Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN trial.

BACKGROUND AND AIMS: Contrast-induced nephropathy (CIN), also known as contrast-associated acute kidney injury (CA-AKI) underlies a significant proportion of the morbidity and mortality following coronary angiographic procedures in high-risk patients and remains a significant unmet need. In pre-clinical studies inorganic nitrate, which is chemically reduced in vivo to nitric oxide, is renoprotective but this observation is yet to be translated clinically. In this study, the efficacy of inorganic nitrate in the prevention of CIN in high-risk patients presenting with acute coronary syndromes (ACS) is reported. METHODS: NITRATE-CIN is a double-blind, randomized, single-centre, placebo-controlled trial assessing efficacy of inorganic nitrate in CIN prevention in at-risk patients presenting with ACS. Patients were randomized 1:1 to once daily potassium nitrate (12 mmol) or placebo (potassium chloride) capsules for 5 days. The primary endpoint was CIN (KDIGO criteria). Secondary outcomes included kidney function [estimated glomerular filtration rate (eGFR)] at 3 months, rates of procedural myocardial infarction, and major adverse cardiac events (MACE) at 12 months. This study is registered with ClinicalTrials.gov: NCT03627130. RESULTS: Over 3 years, 640 patients were randomized with a median follow-up of 1.0 years, 319 received inorganic nitrate with 321 received placebo. The mean age of trial participants was 71.0 years, with 73.3% male and 75.2% Caucasian; 45.9% had diabetes, 56.0% had chronic kidney disease (eGFR <60 mL/min) and the mean Mehran score of the population was 10. Inorganic nitrate treatment significantly reduced CIN rates (9.1%) vs. placebo (30.5%, P < .001). This difference persisted after adjustment for baseline creatinine and diabetes status (odds ratio 0.21, 95% confidence interval 0.13-0.34). Secondary outcomes were improved with inorganic nitrate, with lower rates of procedural myocardial infarction (2.7% vs. 12.5%, P = .003), improved 3-month renal function (between-group change in eGFR 5.17, 95% CI 2.94-7.39) and reduced 1-year MACE (9.1% vs. 18.1%, P = .001) vs. placebo. CONCLUSIONS: In patients at risk of renal injury undergoing coronary angiography for ACS, a short (5 day) course of once-daily inorganic nitrate reduced CIN, improved kidney outcomes at 3 months, and MACE events at 1 year compared to placebo.

Oral nitrate supplementation improves cardiovascular risk markers in COPD: ON-BC, a randomised controlled trial.

BACKGROUND: Short-term studies suggest that dietary nitrate (NO3 -) supplementation may improve the cardiovascular risk profile, lowering blood pressure (BP) and enhancing endothelial function. It is not clear if these beneficial effects are sustained and whether they apply in people with COPD, who have a worse cardiovascular profile than those without COPD. Nitrate-rich beetroot juice (NR-BRJ) is a convenient dietary source of nitrate. METHODS: The ON-BC trial was a randomised, double-blind, placebo-controlled parallel group study in stable COPD patients with home systolic BP (SBP) measurement ≥130 mmHg. Participants were randomly allocated (1:1) using computer-generated, block randomisation to either 70 mL NR-BRJ (400 mg NO3 -) (n=40) or an otherwise identical nitrate-depleted placebo juice (0 mg NO3 -) (n=41), once daily for 12 weeks. The primary end-point was between-group change in home SBP measurement. Secondary outcomes included change in 6-min walk distance (6MWD) and measures of endothelial function (reactive hyperaemia index (RHI) and augmentation index normalised to a heart rate of 75 beats·min-1 (AIx75)) using an EndoPAT device. Plasma nitrate and platelet function were also measured. RESULTS: Compared with placebo, active treatment lowered SBP (Hodges-Lehmann treatment effect -4.5 (95% CI -5.9- -3.0) mmHg), and improved 6MWD (30.0 (95% CI 15.7-44.2) m; p<0.001), RHI (0.34 (95% CI 0.03-0.63); p=0.03) and AIx75 (-7.61% (95% CI -14.3- -0.95%); p=0.026). CONCLUSIONS: In people with COPD, prolonged dietary nitrate supplementation in the form of beetroot juice produces a sustained reduction in BP, associated with an improvement in endothelial function and exercise capacity.

A review on nitrates' health benefits and disease prevention.

