Meta-Analysis

Authors: Celina Borges Migliavaca, Cinara Stein, Verônica Colpani...

BACKGROUND

Chagas disease is a neglected tropical disease. About 6 to 8 million people are chronically infected and 10% to 15% develop irreversible gastrointestinal disorders, including megaesophagus. Treatment focuses on improving symptoms, and isosorbide and nifedipine may be used for this purpose.

METHODOLOGY

We conducted a systematic review to evaluate the effectiveness of pharmacological treatment for Chagas' megaesophagus. We searched MEDLINE, Embase and LILACS databases up to January 2018. We included both observational studies and RCTs evaluating the effects of isosorbide or nifedipine in adult patients with Chagas' megaesophagus. Two reviewers screened titles and abstracts, selected eligible studies and extracted data. We assessed the risk of bias using NIH 'Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group' and RoB 2.0 tool. Overall quality of evidence was assessed using GRADE.

PRINCIPAL FINDINGS

We included eight studies (four crossover RCTs, four before-after studies). Three studies evaluated the effect of isosorbide on lower esophageal sphincter pressure (LESP), showing a significant reduction (mean difference -10.52mmHg, 95%CI -13.57 to-7.47, very low quality of evidence). Three studies reported the effect of isosorbide on esophageal emptying, showing a decrease in esophageal retention rates (mean difference -22.16%, 95%CI -29.94 to -14.38, low quality of evidence). In one study, patients on isosorbide reported improvement in the frequency and severity of dysphagia (moderate quality of evidence). Studies evaluating nifedipine observed a decrease in LESP but no effect on esophageal emptying (very low and low quality of evidence, respectively). Isosorbide had a higher incidence of headache as a side effect than nifedipine.

CONCLUSIONS

Although limited, available evidence shows that both isosorbide and nifedipine are effective in reducing esophageal symptoms. Isosorbide appears to be more effective, and its use is supported by a larger number of studies; nifedipine, however, appears to have a better tolerability profile.

TRIAL REGISTRATION

PROSPERO CRD42017055143. ClinicalTrials.gov CRD42017055143.

Topics: Adolescent; Adult; Aged; Chagas Disease; Esophageal Achalasia; Female; Humans; Isosorbide; Male; Middle Aged; Nifedipine; Treatment Outcome; Young Adult

PubMed: 30265663
DOI: 10.1371/journal.pntd.0006836

Authors: Jay N Cohn

Topics: Black or African American; Heart Failure; Humans; Hydralazine; Isosorbide Dinitrate; Treatment Outcome

PubMed: 28711448
DOI: 10.1016/j.jchf.2017.05.005

Review

Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Authors: Christos Kourek, Alexandros Briasoulis, Adamantia Papamichail...

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include β-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Topics: Humans; Heart Failure; Stroke Volume; Hydralazine; Isosorbide Dinitrate; Angiotensin Receptor Antagonists; Multicenter Studies as Topic; Urea

PubMed: 38542088
DOI: 10.3390/ijms25063113

Authors: Dezhi Qu, Ziheng Yang, Jinyu Zhang...

Isosorbide can be used as a third monomer in the synthesis of aliphatic polyesters, and its V-shaped bridging ring structure can effectively improve the rigidity of the copolyester molecular chain. In this work, a series of degradable polyester materials were prepared by modifying polybutylene succinate and using isosorbide as the third monomer. The degradation tests in this paper were implemented through the hydrolysis of copolyesters in distilled water, degradation in natural water and degradation tests in simulated natural environments. The results showed that PBS and its copolyesters can degrade under natural conditions, and the introduction of isosorbide can accelerate the degradation of copolyesters, which could effectively reduce pollutants in nature.

PubMed: 38006096
DOI: 10.3390/polym15224372

Comparative Study

Authors: Guimin Zhang, Xinling Liu, Jian Xu...

