Efficacy and safety of isosorbide mononitrate plus misoprostol compared to misoprostol alone in the management of the first and second trimester abortion: a systematic review and meta-analysis.

BACKGROUND: However, misoprostol is often used to terminate a pregnancy, but it can also cause side effects. Isosorbide mononitrate (ISMN) can help the cervix mature by increasing the production of prostaglandin E2 and vasodilation. Considering that the results of studies in this field are contradictory, it is the purpose of this study to evaluate the efficacy and safety of vaginal ISMN plus misoprostol compared to misoprostol alone in the management of first- and second-trimester abortions. METHOD: The search process was conducted for MEDLINE through the PubMed interface, Scopus, Web-of-Science, Science Direct, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform until November 10, 2023. Our assessment of bias was based on version 2 of the risk-of-bias tool (RoB2) for randomized trials and our level of evidence quality was determined by GRADE. Meta-analysis of all data was carried out using Review Manager (RevMan) version 5.1. RESULT: Seven randomized clinical trials were included in the systematic review and three in the meta-analysis, with mixed quality. The results of the meta-analysis revealed that in the second-trimester abortion, the inclusion of ISMN in conjunction with vaginal misoprostol results in a noteworthy reduction in the induction abortion interval, specifically by 4.21 h (95% CI: -7.45 to -0.97, P = 0.01). The addition of vaginal ISMN to misoprostol, compared to vaginal misoprostol alone, increased the odds of a completed abortion by 3.76 times. (95% CI: 1.08 to 13.15, P = 0.04). CONCLUSION: The findings of this study can offer valuable insights aimed at enhancing counseling and support for non-surgical methods of medication abortion within professional settings. Moreover, it improves the effectiveness of clinical treatment and reduces the occurrence of unnecessary surgical interventions in the abortion management protocol.

Mononitrate Isosorbide as an Adjunctive Therapy in Schizophrenia: A Randomized Controlled Crossover Trial.

BACKGROUND: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia. METHODS: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns. RESULTS: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology. CONCLUSIONS: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning.

Evaluating the efficacy of outpatient use of isosorbide mononitrate on cervical ripening in pregnant women with unfavourable cervix.

The aim of the present study was to evaluate the efficacy of outpatient administration of nitric oxide donor isosorbide mononitrate for cervical ripening. A randomised clinical trial was performed on term pregnant women with Bishop Score < 6. In the case group, Isosorbide-5-mononitrate capsule and in the control group, placebo was inserted in the posterior vaginal fornix for two consecutive days. The main outcomes were increases in Bishop Score after 48 hours of intervention, number of vaginal deliveries and interval from intervention to delivery.There was a significant increase of the mean Bishop score in the isosorbide group [3.57 ± 1.12 VS 1.54 ± 1.42 respectively (p = .001)]. The other outcome variables did not show a significant difference between the two groups except for headache which was significantly more in the case group. No cases of tachysystole were observed in the two groups. Additionally, haemoglobin levels after delivery did not show a significant difference between the two groups.Impact statement:What is already known on this subject? Cervical ripening in women with an unfavourable cervix and having an indication for induction of labour is an important issue in modern obstetrics. Different methods have been used for cervical ripening and induction of labour including mechanical (i.e. laminaria tents, Dilapan-S, foley catheter), medical (i.e. PGs) and supportive methods. There is no consensus on the best option for cervical ripeningWhat will the results of this study add to the current knowledge of this subject? Outpatient administration of nitric oxide could affect cervical ripening without a significant improvement in the duration of different stages of labour, intervention to delivery interval and number of vaginal deliveries.What are the implications of these findings for clinical practice and/or further research? Due to the contradictory results of various studies, more studies should be performed with greater sample size to evaluate nitric oxide donor isosorbide mononitrate effect on labour duration and reducing caesarean deliveries. Additional data is needed to assess the real impact of NO donors on different stages of labour and its implications.

Combination of Diclofenac and Sublingual Nitrates Is Superior to Diclofenac Alone in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography.