Dietary nitrates (NO3-) are naturally occurring compounds in various vegetables, especially beetroot, which is mainly supplemented in the form of BRJ. Dietary nitrates (NO3-) play a crucial function in human physiology. On consumption, nitrates (NO3-) undergo a conversion process, producing nitric oxide (NO) via a complex metabolic pathway. Nitric oxide (NO) is associated with many physiological processes, entailing immune modulation, neurotransmission, and vasodilation, enabling blood vessel dilation and relaxation, which boosts blood flow and oxygen delivery to tissues, positively influencing cardiovascular health, exercise performance, and cognitive function. There are various analytical processes to determine the level of nitrate (NO3-) present in dietary sources. The impact of dietary nitrates (NO3-) can differ among individuals. Thus, the review revisits the dietary source of nitrates (NO3-), its metabolism, absorption, excretion, analytical techniques to assess nitrates (NO3-) content in various dietary sources, and discusses health effects.

Evaluation and comparison of the effects of a new paste containing 8% L-Arginine and CaCO3 plus KNO3 on dentinal tubules occlusion and dental sensitivity: a randomized, triple blinded clinical trial study.

BACKGROUND: Dentin hypersensitivity, often occurring after dental treatments or from erosive lesions, is a prevalent patient complaint. This study introduces a paste combining 8% L-arginine, calcium carbonate, and potassium nitrate to evaluate its impact on dentinal tubules occlusion, dentin permeability, and tooth sensitivity. METHODS: Dentin surfaces from 24 third molars (thickness: 2 mm) were divided into two groups of 12. One received the experimental paste, while the other received a placebo without desensitizer. Permeability and sealing ability were assessed through scanning electron microscopy (SEM) and dentin permeability measurement. The pastes' effects on hypersensitivity were then examined in a triple-blind, randomized parallel-armed clinical trial with 16 eligible patients. Sensitivity to cold, touch, and spontaneous stimuli was recorded using the VAS scale at various intervals post-treatment. Statistical analysis was conducted using Shapiro-Wilk, Mann-Whitney U, Friedman, and Wilcoxon tests (α = 0.05). RESULTS: The permeability test demonstrated a significant reduction in dentin permeability in the experimental group (P = 0.002) compared to the control (P = 0.178). SEM images revealed most dentinal tubules in the intervention samples to be occluded. Clinically, both groups showed a significant decrease in the three types of evaluated sensitivity throughout the study. However, no significant difference in sensitivities between the two groups was observed, with the exception of cold sensitivity at three months post-treatment (P = 0.054). CONCLUSION: The innovative desensitizing paste featuring 8% L-arginine, calcium carbonate, and potassium nitrate effectively occluded dentinal tubules and reduced dentin permeability. It mitigated immediate and prolonged dentin hypersensitivity to various stimuli, supporting its potential role in managing dentin hypersensitivity. TRIAL REGISTRATION: http://irct.ir : IRCT20220829055822N1, September 9th, 2022.

New lipophilic organic nitrates: candidates for chronic skin disease therapy.

Organic nitrates are widely used, but their chronic efficacy is blunted due to the development of tolerance. The properties of new tolerance free organic nitrates were studied. Their lipophilicity profile and passive diffusion across polydimethylsiloxane membrane and pig ear-skin, and their efficacy in tissue regeneration using HaCaT keratinocytes were evaluated. The permeation results show that these nitrates have a suitable profile for NO topical administration on the skin. Furthermore, the derivatives with higher NO release exerted a pro-healing effect on HaCaT cells. This new class of organic nitrates might be a promising strategy for the chronic treatment of skin pathologies.

l-Arginine/nitric oxide pathway and oxidative stress in adults with ADHD: Effects of methylphenidate treatment.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication. METHODS: In plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry. RESULTS: Of the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 µM [46.2-76.0] vs. CO 44.4 µM [35.0-52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 µM [2.26-3.27]) vs. CO (2.13 µM [1.50-2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 µM [128-159]; +MPH 96.2 µM [70.2-140]; Co 75.9 µM [62.0-94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups. CONCLUSION: Adult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Determining effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of clinical strains of Pseudomonas aeruginosa in biofilm-inspired alginate encapsulates.

