Stimulation of Angiotensin II Receptor Subtype 2 Reduces Preeclampsia-like Symptoms in a Mouse Model of Preeclampsia.

Angiotensin II (AngII) receptor subtype 1 (AT1R) is involved in the pathogenesis of preeclampsia (PE). Angiotensin II receptor subtype 2 (AT2R) can antagonize the effects of AT1R, but its effects during pregnancy are not known. We investigated the effect of AT2R on the pathogenesis of PE using a mouse model and recently developed AT2R agonist (compound 21 [C21]). Blastocysts collected from pregnant imprinting control region (ICR) mice were incubated with adenovirus containing the CD40L gene and transferred into the uterine horns of pseudo-pregnant ICR mice to express PE-like features. Osmotic pumps were placed subcutaneously on the dorsal side with C21 or saline. C21 reduced the plasma soluble fms-like tyrosine kinase 1 (sFlt-1) concentration, ameliorating hypertension. The splenic T and B cell profiles in model mice were analyzed by flow cytometry. The gated percentage of IFN-γ-positive Th cells was significantly increased and the percentage of plasma cells in B cells was significantly decreased; however, the percentages were not altered by C21. sFlt-1 and soluble endoglin concentrations in plasma were measured with an enzyme-linked immunosorbent assay, and sFlt-1 was reduced. C21 could become a candidate PE drug as it ameliorated the pathophysiology of PE as a result of decreased production of sFlt-1.

Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Predictors of overall mortality after endovascular abdominal aortic repair - A single centre study.

OBJECTIVES: A current and ongoing challenge is to reduce patient mortality after endovascular abdominal aortic repair (EVAR). This study aimed to assess the predictors of all-cause mortality after EVAR. METHODS: Data regarding the demographic characteristics, comorbidities, laboratory values, selected anatomical factors, post-EVAR treatment, surveillance and complications of patients who underwent elective EVAR for non-ruptured abdominal aortic aneurysm (AAA) between January 2010 and January 2021 were evaluated. Mortality was assessed until 10 October 2023. Multivariate analyses were performed after adjusting for age, hypertension, diabetes mellitus, dyslipidaemia, sex, smoking, number of lumbar arteries, patency of inferior mesenteric artery (IMA), IMA diameter and reinterventions. RESULTS: This study included 196 patients (183 men and 13 women) with a mean age of 72.4 ± 7.67 years. The overall mortality rate during a mean follow-up period of 5.75 ± 3.1 years was 50.0% (N = 98). The 2-, 5- and 10-year mortality rates were 9.7%, 32.0% and 66.6%, respectively. The mortality rates decreased by 59% in patients with reinterventions (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.23-0.73; p = .002) and by 59% in patients treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (HR: 0.41; 95% CI: 0.26-0.66; p < .001). Chronic anticoagulation was associated with 2.09-fold higher mortality (HR: 2.09; 95% CI: 1.19-3.67; p = .010), and coronary artery disease (CAD) was associated with 1.74-fold higher mortality (HR: 1.74; 95% CI: 1.09-2.78; p = .021). Pre-EVAR AAA diameter and 1-year post-EVAR sac diameter were positively associated with mortality (HR: 1.05; 95% CI: 1.03-1.08; p < .001, and HR: 1.05; 95% CI: 1.03-1.07; p < .001, respectively), that is, an increase of pre-EVAR and/or 1-year post-EVAR AAA diameter by 1 mm was associated with a 5% higher risk of all-cause mortality. CONCLUSIONS: Reinterventions and treatment with ACE inhibitors or ARBs may be associated with decreased post-EVAR mortality. A greater pre-EVAR, a post-EVAR AAA diameter, CAD and chronic anticoagulation were associated with higher all-cause mortality post-EVAR.

In utero chronic intermittent nicotine aerosol exposure increases ischemic heart injury in adult offspring via programming of Angiotensin II receptor-derived TGFß/ROS/Akt signaling pathway.

