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Concept: Isosorbide mononitrate

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Background Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. Methods In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). Results In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. Conclusions Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493 .).

Concepts: Clinical trial, Myocardial infarction, Medical terms, Cardiology, Heart failure, Ejection fraction, Atrial natriuretic peptide, Isosorbide mononitrate

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Although nitric oxide (NO) is a bactericidal component of the macrophage’s innate response to intracellular infections such as tuberculosis (TB), prolonged inhalation of NO gas has little benefit in chemotherapy of TB. The impact of controlled release of NO through intracellular delivery of NO donors to macrophages infected in vitro with Mycobacterium tuberculosis (Mtb) was investigated. Inhalable microparticles (MP) were prepared by spray-drying. Isosorbide mononitrate (ISMN), sodium nitroprusside (SNP), and diethylenetriamine nitric oxide adduct (DETA/NO) were incorporated in poly(lactic-co-glycolic acid) (PLGA) with encapsulation efficiencies of >90% to obtain MP yields of ∼70%. The mass median aerodynamic diameter (MMAD) of the MP was 2.2-2.4 μm within geometric standard deviations (GSD) of ≤0.1 μm. MP were phagocytosed by THP-1 derived macrophages in culture and significantly (P < 0.05) sustained NO secretion into culture supernatant from 6 to 72 h in comparison to equivalent amounts of drugs in solution. Significantly (P < 0.05) higher dose-dependent killing of intracellular Mtb by MP compared to equivalent amounts of drugs in solution was observed on estimation of colony forming units (CFU) surviving 24 h after exposure to drugs or MP. The cytotoxicity of MP toward macrophages was lower than that of dissolved drugs. It was concluded that inhalable MP can target NO donors to the macrophage, control NO release in the macrophage cytosol, and reduce Mtb CFU by up to 3-log in 24 h, at doses that are much lower than those required for cardiovascular effects.

Concepts: Immune system, Tuberculosis, Nitrogen, Mycobacterium, Mycobacterium tuberculosis, Nitric oxide, Nitric acid, Isosorbide mononitrate

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A 66-year-old man with hypertension presented with complaints of excessive daytime sleepiness (Epworth Sleepiness Score 14/24), dyspnea upon exertion, and episodes of noninjurious dream-enacting behavior. He reported tongue biting when sleeping in the right lateral decubitus position. Medications included atenolol 12.5 mg, lovastatin 20 mg, doxazosin 2 mg, amlodipine 5 mg, isosorbide mononitrate 60 mg, and aspirin 81 mg. He denied headaches, visual changes, dysarthria, dysphagia, or localized weakness. He denied use of alcohol, tobacco, or drugs.

Concepts: Hypertension, Ibuprofen, Aspirin, Sleep apnea, Epworth Sleepiness Scale, Somnolence, Excessive daytime sleepiness, Isosorbide mononitrate

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BACKGROUND: Carvedilol has been shown to be more effective than propranolol in decreasing portal pressure. Sufficient data from controlled trials remains limited. This trial compared the relative safety and efficacy between carvedilol and nadolol plus isosorbide mononitrate in preventing variceal rebleeding. METHODS: After successful control of acute esophageal variceal bleeding, eligible patients were randomized to Carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or N+ I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20mg daily. The end points were rebleeding from varices, adverse events or death. RESULTS: After a median follow up of 30 months, recurrent upper gastrointestinal bleeding developed in 37 patients (61%) in the Carvedilol group and 37 patients (62%) in the N+I group (p=0.90). Recurrent bleeding from esophageal varices occurred in 31 patients (51%) in the Carvedilol group and in 26 patients (43%) in the N+I group (p=0.46). Recurrent bleeding from gastric varices occurred in 2 patients (3%) in the Carvedilol group and in 8 patients (13%) in the N+I group (p=0.05). Severe adverse events occurred in 1 patient in Carvedilol group and 17 patients in N+I group (p<0.0001). Fifteen patients of the Carvedilol group and 17 patients in the N+I group died (p=0.83). Two patients in the Carvedilol group and 3 patients in N+I group died of variceal bleeding. CONCLUSIONS: Carvedilol was as effective as nadolol plus isorsorbide-5 -mononitrate mononitrate in the prevention of gastroesophageal variceal rebleeding with fewer severe adverse events and similar survival.

