Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties. 相似文献
BackgroundTestosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear.AimTo investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency.MethodsRats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle.OutcomesErectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation.ResultsIn the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P < .01). Testosterone injection significantly improved each of these parameters (P < .01).Clinical TranslationThe present results provide scientific evidence of the effect of testosterone deficiency on erectile function and the effect of testosterone replacement therapy.Strengths and LimitationsThis study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation.ConclusionTestosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction.Kataoka T, Hotta Y, Maeda Y, Kimura K. Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats. J Sex Med 2017;14:1540–1548.相似文献
Introduction: The cardiovascular (CV) safety of testosterone replacement therapy (TRT) remains a crucial issue in the management of subjects with late-onset hypogonadism. The authors systematically reviewed and discussed the available evidence focusing our analysis on heart-related issues.
Areas covered: All the available data from prospective observational studies evaluating the role endogenous T levels on the risk of acute myocardial infarction (AMI) were collected and analyzed. In addition, the impact of TRT on heart-related diseases, as derived from pharmaco-epidemiological studies as well as from randomized placebo-controlled trials (RCTs), was also investigated.
Expert opinion: Available evidence indicates that endogenous low T represents a risk factor of AMI incidence and its related mortality. TRT in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure (HF). In addition, when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events. 相似文献
IntroductionErectile dysfunction (ED) is associated with neurological damage due to human T-lymphotropic virus 1 (HTLV-1) infection, but hormonal and psychogenic factors also cause ED.AimTo evaluate the association of psychogenic and hormonal factors with ED in men infected with HTLV-1.MethodsIn this cross-sectional study, we compared total testosterone, follicle stimulating hormone, luteinizing hormone, prolactin, anxiety symptoms, depressive symptoms, and neurologic manifestations in HTLV-1-infected men with or without ED. The International Index of Erectile Function was used to determine the degree of ED. Participants were grouped according to Osame’s Motor Disability Scale and the Expanded Disability Status Scale: HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP), probable HAM/TSP, or HTLV-1 carrier. Chi-square and Fisher’s exact tests were used to compare the groups, and regression analyses were used to show predictors of ED.Main Outcome MeasureSexual hormonal levels, psychogenic factors, and neurologic disabilities were found to be associated with ED.ResultsED was associated with age older than 60 years (P < .001), degree of neurologic involvement (P < .001), depression (P = .009), and anxiety (P = .008). In the multivariate analyses, only age and degree of neurological injury remained as risk factors for ED.Clinical ImplicationsNeurological manifestations are a stronger predictor of ED than hormonal and psychogenic factors in HTLV-1-infected men.Strengths & LimitationsThe statistical power of the study was limited due to the low number of participants, but neurologic manifestations were clearly associated with ED. There was no strong association between hormonal and psychogenic factors and ED.ConclusionHormonal and psychogenic factors did not show a strong association with ED in individuals with HTLV-1, but neurological manifestations were strongly associated with ED in these individuals.de Oliveira CJV, Neto, JAC, Andrade RCP, et al. Hormonal and Psychogenic Risk Factors for Erectile Dysfunction in Men with HTLV–1. J Sex Med 2019; 16:1763–1768.相似文献
Diet is a key factor in the aetiology of many diseases, including metabolic syndrome and lower urinary tract disorders. Metabolic syndrome is a growing and increasingly expensive health problem in both the developed and the developing world, with an associated rise in morbidity and mortality. On the other hand, lower urinary tract symptoms affect millions of individuals worldwide, lowering their quality of life. Associations have been established between both conditions in existing literature and the various components of the metabolic syndrome have been linked with the onset and aggravation of symptoms in various forms of LUTS. This current review explores the relationships between these in detail, focusing on their inter-relationships particularly vis-a-vis dietary macronutrient and micronutrient intake. 相似文献