Reno-protective effect of nicorandil and pentoxifylline against potassium dichromate-induced acute renal injury via modulation p38MAPK/Nrf2/HO-1 and Notch1/TLR4/NF-κB signaling pathways.

BACKGROUND: Occupational and environmental exposure to chromium compounds such as potassium dichromate (PDC) (K2Cr2O7) has emerged as a potential aetiologic cause for renal disease through apoptotic, and inflammatory reactions. The known potent antioxidants such as nicorandil (NIC) and/or pentoxifylline (PTX) were studied for their possible nephroprotective effect in PDC-treated rats. METHODS: Forty male Wistar rats were divided into five groups; control, PDC group, NIC+PDC, PTX+PDC group, and combination+PDC group. Nephrotoxicity was evaluated histopathologically and biochemically. Invasive blood pressure, renal function parameters urea, creatinine, uric acid and albumin, glomerular filtration rate markers Cys-C, Kim-1 and NGAL, inflammatory markers IL-1ß, IL-6, TNF-α, TGF-ß, COX-II, p38MAPK, NF-κB and TLR4, oxidative stress SOD, GSH, MDA, MPO, HO-1 and Nrf2 and apoptotic mediators Notch1 and PCNA were evaluated. Besides, renal cortical histopathology was assayed as well. RESULTS: PDC led to a considerable increase in indicators for kidney injury, renal function parameters, invasive blood pressure, oxidative stress, and inflammatory markers. They were markedly reduced by coadministration of PDC with either/or NIC and PTX. The NIC and PTX combination regimen showed a more significant improvement than either medication used alone. Our results demonstrated the nephroprotective effect of NIC, PTX, and their combined regimen on PDC-induced kidney injury through suppression of oxidative stress, apoptosis, and inflammatory response. CONCLUSION: Renal recovery from PDC injury was achieved through enhanced MAPK/Nrf2/HO-1 and suppressed Notch1/TLR4/NF-κB signaling pathways. This study highlights the role of NIC and PTX as effective interventions to ameliorate nephrotoxicity in patients undergoing PDC toxicity.

Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression.

BACKGROUND AND PURPOSE: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways. EXPERIMENTAL APPROACH: We assessed the effects of nicorandil (15 mg·kg-1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted. KEY RESULTS: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue. CONCLUSIONS AND IMPLICATIONS: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings.

Assessment of cardiac parameters after the administration of nicorandil before primary percutaneous coronary intervention.

Objective: To assess cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes and major adverse cardiac events after treatment with nicorandil before primary percutaneous coronary intervention. METHODS: The comparative, analytical study was conducted from October to November 2022 at the Pharmacology Department of Army Medical College, National University of Medical Sciences, Rawalpindi, Pakistan, in collaboration with the Rawalpindi Institute of Cardiology, Rawalpindi. The sample comprised ST-elevated myocardial infarction patients of either gender aged at least 30 years with an ejection fraction of at least 35% undergoing primary percutaneous coronary intervention. Participants were selected based on the above-mentioned inclusion and informed consent was taken before their enrolment in this research study. The sample was randomised into control group A receiving conventional acute coronary syndrome treatment, and intervention group B receiving nicorandil in addition to the conventional treatment. Cardiac troponin I and creatine kinase-myocardial band levels, electrocardiogram changes, and major adverse cardiac events noted and compared. Data was analysed using SPSS 26. RESULTS: Of the 140 patients, 70(50%) were in each of the 2 groups. In group B, 60(85.7%) patients achieved a completely settled ST segment on electrocardiogram compared to 25(35.7%) in group A (p=0.001). There was a significant inter-group difference with respect to cardiac troponin I value 6 hours after percutaneous coronary intervention and major adverse cardiac events (p<0.05), but creatine kinase-myocardial band level was no significantly different between the groups (p=0.761). Conclusion: Prophylactic use of nicorandil in ST-elevated myocardial infarction patients decreased the incidence of reperfusion injury.

Therapeutic potential of nicorandil beyond anti-anginal drug: A review on current and future perspectives.

Nicorandil (NIC) is a well-known anti-anginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic anti-anginal agents. NIC has also been used clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases, including opening of adenosine triphosphate-sensitive potassium (KATP) channel and donation of nitric oxide (NO). In recent years, NIC has been found to show numerous pharmacological activities such as neuroprotective, nephroprotective, hepatoprotective, cardioprotective, and testicular protective effects, among other beneficial effects on the body. The present review dwells on the pharmacological potentials of NIC beyond its anti-anginal action.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Background: Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods: MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results: Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion: This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Mechanism of action and neuroprotective role of nicorandil in ischemic stroke.