BACKGROUND: In utero cigarette smoking/nicotine exposure during pregnancy significantly affects fetal development and increases the risk of cardiovascular disease late in life. However, the underlying molecular mechanisms remain largely unknown. We tested the hypothesis that fetal nicotine aerosol exposure reprograms ischemia-sensitive gene expressions, resulting in increased heart susceptibility to ischemic injury and cardiac dysfunction in adulthood. METHODS: Pregnant rats were exposed to chronic intermittent nicotine aerosol (CINA) or saline aerosol control from gestational day 4 to day 21. Experiments were performed on 6-month-old adult offspring. RESULTS: CINA exposure increased ischemia-induced cardiac injury and cardiac dysfunction compared to the control group, which was associated with over- expression of angiotensin II receptor (ATR) protein in the left ventricle (LV) of adult offspring. Meanwhile, CINA exposure up-regulated cardiac TGF-ß/SMADs family proteins in the LV. In addition, CINA exposure enhanced cardiac reactive oxygen species (ROS) production and increased the DNA methylation level. The levels of phosphorylated-Akt were upregulated but LC3B-II/I protein abundances were downregulated in the hearts isolated from the CINA-treated group. CONCLUSION: Fetal nicotine aerosol exposure leads to cardiac dysfunction in response to ischemic stimulation in adulthood. Two molecular pathways are implicated. First, fetal CINA exposure elevates cardiac ATR levels, affecting the TGFß-SMADs pathway. Second, heightened Angiotensin II/ATR signaling triggers ROS production, leading to DNA hypermethylation, p-Akt activation, and autophagy deficiency. These molecular shifts in cardiomyocytes result in the development of a heart ischemia-sensitive phenotype and subsequent dysfunction in adult offspring.

Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer.

We addressed the heteromerization of the epidermal growth factor receptor (EGFR) with G-protein coupled receptors (GPCR) on the basis of angiotensin-II-receptor-subtype-1(AT1R)-EGFR interaction as proof-of-concept and show its functional relevance during synergistic nuclear information transfer, beyond ligand-dependent EGFR transactivation. Following in silico modelling, we generated EGFR-interaction deficient AT1R-mutants and compared them to AT1R-wildtype. Receptor interaction was assessed by co-immunoprecipitation (CoIP), Förster resonance energy transfer (FRET) and fluorescence-lifetime imaging microscopy (FLIM). Changes in cell morphology, ERK1/2-phosphorylation (ppERK1/2), serum response factor (SRF)-activation and cFOS protein expression were determined by digital high content microscopy at the single cell level. FRET, FLIM and CoIP confirmed the physical interaction of AT1R-wildtype with EGFR that was strongly reduced for the AT1R-mutants. Responsiveness of cells transfected with AT1R-WT or -mutants to angiotensin II or EGF was similar regarding changes in cell circularity, ppERK1/2 (direct and by ligand-dependent EGFR-transactivation), cFOS-expression and SRF-activity. By contrast, the EGFR-AT1R-synergism regarding these parameters was completely absent for in the interaction-deficient AT1R mutants. The results show that AT1R-EGFR heteromerisation enables AT1R-EGFR-synergism on downstream gene expression regulation, modulating the intensity and the temporal pattern of nuclear AT1R/EGFR-information transfer. Furthermore, remote EGFR transactivation, via ligand release or cytosolic tyrosine kinases, is not sufficient for the complete synergistic control of gene expression.

Effectiveness of Chinese herbal medicine compared with angiotensin II receptor blockers in patients with diabetic kidney disease: A hospital-based matched cohort study.

