceptor PDE6 (Corona et al. 2016). Tadalafil was shown to cause back pain and myalgia due to the inhibition of PDE11 (Wang et al. 2013). Avanafil had fewer reported side effects, but its duration of action was too short because of its effective half-life of 1.91–2.54 h (Jung et al. 2010). Based on these afore mentioned issues, PDE5 inhibitors with higher selectivity and longer duration are urgently needed at present.
Tadalafil for the treatment of benign prostatic hyperplasia
Published in Expert Opinion on Pharmacotherapy, 2019
Fabiola Zakia Mónica, Gilberto De Nucci
While PDE5 is expressed in several organs including prostate [23], bladder [24], testis [25], corpus cavernosum [26], vascular smooth muscle [24,27] and platelets [28], and others, the PDE6 isoform is mainly found in the mammalian eye to control phototransduction in the rod and cone segments of retina [29]. Due to the amino acid sequence homology between PDE5 and PDE6 and the similarity of their catalytic domains, the first generation of PDE5 inhibitors (sildenafil and vardenafil) can also inhibit PDE6 [30]. On the other hand, the PDE5/PDE6 ratio (780) makes tadalafil [31] a more selective PDE5 inhibitor than sildenafil and vardenafil. Visual disturbances such as functional blindness, blurred vision, and greater light sensitivity have been linked to PDE6 inhibition [32]. With respect to the cross-reactivity with the isoform PDE11, in cells overexpressing human PDE11, the PDE5/PDE11 ratios for tadalafil, vardenafil, and sildenafil are 40, 9300 and 1000-fold [33]. However, the physiological role of PDE11 is poorly studied. To date, there are no studies that evaluated whether sildenafil, vardenafil or tadalafil interfere with PDE9 activity, an enzyme that preferentially degrades cGMP.
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
Regarding its action toward PDE5, udenafil has a PDE1 selectivity ratio of 1262 compared to 41 for sildenafil and a greater PDE11 selectivity ratio of 96 compared to 7.1 for tadalafil [14]. The function of PDE11 is not currently well understood, but it is widely expressed in the skeletal muscle, testes, heart, prostate, kidney, liver, and pituitary [15]. While optimal dosage times have yet to be established through clinical trials, studies have demonstrated that udenafil reaches peak plasma concentrations (Tmax) at 0.8–1.3 hours and has a half-life of 7.3–12.1 hours, suggesting relatively quick onset and long duration [16]. A summary of the findings from clinical trials on the novel agents as well as the pharmacokinetics of the currently approved agents can be found in Tables 1 and 2, respectively. Udenafil has a longer half-life than sildenafil or vardenafil and a shorter Tmax than tadalafil [22,23]. In a multiple-dose study conducted by Kim et al., udenafil displayed a longer half-life (7–12 hours) than sildenafil (4 hours) but a similar Tmax after 7 weeks [8]. Importantly, another Kim et al. study evaluated the effect of food on the pharmacokinetics of udenafil and determined that the Tmax was delayed under fed conditions. The mean Tmax values after low-fat and high-fat meals were 2.1 hours and 2.6 hours, respectively. Although the oral bioavailability was not altered by food intake, the maximum serum concentration (Cmax) in the low-fat state was reduced by 21% [24]. This information suggests that tadalafil remains superior in its ability to maintain linear pharmacokinetics irrespective to food intake [25].