Effect of chronic use of tadalafil on prostate-specific anti-gene and oxidative stress in obese diabetic patients

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World Journal of Pharmaceutical Sciences ISSN (Print): 2321-3310; ISSN (Online): 2321-3086 Published by Atom and Cell Publishers All Rights Reserved Available online at: http://www.wjpsonline.

1 World Journal of Pharmaceutical Sciences ISSN (Print): ; ISSN (Online): Published by Atom and Cell Publishers All Rights Reserved Available online at: Original Article Effect of chronic use of tadalafil on prostate-specific anti-gene and oxidative stress in obese diabetic patients Haedar Abdulhafith Al-biati 1, Ahmed Salih Sahib 2 *, Faris Abdul Kareem Kazaal 3, Salim Al-Rubaie 4 1 Clinical pharmacy section, Department of Pharmacy, Ministry of Health, Baghdad, Iraq. 2 Department of Pharmacology, Al-Kindy College of Medicine, University of Bagdad, Baghdad, Iraq 3 Department of Internal Medicine, Obesity Therapy and Research Unit, Al-Kindy College of Medicine, University of Bagdad, Baghdad, Iraq. 4 Department of Internal Medicine, Baghdad Teaching Hospital, Baghdad, Iraq ABSTRACT Received: / Revised: / Accepted: / Published: A strong and independent association between obesity, diabetes mellitus and elevation of specific prostate antigene has been widely evidenced in several clinical epidemiologic studies. Preclinical animal models have provided a great deal of information on potential common pathogenic mechanisms underlying these clinical identities. Phosphodiesterase-5 (PDE-5) inhibitors restore NO signaling may improve metabolic parameters through a number of mechanisms. We hypothesized that daily administration of the PDE-5 inhibitor; Tadalafil 10 mg daily will improve metabolic parameters, oxidative stress markers, anti-inflammatory parameters, PSA and body weight in obese diabetic patients and these parameters decreases serum level of prostate specific antigene. Totally, 25 obese diabetic male patients with metabolic syndrome treated with Tadalafil 10 mg daily for three months. Body weight, FPG levels, HbA1C, HOMA-IR, serum prostate-specific antigene, IL-6 and oxidative stress markers were determined monthly. Treatment with tadalafil caused a reduction in fasting glucose levels, HbA1c, HOMA-IR, IL-6, PSA, oxidative stress markers and body weight which were significantly reduced. Tadalafil 10 mg therapy once daily is a safe and effective treatment option for benign prostate hyperplasia glycemic control, and body mass index in diabetic patients with metabolic syndrome. Key words: Tadalafil, prostate-specific anti-gene, oxidative stress, obesity, diabetes. INTRODUCTION Nitric oxide (NO) is involved in many essential biological functions both directly and via its induction of the c-gmp second messenger pathway [1]. People with diabetes have a lower nitric oxide level. This is because the nitric oxide synthase which produces nitric oxide is insulin dependent. Diminished nitric oxide leads to vascular damage including endothelial dysfunction as well as vascular inflammation. This alters smooth muscle relaxation and contractility leading to arterial insufficiency [2]. This in turn can lead to neuropathy and hypoxia-related tissue damage. The NO-cGMP pathway is very well understood in how it causes erectile dysfunction. A drop in NO and consequently cgmp levels lead to failure of the cavernosal smooth muscles to relax resulting in poor arterial flow and therefore erectile dysfunction [3]. Tadalafil and other drugs in its class inhibit the enzyme phosphodiesterase type five which selectively metabolizes cgmp [4]. This result in an up-regulation of cgmp leading to relaxation of the cavernosal smooth muscle. Reduction in the NOcGMP signalling also leads to pelvic atherosclerosis. This consequently resulted in chronic ischemia in the prostate and reduced prostatic blood flow. This in turn leads to an increase in oxidative stress and inflammation. This induces stromal proliferation and transdifferentiation and extracellular matrix production in the prostate by up-regulating TGF-s1 and bfgf, which in turn will lead to BPH [5]. Insulin resistance can lead to sympathetic nervous system activation via an upregulation in IGF-1 and cytosolic-free calcium in smooth muscles and neuronal cells. This leads to an increase in prostate smooth muscle tone and blockage of the bladder outflow tract resulting in LUTS. Nor epinephrine derived from the sympathetic system is the chief neurotransmitter in penile flaccidity and *Corresponding Author Address: Dr. Ahmed Salih Sahib, Head of Pharmacology Department, Al-Kindy College of Medicine, University of Baghdad, Iraq, ahmedsalih73@yahoo.com

