Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

OBJECTIVE: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. BACKGROUND: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co-administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5-HT1B/1D receptor agonist. METHODS: We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. RESULTS: Sumatriptan as well as PL37 each produced a dose-dependent inhibition of ISDN-induced cephalic MH. Median effective dose (ED50 ) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. CONCLUSION: These results suggest that PL37 acts synergistically with sumatriptan to produce an anti-allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. PLAIN LANGUAGE SUMMARY: There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.

Vericiguat in combination with isosorbide mononitrate in patients with chronic coronary syndromes: The randomized, phase Ib, VISOR study.

Vericiguat was developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. Guidelines recommend long-acting nitrates, such as isosorbide mononitrate, for angina prophylaxis in chronic coronary syndromes (CCS), common comorbidities in HF. This study evaluated safety, tolerability, and the pharmacodynamic (PD) interaction between co-administered vericiguat and isosorbide mononitrate in patients with CCS. In this phase Ib, double-blind, multicenter study, patients were randomized 2:1 to receive vericiguat plus isosorbide mononitrate (n = 28) or placebo plus isosorbide mononitrate (n = 13). Isosorbide mononitrate was uptitrated to a stable dose of 60 mg once daily, followed by co-administration with vericiguat (uptitrated every 2 weeks from 2.5 mg to 5 mg and 10 mg) or placebo. Thirty-five patients completed treatment (vericiguat, n = 23; placebo, n = 12). Mean baseline- and placebo-adjusted vital signs showed reductions of 1.4-5.1 mmHg (systolic blood pressure) and 0.4-2.9 mmHg (diastolic blood pressure) and increases of 0.0-1.8 beats per minute (heart rate) with vericiguat plus isosorbide mononitrate. No consistent vericiguat dose-dependent PD effects were noted. The incidence of adverse events (AEs) was 92.3% and 66.7% in the vericiguat and placebo groups, respectively, and most were mild in intensity. Blood pressure and heart rate changes observed with vericiguat plus isosorbide mononitrate were not considered clinically relevant. This combination was generally well-tolerated. Concomitant use of vericiguat with isosorbide mononitrate is unlikely to cause significant AEs beyond those known for isosorbide mononitrate.

Higher than recommend dosage of sublingual isosorbide dinitrate for treating angina pectoris: a case report and review of the literature.

Nitrates primarily cause arterial and venous vasodilation effects, which increases coronary artery blood supply, and decreases cardiac preload and afterload by enhancing nitric oxide (NO) levels. The dosage of nitrates used for angina pectoris widely differs among individuals, and therapeutic resistance and tolerance gradually occur. Increasing doses of nitrates are needed to abolish ischemia chest pain onset in patients with angina pectoris, and to obtain satisfactory therapeutic effects. Here, we report the case of a 37-year-old male who was hospitalized six times, from September 2013 to April 2018, with recurrent angina pectoris. Although the patient was implanted with stents, he still presented with chest pain associated with physical efforts. Diagnosis with acute myocardial infarction was based on his ST-segment changes on electrocardiogram (ECG), elevated troponin-T level and coronary angiography. After the stents were implanted, his chest pain had no relief. Following three times of coronary angiography revealed that distal and small branch vessels still had stenosis, but was not required to revascularization. Due to serious headache resulted from sublingual or oral nitroglycerin; he had to take sublingual isosorbide dinitrate, from 20 mg to 150 mg each time, to obtain rapid relief from angina pectoris without doctor's consent. Followed up to April 2019, the patient has continued to take 100-150 mg sublingual isosorbide dinitrate for angina pectoris onset triggered by physical efforts, and has obtained remarkable relief within a few minutes, without blood pressure decrease and other side effects. Higher than recommend dosage of sublingual isosorbide dinitrate might establish better efficacy for angina pectoris in rarely patient.

Physiological Impact of Afterload Reduction on Cardiac Mechanics and Coronary Hemodynamics Following Isosorbide Dinitrate Administration in Ischemic Heart Disease.