BACKGROUND & AIMS: Acute pancreatitis is a major adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of post-ERCP pancreatitis (PEP). Little is known about the combined effects of sublingual nitrate and NSAIDs. We performed a randomized trial to assess whether the combination of NSAIDs and sublingual nitrate is more effective than NSAIDs alone in preventing PEP. METHODS: In a prospective superiority trial, eligible patients underwent ERCP at 12 endoscopic units in Japan, from March 2015 through May 2018. Patients were randomly assigned to groups given diclofenac suppositories (50 mg) within 15 minutes after the endoscopic procedure alone (diclofenac-alone group, n = 442) or in combination with sublingual isosorbide dinitrate (5 mg) 5 minutes before the endoscopic procedure (combination group, n = 444). The primary endpoint was the occurrence of PEP. RESULTS: PEP developed in 25 patients in the combination group (5.6%), and in 42 patients in the diclofenac-alone group (9.5%) (relative risk 0.59; 95% confidence interval 0.37-0.95; P = .03). Moderate to severe pancreatitis developed in 4 patients (0.9%) in the combination group, and 10 patients (2.3%) in the diclofenac-alone group (relative risk 0.12; 95% confidence interval 0.13-1.26; P = .12). There was no serious adverse event related to the additional administration of sublingual nitrate. CONCLUSIONS: In a randomized controlled trial, we found that prophylaxis with rectal diclofenac and sublingual nitrate significantly reduces the overall incidence of PEP compared with diclofenac suppository alone. ClinicalTrials.gov, no: UMIN 000016274.

Intravaginal administration of isosorbide mononitrate for cervical ripening in prolonged pregnancy: a randomised clinical trial.

Prolonged pregnancies are associated with foetal and neonatal complications. This study was performed to evaluate the efficacy of intravaginal isosorbide mononitrate (IMN) for cervical ripening in prolonged pregnancies. 122 pregnant women were recruited. Women were assigned to 25 µg sublingual misoprostol plus 40 mg isosorbide mononitrate or placebo. Statistical analysis was done using SPSS software (version 23) and T-test, Mann-Whitney and Chi-square test. p ≤ .05 was considered significant. The mean time between beginning of cervical ripening to Bishop score >6 was significantly shorter in IMN plus misoprostol group when compared to misoprostol plus placebo group (p = .02). The mean time from beginning of cervical ripening to the beginning of active phase of Labour was comparable between two groups (p = .274). The misoprostol plus IMN group had significantly shorter interval from the beginning of cervical ripening to the time of delivery. Isosorbide mononitrate in combination with misoprostol has a promising effect on cervical ripening and progress in labour.IMPACT STATEMENTWhat is already known on this subject? Prolonged pregnancy is associated with foetal, neonatal, and maternal complications. Because of these complications, many obstetricians tend toward the induction of prolonged pregnancies to reduce perinatal morbidity and mortality. Isosorbide mononitrate is a nitric oxide donor agent which is used vaginally for cervical ripening in term pregnancies resulting in various outcomes.What do the results of this study add? Isosorbide mononitrate in combination with misoprostol had a greater effect on cervical ripening and progress in labour than misoprostol alone in prolonged pregnancies.What are the implications of these findings for clinical practice and/or further research? According to results of the current study; using isosorbide mononitrate in combination with misoprostol could enhance successful vaginal delivery in prolonged pregnancy. Evaluation of maternal satisfaction by using this protocol is recommended in future studies.

A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute ß-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using ß-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).

Nitric oxide donors increase the pregnancy rate in patients with unexplained infertility undergoing clomiphene citrate stimulation and intrauterine insemination: a randomized controlled pilot study.

This study evaluated the effects of nitric oxide donor's treatment on the pregnancy rate and uterine blood flow in patients with unexplained infertility undergoing clomiphene citrate stimulation and intrauterine insemination. A total of 120 patients were randomly allocated to a control group who received 100 mg clomiphene citrate daily from day 5 to 9 of cycle plus placebo vaginal tablets, and a study group received clomiphene citrate plus isosorbide mononitrate 10 mg vaginal tablets. Vaginal ultrasound was done before treatment and every other day starting from day 12 of cycle to count mature follicles and ovulation was triggered by IM injection of 10 000 IU hCG when one follicle measured 18 ≥ mm followed by intrauterine insemination after 36 h. The endometrial thickness, uterine arteries resistance and pulsation indices, and endometrial vascular flow and vascular flow indices were measured before treatment and at day of hCG injection. Results were analyzed after one cycle treatment using the Mean ± SD, the Student t test and the Fisher Exact test. Significant result was considered at p values <0.05. The study group had significant higher pregnancy rate/cycle, higher endometrial and lower uterine artery blood flow indices (p < 0.05).

Impacts of nicorandil on infarct myocardium in comparison with nitrate: assessed by cardiac magnetic resonance imaging.