Nicorandil is a dual mechanism anti-anginal agent that acts as a nitric oxide (NO) donor and a potassium (K+) channel opener. Recent studies have evaluated the effect of nicorandil on ischemic stroke. Neurons have a low tolerance to hypoxia and therefore the brain tissue is significantly vulnerable to ischemia. Current approved treatments for ischemic stroke are tissue plasminogen activators and clot retrieval methods. The narrow therapeutic time window and lack of efficacy in restoring the dying neurons urge researchers to develop an alternative approach. In the terminal stages of anoxia, K+ channels induce hyperpolarization in various types of neuronal cells, leading to decreased neuronal activity and the preservation of the brain's energy. Nicorandil can open these K+ channels and sustain the hyperpolarization phase, which may have a neuroprotective effect during hypoxia. Additionally, we review how nicorandil can improve overall stroke outcomes through its anti-inflammatory, anti-oxidative, and edema-reducing effects. One of the major components evaluated in stroke patients is blood pressure. Studies have demonstrated that the effect of nicorandil on blood pressure is related to both its K+ channel opening and NO donating mechanisms. Since both hypertension and hypotension need correction before stroke intervention, it's crucial to consider the role of nicorandil and its impact on blood pressure. Previously published studies indicate that the right dosage of nicorandil can improve cerebral blood flow without significant changes in hemodynamic profiles. In this review, we discuss how nicorandil may contribute to better stroke outcomes based on previously published literature and laboratory findings.

Effect of Perioperative Nicorandil on Myocardial Protection in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass, a Retrospective Study.

Background: The potential myocardial protective effect of nicorandil (NICD) in patients undergoing percutaneous coronary intervention has been established. However, its efficacy in the context of cardiac surgery remains controversial. The present study aimed to evaluate the myocardial protective effect of perioperative NICD use in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: We retrospectively gathered data from patients undergoing cardiac bypass surgery between 12/2018 and 04/2021 in Fuwai Hospital. Subsequently, the patients were divided into two groups, NICD group and non-nicorandil (non-NICD) group. A 1, 3 propensity score matching (PSM) was conducted. The primary outcome was the incidence of myocardial injury. The secondary outcomes included the mechanical ventilation (MV) duration, intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of chest drainage, the drainage volume, the total cost, the incidence of acute kidney injury (AKI), and the incidence of acute liver injury (ALI). Subsequently, we divided the entire population into two distinct subgroups based on their administration of NICD, and performed a comprehensive subgroup analysis. Results: A total of 2406 patients were ultimately included in the study. After PSM, 250 patients in NICD group and 750 patients in non-NICD group were included in the analysis. Perioperative NICD reduced the incidence of myocardial injury (47.2% versus 38.8%, P=0.025). Our subgroup analysis revealed that preoperative NICD administration not only provided myocardial protection benefits (45.7% vs 35.8%, OR 0.66, 95% CI [0.45-0.97], P=0.041), but also demonstrated statistically significant reduction in ALI, the ICU and hospital LOS, and the duration of chest drainage (all P<0.05). Conclusion: The perioperative NICD administration may confer myocardial protection in patients undergoing cardiac surgery with CPB. Furthermore, the preoperative utilization of NICD has the potential to mitigate the incidence of postoperative ALI, a reduction in the ICU and hospital LOS, and the duration of chest drainage.

Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF.

BACKGROUND AND PURPOSE: Cognitive impairment is a prevalent adverse consequence of traumatic brain injury (TBI). The neuroprotective effects of nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) has been previously documented, yet its protective effects against cognitive dysfunction post-TBI remain unclear. Hence, the present study was aimed to evaluate whether nicorandil attenuates cognitive dysfunction in TBI rats and the underlying mechanism behind this process. METHODS: The TBI model was established with a controlled cortical impact (CCI). The effects of nicorandil on cognitive dysfunction of rats with TBI were examined through Novel object recognition (NOR) test, Y-maze test, and Morris water maze (MWM) task. After behavioral tests, hippocampal tissue was collected for Quantitative real-time PCR, Western blot analysis, and Enzyme-linked immunosorbent assay (ELISA) assay. RESULTS: We observed that nicorandil administration effectively ameliorates learning and memory impairment in TBI rats. Alongside, nicorandil treatment attenuated oxidative stress in the hippocampus of TBI rats, characterized by the decreased reactive oxygen species generation, malondialdehyde, and protein carbonyls levels, and concurrent promotion of antioxidant-related factors (including superoxide dismutase, glutathione peroxidase, and catalase) activities. Additionally, nicorandil treatment attenuated the inflammatory response in the hippocampus of TBI rat, as evidenced by the upregulated levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α), as well as the downregulated level of IL-10. Mechanistically, nicorandil treatment significantly enhanced the mRNA and protein levels of neurotrophic factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus of TBI rats. CONCLUSION: These findings suggest that nicorandil mitigates cognitive impairment after TBI by suppressing oxidative stress and inflammation, potentially through enhancing BDNF and NGF levels.

