Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats—A Comparison with Mesna

One of the major side effects of cyclophosphamide (CPX)—an alkylating anticancer drug that is still clinically used—is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1β (IL-1β) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1β concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.

Effect of advanced periodontal self-care in patients with early-stage periodontal diseases on endothelial function: An open-label, randomized controlled trial

Although a significant association between periodontal disease and atherosclerotic cardiovascular disease has been reported, their cause-to-effect relationship remains controversial. This randomized controlled clinical trial aimed to investigate the effect of advanced self-care on atherosclerotic cardiovascular disease-related vascular function markers flow-mediated brachial artery dilatation (FMD) and serum asymmetric dimethylarginine (ADMA) level in patients with early-stage periodontal disease. The study was designed as a parallel group, 3-month follow-up, open-label, randomized controlled trial. The control group received standard care for periodontal diseases, whereas the test group additionally applied disinfectant using a custom-fabricated prescription tray for advanced self-care twice a day. Overall, 110 patients provided data for FMD and serum ADMA level. No significant improvements in FMD were observed in the control (mean increase, −0.1%; 95% confidence interval [CI], −1.0–0.8; P = 0.805) or test (mean increase, −0.3%; 95% CI, −1.1–0.4; P = 0.398) group. No significant changes in serum ADMA levels were observed (mean reduction, 0.01 μmol/L; 95% CI, −0.00–0.02; P = 0.366 and mean reduction, 0.00 μmol/L; 95% CI, −0.01–0.01; P = 0.349, respectively). No significant between-group differences were found in FMD (mean difference, −0.2%; 95% CI, −1.4–0.9; p = 0.708) or serum ADMA levels (mean difference, 0.01 nmol/L; 95% CI, −0.00–0.03; p = 0.122). Significant improvements in the average probing pocket depth were observed in the control and test groups. The bleeding on probing score in the test group was significantly reduced, while that in the control group was reduced, although not significantly. Periodontal care for a 3-month duration did not provide better endothelial function although improvements of periodontal status in patients with early-stage periodontal diseases. This trial is registered in UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/; ID: UMIN000023395).

Asymmetric Dimethyl Arginine Level in Children with Sickle Cell Disease: A Cross Sectional Study

Background: Sickle cell disease (SCD) consists of a group of hemoglobinopathies in which individuals inherit hemoglobin variants derived from single point mutations. Asymmetric dimethylarginine (ADMA) contributes to limiting Nitric Oxide (NO) bioavailability in SCD. The aim of the present study was to assess the level of the Asymmetric Dimethyl Arginine in children with sickle cell. Methods: This cohort cross-sectional study was carried out on 60 children which were divided in to 3 equal groups. Group I: SCD children with sickle retinopathy. Group II: SCD children without retinopathy. Group III: healthy control children who were selected from the outpatient clinic. Results: There was a significant increase in ADMA level among participants withSCD. There was a positive significant correlation between ADMA level and family history as well as the incidence of hepatomegaly. There was no significant correlation between ADMA level and demographic and laboratory parameters except LDH. Conclusions: The level of ADMA is elevated in children with sickle cell anemia. High plasma ADMA level is a risk for hepatomegaly in children with sickle cell anemia.

Serum asymmetric dimethyl arginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

Objective: To investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS. Methods: Serum ADMA levels of patients with sporadic ALS (n = 68) and disease control patients (n = 54) were measured using liquid chromatography tandem mass spectrometry. Serum samples were obtained at the time of patient registration for diagnosis. Correlations of ADMA level and other markers (nitric oxide (NO) and neurofilament light chain (NFL) levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRSR) score from the onset of disease (ALSFRSR preslope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan Meier analysis. Results: The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001), and was independently associated with the ALSFRSR preslope (r = 0.505. p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF NfL level (r = 0.456, p = 0.0002) but not with NO level (r = 0.194, p = 0.219). Conclusion: ADMA level is an independent biomarker of ALS disease progression and prognosis, and reflects the degree of motor neuron degeneration. The increased ADMA level in ALS patients was not associated with the inhibition of NO production.