BACKGROUND: Biofilms play a role in recalcitrance and treatability of bacterial infections, but majority of known antibiotic resistance mechanisms are biofilm-independent. Biofilms of Pseudomonas aeruginosa, especially in cystic fibrosis patients infected with the alginate producing strains in their lungs, are hard to treat. Changes in growth-related bacterial metabolism in biofilm affect their antibiotic recalcitrance which could be considered for new therapies designed based on these changes. In this study, effects of nitrate, arginine, and ferrous were investigated on antibiotic recalcitrance in alginate-encapsulated P. aeruginosa strains isolated from cystic fibrosis patients in the presence of amikacin, tobramycin, and ciprofloxacin. Also, expression of an efflux pump gene, mexY, was analyzed in selected strains in the presence of amikacin and ferrous. METHODS: Clinical P. aeruginosa strains were isolated from cystic fibrosis patients and minimum inhibitory concentration of amikacin, tobramycin, and ciprofloxacin was determined against all the strains. For each antibiotic, a susceptible and a resistant or an intermediate-resistant strain were selected, encapsulated into alginate beads, and subjected to minimal biofilm eradication concentration (MBEC) test. After determining MBECs, sub-MBEC concentrations (antibiotics at concentrations one level below the determined MBEC) for each antibiotic were selected and used to study the effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of encapsulated strains. Effects of ferrous and amikacin on expression of the efflux pump gene, mexY, was studied on amikacin sensitive and intermediate-resistant strains. One-way ANOVA and t test were used as the statistical tests. RESULTS: According to the results, the supplements had a dose-related effect on decreasing the number of viable cells; maximal effect was noted with ferrous, as ferrous supplementation significantly increased biofilm susceptibility to both ciprofloxacin and amikacin in all strains, and to tobramycin in a resistant strain. Also, treating an amikacin-intermediate strain with amikacin increased the expression of mexY gene, which has a role in P. aeruginosa antibiotic recalcitrance, while treating the same strain with ferrous and amikacin significantly decreased the expression of mexY gene, which was a promising result. CONCLUSIONS: Our results support the possibility of using ferrous and arginine as an adjuvant to enhance the efficacy of conventional antimicrobial therapy of P. aeruginosa infections.

Moderate doses of dietary nitrate elicit greater effects on blood pressure and endothelial function than a high dose: A 13-week pilot study.

BACKGROUND & AIMS: Few studies have explored the prolonged effects of dietary nitrate on vascular health. This pilot study tested the effects of prolonged consumption (13 weeks) of a range of doses of dietary nitrate (NO3-), provided as beetroot juice (BJ), on blood pressure (BP) and endothelial function in overweight and obese older participants. METHODS AND RESULTS: Sixty-two overweight or obese older participants (60-75 years) were randomized to the following interventions: (1) high NO3- (2) medium NO3-, (3) low NO3-, or (4) placebo. Resting clinic and home BP were measured pre- and post-intervention. Laser Doppler iontophoresis was used to quantify changes in endothelial-dependent and independent microvascular blood flow. RESULTS: This pilot study showed that medium and low doses of NO3- were more effective in lowering resting-clinic SBP (P = 0.04 and, P = 0.03, respectively) than was PL. The lower doses of NO3- also resulted in significant increases in microvascular perfusion (medium, P = 0.02; low, P = 0.002) relative to baseline values. CONCLUSION: These findings indicate that supplementation with medium and low, but not high, doses of NO3- for 13 weeks had positive effects on BP and endothelial function in older overweight and obese adults. These findings require confirmation in larger studies.

Prognostic impact of nitrate therapy in patients with myocardial bridge and coexisting coronary artery spasm.

The aim of this study was to investigate the prognostic impact of nitrate therapy in patients with myocardial bridge (MB) and coexisting coronary artery spasm (CAS). MB often accompanies CAS. Nitrates have been widely used as anti-ischemic drugs in CAS patients, while it is not recommended in MB patients. Thus, we investigated the long-term impact of nitrate on clinical outcomes in patients with both CAS and MB. A retrospective observational study was performed using propensity score matching (PSM) in a total of 757 consecutive MB patients with positive acetylcholine (Ach) provocation test. Patients were divided into two groups according to the regular administration of nitrates (nitrate group: n = 504, No nitrate group; n = 253). The PSM was used to adjust for selection bias and potential confounding factors, and major clinical outcomes were compared between the two groups up to 5 years. Baseline characteristics were well-matched between the two groups following PSM (n = 211 for both groups). There was no significant difference in the incidence of death, myocardial infarction, and major adverse cardiovascular events (MACEs) between the two groups. However, the nitrate group showed a significantly higher rate of recurrent angina which subsequently needed re-evaluation of coronary arteries by follow-up angiography (15.7 vs. 5.7%, Log-rank p = 0.012) compared to the non-nitrate group. Long-term nitrate administration in patients with MB and coexisting CAS did not show benefit in reducing MACE, rather it was associated with a higher incidence of recurrent angina requiring follow-up angiography.