Utility and optimal dose of nicorandil for physiological assessment of the femoropopliteal artery.

BACKGROUND: Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its use in peripheral arteries. AIMS: To identify the utility of nicorandil and its appropriate dose for the physiological assessment on the femoropopliteal artery. METHODS: We retrospectively enrolled patients from three institutes in which physiological assessment was carried out with various doses of nicorandil before treatment. Twenty-four femoropopliteal artery stenotic lesions from 22 patients were included. The nicorandil doses used were 2, 4, and 6 mg. Twenty-two lesions were also assessed using 30 mg of papaverine. The pressure gradient (PG) and peripheral fractional flow reserve (pFFR) were calculated based on the mean and systolic pressure levels. We examined the correlation of each parameter with the peak systolic velocity ratio (PSVR) based on the duplex ultrasound images using Spearman's rank correlation coefficient. Systemic blood pressure was assessed for safety. RESULTS: The correlations were higher for mean pressure-based parameters than for systolic pressure-based parameters. As the nicorandil dose increased, the correlations among PG, pFFR, and PSVR also increased (mean pressure-based PG: 2 mg, r = 0.360; 4 mg, r = 0.498; 6 mg, r = 0.694, mean pressure-based pFFR: 2 mg, r = -0.479; 4 mg, r = -0.469; 6 mg, r = -0.641). The blood pressure after the administration of 6 mg of nicorandil was low, and the median systemic mean pressure was 65 mmHg. CONCLUSION: A 4 mg dose of nicorandil is effective and safe for the mean pressure-based physiological assessment of lesions in the femoropopliteal artery.

Nicorandil alleviates cardiac microvascular ferroptosis in diabetic cardiomyopathy: Role of the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway.

Mitochondria-associated ferroptosis exacerbates cardiac microvascular dysfunction in diabetic cardiomyopathy (DCM). Nicorandil, an ATP-sensitive K+ channel opener, protects against endothelial dysfunction, mitochondrial dysfunction, and DCM; however, its effects on ferroptosis and mitophagy remain unexplored. The present study aimed to assess the beneficial effects of nicorandil against endothelial ferroptosis in DCM and the underlying mechanisms. Cardiac microvascular perfusion was assessed using a lectin perfusion assay, while mitophagy was assessed via mt-Keima transfection and transmission electron microscopy. Ferroptosis was examined using mRNA sequencing, fluorescence staining, and western blotting. The mitochondrial localization of Parkin, ACSL4, and AMPK was determined via immunofluorescence staining. Following long-term diabetes, nicorandil treatment improved cardiac function and remodeling by alleviating cardiac microvascular injuries, as evidenced by the improved microvascular perfusion and structural integrity. mRNA-sequencing and biochemical analyses showed that ferroptosis occurred and Pink1/Parkin-dependent mitophagy was suppressed in cardiac microvascular endothelial cells after diabetes. Nicorandil treatment suppressed mitochondria-associated ferroptosis by promoting the Pink1/Parkin-dependent mitophagy. Moreover, nicorandil treatment increased the phosphorylation level of AMPKα1 and promoted its mitochondrial translocation, which further inhibited the mitochondrial translocation of ACSL4 via mitophagy and ultimately suppressed mitochondria-associated ferroptosis. Importantly, overexpression of mitochondria-localized AMPKα1 (mitoAα1) shared similar benefits with nicorandil on mitophagy, ferroptosis and cardiovascular protection against diabetic injury. In conclusion, the present study demonstrated the therapeutic effects of nicorandil against cardiac microvascular ferroptosis in DCM and revealed that the mitochondria-localized AMPK-Parkin-ACSL4 signaling pathway mediates mitochondria-associated ferroptosis and the development of cardiac microvascular dysfunction.