Relation of asymmetric dimethylarginine with pulmonary morbidities in neonatal respiratory distress syndrome

BACKGROUND: Asymmetric Dimethyl Arginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) is important in different diseases characterized by decreased nitric oxide (NO) availability. We aimed to assess the serum ADMA level in preterm infants suffering from respiratory distress syndrome (RDS) and its relationship with pulmonary outcomes. METHODS: This prospective study included 50 preterm neonates suffering from RDS aging≤32 weeks and weighing≤1500 gm. Serum ADMA levels were estimated in the 1st and 28th day of life by ELISA, and its correlation with surfactant requirement, duration of ventilation, and development of BPD was assessed. RESULTS: Fifty preterm infants with RDS were included, 30 infants were treated with surfactant within 12 hours after birth, the 1stday ADMA level was higher significantly in infants who required surfactant treatment than infants without surfactant treatment, At 36 weeks postmenstrual age, 16 infants were diagnosed with BPD, the 28th day ADMA level was significantly higher in infants with BPD than others without BPD. 1st-day ADMA level was significantly correlated with days on mechanical ventilation but there were no significant correlations between 1st day ADMA and days on CPAP and days on supplemental O2. CONCLUSION: Elevated serum ADMA level in preterm neonates with RDS estimated in the 1st and 28th day of life is a good predictor for pulmonary morbidities such as surfactant requirement, duration of mechanical ventilation, and development of BPD.

Is there a relation between serum methylarginine levels and infertility?

Objectives Infertility is defined as the absence of pregnancy within the reproductive period despite regular sexual intercourse. Methylarginines are formed as a result of methylation of arginine residues in proteins and formed in three forms as asymmetric dimethyl arginine (ADMA), symmetrical dimethyl arginine (SDMA) and monomethylarginine (L-NMMA). So, here, we aimed to evaluate arginine and their derivatives levels in fertile and infertile individuals. Methods Present study were consist of 30 oligozoospermia patients (proven by spermiogram analysis) and 30 healthy individuals with normozoospermia group who were applied to the urology department. With blood samples taken from individuals, serum methylarginine and its derivatives levels were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinic data and demographic characteristics of individuals were also recorded at the same time. Results The serum ADMA level (0.38 ± 0.07) of the oligozoospermia group was found to be significantly higher than the normozoospermia group (0.35 ± 0.05) (p=0.046). A positive correlation were observed between ADMA and SDMA (r=0.686, p=0.000), HArg and SDMA (r=0.611, p=0.001), citrulline and L-NMMA (r=0.595, p=0.001) in patients with oligosospermia. The increase in SDMA, arginine and HArg levels and a decrease in L-NMMA and citrulline levels were not significant as statistically. Also, the ADMA level was found to be high in individuals with low sperm concentration. Conclusions Consequently, serum ADMA levels of individuals with oligozoospermia were statistically significantly higher than those with normozoospermia. As proposal, determination of ADMA levels may be a potential biomarker parameter in terms of early diagnosis of fertility and infertility.

