Synthesis, characterization of poly L(+) lactic acid and its application in sustained release of isosorbide dinitrate.

Poly L(+) lactic acid (PLLA) has become crucial in the biomedical industry for various uses. The direct polycondensation method was used to prepare Poly L(+) Lactic Acid (PLLA). Different catalysts, including metal oxides and metal halides, were used to test the polymerization technique. The effect of the amount of catalysts and the type of coupling agent were investigated. The effect of reaction time and polymerization solvents was also studied. PLLA was loaded with isosorbide dinitrate utilizing the solvent evaporation process. The synthesized polymer-drug system was evaluated by different means such as FT-IR, TGA, DSC, XRD, entrapment efficiency (E.E), drug loading (D.L), particle size analysis, and zeta potential determination. Studies on in-vitro release using UV light at 227 nm at various pH levels were conducted, and the kinetics of release and cytotoxicity using the sulforhodamine B (SRB) assay on human skin fibroblast cells were examined.

Nuevos avances en la terapia de la insuficiencia cardiaca

Las enfermedades del corazón son un tema tratado frecuentemente en las investigaciones médicas, debido a que repercuten ampliamente en el funcionamiento del cuerpo humano. Por lo anterior, se destaca el estudio del tratamiento de las afecciones de este órgano, lo que resulta en una importante tarea para mantener y potenciar los conocimientos sobre los adelantos terapéuticos de las enfermedades relacionadas con el mismo. Se realiza este trabajo con el objetivo de describir los avances en la terapia de la insuficiencia cardiaca. Para ello se realizó una revisión de publicaciones científicas de los últimos dos años. A pesar de que existen diferencias respecto a la terapia propuesta para la insuficiencia cardiaca, las asociaciones americanas y europea de cardiología establecen firmemente la terapia cuádruple (con los inhibidores del receptor de la angiotensina neprilysin, los ß-bloqueadores, los antagonistas de receptor de los mineralocorticoides y los inhibidores del cotransportador-2 de glucosa/sodio) -dirigida a la insuficiencia cardiaca con fracción de eyección reducida-, la recomendación del dinitrato de isosorbide/hidralazina para los pacientes de raza negra, y la utilización de la cardioversión implantable en la prevención de muerte súbita. Se concluye que la armonización de estas guías, en ambos continentes, proporciona un tratamiento único para la insuficiencia cardiaca, aunque necesita un estudio adicional en los pacientes con fracción de eyección del ventrículo izquierdo normal.

Heart diseases are a topic frequently treated in medical researches, due to their wide repercussion on the functioning of the human body; therefore, the study of the treatment of these organ affections is highlighted, being an important task to maintain and enhance knowledge about therapeutic advances in diseases related to it. This work is carried out with the aim of describing the advances in heart failure therapy. A review of the scientific publications of the last two years was performed. Although there are differences regarding the proposed therapy for heart failure, the American and European Associations of cardiology firmly establish the quadruple therapy (with angiotensin receptor inhibitors neprilysin, ß-blockers; mineralocorticoids antagonist receptors and glucose/sodium cotransporters-2 inhibitors-targeted at heart failure with reduced ejection fraction-, the recommendation of isosorbide dinitrate/hydralazine for black patients, and the use of implantable cardioversion in the prevention of the sudden death. It is concluded that the harmonization of these guidelines, in both continents, provides a unique treatment for heart failure, although it needs additional study in patients with normal left ventricular ejection fraction.

Prevention of Preterm Labor by Isosorbide Dinitrate and Nitroglycerin Patch.

BACKGROUND: Preterm labor is one of the most important causes of hospitalization during pregnancy and can lead to serious complications in neonates. OBJECTIVE: This study aims to compare the effect of transdermal nitroglycerin (TNG) patches and sublingual tablets of Isosorbide dinitrate (ISD) for the prevention of preterm delivery. METHODS: A total of 110 healthy pregnant women aged 18-35 years with a healthy and alive fetus and gestational age between 24-34 weeks who had at least 8 regular uterine contractions per hour were included in this single-blinded clinical trial. After exclusion, the women were randomly divided into TNG (n = 50) and ISD (n = 49) groups. After the first dose of medication (TNG or ISD), patients who developed complications such as hypotension, headache, or both, were also excluded from the study. RESULTS: A total of 58 patients completed the treatment course (29 patients in each group). A significant difference in delayed preterm labor and recovery time was reported between the TNG and ISD groups. CONCLUSION: Complications and the number of contractions were not statistically different in the two groups. We concluded that the TNG patch is more effective than ISD in delaying labor. Both drugs are likely to have a similar incidence of side effects.