Nicorandil and carvedilol mitigates motor deficits in experimental autoimmune encephalomyelitis-induced multiple sclerosis: Role of TLR4/TRAF6/MAPK/NF-κB signalling cascade.

Multiple sclerosis (MS) is an inflammatory demyelinating neurodegenerative disease that negatively affects neurotransmission. It can be pathologically mimicked by experimental autoimmune encephalomyelitis (EAE) animal model. ATP-sensitive potassium channels (KATP) plays a crucial role in the control of neuronal damage, however their role in MS are still obscure. Additionally, Carvedilol showed a promising neuroprotective activity against several neurological disorders. Therefore, the present study aimed to investigate the potential neuroprotective effect of KATP channel opener (nicorandil) as well as α and ß adrenoceptor antagonist (Carvedilol) against EAE induced neurodegeneration in mice. Mice was treated with nicorandil (6 mg/kg/day; p.o.) and carvedilol (10 mg/kg/day; p.o.) for 14 days. Nicorandil and carvedilol showed improvement in clinical scoring, behaviour and motor coordination as established by histopathological investigation and immunohistochemical detection of MBP. Furthermore, both treatments downregulated the protein expression of TLR4/ MYD88/TRAF6 signalling cascade with downstream inhibition of (pT183/Y185)-JNK/p38 (pT180/Y182)-MAPK axis leading to reduction of neuroinflammatory status, as witnessed by reduction of NF-κB, TNF-α, IL-1ß and IL-6 contents. Moreover, nicorandil and carvedilol attenuated oxidative damage by increasing Nrf2 content and SOD activity together with reduction of MDA content. In addition, an immunomodulating effect via inhibiting the gene expression of CD4, TGF-ß, and IL-17 as well as TGF-ß, IL-17, and IL-23 contents along with anti-apoptotic effect by decreasing Bax protein expression and Caspase-3 content and increasing Bcl-2 protein expression was observed with nicorandil and carvedilol treatments. In conclusion, nicorandil and carvedilol exerted a neuroprotective activity against EAE induced neuronal loss via inhibition of TLR4/MYD88/TRAF6/JNK/p38-MAPK axis besides antioxidant and anti-apoptotic effects.

Nicorandil attenuates cisplatin-induced acute kidney injury in rats via activation of PI3K/AKT/mTOR signaling cascade and inhibition of autophagy.

Cisplatin is a highly effective antitumor agent, but its clinical use is limited due to critical adverse reactions including acute kidney injury (AKI). Nicorandil is an approved antianginal agent decreasing ischemia by potassium channel opening. The aim of this study was to investigate the nephroprotective effects of nicorandil and the possible role of activating PI3K/AKT/mTOR pathway in ameliorating cisplatin-induced AKI. Forty male Wistar rats were randomly allocated in 4 groups (n = 10). Group I: rats received the vehicle and served as control. Group II: rats received a single dose of cisplatin (7 mg/kg, i.p) on the 10th day of the experiment and served as AKI group. Group III: rats received cisplatin as in group II and nicorandil (3 mg/kg/day, p.o) for 14 days. Group IV: rats received cisplatin and nicorandil as in group III as well as wortmannin (15 µg/kg, i.v) for 14 days. Nicorandil exhibited obvious nephroprotective effects via the activation of PI3K/AKT/mTOR pathway. Moreover, nicorandil succeed to reduce the expression of the autophagy markers beclin-1 and LC-3II/I. In parallel, nicorandil showed anti-inflammatory and antiapoptotic effects via inhibition of NF-κB inflammatory pathway and depression of Bax/Bcl-2 ratio. Wortmannin, the PI3K inhibitor, was used to demonstrate the proposed pathway. Our study showed the nephroprotective effects of nicorandil in cisplatin-induced AKI in rats via activation of PI3K/AKT/mTOR signaling cascade, inhibition of autophagy, anti-inflammatory, anti-apoptotic, anti-oxidant activities. Thus, nicorandil could represent a promising renoprotective agent in cancer patients treated with cisplatin.

Nicorandil Regulates Ferroptosis and Mitigates Septic Cardiomyopathy via TLR4/SLC7A11 Signaling Pathway.