Angiotensin II receptor blockers (ARBs) are one of the standard treatments for diabetic kidney disease (DKD). Some patients may opt for Chinese herbal medicine (CHM) of their own free will. However, there is no real-world evidence regarding the effectiveness and safety of CHM. We aimed to explore the effectiveness of CHM for DKD in comparison to ARBs. We enrolled 732 DKD patients (72 used only CHM and 661 used ARBs) from 2007 to 2016, and all patients were followed until December 2016 at China Medical University Hospital in Taiwan. A total of 355 ARB users and 71 CHM users were analyzed after propensity score matching. The estimated glomerular filtration rate (eGFR) after treatment was 84.9 ± 28.1 ml/min/1.73 m2 in CHM users, which was higher than that (67.8 ± 35.4 ml/min/1.73 m2) in ARB users (p < 0.001). The change in the eGFR was -6.0 ± 21.4 ml/min/1.73 m2 in CHM users and -12.9 ± 24.8 ml/min/1.73 m2 in ARB users (p = 0.029). The blood urea nitrogen (BUN) and creatinine levels of patients taking CHM were 22 ± 16 mg/dl and 0.9 ± 0.4 mg/dl, respectively, and were lower than those (30 ± 28 mg/dl and 1.7 ± 2.0 mg/dl) of patients taking ARBs (p = 0.025 and p = 0.003). Using linear regression with adjustments for age, sex, BMI, baseline eGFR, and HbA1c levels, we found that the declines in the eGFR/baseline eGFR and changes in the urine albumin-creatinine ratio (ACR) were comparable between the two groups (p = 0.86 and 0.73). This study suggests that CHM may have comparable effectiveness to ARBs, which provides insights for further investigations.

Effect of continuing angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers on the day of surgery on myocardial injury after non-cardiac surgery: A retrospective cohort study.

STUDY OBJECTIVE: To evaluate the effect of continuing of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) prescriptions 24 h before surgery on postoperative myocardial injury and blood pressure in patients undergoing non-cardiac surgery. DESIGN: A single-center, retrospective study. SETTING: Operating room and perioperative care area. PATIENTS: 42,432 patients who had been taking chronic ACEI/ARB underwent non-cardiac surgery from January 2012 to June 2022. INTERVENTIONS: Patients who discontinued ACEI/ARB 24 h before surgery (withheld group, n=31,055) and those who continued ACEI/ARB 24 h before surgery (continued group, n=11,377). MEASUREMENTS: Primary outcome was myocardial injury after non-cardiac surgery (MINS) within 7 days postoperatively. MINS was defined as an elevated postoperative cardiac troponin measurement above the 99th percentile of the upper reference limit with a rise/fall pattern. Perioperative blood pressure and clinical outcomes were secondary outcomes. MAIN RESULTS: Among 42,432 patients, MINS occurred in 2848 patients (6.7%) and was the all-cause of death within 30 days in 122 patients (0.3%). Incidence of MINS was significantly higher in the continued group than the withheld group (847/11,377 [7.4%] vs. 2001/31,055 [6.4%]; OR [95% CI] 1.17 [1.07-1.27]; P<0.001). After 1:1 propensity score matching, 11,373 patients were included in each group. There was still a significant difference for the occurrence of MINS between two groups in matched cohort (7.4% vs. 6.6%, OR [95% CI] 1.14 [1.03-1.26]; P=0.015). Time-average weight of mean arterial pressure <65 mmHg during surgery was significantly higher in the continued group (mean 0.11 vs. 0.09 [95% CI of mean difference] [0.01-0.03]; P<0.001). However, there was no significant difference in other clinical outcomes and mortality. CONCLUSIONS: Withholding ACEI/ARB before surgery was associated with a reduced risk of intraoperative hypotension and postoperative myocardial injury, but it did not affect overall clinical outcomes in patients undergoing non-cardiac surgery.

Unmasking Renal Disease in Systemic Lupus Erythematosus: Beyond Lupus Nephritis.