Phosphodiesterase Type 5 Inhibitors and Oral Nitrates in Male Patients with Ischemic Heart Disease.

PURPOSE OF REVIEW: This review sought to define the mechanism of the drug-drug interaction between phosphodiesterase-type-5 (PDE-5) inhibitors and organic nitrates as well as the clinical impact and recommended management across different clinical scenarios. RECENT FINDINGS: This drug-drug interaction results in hemodynamically significant hypotension during episodic PDE-5 use and acute nitrate administration mainly during cardiovascular emergencies with multiple studies describing the expected impact. Chronic co-administration of long-acting nitrates and PDE-5 inhibitors has been observed in practice in a small percentage of patients despite the labeled contraindication without noted adverse effects. Acute nitrate therapy should be avoided in the context of episodic PDE-5 exposure, likely identified through systematic processes. Few data exist defining risk with lower-intensity daily PDE-5 administration. Chronic co-administration is not recommended but may be navigated with careful risk-benefit determination. Future directions also aim to identify potential areas where nitrate synergy may achieve clinical benefit.

Cardiovascular characterization of the novel organic mononitrate NDIBP in rats.

Organic nitrates are widely used to restore endogenous nitric oxide (NO) levels reduced by endothelial nitric oxide synthase dysfunction. However, these drugs are associated with undesirable side effects, including tolerance. This study aims to investigate the cardiovascular effects of the new organic nitrate 1,3-diisobutoxypropan-2-yl nitrate (NDIBP). Specifically, we assessed its effects on blood pressure, vascular reactivity, acute toxicity, and the ability to induce tolerance. In vitro and ex vivo techniques showed that NDIBP released NO both in a cell-free system and in isolated mesenteric arteries preparations through a process catalyzed by xanthine oxidoreductase. NDIBP also evoked endothelium-independent vasorelaxation, which was significantly attenuated by 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO, 300 µM), a nitric oxide scavenger; 1-H-[1,2,4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ, 10 µM), a soluble guanylyl cyclase inhibitor; tetraethylammonium (TEA, 3 mM), a potassium channel blocker; febuxostat (500 nM), a xanthine oxidase inhibitor; and proadifen (10 µM), an inhibitor of cytochrome P450 enzyme. Furthermore, this organic nitrate did not induce tolerance in isolated vessels and presented low toxicity following acute oral administration. In vivo changes on cardiovascular parameters were assessed using normotensive and renovascular hypertensive rats. NDIBP evoked a reduction of blood pressure that was significantly higher in hypertensive animals. Our results suggest that NDIBP acts as a NO donor, inducing blood pressure reduction without having the undesirable effects of tolerance. Those effects seem to be mediated by activation of NO-sGC-cGMP pathway and positive modulation of K+ channels in vascular smooth muscle.

Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN): Rationale, design and protocol for a prospective randomized controlled trial.

BACKGROUND: Although endovascular recanalization therapy demonstrates robust clinical efficacy in acute ischemic stroke (AIS), not all victims of these cerebrovascular accidents can benefit from it and achieve a favorable prognosis after successful reperfusion. Therefore, alternative neuroprotective strategies are urgently needed for AIS patients after vessel recanalization. Nitric oxide (NO) levels are low after AIS and NO donor drugs may be neuroprotective against cerebral ischemia-reperfusion injury. Glyceryl trinitrate (GTN), often used in the clinic as a NO donor, may provide a novel neuroprotective strategy. This rationale, design, and protocol for a prospective pilot study plans to explore the preliminary safety, feasibility, and neuroprotective benefits of Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN). METHODS: AGAIN, a prospective RCT, is proposed for AIS patients after mechanical thrombectomy. Subjects will be randomly assigned in a 1:1 fashion (n = 40) to either the control group or the intervention group. Participants assigned to the intervention group will be administered 800 µg GTN in the catheter immediately after recanalization, whereas those in the control group will be administered the same volume of normal saline. All participants from either group will be given concurrent treatment with standard of care therapies in accordance with the current guidelines for stroke management. The primary outcome is safety [symptomatic intracranial hemorrhage (ICH), hypotension, neurological deterioration, ICH, fatal ICH, as well as headache, tachycardia, emesis, and seizures], whereas secondary outcomes included changes in poststroke functional outcomes, infarction volumes, and blood nitrate index detection. DISCUSSIONS: This study is a prospective randomized controlled trial to test the safety and efficacy of intra-arterial GTN in AIS patients after endovascular therapy. The results from this study will give insight for future GTN studies and new neuroprotective strategies for future AIS treatment strategies. TRIAL REGISTRATION NUMBER: ChiCTR2100045254. Registered on March 21, 2021.