This study mainly explored the role of nicorandil in regulating ferroptosis and alleviating septic cardiomyopathy through toll-like receptor (TLR) 4/solute carrier family 7 member 11 (SLC7A11) signaling pathway. Twenty-four male SD rats were randomly divided into control, Nic (nicorandil), LPS (lipopolysaccharide), and LPS + Nic groups and given echocardiography. A detection kit was applied to measure the levels of lactic dehydrogenase (LDH), cardiac troponin I (cTnI), and creatine kinase-MB (CK-MB); HE staining and the levels of glutathione (GSH), malondialdehyde (MDA), total iron, and Fe2+ of myocardial tissues were detected. Moreover, the expression of TLR4 and SLC7A11 were measured by qRT-PCR and the proteins regulating ferroptosis (TLR4, SLC7A11, GPX4, ACSL4, DMT1, Fpn, and TfR1) were checked by western blot. Myocardial cells (H9C2) were induced with lipopolysaccharide (LPS) and transfected with si-TLR4 or SLC7A11-OE. Then, the viability, ferroptosis, and TLR4/SLC7A11 signaling pathway of cells were examined. Nicorandil could significantly increase left ventricular (LV) ejection fraction (LVEF) while reduce LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV). Also, it greatly reduced the levels of LDH, cTnI, and CK-MB; alleviated the pathological changes of myocardial injury; notably decreased MDA, total iron, and Fe2+ levels in myocardial tissues; and significantly increased GSH level. Besides, nicorandil obviously raised protein levels of GPX4, Fpn, and SLC7A11, and decreased protein levels of ACSL4, DMT1, TfR1, and TLR4. After knockdown of TLR4 or overexpression of SLC7A11, the inhibition effect of nicorandil on ferroptosis was strengthened in LPS-induced H9C2 cells. Therefore, nicorandil may regulate ferroptosis through TLR4/SLC7A11 signaling, thereby alleviating septic cardiomyopathy.

Combination of Nicorandil and Beta-Adrenergic Receptor Blockers in Patients with Coronary Artery Disease: A Real-World Observational Study.

BACKGROUND: The effect of combined nicorandil and beta-adrenergic receptor blockers (BBs) compared with that of BBs alone on long-term clinical outcomes in patients with coronary artery disease (CAD) remains undetermined. METHODS: A multicenter retrospective cohort study was performed. Adult patients who had been hospitalized for CAD and treated for angina with a combination of nicorandil and BBs or BBs alone were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular event (MACE) and their components within a follow-up duration of 2.5 years were analyzed using Kaplan-Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. RESULTS: A total of 137,714 patients were screened, of whom 16,912 individuals (mean age: 61.5 years, men: 67.1%) were successfully enrolled. Among the enrolled participants, 4669 received the combined treatment of nicorandil and BBs, while 12,243 received BBs alone. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (hazard ratio [HR] 0.79, 95% conidence interval [CI] 0.72-0.87) and stroke (HR 0.48, 95% CI 0.42-0.54) but not of MI (HR 1.03, 95% CI 0.92-1.15) or all-cause mortality (HR 0.93, 95% CI 0.64-1.37). Sensitivity analyses revealed similar results. CONCLUSIONS: A combined antiangina treatment of nicorandil and BBs may be more effective than treatment of BBs alone in reducing the long-term incidence of MACE in patients with CAD.

Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

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.

Intravenous nicorandil for patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials.

OBJECTIVES: Pilot studies have suggested the potential benefits of intravenous nicorandil for patients with acute decompensated heart failure (ADHF). However, clinical evidence remains limited. The aim of the study was to summarize the efficacy and safety of intravenous nicorandil for the treatment of ADHF. DESIGN: A systematic review and meta-analysis was performed. The search for relevant randomised controlled trials (RCTs) was conducted in PubMed, Embase, Cochrane's Library, Wanfang, and CNKI databases. A random-effects model was employed to combine the results. RESULTS: Eight RCTs contributed to the meta-analysis. Pooled results showed that acute treatment with intravenous nicorandil could significantly improve the symptom of dyspnea at 24 h after treatment, as evidenced by the five-point Likert scale for dyspnea after treatment (mean difference [MD]: -0.26, 95% confidence interval [CI]: -0.40 to -0.13, p < 0.001). Furthermore, nicorandil significantly reduced serum B natriuretic peptide (MD: -30.03 ng/dl, 95% CI: -47.00 to -13.06, p < 0.001), and N-terminal proBNP (MD: -138.69, 95% CI: -248.06 to -29.31, p = 0.01). In addition, nicorandil significantly improved ultrasonic parameters including left ventricular ejection fraction and E/e' at discharge. Moreover, during the follow-up duration of up to 90 days, intravenous nicorandil significantly reduced the incidence of major adverse cardiovascular events (risk ratio [RR]: 0.55, 95% CI: 0.32 to 0.93, p = 0.03). The incidence of treatment-related adverse events was not significantly different between nicorandil and controls (RR: 1.22, 95% CI: 0.69 to 2.15, p = 0.49). CONCLUSIONS: Results of this study suggest that intravenous nicorandil may be an effective and safe treatment for patients with ADHF.