A 64-year-old Caucasian woman with a history of hypertension and systemic lupus erythematosus (SLE) was referred to a nephrology clinic due to persistent microscopic hematuria and trace proteinuria. Initial tests showed elevated antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), and anti-Sjögren's syndrome-related antigen A (anti-SSA) levels, while other markers remained within normal limits. Over the course of a year, her urine protein-creatinine ratio increased, prompting a renal biopsy. The biopsy revealed focal crescent formation in some glomeruli and mild segmental mesangial hypercellularity in others. Although the possibility of antineutrophilic cytoplasmic antibody (ANCA)-associated nephritis with superimposed IgA nephropathy was considered, negative myeloperoxidase and proteinase 3 antibody tests led to a final diagnosis of IgA nephropathy. The patient's treatment included adding prednisone to her existing valsartan prescription for hypertension, which resulted in improved proteinuria. SLE is an autoimmune disease that can cause chronic inflammation and damage to vital organs. Approximately 50% of SLE patients may experience lupus nephritis (LN), underscoring the importance of urinalysis and renal function tests. This case presents a female patient with SLE and IgA nephropathy, a rare association that requires distinction as it affects disease management. IgA nephropathy is the most common cause of idiopathic glomerulonephritis and can lead to end-stage kidney disease in around 40% of cases. A renal biopsy is also crucial for diagnosing IgA nephropathy in patients with or without another autoimmune disease. Focal crescent formation, a histological feature observed in this case, helped exclude several diagnoses, such as lupus nephritis or pauci-immune glomerulonephritis. The primary goal of treating IgA nephropathy is to prevent disease progression. Initial treatment includes controlling blood pressure, reducing proteinuria, and implementing lifestyle modifications. Corticosteroid therapy may be considered if supportive care is insufficient.

Analyzing Angiotensin II Receptor Type 1 Clustering in PC12 Cells in Response to Hypoxia Using Direct Stochastic Optical Reconstruction Microscopy (dSTORM).

Angiotensin II (Ang II) is a hormone that plays a major role in maintaining homeostasis. The Ang II receptor type 1 (AT1R) is expressed in acute O2 sensitive cells, including carotid body (CB) type I cells and pheochromocytoma 12 (PC12) cells, and Ang II increases cell activity. While a functional role for Ang II and AT1Rs in increasing the activity of O2 sensitive cells has been established, the nanoscale distribution of AT1Rs has not. Furthermore, it is not known how exposure to hypoxia may alter the single-molecule arrangement and clustering of AT1Rs. In this study, the AT1R nanoscale distribution under control normoxic conditions in PC12 cells was determined using direct stochastic optical reconstruction microscopy (dSTORM). AT1Rs were arranged in distinct clusters with measurable parameters. Across the entire cell surface there averaged approximately 3 AT1R clusters/µm2 of cell membrane. Cluster area varied in size ranging from 1.1 × 10-4 to 3.9 × 10-2 µm2. Twenty-four hours of exposure to hypoxia (1% O2) altered clustering of AT1Rs, with notable increases in the maximum cluster area, suggestive of an increase in supercluster formation. These observations could aid in understanding mechanisms underlying augmented Ang II sensitivity in O2 sensitive cells in response to sustained hypoxia.

Factors associated with all-cause mortality following endovascular abdominal aortic aneurysm repair.

