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.

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.).

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.

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.

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.

A randomized phase II study of irinotecan plus cisplatin versus irinotecan plus capecitabine with or without isosorbide-5-mononitrate in advanced non-small-cell lung cancer.

BACKGROUND: We investigated the efficacy of irinotecan/cisplatin (IP) versus irinotecan/capecitabine (IX) with or without isosorbide-5-mononitrate (ISMN) in chemo-naïve advanced non-small-cell lung cancer. PATIENTS AND METHODS: Initially, 74 patients were randomly assigned to either IP or IX. Given the potential benefits of ISMN on chemotherapy, the protocol was amended during the study. Subsequently, 72 patients were randomly assigned to either IP + ISMN or IX + ISMN. Patients were treated with predefined second-line therapies (docetaxel/capecitabine for IP or IP + ISMN, docetaxel/cisplatin for IX or IX + ISMN) when disease progressed. RESULTS: A total of 146 received treatment. Response rate (RR), median progression-free survival (PFS) and overall survival (OS) were 49%, 5.5 months, 14.5 months in IP; 33%, 3.3 months, 13.0 months in IP + ISMN; 30%, 4.3 months, 16.1 months in IX; and 25%, 3.4 months, 13.6 months in IX + ISMN, respectively. While IP arm showed a trend toward higher RR and longer PFS than IX arm, IX arm showed a trend toward longer OS than IP arm. No significant differences were observed between IP + ISMN and IX + ISMN. CONCLUSION: IP showed better RR and PFS but no OS benefit when compared with IX. The addition of ISMN to IP or IX chemotherapy did not seem to improve the treatment outcome.

Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding.

BACKGROUND AND AIM: 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 the carvedilol group, 61 patients, using carvedilol 6.25-12.5 mg daily or the N + I group, 60 patients, using nadolol 40-80 mg plus isorsorbide-5-mononitrate 20 mg 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 two patients (3%) in the carvedilol group and in eight patients (13%) in the N + I group (P = 0.05). Severe adverse events occurred in one patient in the carvedilol group and 17 patients in the 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 three patients in the 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.

Comparison of a shortened isosorbide dinitrate-potentiated head-up tilt testing with the conventional protocol: tolerance and diagnostic accuracy.

BACKGROUND: The head-up tilt test (HUT) is widely used to investigate unexplained syncope; however, in clinical practice, it is long and sometimes not well tolerated. OBJECTIVES: To compare the sensitivity, specificity, accuracy, and patients' tolerance of a conventional and shortened HUT. METHODS: Patients with a history of vasovagal syndrome (VVS) were randomized to a conventional HUT (group I) consisting of 20-minute passive tilt followed by 25 minutes after administration of sublingual isosorbide dinitrate (ISDN), or a shortened HUT (group II) where ISDN was given immediately after tilt and observed for 25 minutes. The control group consisted of age- and gender-matched subjects without VVS symptoms. A specific questionnaire to evaluate tolerance was applied. RESULTS: Sixty patients (29 ± 10 years, 82% female) were included. In group I, 22/30 patients had a positive HUT compared to 21/30 in group II (73% vs 70%, P = 0.77). There was also no difference in the accuracy between the two protocols (63% vs 73%, P = 0.24). The time to positivity was shorter in group II (13.2 minutes vs 30 minutes, P < 0.001). Within the control group (n = 60), the frequency of false-positives was 47% and 23% for the conventional and shortened HUT, respectively (P = 0.058). After conventional HUT, 65.2% subjects reported that the test was too long compared to 25% subjects after the shortened HUT (P = 0.002). CONCLUSION: In this study, the HUT without passive phase was not inferior to the conventional HUT regarding sensitivity, specificity, and accuracy. Furthermore, the shortened ISDN-potentiated protocol allowed faster diagnosis and was better tolerated.

Interruption of a study of cervical ripening with isosorbide mononitrate due to adverse effects.