In this pilot study, we compared the infarct and edema size in acute myocardial infarction (MI) patients treated by nicorandil with those treated by nitrate, using cardiac magnetic resonance (CMR) imaging. Fifty-two acute MI patients who underwent emergency percutaneous coronary intervention (PCI) were enrolled, and were assigned to receive nicorandil or nitrate at random just before reperfusion. For the assessment of infarct and edema areas, short-axis delayed enhancement (DE) and T2-weight (T2w) CMR images were acquired 6.1 ± 2.4 days after the onset of MI. A significant correlation was observed between the peak creatinine kinase (CK) level and the infarct size on DE CMR (r = 0.62, p < 0.05), as well as the edema size on T2w CMR (r = 0.70, p < 0.05) in patients treated by nicorandil (28 patients). A similar correlation was seen between the peak CK level and the infarct size on DE CMR (r = 0.84, p < 0.05), as well as the edema size on T2w CMR (r = 0.84, p < 0.05) in patients treated by nitrate (24 patients). The maximum CK level was significantly lower in patients treated by nicorandil rather than nitrate (1991 ± 1402, 2785 ± 2121 IU/L, respectively, p = 0.03). Both the edema size on T2w CMR and the infarct size on DE CMR were significantly smaller in patients treated by nicorandil rather than nitrate (17.7 ± 9.9, 21.9 ± 13.7 %; p = 0.03, 10.3 ± 6.0, 12.7 ± 6.9 %, p = 0.03, respectively). The presence and amount of microvascular obstruction were significantly smaller in patients treated by nicorandil rather than nitrate (39.2, 64.7 %; p = 0.03; 2.2 ± 1.3, 3.4 ± 1.5 cm(2); p = 0.02, respectively). Using CMR imaging, we demonstrated that the complementary use of intravenously and intracoronary administered nicorandil during PCI favorably acts more on the damaged myocardium after MI than nitrate. We need a further powered prospective study on the use of nicorandil.

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.

Pharmacokinetic properties of isosorbide-5-mononitrate under fasting and fed conditions in healthy male subjects.

OBJECTIVE: This study was performed to compare the pharmacokinetic properties and relative bioavailability of two isosorbide-5-mononitrate (5-ISMN) sustained-release drugs in healthy Korean subjects under fasting and fed conditions. METHODS: A total of 60 healthy volunteers (30 each in the fasting and fed arms of the study) were enrolled in the study and were randomized to treatment. After the administration of a single dose of one of the investigational products, blood samples were collected at specific time intervals from 0 to 36 hours. The plasma concentrations of 5-ISMN were measured by LC-MS/MS. The pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of the parameters were obtained by analysis of variance on logarithmically transformed data. RESULTS: The corresponding 90% CIs of AUClast and Cmax for the test/reference geometric mean ratio were 90.75 - 98.44% and 92.28 - 98.33%, respectively, under fasting conditions. In the fed state study, the 90% CIs for the geometric mean ratio of test to reference drugs were 94.79 - 103.33% for AUClast and 99.86 - 108.02% for Cmax. CONCLUSION: The test product is equivalent to the reference product in subjects under fasting and fed conditions within the Korean regulatory bioequivalence criteria. Both formulations were safe and well tolerated, and there were no noteworthy differences in the safety profiles between the test and reference drugs.

CGRP mediate the isosorbide-5-mononitrate cardiovascular response in healthy Chinese male volunteers through a XOR-independent pathway.

OBJECTIVES: This study was designed to determine whether xanthine oxidoreductase (XOR) is involved in Isosorbide- 5-mononitrate (IS-5-MN) metabolism, and to elucidate the role of the neuropeptide calcitonin gene-related peptide (CGRP) in the IS-5-MN response. METHODS: In 15 Chinese volunteers, we observed the relationship between baseline XOR-mRNA expression in peripheral blood mononuclear cells (PBMCs) and the response to 20 mg IS-5-MN. IS-5-MN pharmacokinetics profiles, changes in plasma concentrations of CGRP, and CGRPmRNA expression in PBMCs were assessed in vivo and in vitro. RESULTS: Individuals with a lower baseline XOR-mRNA expression showed lower plasma XOR activity and significantly greater changes in SBP (ΔSBP) after IS-5-MN administration. Individuals with a lower baseline XOR-mRNA expression also showed significantly greater increases in plasma concentrations of CGRP. There were no differences in IS-5-MN AUC between the two groups. IS-5-MN significantly up-regulated the expression of CGRP α- and CGRP ß-mRNA in PBMCs, which were not affected by the XOR inhibitor allopurinol. CONCLUSIONS: Our study suggests that CGRP may contribute to the response to IS-5 MN in a XOR-independent pathway.