Sleep-related breathing disorders in patients with pulmonary hypertension

Introduction There are some evidences of sleep-related breathing disorders (SRBD) association with pulmonary hypertension (PH). Only limited information regarding the SRBD prevalence in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients, is available. Purpose To estimate the features of SRBD and the asymmetric dimethylarginine (ADMA) level in PAH and CTEPH patients and their relationship with the severity of PH. Methods There were included 31 patients (45% male; 55% female) with a verified diagnosis of precapillary PH: 22.6% – with PAH; 9,7% with PAH associated with adult congenital heart disease; 64.5% – with CTEPH; 3.2% with PAH associated with connective tissue disease. Patients underwent a general clinical examination, questionnaires, a comprehensive assessment of respiratory function, a complete polysomnographic study, ECG and ECHO studies, assessment of clinical and biochemical blood tests, including an assessment of ADMA and NT-proBNP levels. Results SRBD of a predominantly obstructive nature were found in 74.2% of the examined: 38.7% were mild, 22.6% were moderate, 12.9% were severe. In 35% of patients, episodes of periodic breathing during sleep were recorded. There was no association SRBD with PH functional class and hemodynamic parameters. Moderate correlation was observed between the apnea-hypopnea index and remodeling indices of the heart chambers according to ECHO: for the end-diastolic size of the left ventricle (ρ=0.54; p=0.005); for an indicator of the ratio of the size of the ventricles (RV/LV) (ρ=−0.41, p=0.05). The presence of SRBD wasn't associated with the level of peripheral blood saturation according to pulse oximetry in sleep and during wakefulness. Negative moderate correlation was observed between NT-proBNP level and the average peripheral blood saturation at night in the entire examined group (ρ=−0.40; p=0.035). All patients showed an increase in ADMA, with no association between ADMA and SRBD severity. Conclusions The incidence of SRBD is extremely high in PAH and CTEPH patients. However, there no association between presence and severity of PH, including with right heart remodeling. But the severity of nocturnal hypoxemia is associated with an increase in NT-proBNP level, a proven marker of poor prognosis in PAH and CTEPH groups of patients. SRBD severity indices (apnea-hypopnea index and desaturation index) are associated with ECHO parameters characterizing remodeling of left heart chambers. Increasing ADMA level as a marker of endothelial dysfunction was related with PH severity, but not with SRBD. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Almazov National Medical Research Centre

The Effect of Atorvastatin on ADMA Level and Erectile Function in patients with Vasculogenic Erectile Dysfunction

Background Erectile dysfunction (ED), the inability to achieve and/or maintain an erection sufficient to permit satisfactory intercourse, is a highly prevalent disease whose aetiology is mostly vasculogenic. It is associated with subclinical coronary artery disease (CAD) and is nowadays considered a marker of future cardiovascular events. The higher prevalence of ED in patients with cardiovascular risk factors(CVRF) reflects the underlying endothelial dysfunction. ADMA is a naturally occurring amino acid that exists as a result of proteolysis of methylated proteins. Several factors, such as oxidative stress and increased levels of low-density lipoproteins (LDLs), are responsible for induced production of ADMA in endothelial cells. In our study, atorvastatin administration resulted in a significant decrease in ADMA levels and improvement of erectile function Aim To demonstratethe effect of Atorvastatin on ADMA level and erectile function in patients with normal or high LDL level vasculogenic erectile dysfunction. Patients and Methods The study will include 30 patients aged 30-60 years old with vasculogenic erectile dysfunction.The patients will be collected from The Andrology Outpatient Clinic – Ain-Shams University Hospitals. Results Among the study group 10 subjects showed moderate elevation of plasma ADMA (33.3%), 10 subjects with high level (33.3%) and 10 subjects with normal level (33.3%), while in control group only 5 subjects had high ADMA level, one subjects with moderate elevation and 24 subjects had normal level (80%) There was high significant reduction in both ADMA and LDL level after atorvastatin treatment and significant improvement in IIEF score, However no significant change in Testosterone level CONCLUSIONS We demonstrated that short-term treatment with atorvastatin has great influence on plasma ADMA levels with marked improvement in lipid profile (LDL) and erectile function in both normolipidemic and dyslipidenic patients.

Investigated of vitreous and serum Asymmetric Dimethylarginine levels in diabetic retinopathy

Purpose To investigate the intravitreal and blood Asymmetric dimethylarginine (ADMA) level in diabetic retinopathy (DR). Materials and Methods Twenty eyes of 20 patients with DR with the decision of vitrectomy, and 20 eyes of 20 patients without diabetes as a control group were included in the study. During vitrectomy, vitreous and minimum 3ml peripheral blood samples were taken simultaneously. Serum and vitreous ADMA levels were compared between the two groups. Results The serum ADMA level was higher in the diabetic group compared to the non-diabetic group (p=0,009). However, there was no statistically significant difference between the mean vitreous ADMA levels. There was no correlation between serum and vitreous ADMA levels. Conclusion In patients with diabetic retinopathy, serum ADMA levels increased, but no increase in vitreous ADMA levels was detected.