The cost-effectiveness of isosorbide-5-mononitrate (5-ISMN) and isosorbide dinitrate (ISDN) in real-world use in patients with coronary heart disease (CHD; either angina pectoris or myocardial infarction) was retrospectively compared. In this retrospective real-world evaluation, patients with established CHD satisfying the following criteria were selected from information system of two tertiary hospitals in China: with pharmacy claiming for at least one injection of 5-ISMN or ISDN between July 2008 and May 2017; and, CHD patients. By using propensity score matching (PSM), we compared clinical aspects of efficacy, safety, length of hospital stay and cost during hospitalization between 5-ISMN and ISDN group. All data were processed by R statistical package v.2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Of 5609 patients selected, 4047 received 5-ISMN and 1562 received ISDN. After PSM, we acquired 1555 pairs based on balancing of age, sex, insurance and comorbidities on admission. The frequency (4.2 ± 6.6-times vs 6.5 ± 9.5-times; p < 0.05) and total dosage (47.5 ± 153.4 vs 136.4 ± 261.0 mg; p < 0.05) of sublingual nitroglycerin use decreased and hypotension incidence lowered (8.0 vs 13.0%; p < 0.05) in 5-ISMN group compared with ISDN group. Hospital stay (16.0 ± 11.3 days vs 17.7 ± 13.2; p < 0.05) and hospitalization expenditure ([the ratio of cost in the study to the average hospitalization cost in the city] [odds ratio: 2.5 vs 2.6; p < 0.05]) were reduced in 5-ISMN group as with that of ISDN group. Moreover, the main component of hospitalization cost was medical consumables and medications in both the groups. In the present retrospective real-world evaluation, by using PSM analysis, we found that newer injection agent of 5-ISMN was associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization expenditure related to its comparator ISDN in patients with established CHD. Further evaluation and clinical experience are need in different circumference for the usage of ISDN.

Topics: Administration, Sublingual; Aged; Aged, 80 and over; China; Coronary Disease; Cost-Benefit Analysis; Female; Health Care Costs; Humans; Hypotension; Incidence; Isosorbide; Isosorbide Dinitrate; Length of Stay; Male; Middle Aged; Nitric Oxide Donors; Nitroglycerin; Pragmatic Clinical Trials as Topic; Propensity Score; Retrospective Studies; Vasodilator Agents

PubMed: 32301331
DOI: 10.2217/cer-2019-0099

Randomized Controlled Trial

Authors: Gordon W Blair, Esther Janssen, Michael S Stringer...

BACKGROUND AND PURPOSE

Cerebral small vessel disease-a major cause of stroke and dementia-is associated with cerebrovascular dysfunction. We investigated whether short-term isosorbide mononitrate (ISMN) and cilostazol, alone or in combination, improved magnetic resonance imaging-measured cerebrovascular function in patients with lacunar ischemic stroke.

METHODS

Participants were randomized to ISMN alone, cilostazol alone, both ISMN and cilostazol, or no medication. Participants underwent structural, cerebrovascular reactivity (to 6% carbon dioxide) and phase-contrast pulsatility magnetic resonance imaging at baseline and after 8 weeks of medication.

RESULTS

Of 27 participants (mean age, 68±7.7; 44% female), 22 completed cerebrovascular reactivity and pulsatility imaging with complete datasets. White matter cerebrovascular reactivity increased in the ISMN (β=0.021%/mm Hg [95% CI, 0.003-0.040]) and cilostazol (β=0.035%/mm Hg [95% CI, 0.014-0.056]) monotherapy groups and in those taking any versus no medication (β=0.021%/mm Hg [95% CI, 0.005-0.037]).

CONCLUSIONS

While limited by small sample size, we demonstrate that measuring cerebrovascular function with magnetic resonance imaging is feasible in clinical trials and that ISMN and cilostazol may improve cerebrovascular function. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481323. URL: www.isrctn.com; Unique identifier: ISRCTN12580546. URL: www.clinicaltrialsregister.eu; Unique identifier: EudraCT 2015-001953-33.

Topics: Aged; Cerebral Small Vessel Diseases; Cilostazol; Female; Hemodynamics; Humans; Isosorbide Dinitrate; Lipoproteins; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome; Vasodilator Agents

PubMed: 34847709
DOI: 10.1161/STROKEAHA.121.034866

Review

Authors: Alok Sharma, Monica Colvin-Adams, Clyde W Yancy...

African Americans are disproportionately affected by heart failure, with a high prevalence at an early age. Hypertension, diabetes, obesity, and chronic kidney disease are all common in African Americans and all predispose to heart failure. Neurohormonal imbalances, endothelial dysfunction, genetic polymorphisms, and socioeconomic factors also contribute. In general, the same evidence-based treatment guidelines that apply to white patients with heart failure also apply to African Americans. However, the combination of hydralazine and isosorbide dinitrate is advised specifically for African Americans.