The interaction among OSA, CPAP, and medications in patients with comorbid OSA and cardiovascular/cerebrovascular disease: a randomized controlled trial.

BACKGROUND: Most patients with comorbid sleep apnea (OSA), cardiovascular (CV) disease, and/or cerebrovascular (CeV) disease simultaneously take medications. Whether OSA and continuous positive airway pressure (CPAP) interact with CV/CeV medications remains unknown. This study aimed to determine the interaction among OSA, CPAP, and CV/CeV medications; the effects of medications on major adverse cardiac and cerebrovascular events, and survival in patients with comorbid OSA and CV/CeV. METHODS: This was a post hoc analysis of the data from one center of the Sleep Apnea Cardiovascular Endpoints Study. Participants (aged 45-75 years) with comorbid OSA and CV/CeV were randomized to receive usual care with or without CPAP from December 2008 to November 2013. The primary endpoint was death and the secondary endpoint was a composite of death, myocardial infarction, stroke, hospitalization for unstable angina, heart failure, and transient ischemic attack. RESULTS: In total, 131 patients were analyzed. Sixty-three were in the CPAP group and 68 were in the usual care group, 41 had good adherence to CPAP (65.1%), and the median follow-up time was 43.0 (35.0, 54.0) months. In Cox regression analysis, ACE inhibitors and nitrates were independent factors for decreased survival in patients with comorbid OSA and CV/CeV (chi-square = 22.932, P = 0.003; ACE inhibitors: OR 7.241, P = 0.048, 95% CI 1.016-51.628; nitrates: OR 18.012, P = 0.011, 95% CI 1.923-168.750). ACE inhibitors increased mortality and secondary endpoints in the CPAP group (chi-square = 4.134, P = 0.042) but not in patients with good CPAP adherence. Clopidogrel and nitrates decreased survival in usual care group (clopidogrel: chi-square = 5.312, P = 0.021; nitrates: chi-square = 6.417, P = 0.011), but not in CPAP group. CONCLUSIONS: OSA may predispose patients with CV/CeV and CV/CeV medications to a negative effect. CPAP treatment may neutralize the negative effects of OSA by relieving chronic intermittent hypoxia. Trial registration ClinicalTrials.gov (NCT00738179, first registration date: 20/08/2008).

Pharmacokinetic Profile, Safety, and Tolerability of Topical Berdazimer Gel, 10.3% in Patients With Molluscum Contagiosum.

BACKGROUND: Berdazimer (SB206), gel 10.3% is a novel, topical, nitric oxide–releasing agent intended for molluscum contagiosum (MC) treatment. METHODS: A 12-week, open-label, multicenter trial evaluated the safety, tolerability, and pharmacokinetic (PK) parameters of berdazimer gel, 10.3% applied topically once daily for the treatment of MC. Patients were aged ≥6 months with >20 molluscum lesions. The primary endpoint was the PK profile of the hydrolyzed N-methylaminopropyl-trimethoxysilane (hMAP3) monomer and nitrate during a 2-week period of once-daily berdazimer gel, 10.3% application (PK period) under maximal use conditions. Safety and tolerability were evaluated throughout the 12-week study period. RESULTS: Half of the 34 enrolled patients (17) were female and most (97.1% [33/34]) were white. Patients were 2 to 12 years old (mean, 5.3 years) with a mean of 50 MC lesions at baseline (mean time since MC awareness, 12.4 months). No patients had quantifiable plasma hMAP3 concentrations on day 1. On day 15, 2 patients had quantifiable plasma hMAP3 concentrations; however, the maximum concentration (33.9 ng/mL) was >10-fold lower than the no observed adverse effect level (NOAEL) in an animal toxicology study. Mean nitrate concentration–time profiles were similar on days 1 and 15 and remained flat for all patients throughout the 2-week PK period. The highest plasma methemoglobin level observed was 3.2%. Application-site pain (13/34 [38.2%]) and application-site erythema (6/34 [17.6%]) were the most frequent treatment-emergent adverse events (TEAEs), and most TEAEs were mild or moderate. CONCLUSIONS: Once-daily berdazimer gel, 10.3% was well-tolerated with minimal systemic absorption. J Drugs Dermatol. 2022;21(10):1104-1110. doi:10.36849/JDD.6938.