2 detumescence. An up regulation on the sympathetic pathway can therefore lead to ED [6]. The aim of this study is to investigate the effect of tadalafil on serum level of prostate-specific antigene, anti-inflammatory marker and oxidative stress in obese diabetic patients with metabolic syndrome. PATIENTS AND METHOD Ahmed et al., World J Pharm Sci 2016; 4(6): color product; forming an MDATBA2 adduct that absorbs strongly at532 nm.[10,11]. Serum TAS was measured by Miller et al. method. This method is used TAS kits. PSA was measured by ELISA kit [12]. Insulin resistance is calculated from fasting serum insulin (FSI) and fasting serum glucose (FSG) using the homeostasis model assessment (HOMA) by following formula [13]. IR values were determined for the patients and control subjects. This is a randomized, prospective clinical trial carried out at Obesity Therapy and Research Unit, Al-Kindy College of Medicine, Baghdad, Iraq. Totally, 25 male patients with metabolic syndrome, aged ± 6.8 years (M±SD) were randomly assigned. They received 10 mg of Tadalafil once daily for three months. The inclusion criteria were: patient with of metabolic syndrome which were defined as fasting plasma glucose (FPG) 126 mg/dl or two hrs plasma glucose 200 mg/dl, serum concentration of TG <400 mg/dl, serum cholesterol having 150 mg/dl, <20 mg/dl of HDL, and BMI more than 24. Exclusion criteria were: history of myocardial infarction or stroke, taking organic nitrate, insulin therapy, incidence of diseases (such as liver, renal or thyroid disorders), consumption of antioxidant supplements in the past two months, and medications altering cytochrome P450 3A4 (CYP3A4), or history of non arteritic ischemic optic neuropathy. Venous blood samples (10 ml) were collected between eight and nine am after fasting for hrs. at baseline and after one month, two months and three months of tadalafil administration. The measurements were performed on frozen serum samples. Glycemic control indices included FPG and hemoglobin A1c (HbA1C). HbA1c was determined using chromatography method by DS5 Drew Scientific machine (ion exchange chromatography) [7]. IL-6 is measured using IL-6 linked immunosorbent enzyme linked sandwich immunoassay using IL-6 kit [8]. Serum GSH concentration was measured by modification procedureusingellman's reagent (5, 5'- dithiobis-(2- nitrobenzoic acid) or DTNB [9]. The method of measurement of serum MDA was based on the reaction with thiobarbituric acid (TBA) at C and ph 2-3 for 15 minutes to form pink HOMA-β=FSI (µiu/ml) x FPG (mmol/l)/22.5. The statistical tests were conducted by paired sample t-test, independent sample t-test. Ethical approval was obtained from the institutional Medical Ethics Committee; the participants signed a written informed consent. RESULTS The results of this study showed that there is a significant decrease (p 0.05) in PSA-1 after 2 and three months periods of tadalafil treatment compared to pre-treatment value (18.95%) (Fig1). In addition, there is a significant decrease (p 0.05) in BMI after one, two and three months periods of tadalafil treatment compared to pre-treatment value (10.9%) (Fig2). The improvement in glycemic control of the studied patients was seen; fasting blood glucose level decreased significantly after three months period by 17.08%; while glycosylated hemoglobin levels decreased significantly after three months period by 5.094% compared to the pre-treatment group. At the same time, Homa-IR was decreased significantly after three month of treatment (p 0.05). Administration of tadalafil had been resulted in improvement of oxidative stress markers of the patients, serum level of GSH significantly increased by (61.54%) after three months treatment with tadalafil ; serum MDA decreased significantly by (21.57%) after three months period compared to pre-treatment value, serum levels of TAS was increased significantly after 3 months period by (22.72%) compared to pre-treatment value. The serum level of IL-6 decreased significantly by % after three months treatment with tadalafil (Table 1) (Fig 3). 358