Understanding the cardiac-coronary interaction is fundamental to developing treatment strategies for ischemic heart disease. We sought to examine the impact of afterload reduction following isosorbide dinitrate (ISDN) administration on LV properties and coronary hemodynamics to further our understanding of the cardiac-coronary interaction. Novel methodology enabled real-time simultaneous acquisition and analysis of coronary and LV hemodynamics in vivo using coronary pressure-flow wires (used to derive coronary wave energies) and LV pressure-volume loop assessment. ISDN administration resulted in afterload reduction, reduced myocardial demand, and increased mechanical efficiency (all P<0.01). Correlations were demonstrated between the forward compression wave (FCW) and arterial elastance (r=0.6) following ISDN. In the presence of minimal microvascular resistance, coronary blood flow velocity exhibited an inverse relationship with LV elastance. In summary this study demonstrated a reduction in myocardial demand with ISDN, an inverse relationship between coronary blood flow velocity and LV contraction-relaxation and a direct correlation between FCW and arterial elastance. The pressure volume-loop and corresponding parameters b The pressure volume loop before (solid line) and after (broken line) Isosorbide dintrate.

Combination Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD (HIDE): A Randomized, Placebo-Controlled, Pilot Trial.

Background: Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown. Methods: Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over 3 weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times per day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension (i.e., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve on positron emission tomography. Results: A total of 17 individuals were randomized to ISD/HY (N=7) or placebo (N=10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in two participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year) than placebo (1.83 events/patient-year, P=0.04). In contrast, nausea (ISD/HY, 1.90 events/patient-year; placebo, 0.50 events/patient-year, P=0.03) was significantly more frequent, and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/patient-year) than placebo (6.31 events/patient-year). We did not detect between-group differences in the change in E' (P=0.34); ISD/HY showed a mean increase of 0.6 cm/s (SD 1.1), and placebo showed a mean decrease of 0.04 cm/s (SD 0.9). Changes in coronary flow reserve were minimal, -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, P=0.19. Conclusions: ISD/HY appears to be well tolerated in patients being treated with maintenance HD, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo.

A randomized controlled trial comparing isosorbide dinitrate-oxytocin versus misoprostol-oxytocin at management of foetal intrauterine death.

BACKGROUND: The metabolic activity of endogenous nitric oxide (NO) and the medical use of nitrovasodilatory drugs like isosorbide dinitrate have been shown to be potential inducers inducers of cervical ripening prior to surgical evacuation of the uterus. OBJECTIVE: To assess the therapeutic efficacy and safety of combined isosorbide dinitrate-oxytocin in the management of intrauterine foetal death (IUFD). METHODS: Sixty women with IUFD after 20 weeks of gestation requesting uterine evacuation were randomly selected to receive isosorbide dinitrate gel solution (80 mg/1.5 mL; n = 30) or misoprostol gel solution (100 mcg/1.5 mL; n = 30) every 3 h with a maximum of four doses or until a Bishop score >7 was reached. Subsequently, patients received a high dose of intravenous oxytocin until complete uterus evacuation was achieved. Therapeutic efficacy was evaluated by mean the relative risk of the foetal expulsion based on comparison of event rates, and the proportion of women induced to labor at 7, 10 and 15 h after the administration of isosorbide dinitrate or misoprostol. Safety was assessed on the basis of woman´s vital signs and evaluation of adverse effects, including headache, abdominal pain, pelvic pain, lower back pain, nausea, dizziness and vomiting. RESULTS: The foetal expulsion rate using the isosorbide dinitrate-oxytocin combination was approximately 4.4 times, and at least 2.1 times, the foetal expulsion rate with the misoprostol-oxytocin regimen at any given point in time. The proportion of women achieved vaginal delivery at 15 hours was 100% for the isosorbide dinitrate-oxytocin group and 86.7% for the misoprostol-oxytocin group. The average delivery induction interval was significantly lower when isosorbide dinitrate-oxytocin was used (8.7 ± 3.1 h) than when misoprostol-oxytocin (11.9 ± 3.1 h) was used. A total of 20% of patients in the isosorbide dinitrate-oxytocin group recorded headache, and no cases of uterine tachysystole, haemorrhage or coagulopathy were recorded. CONCLUSION: This study indicates that intravaginal isosorbide dinitrate followed by intravenous oxytocin was more effective than the conventional method used to induce labour in the medical management of foetal death in pregnancies after 20 weeks of gestation. TRIAL REGISTRATION: Clinicaltrials.gov NCT02488642.

