Ipidacrine (Axamon), A Reversible Cholinesterase Inhibitor, Improves Erectile Function in Male Rats With Diabetes Mellitus-Induced Erectile Dysfunction

Sexual Medicine - Tập 10 - Trang 100477 - 2022
Vladimir Bykov1, Evgenia Gushchina2, Sergey Morozov2, Natalia Zhuravskaya2, Kirill Kryshen3, Valery Makarov3, Aleksandr Matichin3, Alena Zueva3
1N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg, Russia
2PIQ-PHARMA LLC, Oruzheyniy pereulok, Moscow, Russia
3Institute of Pre-clinical Research Ltd, Leningradskaya Region, Russia

Tóm tắt

ABSTRACTSBackgroundManagement of diabetes mellitus-induced erectile dysfunction (DMED) is challenging because of its insufficient responses to phosphodiesterase type 5 inhibitors.AimTo compare the effects of ipidacrine, a reversible cholinesterase inhibitor, and sildenafil on DMED in a rat model of streptozotocin (STZ)-induced diabetes.MethodsErectile dysfunction (ED) caused by STZ-induced diabetes mellitus was modeled in adult male Wistar rats, which were randomized to 4 groups: untreated diabetic rats, sildenafil (5 mg/kg), ipidacrine (3.6 mg/kg) and ipidacrine (6.7 mg/kg). The test drug (ipidacrine), comparator (sildenafil) or control substance (1% starch solution) were administered orally for 5 days or 14 days. Erectile function was assessed by the change in the maximum intracavernous pressure (ICPmax) following cavernous nerve electrical stimulation. The mean arterial pressure (MAP) was recorded, and the ICPmax/MAP ratio was calculated. Sexual behavior, cholinesterase activity and blood testosterone level tests assessed.Main Outcome MeasureThe quantitative value of ICPmax/MAP 14 days after the start of administration of the test drug and the comparison drug.ResultsAnimals with STZ-induced diabetes mellitus showed a significant decrease in ICPmax and ICPmax/MAP ratio compared to the intact control group. When ipidacrine was administered to rats with DMED for 14 days, an increase in these indicators was noted. It was proved that ipidacrine at a dose of 6.7 mg/kg has noninferiority compared to sildenafil on the DMED model. Significant increase in ICPmax compared to STZ-control after electrostimulation of the cavernous nerve was recorded following administration of ipidacrine at a dose of 6.7 mg/kg (P < .05) and sildenafil at a dose 5 mg/kg (P < .05). Neither the test drug, nor the comparator were associated with increase in testosterone levels in blood; as well both drugs did not promote activation of sexual behavior.Clinical ImplicationsIpidacrine may be considered as an effective therapy for DMED but needs to be verified in human investigations.Strengths & LimitationsThe role of ipidacrine, was firstly demonstrated in rats with DMED. However, the results were obtained in animal experiments, and will be further tested in the study of receptor interactions and the determination of cellular targets.ConclusionThis is the first study to show that administration of ipidacrine, the reversible cholinesterase inhibitor, improved erectile function in diabetic rats and these results may be beneficial in further studies using ipidacrine for treatment of DMED, particularly in non-responders to PDE5 inhibitors.