PURPOSE OF INVESTIGATION: The objective of this study was to evaluate cervix length and the presence of cervical gland area (CGA) in ultrasounds performed before and after the administration of vaginal isosorbide mononitrate (IMN) for cervical ripening. METHODS: We performed an observational, descriptive, and longitudinal study of pregnant patients indicated for labor induction and with a Modified Bishop Score (MBS) lower than six. For cervical ripening, 40 mg of vaginal IMN was administered at 0, 16, and 24 hours after the initiation of cervix preparation. RESULTS: After enrolling 11 patients, the study had to be discontinued due to adverse effects. Three patients requested that they be withdrawn. Headaches were reported by all patients. Nausea, dizziness, dyspnea, and vomiting were also reported. The average cervical lengths at 0, 16, 24 and 36 hours were 27.6, 27.7, 25.9, and 23.0 mm, respectively. CGA disappeared in one of seven patients. CONCLUSIONS: The use of IMN appears to increase the MBS, slightly reducing cervical length without altering the appearance of CGA. Considering the importance of maternal wellbeing during labor, the routine use of IMN cannot be recommended for cervical ripening in the third trimester due to the frequency and intensity of side-effects.

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.

Long-term oral nitrate therapy is associated with adverse outcome in diabetic patients following elective percutaneous coronary intervention.

BACKGROUND: To assess the impact of long-term oral nitrate therapy on clinical outcome following percutaneous coronary intervention (PCI) in patients with type II diabetes. METHODS: The incidence of major adverse cardiovascular events (MACEs) following elective PCI for stable coronary artery disease was evaluated in 108 patients with type II diabetes (age 64.6±10.5 years, 67.7% men). Major adverse cardiovascular events were defined as the need for revascularization, non-fatal myocardial infarction or cardiovascular death. Multivariate Cox regression analysis was used to evaluate the predictive value of MACEs by clinical characteristics and the prescription of long-term nitrate therapy. RESULTS: Isosorbide mononitrate (ISMN) was prescribed to 46 patients with an average dose of 44.3±15.2 mg/day. After a mean follow up of 25.3±25 months, 16 patients developed MACEs. Patients who received ISMN were more likely to suffer from MACEs (26.1% vs. 6.5%, P=0.01), mainly driven by a higher rate of acute coronary syndrome (13.0 vs 0%, P=0.01). Average daily dose of nitrate and other cardiovascular medication was not associated with MACEs. Multivariate Cox regression analysis revealed that prescription of only ISMN (Hazard Ratio 3.09, 95% CI 1.10-10.21, P=0.04) was an independent predictor for the development of MACEs. CONCLUSION: Long-term oral nitrate therapy was associated with MACEs following elective coronary artery revascularization by PCI in patients with type II diabetes.

Comparison of isosorbide mononitrate and misoprostol for cervical ripening in termination of pregnancy between 8 and 12 weeks: a randomized controlled trial.

AIM: The present study was undertaken to compare the efficacy of isosorbide mononitrate (IMN) and misoprostol for cervical ripening in termination of pregnancy between 8 and 12 weeks. MATERIALS AND METHODS: This prospective randomized single blind study enrolled 40 women with singleton pregnancy seeking surgical termination of pregnancy between 8 and 12 weeks of gestation. They were divided into two groups--group I received IMN 40 mg while group II received misoprostol 40 mg vaginally, 3 h prior to suction and evacuation. All women were monitored for effects of cervical ripening and adverse effects. RESULTS: The mean sizes of dilators that could be negotiated without any resistance was 5.9 ± 1.33 in group I and 8.6 ± 0.94 in group II (p < 0.001, 95% CI 0.58, 0.41). The mean dilator sizes at which resistance was first encountered was 6.9 ± 1.37 in group I and 9.9 ± 1.23 in group II (p < 0.001, 95% CI 0.60, 0.54). The mean blood loss was 61.5 ± 13.86 ml in group I and 36.25 ± 12.80 ml in group II (p < 0.001, 95% CI 6.07, 5.63). Headache was the most common adverse effect seen with IMN use. CONCLUSION: The results show that IMN has a definite role and better safety profile than misoprostol in first trimester cervical ripening, although misoprostol is more effective and causes less blood loss.

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.

Addition of propranolol and isosorbide mononitrate to endoscopic variceal ligation does not reduce variceal rebleeding incidence.