Topics: Adrenergic beta-Antagonists; Black or African American; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiotonic Agents; Defibrillators, Implantable; Digoxin; Drug Combinations; Health Status Disparities; Heart Failure; Heart Transplantation; Heart-Assist Devices; Humans; Hydralazine; Hypertension; Incidence; Isosorbide Dinitrate; Mineralocorticoid Receptor Antagonists; Prevalence; Quality of Health Care; Socioeconomic Factors; Vasodilator Agents

PubMed: 24789589
DOI: 10.3949/ccjm.81a.13045

Authors: G P Dubé, Y H Baik, C Van Breemen...

We studied the effects of isosorbide dinitrate and diltiazem on histamine-stimulated 45Ca fluxes and contractions of isolated porcine coronary artery. Isosorbide dinitrate was slightly more potent as an inhibitor of intracellular compared to extracellular calcium-dependent contraction. Isosorbide dinitrate inhibited histamine-stimulated calcium efflux and intracellular calcium-dependent contraction over similar concentration ranges. Isosorbide dinitrate partially inhibited histamine-stimulated calcium influx, but this effect was significant only at high concentration and correlated weakly with inhibition of contraction that was dependent on extracellular calcium. Diltiazem more potently inhibited extracellular vs. intracellular calcium-dependent contraction. Diltiazem partially inhibited histamine-stimulated calcium efflux and intracellular calcium-dependent contraction to similar extents (55-60%) and produced similar concentration-response relationships for inhibition of histamine-stimulated calcium influx and extracellular calcium-dependent contraction. The data suggest that alterations of cellular calcium metabolism are major mechanisms of vascular smooth muscle relaxation by isosorbide dinitrate and diltiazem, but that the specific alterations differ for the two drugs. Isosorbide dinitrate may inhibit contraction primarily by enhancing intracellular calcium sequestration, but possibly also by inhibiting agonist-stimulated calcium influx at high isosorbide dinitrate concentrations. Diltiazem primarily inhibits stimulated calcium influx, but may also inhibit intracellular calcium release.

Topics: Animals; Calcium; Calcium Radioisotopes; Coronary Vessels; Diltiazem; Histamine; In Vitro Techniques; Isosorbide Dinitrate; Muscle Contraction; Muscle, Smooth, Vascular; Swine

PubMed: 3350038
DOI: 10.1016/0014-2999(88)90346-9

Authors: Isa Amalie Olofsson, Katrine Falkenberg, Jes Olesen...

INTRODUCTION

In the general population 4% have never experienced a headache. Freedom from headache could be due to distinctive protective mechanisms or a lack of environmental risk factors for headache. Isosorbide-5-mononitrate is an organic nitrate which in the body is metabolised to nitric oxide. The nitric oxide pathway plays a crucial role in the primary headaches. We hypothesized that people who are free from headache are protected by distinctive mechanisms in the nitric oxide pathway.

METHODS

We performed an observer blinded case-control study using nitric oxide to provoke a headache. 32 headache free male participants and 26 randomly selected male controls received 60 mg Isosorbide-5-mononitrate orally on the study day. Participants fill out a headache diary with headache intensity and characteristics until 12 hours after administration of Isosorbide-5-mononitrate. Primary endpoint were areas under the curve of headache intensity score.

RESULTS

All 58 participants completed the study. There was no significant difference in headache incidence, headache intensity score or migraine-like attack between headache free participants and controls.

CONCLUSION

We show that men who have never experienced a headache develop a headache when provoked with Isosorbide-5-mononitrate. This indicates that freedom from headache in men is not related to the nitric oxide pathway which is involved in the primary headache disorders.

Topics: Case-Control Studies; Cervical Ripening; Female; Headache; Humans; Isosorbide Dinitrate; Male; Nitric Oxide; Nitric Oxide Donors; Pregnancy

PubMed: 34875880
DOI: 10.1177/03331024211060002

Review

Authors: Tamanrit Johal, Christoph C Lees, Thomas R Everett...

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.

Topics: Aldehyde Oxidoreductases; Clinical Trials as Topic; Endothelium, Vascular; Female; Humans; Isosorbide Dinitrate; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; S-Nitrosothiols; Sildenafil Citrate; Sulfonamides

PubMed: 24313856
DOI: 10.1111/bcp.12301