New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline.

BACKGROUND: There are few medicines in clinical use for managing preterm labor or preventing spontaneous preterm birth from occurring. We previously developed two target product profiles (TPPs) for medicines to prevent spontaneous preterm birth and manage preterm labor. The objectives of this study were to 1) analyse the research and development pipeline of medicines for preterm birth and 2) compare these medicines to target product profiles for spontaneous preterm birth to identify the most promising candidates. METHODS: Adis Insight, Pharmaprojects, WHO international clinical trials registry platform (ICTRP), PubMed and grant databases were searched to identify candidate medicines (including drugs, dietary supplements and biologics) and populate the Accelerating Innovations for Mothers (AIM) database. This database was screened for all candidates that have been investigated for preterm birth. Candidates in clinical development were ranked against criteria from TPPs, and classified as high, medium or low potential. Preclinical candidates were categorised by product type, archetype and medicine subclass. RESULTS: The AIM database identified 178 candidates. Of the 71 candidates in clinical development, ten were deemed high potential (Prevention: Omega-3 fatty acid, aspirin, vaginal progesterone, oral progesterone, L-arginine, and selenium; Treatment: nicorandil, isosorbide dinitrate, nicardipine and celecoxib) and seven were medium potential (Prevention: pravastatin and lactoferrin; Treatment: glyceryl trinitrate, retosiban, relcovaptan, human chorionic gonadotropin and Bryophyllum pinnatum extract). 107 candidates were in preclinical development. CONCLUSIONS: This analysis provides a drug-agnostic approach to assessing the potential of candidate medicines for spontaneous preterm birth. Research should be prioritised for high-potential candidates that are most likely to meet the real world needs of women, babies, and health care professionals.

Reforming the Uniformity of Solid Electrolyte Interphase by Nanoscale Structure Regulation for Stable Lithium Metal Batteries.

The stability of high-energy-density lithium metal batteries depends on the uniformity of solid electrolyte interphase (SEI) on lithium metal anodes. Rationally improving SEI uniformity is hindered by poorly understanding the effect of structure and components of SEI on its uniformity. Herein, a bilayer structure of SEI formed by isosorbide dinitrate (ISDN) additives in localized high-concentration electrolytes was demonstrated to improve SEI uniformity. In the bilayer SEI, LiNx Oy generated by ISDN occupies top layer and LiF dominates bottom layer next to anode. The uniformity of lithium deposition is remarkably improved with the bilayer SEI, mitigating the consumption rate of active lithium and electrolytes. The cycle life of lithium metal batteries with bilayer SEI is three times as that with common anion-derived SEI under practical conditions. A prototype lithium metal pouch cell of 430 Wh kg-1 undergoes 173 cycles. This work demonstrates the effect of a reasonable structure of SEI on reforming SEI uniformity.

Isosorbide DiNitrate Effect on Hemodynamic Profile, Liver Stiffness, and Exercise Tolerance in Fontan Circulation (The NEET Clinical Trial).

After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2 years (range 11.2-39.0 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO2 (1401 ± 428 to 1428 ± 436 mL/min, p = 0.128), but VO2 at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302 mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0 mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4 weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO2 at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer duration studies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241.

Revisiting nitrates use in pre-shock state of contemporary cardiogenic shock classification.

Patients at each shock stage may behave and present differently with a spectrum of shock severity and adverse outcomes. Shock severity, shock aetiology, and several factors should be integrated in management decision-making. Although the contemporary shock stages classification provided a standardized shock severity assessment, individual agents or management strategy has not yet been studied in the context of each shock stage. The pre-shock state may comprise a wide range of presentations. Nitrate therapy has potential benefit in myocardial infarction and acute heart failure. Herein, this review aims to discuss the potential use of nitrate therapy in the context of the pre-shock state or stage B of the contemporary shock classification given its various presentations.

Modification of Nitrate Ion Enables Stable Solid Electrolyte Interphase in Lithium Metal Batteries.

