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Effects of Repeated Dosing with Udenafil (Zydena) on Cognition, Somatization and Erection in Patients with Erectile Dysfunction: a Pilot Study

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Effects of Repeated Dosing with Udenafil (Zydena) on Cognition, Somatization and Erection in Patients with Erectile Dysfunction: a Pilot Study International Journal of Impotence Research (2011) 23, 109–114 & 2011 Macmillan Publishers Limited All rights reserved 0955-9930/11 www.nature.com/ijir ORIGINAL ARTICLE Effects of repeated dosing with Udenafil (Zydena) on cognition, somatization and erection in patients with erectile dysfunction: a pilot study YS Shim1, C-U Pae2,SWKim3, HW Kim4,JCKim5 and JS Koh5 1Department of Neurology, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea; 2Department of Psychiatry, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea; 3Department of Urology, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Korea; 4Department of Urology, The Catholic University of Korea, St. Paul’s Hospital, Seoul, Korea and 5Department of Urology, The Catholic University of Korea, Bucheon St. Mary’s Hospital, Bucheon, Korea The PDE5 inhibitors have recently been found to have cognitive-enhancing effects in animal models. To investigate the efficacy of repeated dosing with a PDE5 inhibitor on cognitive function and somatization in patients with erectile dysfunction, 27 patients with erectile dysfunction received udenafil (100 mg) at 3-day intervals for 2 months. The international index of erectile function-5 (IIEF-5), a cognitive battery (the Korean version of mini-mental state examination (K-MMSE), the frontal assessment battery (K-FAB), the Seoul verbal learning test) and a physical health questionnaire-15 (PHQ-15) were performed at baseline and at 2 months, following the administra- tion of udenafil. The patients were divided on the basis of their IIEF-5 score into responders (change47) and non-responders. The mean IIEF-5 score was significantly increased after treatment (7.92±3.83 to 16.33±4.75, Po0.001). The scores of K-MMSE (27.03±1.58 to 28.07±1.57, P ¼ 0.001), K-FAB (13.65±1.96 to 15.41±1.85, Po0.001) and PHQ-15 (18.92±4.96 to 17.63±4.75, P ¼ 0.003) were significantly improved after treatment. In addition, the responders (n ¼ 16) had more improved cognitive function (r ¼ 0.603, P ¼ 0.001) and somatization (r ¼À0.402, P ¼ 0.038) than non-responders (n ¼ 11). Repeated dosing with a PDE5 inhibitor seems to improve cognitive function and somatization, as well as erectile function in patients with erectile dysfunction. International Journal of Impotence Research (2011) 23, 109–114; doi:10.1038/ijir.2011.13; published online 5 May 2011 Keywords: PDE5 inhibitor; cognition; somatization disorder; erectile dysfunction Introduction in some countries, such as Korea, Russia, Ukraine and Malaysia, because of the reported safety and Orally administrated PDE5 inhibitors competitively efficacy of udenafil in the treatment of erectile inhibit PDE5, which physiologically inactivates dysfunction.2–4 The PDE5 inhibitors are commonly cyclic guanosine monophosphate (cGMP) in the used for erectile dysfunction, but there have been erectile bodies. Thus, PDE5 inhibitors increase several different attempts to evaluate additional nitric oxide-stimulated cGMP concentration in beneficial effect of PDE5 inhibitors in treatments patients with erectile dysfunction.1 Three PDE5 for pulmonary hypertension,5 benign prostate inhibitors (sildenafil, tadalafil and vardenafil) have hyperplasia6 and stroke.7 been widely used. Udenafil (Zydena), which is the In a recent study, PDE5 has been identified in most recently developed PDE5 inhibitor, is also used the rat brain, including the cortex and hippo- campus.8,9 PDE5 inhibitors readily cross the blood–brain barrier and increase cGMP concentra- tions in the intracellular pathway activated by Correspondence: Professor JS Koh, Department of Urology, N-methy-D-aspartic acid receptors, which is be- The Catholic University of Korea, Bucheon St. Mary’s lieved to mediate long-term potentiation and Hospital, 2, Sosadong, Wonmigu, Bucheon, Kyunggido 10–12 420-717, Korea. memory consolidation. Thus, some valuable E-mail: [email protected] animal models have been utilized to confirm the Received 30 November 2010; revised 30 March 2011; cognitive-enhancing effect of PDE5 inhibitors. Sub- accepted 10 April 2011; published online 5 May 2011 chronic administration of sildenafil has been shown Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 110 to increase cortical cGMP levels13 and sildenafil taking drugs that inhibited or induced hepatic reversed cognitive deficits in rats produced by cytochrome P4503A4, PDE5 inhibitors, nitrates, diabetes,14 anticholinergics15 and hyperammonemia.10 a-blockers, antidepressants or other neuropsychia- Despite positive findings in animal models, in tric medication and (3) patients who were not vivo data are limited and no conclusive remarks can willing to use appropriate methods of contraception be made. There has been only one study, as far as we with their sex partners or patients and their sex know, to investigate the impact of a PDE5 on partners were planning to achieve pregnancy. cognitive function