BACKGROUND & AIMS: Endoscopic variceal ligation (EVL) and propranolol are standard secondary prophylaxis therapies for variceal bleeding. Addition of isosorbide mononitrate (ISMN) to propranolol improves its hemodynamic efficacy; we investigated whether a combination of EVL and propranolol/ISMN was more effective than EVL alone for secondary prophylaxis. METHODS: Patients with a prior variceal bleed were randomly assigned to groups given a combination (n = 88) of EVL, propranolol (dose titrated to reduce heart rate to 55 beats per minute), and ISMN (40 mg/day) or EVL alone (n = 89). Primary end points were rebleeding or death; secondary end points were new complications of portal hypertension or serious adverse effects. RESULTS: The actuarial probabilities of rebleeding 2 years after therapy were 27% in the combination group and 31% in the EVL alone group (P = .822). Two patients in the combination group and 3 patients in the EVL alone group died during the study period (P = .682); no deaths were caused by variceal hemorrhage. In cirrhotic patients, the actuarial probabilities of rebleeding were 24% and 30%, respectively (P = .720). Secondary end points were comparable between groups. In multivariate analyses, presence of ascites (P = .003), serum albumin < 3.3 g/dL (P = .008), and hepatic venous pressure gradients > or = 18 mm Hg (P = .009) were independent risk factors for variceal rebleeding. CONCLUSIONS: EVL alone is sufficient to prevent variceal rebleeding in cirrhotic and noncirrhotic patients with history of variceal bleeding. Addition of propranolol and ISMN to EVL does not reduce the incidence of variceal rebleeding but increases severe adverse effects. Risk factors for rebleeding include ascites, low serum albumin, and high hepatic venous pressure gradients.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

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.

Effectiveness of hydralazine/isosorbide dinitrate in racial/ethnic subgroups with heart failure.

BACKGROUND: The addition of hydralazine/isosorbide dinitrate (H-ISDN) to a standard heart failure treatment regimen in the African-American Heart Failure Trial was associated with a 43% reduction in mortality. However, the effectiveness of H-ISDN in a community sample of African-American patients and other racial/ethnic groups is unknown. OBJECTIVE: The aim of this study was to assess the associations between treatment with H-ISDN and mortality or hospitalization for heart failure in veterans with the disease. METHODS: For this retrospective cohort study, electronic data on outpatient prescriptions, comorbidity, and other heart failure risk factors were analyzed in veterans with heart failure. Patients were classified based on whether they were prescribed H-ISDN and subclassified based on race/ethnicity (African American, Hispanic, or white). Patients who were prescribed H-ISDN were subclassified based on time of initiation of H-ISDN treatment (0-121, 122-365, or >365 days after diagnosis). Data were analyzed using propensity-adjusted Cox regression analyses, with exposure to H-ISDN modeled as a time-varying covariate. RESULTS: Data from 76,828 veterans were analyzed (98% men, 2% women). H-ISDN prescription was not associated with the risk of death in 5 of the 9 subgroups predefined by race/ethnicity or time of initiation of H-ISDN; however, H-ISDN was associated with an increased risk of death in the 4 subgroups with longer times to initiation. H-ISDN was associated with a significantly increased risk of heart failure hospitalization in all but 1 of the 9 subgroups. The risk of both mortality and hospitalization associated with H-ISDN was significantly lower in African-American patients than in those who were Hispanic or white. Concurrent prescription of other, evidence-based heart failure therapies (eg, angiotensin-converting enzyme inhibitors, beta-blockers, and combinations) had strong, statistically significant associations with reduced mortality. CONCLUSIONS: In this population of veterans with heart failure, H-ISDN prescription was not associated with significant reductions in mortality or hospitalization in any of the subgroups defined by race/ethnicity and time of initiation of H-ISDN analyzed compared with the group that did not receive H-ISDN. It is possible, or even likely, that unmeasured differences in important risk factors-particularly heart failure severity and left ventricular dysfunction-between the group that received H-ISDN and the one that did not masked a beneficial effect of H-ISDN. Therefore, our conclusions must be regarded as hypothesis generating and need to be tested in subsequent randomized trial(s).

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.