Drug-induced Hemolysis in G6PD Deficiency: an Unusual Presentation of a Common Clinical Condition.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency can present a diagnostic dilemma owing to the varying degrees of disease severity and the wide range of precipitating factors. Here, we report a case of a 56-year-old man who presented with signs and symptoms of heart failure and, during the course of treatment, developed intravascular hemolysis. On investigation, he was found to be G6PD deficient. Following discontinuation of the fixed-dose combination of isosorbide dinitrate and hydralazine, the clinical condition of the patient improved, and there were no further episodes of hemolysis. The case highlights the need for a high degree of suspicion of G6PD deficiency in patients with unexplained signs and symptoms of intravascular hemolysis.

Microvascular ischemia in patients with successful percutaneous coronary intervention: effects of ranolazine and isosorbide-5-mononitrate.

OBJECTIVE: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients. PATIENTS AND METHODS: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug. RESULTS: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline. CONCLUSIONS: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.

Efficacy and safety of the combination of isosorbide dinitrate spray and chitosan gel for the treatment of diabetic foot ulcers: A double-blind, randomized, clinical trial.

AIM: To evaluate whether a combination of isosorbide dinitrate spray and chitosan gel (10%) topically applied can have additive benefits for management of diabetic foot ulcers. METHODS: In a randomized, placebo-controlled, double-blinded clinical trial, 68 patients were divided into four groups: Group 1: treated with chitosan gel; Group 2: isosorbide dinitrate spray; Group 3: combination of isosorbide dinitrate spray and chitosan gel; Group 4: placebo. RESULTS: Histological analyses showed a significant regeneration in all groups ( p < 0.001). On the final assessment of the ulcer, using the combination was found a wound closure percentage of 71 ± 30, 70 ± 27 using isosorbide dinitrate, 58 ± 30 with chitosan and 50 ± 16 with placebo. The number of patients who achieved complete ulcer closure was six using the combination, four with isosorbide dinitrate, three with chitosan and one with placebo. The progression in the healing process of the ulcer showed marked inmunohistochemical differences of Von Willebrand Factor, desmin, vascular endothelial growth factor-A and α-smooth muscle actin in all groups ( p < 0.001), but without notable differences between them. CONCLUSION: The combination was better than placebo to reduce the dimensions of the ulcer, accelerate healing and increase the number of patients who achieved complete closure of the ulcer, but the combination was not better than chitosan or isosorbide dinitrate used separately.

High sucrose/fat diet and isosorbide mononitrate increase insulin resistance, nitric oxide production and myocardial apoptosis in a hypertensive rat model.

The present study aimed to investigate the association between insulin resistance (IR), nitric oxide (NO) production and myocardial apoptosis in a background of coexisting hypertension in a rodent animal model. A hypertensive rat model was established by feeding Wistar and spontaneously hypertensive rats (SHR) with a high sucrose/fat (HSF) diet for 12 weeks, in conjunction with isosorbide mononitrate (ISMN). Increased IR, NO content, apoptotic gene and protein expression, and morphological alterations within rat myocardium were evaluated. Following a total of 12 weeks of feeding with HSF and ISMN resulted in increased IR and NO content within the myocardial tissue of Wistar and SHR rats. HSF and ISMN activated myocardial apoptosis by downregulating the gene transcription and protein expression levels of the anti­apoptotic B­cell lymphoma 2 (Bcl­2), and increasing the pro­apoptotic Bcl­2 associated X protein. Apoptosis was demonstrated by DNA fragmentation in terminal deoxynucleotidyl­transferase­mediated dUTP nick end labelling assay. In all experiments, the combination of HSF and ISMN was associated with more pronounced effects, indicating the possible synergistic effects. In addition, the correlation analysis in the Wistar rats fed with HSF only, revealed a positive association between NO production and IR. The results of the present study indicated that HSF and ISMN simultaneously increased IR, NO production and myocardial apoptosis in the hypertensive rat model, and may therefore contribute to investigations into the long­term clinical use of ISMN in hypertensive patients.

Intermittent Nitrate Use and Risk of Hip Fracture.