The lifespan of high-energy-density lithium metal batteries (LMBs) is hindered by heterogeneous solid electrolyte interphase (SEI). The rational design of electrolytes is strongly considered to obtain uniform SEI in working batteries. Herein, a modification of nitrate ion (NO3 - ) is proposed and validated to improve the homogeneity of the SEI in practical LMBs. NO3 - is connected to an ether-based moiety to form isosorbide dinitrate (ISDN) to break the resonance structure of NO3 - and improve the reducibility. The decomposition of non-resonant -NO3 in ISDN enriches SEI with abundant LiNx Oy and induces uniform lithium deposition. Lithium-sulfur batteries with ISDN additives deliver a capacity retention of 83.7 % for 100 cycles compared with rapid decay with LiNO3 after 55 cycles. Moreover, lithium-sulfur pouch cells with ISDN additives provide a specific energy of 319 Wh kg-1 and undergo 20 cycles. This work provides a realistic reference in designing additives to modify the SEI for stabilizing LMBs.

The Efficacy of the Transdermal Isosorbide Dinitrate Patch in Patients With Chronic Limb-Threatening Ischemia.

Recently, the number of patients with peripheral artery disease (PAD), including those with chronic limb-threatening ischemia (CLTI), has increased because of the increasing number of diabetic or dialysis patients worldwide. Revascularization is an important therapy for patients with CLTI. However, we sometimes experience refractory cases with insufficient peripheral circulation or microcirculation after revascularization. In this situation, additional therapy can be administered, such as low-density lipoprotein apheresis, high-pressure oxygen therapy, and spinal cord stimulation. However, they are not effective in some cases. Some reports have also indicated that transdermal isosorbide dinitrate patch (ISDN-P) is a useful therapy for PAD. As the efficacy of ISDN-P for patients with CLTI is not well-known, we examined it in this study. We assessed the skin perfusion pressure (SPP) after affixing an ISDN-P on the foot, because SPP measurement has proved useful in the assessment of PAD and is a good indicator of wound healing potential. The SPP (dorsal and plantar aspects) after ISDN-P application on the foot of healthy volunteers increased (n = 8; mean ± SD, 12.6 ± 7.9 [P = .12], and 21.2 ± 7.7 mm Hg [P < .05], respectively), as did SPP of patients with CLTI (n = 10; mean ± SD, 19.8 ± 2.5 [P < .01], and 14.1 ± 5.9 mm Hg [P < .05], respectively). All the patients who received an ISDN-P on the foot had no major complication, and no significant change in blood pressure. In conclusion, the ISDN-P is one of the effective and safe therapies for patients with CLTI.

Mechanism of Isosorbide Dinitrate Combined with Exercise Training Rehabilitation to Mobilize Endothelial Progenitor Cells in Patients with Coronary Heart Disease.

it was to explore effect of isosorbide dinitrate combined with exercise training and rehabilitation on endothelial progenitor cells (EPCs) in coronary heart disease. EPCs were isolated and cultured from peripheral blood of coronary heart disease patients, and morphology and surface markers were detected. Then, 116 patients were rolled into treatment group (isosorbide dinitrate + exercise rehabilitation training) and control group (isosorbide dinitrate). Characteristics of EPCs cells after treatment were compared. The mononuclear cells were round and small in size and were not evenly distributed in the culture plate. EPCs cells grew as colonies after 8d-culture, and the surrounding cells grew outward in a germinating manner with colonies as the center, forming multiple cell populations. Positive rates of EPCs surface markers CD133, CD34, and vascular endothelial growth factor receptor (KDR) were 11.25±3.07%, 48.18±9.13%, and 76.36±8.27%, respectively. Proliferation activity of EPCs in the treatment group was dramatically higher versus controls at day three, five, and seven (P<0.05). Adhesion ability of EPCs in treatment group was dramatically higher than controls at day three, five, and seven (P<0.05). Migration ability of EPCs in treatment group was dramatically higher versus control group at day three, five, and seven (P<0.05). In short, isosorbide dinitrate plus exercise rehabilitation greatly enhanced the proliferation activity, adhesion ability, and migration ability of EPCs cells, which also played a beneficial role in the repair of endothelial injury, with notable effects.

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.

EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect.

For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers-isosorbide dinitrate (ISDN, Nitrol®) and sildenafil citrate-strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.

Preparation and optimization of fast disintegrating tablets of isosorbide dinitrate using lyophilization method for oral drug delivery.

Background: Orally disintegrating tablets rapidly disintegrate in saliva and then swallowed without the need for water. Materials & methods: The orally disintegrating tablets were prepared by freeze-drying of an aqueous dispersion of isosorbide dinitrate containing a matrix former (gelatin), a cryoprotectant (mannitol), a plasticizer (glycerin) and a dissolution enhancer (Tween/polyethylene glycol). Results: Results demonstrated that the selected formulation, Ft9, disintegrated within 1 min and showed faster dissolution rate compared with the commercial tablet. Conclusion: Having a fast disintegration time, the developed lyophilized tablet does not need to be swallowed as a whole. So, it is a convenient solid oral dosage form for the patients who have difficulty with swallowing such as the pediatric and elderly ones.