Tài liệu tham khảo

Castro, 2010, Epidemiology of erectile dysfunction. Risk factors, Arch Esp Urol, 8, 637 De Rose, 2019, Epidemiology of sexual disorders in general medical practice: An Italian survey, Urologia, 2, 79, 10.1177/0391560319842955 Nicolosi, 2003, Epidemiology of erectile dysfunction in four countries: Cross-national study of the prevalence and correlates of erectile dysfunction, Urology, 1, 201, 10.1016/S0090-4295(02)02102-7 Fonseca, 2005, Endothelial and erectile dysfunction, diabetes mellitus, and the metabolic syndrome: Common pathways and treatments?, Am J Cardiol, 12B, 13M, 10.1016/j.amjcard.2005.07.005 Phé, 2012, Erectile dysfunction and diabetes: A review of the current evidence- based medicine and a synthesis of the main available therapies, Diabetes Metab, 1, 1, 10.1016/j.diabet.2011.09.003 Shah, 2018, A meta-analysis on efficacy and tolerability of sildenafil for erectile dysfunction in patients with diabetes mellitus, Indian J Sex Transm Dis AIDS, 39, 1, 10.4103/ijstd.IJSTD_99_17 Perimenis, 2002, Switching from long-term treatment with self-injections to oral sildenafil in diabetic patients with severe erectile dysfunction, Eur Urol, 41, 387, 10.1016/S0302-2838(02)00032-5 Andersson, 2011, Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction, Pharmacol Rev, 4, 811, 10.1124/pr.111.004515 Awad, 2011, Evolution in the concept of erection anatomy, Surg Radiol Anat, 4, 301, 10.1007/s00276-010-0707-4 Giuliano, 2004, Neural control of erection, Physiol Behav, 2, 189, 10.1016/j.physbeh.2004.08.014 Jung, 2014, Clinical neuroanatomy and neurotransmitter- mediated regulation of penile erection, Int Neurourol J, 2, 58, 10.5213/inj.2014.18.2.58 Stief, 1989, Acetylcholine as a possible neurotransmitter in penile erection, J Urol, 6, 1444, 10.1016/S0022-5347(17)41342-5 Valji, 1987, The veno-occlusive mechanism of the canine corpus cavernosum: Angiographic and pharmacologic studies, J Urol, 6, 1467, 10.1016/S0022-5347(17)43676-7 Lasker, 2013, Analysis of erectile responses to BAY 41-8543 and muscarinic receptor stimulation in the rat, J Sex Med, 3, 704, 10.1111/j.1743-6109.2012.02912.x Sjöstrand, 1979, Principal mechanisms controlling penile retraction and protrusion in rabbits, Acta Physiol Scand, 2, 199, 10.1111/j.1748-1716.1979.tb06390.x Brindley, 1986, Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis, Br J Pharmacol, 3, 495, 10.1111/j.1476-5381.1986.tb10191.x Stief, 1989, Possible role for acetylcholine as a neurotransmitter in canine penile erection, Urol Int, 44, 357, 10.1159/000281540 Aydin, 2001, Effects of sildenafil citrate, acetylcholine, and sodium nitroprusside on the relaxation of rabbit cavernosal tissue in vitro, Urology, 58, 119, 10.1016/S0090-4295(01)01006-8 Bykov, 2013, Pharmaceutical compositions containing ipidacrine and use thereof to treat potency disorders and other sexual activity disorders, Priority Data, EP2886119 Ogura, 2000, Comparison of inhibitory activities of donepezil and other cholinesterase inhibitors on acetylcholinesterase and butyrylcholinesterase in vitro, Methods Find Exp Clin Pharmacol, 8, 609, 10.1358/mf.2000.22.8.701373 Kojima, 1991, NIK-247 blocks voltage-dependent ionic currents in crayfish axon, Jpn J Pharmacol, 57, 545, 10.1016/S0021-5198(19)39800-2 Kojima, 1998, Ipidacrine (NIK-247): A review of multiple mechanisms as an antidementia agent, CNS Drug Rev, 3, 247, 10.1111/j.1527-3458.1998.tb00067.x Maksimova, 2013, Neyromidin in the treatment of stage I hypertensive dyscirculatory encephalopathy, Ter Arkh, 8, 87 Maksimova, 2013, Neyromidin in ischemic stroke, Zh Nevrol Psikhiatr Im S Korsakova, 3, 34 Shirokov, 2011, Focal neuropathies: New possibilities for pharmacological treatment, Zh Nevrol Psikhiatr Im S Korsakova, 6, 49 Barantsevich, 2011, Efficacy of neuromidin in alcoholic encephalopathy, Zh Nevrol Psikhiatr Im S Korsakova, 3, 49 Sima, 2010, Encephalopathies: The emerging diabetic complications, Acta Diabetol, 4, 279, 10.1007/s00592-010-0218-0 Russell, 2014, Diabetic neuropathies, Continuum (Minneap Minn), 5, 1226 Deli, 2013, Diabetic neuropathies: Diagnosis and management, Neuroendocrinology, 4, 267, 10.1159/000358728 Vinik, 2003, Diabetic autonomic neuropathy, Diabetes Care, 5, 1553, 10.2337/diacare.26.5.1553 FDA, 2016, Non-inferiority clinical trials to establish effectiveness, guidance for industry Sharma, 2019, Development and characterization of late- stage diabetes mellitus and -associated vascular complications, Life Sci, 216, 295, 10.1016/j.lfs.2018.11.005 Sherwani, 2016, Significance of HbA1c test in diagnosis and prognosis of diabetic patients, Biomark Insights, 11, 95, 10.4137/BMI.S38440 Guidance for industry, 2005, Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers Bai, 2015, Resveratrol and sildenafil synergistically improve diabetes-associated erectile dysfunction in streptozotocin-induced diabetic rats, Life sciences, 135, 43, 10.1016/j.lfs.2015.04.020 De Young, 2003, Effect of PDE5 inhibition combined with free oxygen radical scavenger therapy on erectile function in a diabetic animal model, Int J Impot Res, 5, 347, 10.1038/sj.ijir.3901026 Rehman, 1998, Intracavernous pressure responses to physical and electrical stimulation of the cavernous nerve in rats, Urology, 51, 640, 10.1016/S0090-4295(97)00693-6 Zhao, 2018, Comparison of two cannulation methods for assessment of intracavernosal pressure in a rat model, PLoS One, 13 Liu, 2010, Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction, J Sex Med, 12, 3868, 10.1111/j.1743-6109.2010.01844.x Nunes, 2018, Blockade of toll-like receptor 4 attenuates erectile dysfunction in diabetic rats, J Sex Med, 9, 1235, 10.1016/j.jsxm.2018.07.005 Voss, 1970, Red cell and plasma cholinesterase activities in microsamples of human and animal blood determined simultaneously by a modified acetylthiocholine- DTNB procedure, Toxicol Appl Pharmacol, 3, 764, 10.1016/0041-008X(70)90082-7 Eyer, 2003, Molar absorption coefficients for the reduced Ellman reagent: Reassessment, Anal Biochem, 2, 224, 10.1016/S0003-2697(02)00506-7 D'Agostino, 2003, Non-inferiority trials: Design concepts and issues - The encounters of academic consultants in statistics, Stat Med, 2, 169, 10.1002/sim.1425 Rubio-Aurioles, 2006, Comparing vardenafil and sildenafil in the treatment of men with erectile dysfunction and risk factors for cardiovascular disease: A randomized, double-blind, pooled crossover study, J Sex Med, 6, 1037, 10.1111/j.1743-6109.2006.00310.x Whitehead, 2016, Estimating the sample size for a pilot randomized trial to minimize the overall trial sample size for the external pilot and main trial for a continuous outcome variable, Stat Methods Med Res, 3, 1057, 10.1177/0962280215588241 Al-Oanzi, 2019, Erectile dysfunction attenuation by naringenin in streptozotocin-induced diabetic rats, J Food Biochem, 7, e12885 Hatzimouratidis, 2010, Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation, Eur Urol, 57, 804, 10.1016/j.eururo.2010.02.020 Blonde, 2006, Sildenafil citrate for erectile dysfunction in men with diabetes and cardiovascular risk factors: A retrospective analysis of pooled data from placebo- controlled trials, Curr Med Res Opin, 11, 2111, 10.1185/030079906X148256 Bel'skaia, 2012, The use of ipidacrinum (neuromidin) in mononeuropathies, Zh Nevrol Psikhiatr Im S Korsakova, 10, 31