PURPOSE: Nitrates, commonly used antianginal medications, also have a beneficial effect on bone remodeling and bone density, particularly with intermittent use. However, their effect on fracture risk is not clear. We examined the relation of short-acting nitrate use (proxy for intermittent use) with the risk of hip fracture in a large cohort of older adults with ischemic heart disease. METHODS: Participants aged 60 years or more with ischemic heart disease and without a history of hip fracture from The Health Improvement Network, an electronic medical records database in the United Kingdom, were included. The association of incident (new) use of short-acting nitrate formulations (nitroglycerin sublingual/spray/ointment or isosorbide dinitrate injection/sprays) with incident (new-onset) hip fracture risk was examined by plotting Kaplan-Maier curves and calculating hazard ratios using Cox proportional hazards regression models. Competing risk by death was analyzed in separate analyses. RESULTS: Among 14,451 pairs of matched nitrate users and nonusers (mean age, 72 ± 7.6 years, 41% women for each cohort), 573 fractures occurred during follow-up (257 nitrate users; 316 nonusers). Hip fracture risk was 33% lower among short-acting nitrate users compared with nonusers (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .0008). Competing risk analysis by death did not change effect estimates. CONCLUSIONS: In this large population-based cohort of older adults with ischemic heart disease, we found a significant reduction in hip fracture risk with the use of short-acting nitrates (intermittent use). Future studies are warranted given the potential for nitrates to be potent, inexpensive, and readily available antiosteoporotic agents.

Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate Therapy in Patients With Heart Failure and Reduced Ejection Fraction: Findings From the Get With The Guidelines-Heart Failure Registry.

BACKGROUND: In clinical trials, hydralazine-isosorbide dinitrate (H-ISDN) for heart failure with reduced ejection fraction reduced morbidity and mortality among black patients and patients with intolerance to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The effectiveness of H-ISDN in clinical practice is unknown. METHODS AND RESULTS: Using data from a clinical registry linked with Medicare claims, we examined the use and outcomes of H-ISDN between 2005 and 2011 among older patients hospitalized with heart failure and reduced ejection fraction. We adjusted for demographic and clinical characteristics using Cox proportional hazards models and inverse probability weighting. Among 4663 eligible patients, 22.7% of black patients and 18.2% of patients not on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker were newly prescribed H-ISDN therapy at discharge. By 3 years, the cumulative incidence rates of mortality and readmission were similar between treated and untreated patients. After multivariable adjustment, 3-year outcomes remained similar for mortality [black patients: hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.75-1.13; other patients: HR, 0.93; 95% CI, 0.79-1.09], all-cause readmission (black patients: HR, 0.98; 95% CI, 0.84-1.13; other patients: HR, 1.02; 95% CI, 0.90-1.17), and cardiovascular readmission (black patients: HR, 0.99; 95% CI, 0.82-1.19; other patients: HR, 0.94; 95% CI, 0.81-1.09). A post hoc analysis of Medicare Part D data revealed low postdischarge adherence to therapy. CONCLUSIONS: Guideline-recommended initiation of H-ISDN therapy at hospital discharge was uncommon, and adherence was low. For both black patients and patients of other races, there were no differences in outcomes between those treated and untreated at discharge.

Cervical ripening before first trimester surgical evacuation for non-viable pregnancy.