Photobiomodulation therapy and 3% potassium nitrate gel as treatment of cervical dentin hypersensitivity: a randomized clinical trial.

OBJECTIVES: This randomized controlled trial aimed to evaluate different protocols for dentin hypersensitivity treatment with low-power lasers and desensitizing agents, and the association between low-power lasers and desensitizing agents. MATERIALS AND METHODS: Fifty-four patients (303 teeth) were randomly allocated to three groups: G1, 3% nitrate potassium gel, UltraEZ (n = 17); G2, photobiomodulation therapy (PBM) with a low-level infrared laser (n = 17), 100 mW, spot size of 0.028 cm2, and dose of 1 J per point; and G3, nitrate potassium + PBM (n = 20). Treatments were applied to the buccal cervical region at intervals of 72 h, and all protocols were performed in three sessions. The patients' response to evaporative stimuli was rated using the visual analog scale (VAS). Re-evaluations were performed immediately after each application and 1 week, 1 month, and 3 months after treatment. A two-way repeated measures test and Tukey's post hoc test were used for multiple comparisons (α = 5%). RESULTS: There was a reduction in pain levels at the end of treatment in all groups. There were no significant differences in VAS score changes between the groups immediately after treatment and after the third month, compared to the baseline (p > 0.05). CONCLUSION: Under the limitations of this in vivo study, the proposed three-session protocol was effective in reducing dentin hypersensitivity after 3 months, regardless of the desensitization mechanism used. Conservative and long-term protocols are interesting for the control of pain caused by dentin hypersensitivity. CLINICAL RELEVANCE: The increase in cervical dentin hypersensitivity prevalence warrants easy-to-apply and long-lasting desensitizing protocols for pain control.

The Generation of Nitric Oxide from Aldehyde Dehydrogenase-2: The Role of Dietary Nitrates and Their Implication in Cardiovascular Disease Management.

Reduced bioavailability of the nitric oxide (NO) signaling molecule has been associated with the onset of cardiovascular disease. One of the better-known and effective therapies for cardiovascular disorders is the use of organic nitrates, such as glyceryl trinitrate (GTN), which increases the concentration of NO. Unfortunately, chronic use of this therapy can induce a phenomenon known as "nitrate tolerance", which is defined as the loss of hemodynamic effects and a reduction in therapeutic effects. As such, a higher dosage of GTN is required in order to achieve the same vasodilatory and antiplatelet effects. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a cardioprotective enzyme that catalyzes the bio-activation of GTN to NO. Nitrate tolerance is accompanied by an increase in oxidative stress, endothelial dysfunction, and sympathetic activation, as well as a loss of the catalytic activity of ALDH2 itself. On the basis of current knowledge, nitrate intake in the diet would guarantee a concentration of NO such as to avoid (or at least reduce) treatment with GTN and the consequent onset of nitrate tolerance in the course of cardiovascular diseases, so as not to make necessary the increase in GTN concentrations and the possible inhibition/alteration of ALDH2, which aggravates the problem of a positive feedback mechanism. Therefore, the purpose of this review is to summarize data relating to the introduction into the diet of some natural products that could assist pharmacological therapy in order to provide the NO necessary to reduce the intake of GTN and the phenomenon of nitrate tolerance and to ensure the correct catalytic activity of ALDH2.

Impact of prehospital IV furosemide or nitrate application on hospital outcome in acute heart failure patients.