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.

Radioprotective Properties of Indralin in Combination with Monizol in the Treatment of Local Acute and Delayed Radiation Injuries Caused by Local Skin γ-Irradiation.

Female rats were exposed to local γ-irradiation of the right hindpaw in doses of 30-50 Gy at 131-154 sGy/min dose rate. Radioprotector indralin was administered per os 15 min prior to irradiation, monizol was injected intraperitoneally 5 min after irradiation. Indralin showed marked radioprotective properties both for acute and delayed symptoms of local radiation injuries. In combination with monizol, radioprotective effect of indralin was potentiated to dose reduction factor of 1.4-1.5 both for radiation burn severity reduction and for restriction of postradiational contracture development and amputation of the irradiated limb.

How to limit radial artery spasm during percutaneous coronary interventions: The spasmolytic agents to avoid spasm during transradial percutaneous coronary interventions (SPASM3) study.

AIMS: To compare the efficacy of three vasodilators in preventing radial artery spasm (RAS) in patients undergoing transradial percutaneous coronary interventions (PCI). METHODS AND RESULTS: 731 patients were randomized to receive diltiazem 5 mg, verapamil 2.5 mg, or isosorbide dinitrate (ISDN) 1 mg before coronary intervention. RAS occurred in 20.1% in the whole population and was significantly reduced by verapamil and ISDN compared to diltiazem (16.2, 17.2, and 26.6%, respectively; P < 0.006). There was also a trend towards less severe pain (more than 8 on a numerical scale from 0 [no pain] to 10 [maximal pain]), and less severe RAS (complete catheter blockage or severe pain), among patients treated by verapamil compared to ISDN and diltiazem (1.3% vs. 2.8% vs. 2.9%, P = 0.43 and 5.1% vs. 6.2% vs. 9.5%, respectively, P = 0.13). No difference was found between the three vasodilators in terms of crossover or safety events. Female gender, failure at first attempt to access the radial artery, emergency procedures, and the use of diltiazem were independent predictors of RAS. CONCLUSION: Verapamil and ISDN considerably reduce the incidence of RAS compared to diltiazem during transradial PCI.

The nitric oxide pathway and possible therapeutic options in pre-eclampsia.

Pre-eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short- and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide-soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre-eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S-nitrosothiols; l-arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3',5'-monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre-eclampsia is explored.

Comparison of the efficacy of isosorbide mononitrate and doxazosin in the treatment of lower urinary tract symptoms and benign prostatic hyperplasia: a randomized clinical trial.

OBJECTIVE: We aimed to compare the efficacy of isosorbide mononitrate and doxazosin in the treatment of lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: 80 patients with LUTS were included in this randomized clinical study. All patients were evaluated with uroflowmetry, post-void residual (PVR) urine, prostate volume, International Prostate Symptom Score (IPSS), serum PSA, urinalysis and culture. 40 patients were prescribed doxazosin for 4 weeks, another 40 were prescribed isosorbide mononitrate for 4 weeks. Urologic re-evaluation was done at the end of the study. RESULTS: 74 patients completed the study. The mean age of patients was 59.6 ± 0.7 years, the mean PSA value was 1.7 ± 0.1 ng/ml and the mean prostate volume was 41.9 ± 1.7 ml. Doxazosin markedly improved IPSS (from 16.2 ± 0.7 to 9.5 ± 0.5), maximum urinary flow rate (from 10.9 ± 0.7 to 12.8 ± 0.6 ml/s) and PVR urine (from 68.1 ± 9.4 to 39.0 ± 4.4 ml) (p < 0.0001, p < 0.0001, p = 0.0004, respectively). Isosorbide only improved IPSS (from 16.5 ± 0.9 to 14.6 ± 0.8) (p = 0.032). CONCLUSIONS: Daily administration of isosorbide does not seem to be an alternative to α-blocker therapy. Controlled, randomized novel studies are required to establish that whether nitric oxide donors are an effective alternative in LUTS treatment.

Evaluation of novel immediate-/controlled-release tablets of isosorbide-5-mononitrate (5-ISMN): in vitro-in vivo correlation.