Background: Knowledge of factors that influence all-cause mortality after endovascular abdominal aortic aneurysm repair (EVAR) could improve therapeutic strategies post-EVAR and thus patient prognosis. Our study aimed to evaluate the association between sociodemographic information, comorbidities, laboratory parameters, treatment, selected anatomical and genetic factors and all-cause mortality post-EVAR. Patients and methods: We reviewed all patients who had undergone elective EVAR for non-ruptured abdominal aortic aneurysm (AAA) between January 2010 and December 2019. AAA size (maximum diameter and volume) was measured using CT-angiography. Sac expansion was defined as at least 5 mm increase, sac regression as at least 5 mm decrease in the sac diameter determined at 36±3 months post-EVAR in relation to pre-EVAR AAA diameter. Adjustments were performed for age, hypertension, diabetes mellitus, dyslipidaemia, sex, smoking, number of lumbar arteries, patency of inferior mesenteric artery and number of reinterventions post-EVAR. Results: One hundred and sixty-two patients (150 men, 12 women) with a mean age of 72.6±7.3 years were included in the analysis. Pre-EVAR AAA diameter (HR 1.07; 95% CI 1.03 - 1.12; p=0.001), pre-EVAR AAA volume (HR 1.01; 95% CI 1.002 - 1.011; p=0.008), post-EVAR sac diameter (HR 1.06; 95% CI 1.03 - 1.10; p=0.000), post-EVAR sac volume (HR 1.01; 95% CI 1.002 - 1.011; p=0.006) and anticoagulation therapy (HR 2.46; 95% CI 1.18 - 5.14; p=0.019) were associated with higher mortality in multivariate analysis. Sac regression (HR 0.42; 95% CI 0.22 - 0.82; p=0.011), and treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) (HR 0.71; 95% CI 0.36 - 0.97; p=0.047) were associated with lower mortality. Conclusions: Greater pre- and post-EVAR diameter and volume, failure of sac regression and anticoagulation were associated with higher mortality post-EVAR. Reduced mortality was observed in patients treated with ACE inhibitors or ARBs, and in patients with AAA sac regression.

Use of calcium channel blockers and risk of breast cancer among women aged 55 years and older: a nationwide population-based cohort study.

This retrospective cohort study was aimed to compare the incidence of breast cancer among women aged ≥55 who received calcium channel blockers and angiotensin converting enzyme inhibitors/angiotensin II receptor blockers. We used the 2002-2015 Health and Welfare Database in Taiwan. Women 55 years and older who initiated antihypertensive treatment were included. Breast cancer risk for patients receiving calcium channel blockers was compared to those receiving angiotensin converting enzyme inhibitors/angiotensin II receptor blockers. Cox proportional hazards models were used to generate adjusted hazard ratios for breast cancer. We found that the risk of breast cancer was similar between calcium channel blockers users and angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (adjusted hazard ratio [aHR] and 95% CI = 1.03 [0.80 to 1.34]). No significant risk increase was observed in the stratified analysis by dihydropyridine (aHR = 1.02 [0.78 to 1.33]) and non-dihydropyridine calcium channel blockers (aHR = 1.23 [0.48 to 3.20]). No difference in the risk of breast cancer associated with calcium channel blockers exposure was observed in patients who used hormone replacement therapy (aHR = 1.02 [0.29 to 3.58]). The risk for breast cancer was observed to be significantly lower in patients receiving calcium channel blockers than in those receiving angiotensin converting enzyme inhibitors/angiotensin II receptor blockers at a treatment duration of 5 or more years (aHR = 0.57 [0.33 to 0.98]). In conclusion, the risk for breast cancer is similar for calcium channel blockers and angiotensin converting enzyme inhibitors/angiotensin II receptor blocker users in an Asian population.

Association of MICA and AT1R antibodies with antibody-mediated rejection and cardiac allograft vasculopathy in a pediatric heart transplant recipient.

BACKGROUND: Recipient antibodies against mismatched donor-specific human leukocyte antigens (HLA) are known to be associated with antibody-mediated rejection (AMR), posing increased risks of cardiac allograft vasculopathy (CAV), graft dysfunction, and graft loss after heart transplant (HTx). However, the impact of non-HLA antibodies on HTx outcome is not yet well defined. CASE DESCRIPTION: Here we report a case of a pediatric patient, who was retransplanted after developing CAV in his first heart allograft. Five years post 2nd HTx, the patient presented with graft dysfunction and mild rejection (ACR 1R, AMR 1H, C4d Neg) in the cardiac biopsy in the absence of HLA donor-specific antibodies (DSAs). We detected strong antibodies against non-HLA antigens, including angiotensin II receptor type 1 (AT1R) and donor-specific MHC class I chain-related gene A (MICA), in the patient's serum that were implicated in the AMR and accelerated CAV of his second allograft, and likely played a role in the loss of his first allograft as well. CONCLUSION: This case report underscores the clinical relevance of non-HLA antibodies in heart transplantation and highlights the value of incorporating these tests in the immunological risk assessment and post-transplant monitoring of HTx recipients.