in humans, with a double-blind design along with only a single dose. A single dose of sildenafil (50 or 100 mg) was shown not to have Study design an effect on putative N-methy-D-aspartic acid Thirty-three men who were diagnosed with erectile receptor-mediated memory deficits in schizophrenia dysfunction by clinical history and physical exam- patients. It was suggested that the doses used in the ination were enrolled in this prospective study. study were not optimal and repeated dosing may be After erectile dysfunction had been confirmed, an necessary to achieve therapeutic effects.16 electocardiography was obtained. Patients were Therefore, we conducted this study to assess scheduled for three sessions at 1-month intervals. whether or not repeated dosing with a PDE5 At baseline, we administered the IIEF-5 for erectile inhibitor improves cognitive function and somatiza- dysfunction, physical health questionnaire (PHQ)- tion, as well as erectile function in patients with 15 for somatization and a cognitive battery for erectile dysfunction. cognition. The PHQ–15 is a somatic symptom severity subscale. It assesses 15 somatic symptoms or symptom clusters that account for more than 90% Materials and methods of all physical complaints (excluding upper respira- tory tract symptoms) reported by outpatients. Each The study was conducted at the Clinical Trials item is rated on a scale from 0 to 2. Scoring simply Centre of the Catholic University of Korea. The requires adding the numbers circled, and scores can study protocol was approved by the Institutional range from 0 to 30. The PHQ–15 has already been Review Board. All procedures were performed in validated in primary-care settings.19,20 The cognitive accordance with the recommendation of the battery consisted of the Korean version of the mini- Declaration of Helsinki on biomedical research mental state examination (K-MMSE) for general involving human subjects. All subjects gave written cognitive function,21 the Seoul verbal learning test informed consent before being enrolled. (SVLT) for episodic memory and learning22 and the Korean version of the frontal assessment battery (K-FAB) for frontal executive function.23 The SVLT is the modified Korean version of the Hopkins Subjects verbal learning test,24 and by performing the SVLT, The inclusion criteria were as follows: (1) male scores of three trials and delayed recalls were patients between 40 and 70 years of age, (2) patients recorded for the evaluation of learning and memory who complained of erectile dysfunction for a mini- consolidation. mum of 3 months, (3) patients who had a regular Following the initial baseline evaluation, patients female sex-partner during the study, (4) patients were given udenafil (100 mg) every 3 days for whose international index of erectile function-5 1 month, after which the patients had a follow-up (IIEF-5) score was 21 points on a screening test o evaluation (second visit). This was followed by and (5) patients who did not complain of cognitive an assessment of the IIEF-5 and adverse events. impairment. Erectile dysfunction was defined as an After the assessment, patients were given udenafil inability to attain and/or maintain a penile erection (100 mg) for another month and the IIEF-5, adverse sufficient for satisfactory sexual performance.17 events, the physical health questionnaire-15 The severity of erectile dysfunction was classified (PHQ-15), and cognitive battery were administered based on baseline IIEF erectile function domain (third visit). score into mild (17–21), mild to moderate (12–16), Subjects were divided into two groups (responder moderate (8–11) and severe (5–7).18 The etiology of and non-responder) according to the change in erectile dysfunction was determined by the study IIEF-5 at third visit. Subjects with an increase in investigator based on patient history, as well as the IIEF-5 score (47) were considered to be res- physical and laboratory examination findings. ponders.4 Exclusion to study participation included (1) history of a cerebral vascular accident, myocardial infarc- tion, achromatopsia, dyschromatopsia, retinitis pig- mentosa, head trauma, psychiatric disorder and Statistical analysis dementia (according to DSM-IV or whose MMSE Statistical analyses were performed using the Sta- scores were o24), (2) patients who were currently tistical Package for the Social Sciences (SPSS International Journal of Impotence Research Effect of repeated dosing with udenafil on cognition, somatization and erection YS Shim et al 111 version 15.0. for Windows; SPSS Inc., Chicago, IL, Table 1 Patients’ demographics and baseline characteristics USA). Continuous data were reported as the mean±s.d. Changes from baseline to the end of Characteristics n ¼ 27 treatment were assessed using the Wilcoxon signed- ± rank test. The age and disease duration distribu- Age (years) 54.81 7.21 Disease duration (months) 33.48±23.70 tions, and the results of baseline evaluations, such as the IIEF-5, PHQ-15, K-MMSE, SVLT, and K-FAB Etiology of erectile dysfunction, n (%) and the changes after treatment, were compared Psychogenic 7 (22.2) between the responder and non-responder groups Organic 13 (48.2) using the Mann–Whitney U-test.
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