3 Ahmed et al., World J Pharm Sci 2016; 4(6): Table 1: Effect of tadalafil administration for three months on prostate-specific antigene, glycemic state, inflammatory markers and oxidative stress on diabetic obese patients. Varible Pretreatment 1Month 2Months 3Months % change PSA-(ng/mL) 2.353± ± ± 1.671* ± 1.610* 18.95% BMI (kg/m2) 38.34± ± 6.81* 36.71±6.28* 34.16± 5.69* 10.9 FSG) (mmol/l) 10.01± ± ± ±1.13* HbA1c 8.008± ±0.7* HOMA-IR index 4.3± ±1.22* IL-6 (pg/ml) 4.43± ±2.02* 4.010±2.03* 3.55± 1.3* TAS(mmol/ l) 1.1± ±0.32* 1.15±0.33* 1.35±0.38* MDA (µmol/ l) 1.9± ±0.31* 1.71± 0.30* 1.49±0.29* GSH (µmol/ l) 0.13± ± ±0.042* 0.21±0.042* Results represent mean±sd; *Significant change where p 0.05, BMI: Body mass index, FBG: Fasting blood glucose, HbA1c: Glycosylated hemoglobin, TAS: total anti- oxidant status, MDA: malodialdehyde, GSH: reduced glutathione. 359

4 Ahmed et al., World J Pharm Sci 2016; 4(6): DISCUSSION According to the results of this study, PSA decreases significantly after three months of treatment. PDE5I increases cgmp by inhibiting PDE5 which selectively breaks down cgmp. This leads to better perfusion and fewer signaling on the prostate to enlarge. This also increases pelvic perfusion leading to reduced ischemia. This may lead to less oxidative stress on the prostate and a reduction in signaling for the prostate to enlarge. An increase in NO also inhibits the RhoA/Rho- Kinase pathway which will reduce the contractility of bladder musculature leading to a decrease in LUTS. PDE5I also reduces autonomic hyperactivity by reducing the inflammation and oxidative stress caused by the metabolic syndrome [14]. Efficacy of tadalafil 5mg daily for the treatment of BPH-LUTS, tadalafil 5mg once a day resulted in statistically significant improvement in LUTS secondary to BPH compared with placebo on IPSS. Tadalafil 5mg demonstrated further benefit compared to 2.5mg. 10mg and 20mg provided minimal further improvement over 5mg [15, 16, 17]. The current study is in agreement with results of [18], which showed that chronic inhibition of PDE-5 improves insulin action in a mouse model of diet-induced obesity and one potential mechanism by which PDE-5 inhibition may improve insulin action is prevention of endothelial dysfunction. It has been found that endothelial dysfunction may be causative of IR and Type 2 diabetes [19]. Endothelial dysfunction is characterized by a decrease in NO level, reducing cgmp production and impairing muscle glucose uptake [20]. Thus, it is possible that preventing a decrease in cgmp levels by inhibiting PDE-5 intervenes downstream of the site of endothelial dysfunction, resulting in improvement. Atherosclerosis-induced arterial insufficiency is a common clinical problem in the elderly. Studies have shown that there is an association between the development of BPH and manifestations of atherosclerotic disease such as noninsulindependent diabetes mellitus, hypertension, or dyslipidemia, suggesting that BPH is a component of the metabolic syndrome and that the underlying cause of BPH might be systemic rather than local [21,22]. Atherosclerosis is well - known to be an inflammatory process involving a number of proinflammatory cytokines, and it is considered that there is a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. It has been reported that chronic treatment with tadalafil has an anti-inflammatory effect on endothelial cells [23] and such an effect may contribute to its effect on the prostate. This was further supported by the finding that tadalafil was able to blunt inflammatory responses induced by metabolic as well as inflammatory stimuli in human myofibroblast prostatic cells [24]. The role of the NO pathway in the prostate and its relation to smooth muscle tone and LUTS have been discussed by previous authors [25]. CONCLUSION Tadalafil 10 mg therapy once daily is a safe and effective treatment option for benign prostate hyperplasia, glycemic control, and body mass index in diabetic patients with metabolic syndrome. ACKNOWLEDGMENTS The authors acknowledge the participation and cooperation of the patients enrolled for the study. 360

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MMM. Topic The use of Tadalafil 5mg daily for the treatment of BPH-LUTS

MMM. Topic The use of Tadalafil 5mg daily for the treatment of BPH-LUTS Dr Tan & Partners MMM Vol. 1 No. 1 Morbidity & Mortality Meeting 14 th November 2014 Introduction Topic The use of Tadalafil 5mg daily for the treatment of BPH-LUTS Tadalafil 5mg daily is a well established