BACKGROUND: Medications or mechanical dilators are often used to soften and dilate the cervix prior to surgical evacuation of the uterus for non-viable pregnancy, or miscarriage. The majority of miscarriages occur in the first trimester. The aim of cervical ripening is to reduce the possibility of injury to the uterus and cervix and improve the surgical ease of the procedure. Cervical ripening agents can have adverse effects and it is uncertain as to whether these risks outweigh the benefits of their use. OBJECTIVES: To systematically review the benefits and harms of using cervical ripening agents prior to surgical evacuation of non-viable pregnancy prior to 14 weeks' gestation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2015) and reference lists of retrieved papers. SELECTION CRITERIA: Randomised controlled trials (published in full-text form, or as abstracts only), which assessed the use of pharmacological or mechanical agents to ripen the cervix in women undergoing dilation and curettage or vacuum aspiration for non-viable pregnancy at less than 14 weeks' gestation were eligible for inclusion. Cluster-randomised controlled trials and trials using a cross-over design were not eligible for inclusion.Unpublished randomised controlled trials and quasi-randomised trials would have been eligible for inclusion but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data were checked for accuracy. MAIN RESULTS: We included nine trials with 469 women. A diverse set of medications and regimens were studied in these trials, making the comparisons available for meta-analysis limited. The comparisons draw data from six trials with 383 participants. All trials were relatively small and had several aspects of unclear risk of bias with few of this review's outcomes reported. Due to this, no data from three trials were able to be used despite them meeting inclusion criteria.We carried out four comparisons: isosorbide mononitrate or dinitrate compared with misoprostol; misoprostol compared with placebo; chemical dilation (use of medications) compared with mechanical dilation; and any cervical preparation compared with placebo.None of the included studies reported data on the review's primary outcome: cervical or uterine injury (perforation, laceration, creation of a false passage).No clear difference was shown between isosorbide compounds and misoprostol for the outcome need for manual cervical dilation (average risk ratio (RR) 0.76, 95% confidence interval (CI) 0.10 to 5.64; three trials, 150 women; Tau² = 2.11; I² = 69%), however the data were heterogenous. In terms of adverse effects, misoprostol was associated with more vomiting (RR 0.11, 95% CI 0.01 to 0.85; two trials, 120 women), however there were no clear differences between isosorbide compounds and misoprostol in relation to other reported adverse effects (headache, nausea or hypotension). The dosing regimens differed in terms of dose, number of administrations and route of administration in the different trials. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators in a single trial (65 women) that measured difficulty in cervical dilation, excessive bleeding and adverse effects.Misoprostol was shown to be more effective than placebo for cervical ripening (reduced need for manual cervical dilation) (RR 0.14, 95% CI 0.08 to 0.26; one trial, 120 women), and surgical time was reduced when misoprostol was used (mean difference (MD) -3.15, 95% CI -3.59 to -2.70; one trial, 120 women). However, compared to placebo, misoprostol, was associated with more abdominal pain (RR 29.00, 95% CI 1.77 to 475.35; one trial, 120 women), although no clear differences in the risk of other adverse effects (nausea, vomiting, headache or fever) were observed between groups.There was no clear differences between chemical dilation and mechanical dilators for the outcomes: difficulty in cervical dilation, excessive bleeding or adverse effects.Compared with placebo, any cervical preparation reduced the need for manual cervical dilatation (average RR 0.25, 95% CI 0.07 to 0.89; two trials, 168 women; Tau² = 0.67; I² = 81%), and reduced surgical time (MD -2.55, 95% CI -3.67 to -1.43, two trials, 168 women; Tau² = 0.63; I² = 96%).None of the included trials reported on the review's other secondary outcomes, including: injury to bladder or bowel, miscarriage/preterm birth in a subsequent pregnancy, analgesia use after administration of ripening agent but before surgery, or analgesia use after surgery. AUTHORS' CONCLUSIONS: This review found no evidence to evaluate cervical ripening prior to first trimester surgical evacuation for miscarriage for reducing the rate of cervical or uterine injury, however, this may be because these outcomes are very rare. Cervical preparation was shown to reduce the need for manual cervical dilatation compared with placebo.Misoprostol and isosorbide mononitrate and dinitrate were similarly effective in ripening the cervix, however there was more vomiting with misoprostol. Mechanical (Dilapan-S hygroscopic) dilators performed similarly to chemical dilators.The nine studies included in this review were small and the methodological quality of the trials was mixed, and for the most part, not well-described; thus any conclusions drawn from the data included in this review must be treated with caution. Consequently, large, high-quality trials are required to determine whether the benefits of this treatment outweigh the risks. Further research should be powered to assess the rate of cervical and uterine injury between interventions. Future research should also guide clinicians in deciding whether the benefits of reduced manual cervical dilatation outweigh the risks of adverse effects associated with these agents (nausea, vomiting, headache, fever, diarrhoea and pain). Women's satisfaction and outcomes of future pregnancies should also be assessed.

Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.

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.).

Relationship between Nitrate-Induced Headache and Coronary Artery Lesion Complexity.