The aim of the present study was to develop the novel immediate-controlled release (ICR) tablets of isosorbide-5-mononitrate (5-ISMN) composed of an osmotic pump tablet core coated with an immediate-release layer. The novel ICR tablets of 5-ISMN could release drug quickly and continuously through a semi-permeable membrane (SPM) composed of ethylcellulose (EC)/polyethylene glycol (PEG) 4000 and cellulose acetate (CA)/PEG4000. Release tended to decrease with storage time. However, the drug release rates changed little for the SPM composed of EC/PVP K30. The weight loss test also confirmed these results. The major release mechanism was diffusion according to the Higuchi equation. The relative bioavailability of the ICR tablets compared to the reference formulation in the single and multiple dose regiments were 90.9 and 111.2%, respectively. They were both bioequivalent to the reference formulation. In vitro-in vivo correlation (IVIVC) studies demonstrated that the dissolution in vitro simulated the absorption in vivo well. In general, 5-ISMN ICR tablets composed of an osmotic pump tablet core and an immediate-release layer may be promising in providing immediate and constant drug delivery with minimum fluctuations during long storage time.

Effects of acute vasodilation on the hemodynamic response to muscle metaboreflex.

The aim of the present study was to test the contribution of stroke volume (SV) in hemodynamic response to muscle metaboreflex activation in healthy individuals. We hypothesized that an acute decrease in cardiac afterload and preload due to the administration of a vasodilating agent could reduce postexercise muscle ischemia (PEMI)-induced SV response. Ten healthy males (age 33.6 ± 1.3 yr) were enrolled and randomly assigned to the following study protocol: 1) PEMI session, 2) control exercise recovery (CER) session, 3) PEMI after sublingual administration of 5 mg of isosorbide dinitrate (ISDN), and 4) CER after ISDN. Central hemodynamics were evaluated by means of impedance cardiography. The main findings were a blunted SV response during metaboreflex following acute arterial and venous vasodilation, associated with a reduction in cardiac diastolic time and filling, and a decrement of systemic vascular resistance. These hemodynamic changes restrain blood pressure response during metaboreflex activation. Our results indicate that hemodynamic response to metaboreflex activation is a highly integrated phenomenon encompassing complex interplay between heart rate, cardiac performance, preload, and afterload and that impairment of one or more of these parameters leads to altered hemodynamic response to metaboreflex.

Ibuprofen plus isosorbide dinitrate treatment in the mdx mice ameliorates dystrophic heart structure.

BACKGROUND: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. AIMS: To evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. METHODS: Three groups of mice were studied: mdx mice treated with IBU (50 mg kg⁻¹)+ISDN (30 mg kg⁻¹) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. RESULTS: Treatment for 10-11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. CONCLUSIONS: Treatment for 10-11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation.

Lack of effect of nitrates on exercise stress test results in patients with microvascular angina.

PURPOSE: To assess the effects of short-acting nitrates on exercise stress test (EST) results and the relation between EST results and coronary blood flow (CBF) response to nitrates in patients with microvascular angina (MVA). METHODS: We completed 2 symptom/sign limited ESTs on 2 separate days, in a random sequence and in pharmacological washout, in 29 MVA patients and in 24 patients with obstructive coronary artery disease (CAD): one EST was performed without any intervention (control EST, C-EST), and the other after sublingual isosorbide dinitrate, 5 mg (nitrate EST, N-EST). CBF response to nitroglycerin (25 µg) was assessed in the left anterior descending coronary artery by transthoracic Doppler-echocardiography. RESULTS: At C-EST. ST-segment depression ≥1 mm (STD) was induced in 26 (90 %) and 23 (96 %) MVA and CAD patients, respectively (p=0.42), whereas at N-EST, STD was induced in 25 (86 %) and 14 (56 %) MVA and CAD patients, respectively (p=0.01). Time and rate pressure product at 1 mm STD increased during N-EST, compared to C-EST, in CAD patients (475±115 vs. 365±146 s, p<0.001; and 23511±4352 vs. 20583±6234 bpm∙mmHg, respectively, p=0.01), but not in MVA patients (308±160 vs. 284±136 s; p=0.19; and 21290±5438 vs. 20818±4286 bpm∙mmHg, respectively, p=0.35). In MVA patients, a significant correlation was found between heart rate at STD during N-EST and CBF response to nitroglycerin (r=0.40, p=0.04). CONCLUSIONS: Short-acting nitrates improve EST results in CAD, but not in MVA patients. In MVA patients a lower nitrate-dependent coronary microvascular dilation may contribute to the lack of effects of nitrates on EST results.