An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals.

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review.

Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

The Role of ACE-Inhibitors and ARBs in reducing hypertrophic scarring following bilateral breast reduction.

BACKGROUND: The angiotensin-renin system (ARS) has been shown to play a role in the promotion of tissue fibrosis through angiotensin II activation of the angiotensin-receptor 1 and subsequently transforming growth factor beta-1 (TGF- ß1). Breast reduction surgery is known to have a potential complication of hypertrophic scarring. The primary objective of this study is to assess whether the use of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blockers (ARBs) by patients undergoing bilateral reduction mammoplasty is correlated with a reduction in hypertrophic scarring complications post-operatively. METHODS: A retrospective chart review of all patients who received bilateral breast reduction surgery in our province over a 10-year period was performed. Patient charts were reviewed for post-operative hypertrophic scarring as well as medications being used around the time of surgery. The rate of hypertrophic scarring within patients treated with an ACEi or ARB for existing hypertension were compared with the rest of the population. RESULTS: A total of 981 patients met the inclusion criteria of the study. The overall incidence of hypertrophic scarring was 6%. Within the population, 132 (14%) of patients had a clinical diagnosis of hypertension. Of the patients who were managed with an ACEi or ARB, one (2%) patient developed hypertrophic scarring post-operatively. This was significantly less than the total population and the remainder of the population with hypertension treated with a medication other than an ACEi or ARB. CONCLUSIONS: This study investigated the impact of routine ACEi or ARB use by patients undergoing bilateral reduction mammoplasty and demonstrated a statistically significant reduction in the incidence of hypertrophic scarring. This study is one of the first to investigate ACEi or ARB use in humans to reduce rates of unsightly scarring. LEVEL OF EVIDENCE: Level III.

Antihypertensive Use and the Risk of Cataract in Patients with Hypertension: A Nationwide Case-control Study.

PURPOSE: This study aims to investigate the association between antihypertensive use and the risk of cataract in a matched case-control study. METHODS: We analysed the Korean National Health Insurance Service-Health Screening Cohort database from 2002 to 2013. We defined 'cases' as patients prescribed antihypertensives and underwent their first eye cataract surgery between 2010 and 2013. 'Controls' were patients prescribed antihypertensives and no history of cataract surgery or diagnosis between 2002 and 2013. Four controls were matched to each case by several variables. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated for cataract risk using a conditional logistic regression model after adjustment. RESULTS: The analyses comprised 12,166 cases and 48,664 controls. The adjusted ORs for cataracts were 1.18 (95% CI: 1.12-1.24) in thiazide diuretics, 1.12 (95% CI: 1.07-1.18) in beta-blockers, 0.94 (95% CI: 0.90-1.00) in calcium channel blockers, 1.22 (95% CI: 1.14-1.30) in angiotensin-converting enzyme (ACE) inhibitors, and 0.97 (95% CI: 0.91-1.03) in angiotensin II receptor blockers compared to 'non-use' of each antihypertensive. CONCLUSION: In a nationwide case-control study, the use of thiazide diuretics, beta-blockers, or ACE inhibitors do not represent minimal clinical important difference in the risk of cataract and the use of calcium channel blockers or angiotensin II receptor blockers is not associated with an increased risk of cataracts compared to non-use of each antihypertensive. Given the benefits of treating hypertension, such as the reduction in further complications, we suggest there is no need to change current clinical practice for antihypertensives.