OBJECTIVE: The aim of the present study was to investigate the association between nitrate-induced headache (NIH) and the complexity of coronary artery lesions in patients with stable coronary artery disease (CAD). SUBJECTS AND METHODS: Two hundred and seventy-five patients with anginal chest pain who underwent coronary angiography were enrolled in the present study. NIH was defined as the presence of headache due to nitrate treatment (isosorbide mononitrate 40 mg) after excluding confounding factors. Coronary artery lesion complexity was assessed by the SYNTAX score (SXscore) using a dedicated computer software system. RESULTS: The mean SXscore was lower in the patients with NIH than in patients without NIH (7.3 ± 5.2 vs. 14.4 ± 8.5, respectively; p < 0.001). Additionally, patients with NIH had a lower rate of multivessel disease compared with those without NIH (the mean number of diseased vessels was 1.5 ± 0.7 and 2.0 ± 07, respectively; p < 0.001). In multivariate analysis, increasing age (p = 0.02) and headache (p = 0.001) were found to be independent determinants of SXscore. CONCLUSION: The present study demonstrated an independent inverse association between NIH and SXscore. The NIH could provide important predictive information about coronary artery lesion complexity in patients with stable CAD.

Poor tolerance and limited effects of isosorbide-5-mononitrate in microvascular angina.

OBJECTIVES: To assess the effects of isosorbide-5-mononitrate (ISMN) in patients with microvascular angina (MVA). METHODS: We randomized 20 MVA patients, treated with a ß-blocker or a calcium antagonist, to 60 mg slow-release ISMN (halved to 30 mg if not tolerated) or placebo once a day for 4 weeks; the patients were then switched to the other treatment for another 4 weeks. Their clinical status was assessed with the Seattle Angina Questionnaire (SAQ) and the EuroQoL score for quality of life. The exercise stress test (EST), coronary blood flow (CBF) response to nitrate and the cold pressor test (CPT), brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) were also assessed. RESULTS: Nine patients (45%) did not complete the ISMN phase due to side effects; 2 patients refused a follow-up. Nine patients completed the study. The SAQ and EuroQoL scores were significantly better with ISMN than with placebo, although the differences were small. No differences were found between the treatments in the EST results, CBF response to nitroglycerin (p = 0.55) and the CPT (p = 0.54), FMD (p = 0.26) and NMD (p = 0.35). CONCLUSIONS: In this study, a high proportion of MVA patients showed an intolerance to ISMN; in those tolerating the drug, significant effects on their angina status were observed, but the benefit appeared to be modest and independent of effects on coronary microvascular function.

Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies: evidence from Phase I studies in healthy volunteers.

We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs' efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug's pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0-t, and AUC0-∞). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5-1 hour - a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone.

Long-term isosorbide mononitrate treatment impairs endothelial function in patients with coronary artery disease.

BACKGROUND: Sustained use of nitrates is associated with adverse effects on vascular function by increasing oxidative stress. It remains unclear whether oxidative stress impairs endothelial function in patients with coronary artery disease (CAD) during long-term oral use of nitrates. The purpose of this study was to evaluate the effects of long-term isosorbide mononitrate (ISMN) treatment on oxidative stress and endothelial function in patients with CAD. MATERIALS AND METHODS: In this prospective, double-blinded, placebo-controlled, randomized, single-center study, 60 patients were assigned to treatment with ISMN 20 mg retarded release orally twice per day (ISMN group, n=30) or placebo (control group, n=30) for 1 year. The primary endpoint was the change in brachial artery endothelium-dependent dilation [flow-mediated dilation (FMD)] from baseline to follow-up. Furthermore, serum superoxide dismutase, malondialdehyde, and hypersensitive C-reactive protein levels were also measured at baseline and follow-up. RESULTS: The FMD decreased significantly (from 5.97±2.88 to 5.33±2.56%) in the ISMN group, whereas it increased from 6.27±3.23 to 6.96±2.84% in the control group after treatment for 1 year. There was a significant difference in the changes in FMD when the two groups were compared (-0.64±1.83 vs. 0.69±1.77%, P=0.006). There were no significant changes in serum superoxide dismutase, malondialdehyde, and hypersensitive C-reactive protein levels in the two groups. CONCLUSION: Long-term ISMN treatment may impair endothelial function in patients with CAD.