Concepts: Clinical trial, Gastroenterology, Esophageal varices, Gastric varices, Portal hypertension, Beta blocker, Propranolol, Isosorbide mononitrate

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Based upon the findings of the African-American Heart Failure Trial, the US Food and Drug Administration approved the fixed-dose combination of isosorbide dinitrate (ISDN) and hydralazine hydrochloride (HYD) (FDC-ISDN/HYD) as a new drug for treatment of heart failure (HF) in self-identified African Americans. According to the FDA, FDC-ISDN/HYD has no therapeutic equivalent. However, off-label combinations of the separate generic drugs ISDN and HYD (OLC-ISDN+HYD) or isosorbide mononitrate (ISMN) and HYD (OLC-ISMN+HYD) are routinely substituted without any supporting outcome data. We conducted an exploratory retrospective propensity-matched cohort study using Medicare data to determine whether a survival difference exists between these treatments in medication-adherent patients.

Concepts: Pharmacology, Black people, Generic drug, African American, Southern United States, Food and Drug Administration, Lyndon B. Johnson, Isosorbide mononitrate

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In January 2012, 664 cases of pyrimethamine toxicity and 151 deaths were reported among cardiac patients that had recently received free medicines from pharmacy of Punjab Institute of Cardiology, Lahore, Pakistan. These patients, ages ranged from 58 to 75 years, were prescribed simvastatin, clopidogrel, aspirin soluble, isosorbide mononitrate, and amlodipine. On examination of medications being given to them, it was found that a particular batch of isosorbide mononitrate tablets was contaminated with 50 mg pyrimethamine. Cardiac patients were taking isosorbide contaminated with pyrimethamine twice daily (100 mg pyrimethamine/day), whereas therapeutic dose of pyrimethamine for malaria is 25 mg/week. Postmortem urine, cardiac blood, and femoral blood specimens of three deceased males were submitted to author’s laboratory for analysis. Postmortem toxicological analysis revealed that pyrimethamine concentration fell within the range of 1-10 μg/mL by liquid chromatography. Clinical, autopsy, histopathological, and toxicological findings strongly suggested toxicity due to pyrimethamine accumulation that resulted in deaths of these cardiac patients.

Concepts: Pharmacology, Medicine, Death, Myocardial infarction, Toxicology, Toxicity, Autopsy, Isosorbide mononitrate

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To the Editor: In their article on the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial, Redfield et al. (Dec. 10 issue)(1) show a significant linear relationship between the dose of isosorbide mononitrate and daily physical activity quantified by means of accelerometers. They interpret the findings to indicate an adverse effect of isosorbide mononitrate in patients with heart failure and a preserved ejection fraction. We favor a different view - that the use of isosorbide mononitrate at a dose of up to 120 mg per day caused subtle but disabling symptoms such as headache, . . .

Concepts: Myocardial infarction, Cardiology, Heart failure, Ejection fraction, Nitrate, Nitrates, Nitrite, Isosorbide mononitrate

0

To the Editor: In their article on the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial, Redfield et al. (Dec. 10 issue)(1) show a significant linear relationship between the dose of isosorbide mononitrate and daily physical activity quantified by means of accelerometers. They interpret the findings to indicate an adverse effect of isosorbide mononitrate in patients with heart failure and a preserved ejection fraction. We favor a different view - that the use of isosorbide mononitrate at a dose of up to 120 mg per day caused subtle but disabling symptoms such as headache, . . .

Concepts: Myocardial infarction, Cardiology, Heart failure, Ejection fraction, Nitrate, Nitrates, Nitrite, Isosorbide mononitrate

0

To the Editor: In their article on the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial, Redfield et al. (Dec. 10 issue)(1) show a significant linear relationship between the dose of isosorbide mononitrate and daily physical activity quantified by means of accelerometers. They interpret the findings to indicate an adverse effect of isosorbide mononitrate in patients with heart failure and a preserved ejection fraction. We favor a different view - that the use of isosorbide mononitrate at a dose of up to 120 mg per day caused subtle but disabling symptoms such as headache, . . .

Concepts: Myocardial infarction, Cardiology, Heart failure, Ejection fraction, Nitrate, Nitrates, Nitrite, Isosorbide mononitrate

0

To the Editor: In their article on the Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial, Redfield et al. (Dec. 10 issue)(1) show a significant linear relationship between the dose of isosorbide mononitrate and daily physical activity quantified by means of accelerometers. They interpret the findings to indicate an adverse effect of isosorbide mononitrate in patients with heart failure and a preserved ejection fraction. We favor a different view - that the use of isosorbide mononitrate at a dose of up to 120 mg per day caused subtle but disabling symptoms such as headache, . . .

Concepts: Myocardial infarction, Cardiology, Heart failure, Ejection fraction, Nitrate, Nitrates, Nitrite, Isosorbide mononitrate