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  • The major concern of PDE I use in liver cirrhosis

    2020-03-31

    The major concern of PDE-5-I use in liver cirrhosis is the potentially harmful effect on systemic blood pressure. Data of clinical studies are conflicting [27], [30], [31], [32], but available patient details suggest that in advanced liver cirrhosis, PDE-5-Is lower systemic blood pressure to a greater extent than in less progressed cirrhosis. This may be explained by the fact that in progressed cirrhosis, the metabolic capacity of CYP3A is diminished leading to a higher systemic load of a PDE-5-I. In addition, the drug may bypass the cirrhotic liver by shunts. In the present study, MAP was significantly lowered in the highest dose group (100mg) from 98.9±8.1mmHg pre-dose on day by 6.0±7.4% (equivalent to 6.2mmHg) post-dose on day 6. However, this change was well tolerated with no symptomatic hypotension and no concomitant increase in Loteprednol etabonate sale rate. We regard them as non-relevant. When assessing the risks of PDE-5-Is and NSBB in liver cirrhosis it must be considered that NSBB are often not well tolerated due to cardiovascular side effects (bradycardia, hypotension) and that they may even be harmful to selected patients (porto-pulmonal hypertension, tense ascites, spontaneous bacterial peritonitis) [41], [42]. Both, NSBB and udenafil lower portal pressure, but they have a completely different mode of action. NSBB act by lowering heart rate, cardiac output and portal tributary blood flow by increasing splanchnic vascular resistance [11], [19], [43]. PDE-5-Is act by dilation of sinusoids leading to a decreased intrahepatic resistance and enhanced hepatic blood flow. Theoretically, both drugs could be combined to increase the effects. However, an additional hypotensive risk must then be kept in mind.
    Conflict of interest
    Jong Kwan Park had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Chen Zhao, Sae Woong Kim, Dae Yul Yang, Je Jong Kim, Nam Cheol Park, Sung Won Lee, Jae Seung Paick, Tai Young Ahn, Kweon Sik Min, Kwangsung Park, Jong Kwan Park. Chen Zhao, Jong Kwan Park. Chen Zhao, Jong Kwan Park. Chen Zhao, Jong Kwan Park. Jong Kwan Park. Chen Zhao. Chen Zhao, Sae Wong Kim, Dae Yul Yang, Je Jong Kim, Nam Cheol Park, Sung Won Lee, Jae Seung Paick, Tai Young Ahn, Kweon Sik Min, Kwangsung Park, Jong Kwan Park. Chen Zhao, Jong Kwan Park. Jong Kwan Park. (specify): None. I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: The authors received a grant from Dong-A Pharmaceutical Company (Study No.: DA8159_EDD_II). Collection of the data and preparation. Introduction Phosphodiesterase type 5 inhibitors (PDE5-Is) are currently the first-line oral therapy for patients complaining of erectile dysfunction (ED) of any type or etiology [1]. However, on-demand treatment of ED with PDE5-Is can eliminate spontaneity from sexual activity and be burdensome for patients and their partners [2]. Once-daily dosing of a PDE5-I is an alternative for couples who prefer spontaneous rather than scheduled sexual activities or for those who anticipate frequent sexual encounters. Recent clinical tests have shown that daily dosing of PDE5-Is results in a higher ED treatment effect at a comparatively lower dose than on-demand dosing [3], Loteprednol etabonate sale [4], [5]. Long-term administration of PDE5-Is is known to inhibit declining of vascular endothelial cell function, thus accelerating vascular relaxation [6]. Such effects have been reported in human subjects administered sildenafil or vardenafil [7], [8]. Thus daily dosing of PDE5-Is may be an ideal treatment for ED. Udenafil (Zydena; Dong-A, Seoul, Korea) is a selective PDE5-I that was recently developed for the treatment of ED. Based on clinical kinetics data of phase 1 trials involving healthy male subjects, udenafil is rapidly absorbed, reaching peak plasma concentrations at 0.8–1.3h, then declining monoexponentially with a terminal half-life (T1/2) between 7.3 and 12.1h in the single-dose group [9], [10], [11]. Time of maximal concentration (Tmax) of udenafil is similar to that of sildenafil (0.8h) or vardenafil (0.7h) and shorter than tadalafil (2h), implying that the onset of the efficacy would be as fast as that of sildenafil or vardenafil [12]. In a multiple-dose study, the concentration-time profiles on day 7 were comparable with the concentration-time profiles on day 1. The pharmacokinetic parameters showed similar individual values for maximal drug concentration, Tmax, area under the curve from time 0h to infinity, and renal clearance between days 1 and 7 [13]. In various animal models, it has also been confirmed that PDE5 inhibition by udenafil significantly inhibits the decline of vascular endothelial cell function and inhibits the decrease in endothelial cell and smooth muscle content when administered daily for an extended period of time [14], [15], [16]. Given this background, an investigative clinical trial was performed to evaluate the efficacy and safety of a once-daily low dose of udenafil in the treatment of ED and to determine the optimal clinical dose and dosing schedule.