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  • br torsion is a urological emergency that may occur at

    2019-09-11


    torsion is a urological emergency that may occur at any age. To establish blood flow surgical detorsion is required in most cases while detorsion can sometimes be achieved by hand assistance. Regardless of the correction method 2 phases (I/R) negatively affect germ cells. The torsion phase decreases the oxygen supply and cell energy, and the detorsion phase affects reactive radical formation. After reperfusion some oxidative stress parameters were noted in organs such as the liver, heart, Phosphatase Inhibitor Cocktail 1 (100X in DMSO) and colon, in addition to the testis.,
    Introduction Erectile dysfunction (ED) is a common disorder that increases in incidence with age (Prins et al., 2002); indeed, up to 50% of men between 40 and 70 years old could be affected (Feldman et al., 1994, Johannes et al., 2000). ED is defined as the inability to induce or maintain an erection sufficient for satisfactory sexual performance. Relaxation of the smooth muscles of the corpus cavernosum is required for an erection. Cyclic guanosine monophosphate (cGMP) levels are important for the maintenance of an erection because, together with nitric oxide (NO), cGMP is involved in the relaxation of the smooth muscles of the corpus cavernosum. It is known that phosphodiesterase type 5 (PDE5) has a catalytic action on cGMP. The structure of PDE5 inhibitors are similar to the cGMP molecule and compete with cGMP at the catalytic site of PDE5, thus increasing cGMP levels and the erectile process (Salem et al., 2006). Udenafil, (5-[2-propyloxy-5-(1-methyl-2-pyrollidinylethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one), is a potent and selective inhibitor of PDE5, an enzyme that catabolizes cyclic guanosine monophosphate (cGMP) in the corpus cavernosum (Oh et al., 2000, Doggrell, 2007). Udenafil (Zydena®) was developed by Dong-A Pharmaceutical Company (Yongin, Republic of Korea) for oral administration to male patients suffering from ED. Although it has not yet been approved by the U.S. Food and Drug Administration (FDA) nor the European Medicines Agency (EMEA), it has been approved by the Korean Food and Drug Administration (KFDA) and is currently used in the Republic of Korea. The absolute oral bioavailability of udenafil at a dose of 30mg/kg was 38.0% in rats (Shim et al., 2003), but to our knowledge, the value in humans has not been reported. Absorption of udenafil from rat intestinal tract is known to be complete (about 99% of an oral dose of 30mg/kg; Shim et al., 2003). Thus, the relatively low bioavailability (38%) in rats may be related to the hepatic, gastric, and intestinal first-pass effects (Shim et al., 2003). It was also reported that the bioavailability of udenafil can be altered by P-glycoprotein (P-gp) and/or CYP3A4 and they may induce changes in the pharmacokinetics of udenafil in patients (Ji et al., 2007). Tmax of udenafil in rats has been reported to be 35.5±12.1min at a dose of 30mg/kg (Shim et al., 2003), whereas that in humans is 1.5h (1–3h) at a 100-mg dose in healthy males (Bae et al., 2008). However, this Tmax value needs to be shortened to satisfy patient demand in the erectogenic market, not least because avanafil, a competitor, is a short-acting drug that exerts its pharmacological effect within 30min (Hatzimouratidis and Hatzichristou, 2008). In comparison with oral administration, intranasal drug delivery may provide an improvement in bioavailability while shortening Tmax (Costantino et al., 2007, Ugwoke et al., 2001). This has already been demonstrated in a study comparing the nasal and oral administration of sildenafil citrate, another PDE5 inhibitor (Elshafeey et al., 2009). Thus, it is expected that intranasal delivery of udenafil may also achieve rapid onset of action and improved bioavailability by avoiding the first-pass effect in the liver and intestine (Romeo et al., 1998). Enhancement of drug solubility is necessary for the intranasal delivery of udenafil. Because its aqueous solubility is only 0.02mg/ml, a microemulsion system may be an effective strategy to overcome this low aqueous solubility. A microemulsion is defined as a thermodynamically stable and transient dispersion consisting of oil, surfactant, cosurfactant, and aqueous phases (Eccleston, 1992). The advantages of microemulsion as a drug delivery system are the enhancement of drug solubilization and absorption across mucosal membranes (Gao et al., 1998). Here, we report the development of an udenafil-loaded microemulsion system for intranasal delivery and characterization of its physicochemical properties. Its permeation-enhancing effect and improved bioavailability were also evaluated in vitro in cell monolayers and in vivo in an animal model.