Vericiguat, organic nitrates, and heart failure in African Americans.

African Americans (AA) have a higher prevalence of heart failure (HF) when compared with White Americans (3% vs 2%), respectively and HF comes on at an earlier age and is more severe in AA. The A-HEFT trial with the combination of hydralazine and isosorbide dinitrate (ISDNHYD) for self-described AA with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF) showed reduction in mortality and HF hospitalizations with a class I level of evidence A recommendation in the ACC/AHA guidelines. Vericiguat is an oral soluble guanylate cyclase stimulator that enhances the cyclic guanosine monophosphate (GMP) pathway. A randomized, double-blind, placebo-controlled trial in patients with higher risk HFrEF in which AA were underrepresented found that vericiguat reduced the composite primary outcome of cardiovascular death or first HF hospitalization. In the new era of guideline directed medical therapies of quadruple therapy - hydralazine and isosorbide dinitrate should be preferred over vericiguat in AA with HFrEF.

Captopril Versus Hydralazine-Isosorbide Dinitrate Vasodilator Protocols in Patients With Acute Decompensated Heart Failure Transitioning From Sodium Nitroprusside.

BACKGROUND: The role of oral vasodilators in the management of acute decompensated heart failure (ADHF) is not clearly defined. We evaluated the use of captopril vs hydralazine-isosorbide dinitrate (H-ISDN) in the transition from sodium nitroprusside (SNP) in patients with ADHF. METHODS AND RESULTS: A retrospective chart review was performed of 369 consecutive adult patients in the intensive care unit with ADHF and reduced ejection fraction, who received either a captopril or an H-ISDN protocol to transition from SNP. Captopril patients were matched 1:2 to H-ISDN patients, based on serum creatinine and race (Black vs non-Black). Baseline demographics, serum chemistry and use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were similar in both groups. Time to SNP discontinuation (46.9 vs 40.4 hours, P = 0.11) and length of hospital stay (9.86 vs 7.99 days, P = 0.064) were similar in both groups. Length of hospital stay in the intensive care unit was statistically shorter in the H-ISDN group (4.11 vs 3.96 days, P = 0.038). Fewer H-ISDN protocol patients were discharged on ACEis/ARBs (82.9 % vs 69.9%, P = 0.003) despite similar kidney function at time of discharge (serum creatinine 1.1 vs 1.2, P = 0.113). No difference was observed in rates of readmission (40.7% vs 50%, P = 0.09) or mortality (16.3% vs 17.5 %, P = 0.77) at 1 year postdischarge. CONCLUSION: Similar inpatient and 1-year outcomes were observed between patients using H-ISDN vs ACEi when transitioning from SNP, even though fewer H-ISDN protocol patients were discharged taking ACEis/ARBs despite similar kidney function.

Fluorescent sensing for some nitric oxide donors in dosage forms and biological matrices.

New fluorescent sensing of some nitric oxide donors, nitroglycerin and isosorbide dinitrate was developed in our laboratories. Two fluorescent reagents, 2-(2-hydroxyethylamino)-4,6-dimethylpyridine-3-carbonitrile, 3a and 2-(3-chloro-phenylamino)-4,6-dimethylpyridine-3-carbonitrile, 3b were synthesized in our laboratories and a comparative study was performed between them from the point of fluorescence intensity. The fluorophore, 3a, was selected for the analytical study as it exhibit higher quantum yield value. The interaction between the selected drugs and the fluorophore was noticed to be quenching. The mechanism of quenching was studied and it was supposed to be collisional quenching through photo induced electron transfer process. The proposed sensing method was applied successfully for the analysis of nitroglycerin and isosorbide dinitrate in dosage forms within concentration range of (0.05-0.5 µg/mL) with percentage recoveries of 99.9 ± 0.5 and 99.9 ± 0.7 respectively. The studied drugs, nitroglycerin and isosorbide dinitrate, were also probed in spiked biological matrices such as plasma samples with percentage recoveries of 99.1 ± 1.97 and 100.7 ± 1.96 and urine samples with percentage recoveries of 100.4 ± 1.8 and 100.3 ± 1.7 respectively. In vivo analysis of both drugs in real plasma was also investigated. The sensing method exhibit well intra-day and inter day precision with %RSD < 2%.