OBJECTIVES: This study aims to evaluate the association between prehospital intravenous therapy and clinical outcomes in the patients with acute heart failure. METHODS: We conducted a prospective, multicenter observational study of consecutive AHF patients. Univariate and logistic regression analysis were performed to determine association between prehospital furosemide or nitrates administration and hospital outcome (death, length of stay). RESULTS: Data on a total of 1239 patients were processed. The mean age in the whole cohort was 71 ± 11.8 years with a gender distribution (M/F) of 634/605 patients. By prehospital treatment whole cohort was divided into 4 groups: F+ group with prehospital IV furosemide administration of 602 patients (48.6 %), F- group without prehospital IV furosemide administration of 637 patients (51.4 %), N+ group with prehospital IV nitrates administration of 110 patients (8.9 %) and N- group without IV nitrates administration of 1129 patients (91.1 %). Group of combined F+/N+ was not created. Ninety-four patients (7.6 %) died during the index hospitalization. Hospital mortality (p = 0.138) and length of stay (p = 0.101) did not differ in F+ vs F-. The patients with prehospital nitrates administration did not differ in mortality, but a shorter length of stay in univariate analysis (p = 0.03) was recorded. After adjusting for age, systolic BP and mode of referral to hospitalization, early IV furosemide usage nor nitrates showed no impact on hospital mortality and length of stay. CONCLUSIONS: Prehospital treatment with IV furosemide or nitrates in AHF patients seemed to have no major impact on hospital mortality or length of hospitalization after adjustment for several cofounders (Tab. 2, Ref. 16).

Hypercontractile Esophagus From Pathophysiology to Management: Proceedings of the Pisa Symposium.

Hypercontractile esophagus (HE) is a heterogeneous major motility disorder diagnosed when ≥20% hypercontractile peristaltic sequences (distal contractile integral >8,000 mm Hg*s*cm) are present within the context of normal lower esophageal sphincter (LES) relaxation (integrated relaxation pressure < upper limit of normal) on esophageal high-resolution manometry (HRM). HE can manifest with dysphagia and chest pain, with unclear mechanisms of symptom generation. The pathophysiology of HE may entail an excessive cholinergic drive with temporal asynchrony of circular and longitudinal muscle contractions; provocative testing during HRM has also demonstrated abnormal inhibition. Hypercontractility can be limited to the esophageal body or can include the LES; rarely, the process is limited to the LES. Hypercontractility can sometimes be associated with esophagogastric junction (EGJ) outflow obstruction and increased muscle thickness. Provocative tests during HRM can increase detection of HE, reproduce symptoms, and predict delayed esophageal emptying. Regarding therapy, an empiric trial of a proton pump inhibitor, should be first considered, given the overlap with gastroesophageal reflux disease. Calcium channel blockers, nitrates, and phosphodiesterase inhibitors have been used to reduce contraction vigor but with suboptimal symptomatic response. Endoscopic treatment with botulinum toxin injection or pneumatic dilation is associated with variable response. Per-oral endoscopic myotomy may be superior to laparoscopic Heller myotomy in relieving dysphagia, but available data are scant. The presence of EGJ outflow obstruction in HE discriminates a subset of patients who may benefit from endoscopic treatment targeting the EGJ.

Beneficial effects of inorganic nitrate in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic representation of the metabolic disorders. Inorganic nitrate/nitrite can be converted to nitric oxide, regulate glucose metabolism, lower lipid levels, and reduce inflammation, thus raising the hypothesis that inorganic nitrate/nitrite could be beneficial for improving NAFLD. This study assessed the therapeutic effects of chronic dietary nitrate on NAFLD in a mouse model. 60 ApoE-/- mice were fed a high-fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis with associated NAFLD. The mice were then randomly assigned to different groups (20/group) for a further 12 weeks: (i) HFD + NaCl (1 mmol/kg/day), (ii) HFD + NaNO3 (1 mmol/kg/day), and (iii) HFD + NaNO3 (10 mmol/kg/day). A fourth group of ApoE-/- mice consumed a normal chow diet for the duration of the study. At the end of the treatment, caecum contents, serum, and liver were collected. Consumption of the HFD resulted in significantly greater lipid accumulation in the liver compared to mice on the normal chow diet. Mice whose HFD was supplemented with dietary nitrate for the second half of the study, showed an attenuation in hepatic lipid accumulation. This was also associated with an increase in hepatic AMPK activity compared to mice on the HFD. In addition, a significant difference in bile acid profile was detected between mice on the HFD and those receiving the high dose nitrate supplemented HFD. In conclusion, dietary nitrate attenuates the progression of liver steatosis in ApoE-/- mice fed a HFD.