A GC-MS/MS Method for Trace Level Quantification of Six Nitrosamine Impurities (NDMA, NDEA, NEIPA, NDIPA, NDPA, and NDBA) in Commercially Used Organic Solvents: Dichloromethane, Ethyl Acetate, Toluene, and O-xylene.

Nitrosamines, the probable carcinogens have been reported with Angiotensin II Receptor Blocker (ARB) drugs, Ranitidine, and other medicines. Solvents play a vital role in the pharmaceutical industry in the separation, purification, and cleaning process for manufacturing APIs and drug products. According to the FDA and EMA, solvents used in the drug manufacturing process are potential root causes of Nitrosamine impurities. Hence, monitoring nitrosamines in solvents is an essential step for manufacturers. A sensitive direct injection GC-MS/MS, an essential analytical tool for low-level nitrosamine quantification in solvents, was developed by utilizing multiple reactions monitoring mode (MRM) for the simultaneous determination of six nitrosamines, namely, NDMA, NDEA, NEIPA, NDIPA, NDPA and NDBA in common solvents such as dichloromethane, ethyl acetate, toluene, and o-xylene. NDMA-d6 was used as an internal standard. The FDA reported a combined direct injection method for nitrosamine impurity assay by GC-MS/MS, which had several challenges for commercial-grade solvents in terms of interferences and resolution of unknown impurities and nitrosamine peaks. A novel method was developed to optimize the critical parameters of GC-MS/MS according to the solvent samples. The method validation was performed through the following parameters, sensitivity, linearity, accuracy, precision, specificity, and stability. The quantification of nitrosamines in commercial-grade solvents ranged from 100 ppb to 8000 ppb with respect to the sample concentration of 25 mg/mL with good sensitivity in LOQ level. The quantification ranged from 5 ppb (for NDMA, NDEA, NEIPA, NDIPA, NDPA) and 13 ppb (NDBA) to 2000 ppb with respect to the sample concentration of 100 mg/mL for analytical grade solvents with good sensitivity in the proposed method. Hence, it will be useful to quantify the low-level nitrosamines in commercial-grade solvents as well as analytical-grade solvents.

Rapid Quantitation of Four Nitrosamine Impurities in Angiotensin Receptor Blocker Drug Substances.

Starting in July 2018, the FDA alerted patients and health care professionals to the recall of ARBs such as valsartan by several pharmaceutical companies because of their potential contamination with carcinogenic nitrosamine impurities, including: (1) N-nitrosodimethylamine (NDMA), (2) N-nitrosodiethylamine (NDEA), (3) N-nitrosoethylisopropylamine (NEIPA), (4) N-nitrosodiisopropylamine (NDIPA), (5) N-nitrosodibutylamine (NDBA) and (6) N-nitroso-N-methyl-4-aminobutyric acid (NMBA). The FDA initiated a laboratory investigation to develop analytical procedures to test multiple lots of marketed ARB drugs to determine the possible presence of carcinogenic impurities and, if present, quantitate the levels of these impurities. Here the FDA laboratory developed and validated an automated micro-solid phase extraction MS/MS method, where all the analytes are not separated prior to elution to the MS, to simultaneously quantify NEIPA, NDIPA, NDBA and NMBA in ARB drug substances with an instrument sample analysis time of 12 seconds. The method was validated according to the ICH Q2(R1) guideline, and was determined to be specific, accurate, precise and linear over the corresponding nitrosamine analytical ranges. The method has been successfully implemented to quantitate the four nitrosamine impurities in 129 generic losartan, valsartan, olmesartan, irbesartan and telmisartan drug substance samples from 32 lots; and 32 losartan and valsartan drug product samples from 6 lots.

Repurposing of drugs for combined treatment of COVID-19 cytokine storm using machine learning.

Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) induced cytokine storm is the major cause of COVID-19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor­Kappa B (NF­κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS­CoV­2 induced cytokine storm pathway. We developed machine-learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID­19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.