Effect of Nicorandil, Diltiazem, or Isosorbide Mononitrate for Oral Antispastic Therapy After Coronary Artery Bypass Grafting Using Radial Artery Grafts-A Pilot Randomized Controlled Trial (ASRAB-Pilot): Rationale and Study Protocol.

INTRODUCTION: The current evidence for chronic oral antispastic medication use after coronary artery bypass grafting using radial artery grafts (RA-CABG) is controversial. Calcium channel blockers, such as diltiazem, are the most commonly used antispastic medications after RA-CABG; other options include nitrates and nicorandil, but to date no sufficiently powered randomized controlled trials have been conducted to compare their efficacy. METHODS: This is a single-center, open-label, parallel three-arm, pilot randomized controlled trial. Patients without contraindications to any study medications and who successfully underwent RA-CABG surgery will be consecutively screened. Eligible patients will be randomized in a ratio of 1:1:1 (a total of 150 patients, 50 per arm) to receive nicorandil 5 mg orally thrice daily, diltiazem 180 mg orally once daily, or isosorbide mononitrate 50 mg orally once daily for 24 weeks. The primary outcomes are RA graft failure at week 1 and week 24. The secondary outcomes include major adverse cardiovascular event (MACE, a composite of all-cause death, myocardial infarction, stroke, and unplanned revascularization) and angina recurrence. The safety outcomes include hypotension occurrence, withdrawal of renin angiotensin aldosterone system inhibitors, serious adverse events, and other concerned adverse events within 24 weeks. CONCLUSION: This pilot trial will compare the preliminary effects of nicorandil, diltiazem, and isosorbide mononitrate on angiographic and clinical outcomes in patients who have undergone RA-CABG. Recruitment began in June 2020, and the estimated primary completion date is early 2023. Results of this study will provide much needed information for design of large confirmatory trials on the effectiveness of oral antispastic medications after RA-CABG.

Efficacy and safety of nicorandil monotherapy and nicorandil-clopidogrel combination therapy on cardiac function in patients with coronary heart disease.

OBJECTIVES: To compare the efficacy and safety of nicorandil monotherapy and nicorandil-clopidogrel combination therapy on cardiac function in patients with coronary heart disease (CHD). METHODS: The clinical data of 200 patients with CHD were retrospectively analyzed. The patients were divided into two groups according to different treatment methods. Group A (n = 100) received nicorandil-clopidogrel combination therapy (intravenously injected with 25 mg of nicorandil and orally administered 300 mg of clopidogrel for 3 months), and Group B (n = 100) received nicorandil monotherapy (intravenously injected with 25 mg of nicorandil for 3 months). The primary endpoints included cardiac function indices and ST-segment behavior on electrocardiogram (ECG) before and after treatment. The secondary endpoints included adverse reactions, clinical efficacy, platelet aggregation, activated partial thromboplastin time (APTT), high-sensitivity cardiac troponin T (hs-cTnT), and creatine kinase isoenzyme MB (CK-MB) levels after treatment. Multivariate regression analyses were used to assess the contribution of a single drug to the ultimate outcome. RESULTS: After treatment, both groups exhibited significant decreases in brain natriuretic peptide (BNP) and N-terminal pro-hormone BNP levels compared with before treatment, with the levels significantly lower in Group A than in Group B (P < 0.05). After treatment, left ventricular ejection fraction was significantly increased in both groups compared with before treatment, and that was much higher in Group A than in Group B (P < 0.05). After treatment, the frequency and duration of ST-segment depression were decreased in both groups compared with before treatment, and they were much lower in Group A than in Group B (all P < 0.05). The total incidence of adverse reactions in Group A (4.00%) was slightly lower than that in Group B (7.00%), with no significant difference (P > 0.05). Group A (92.00%) had a higher overall response rate than Group B (81.00%) (P < 0.05). CONCLUSION: Nicorandil-clopidogrel combination therapy exhibited enhanced clinical efficacy in patients with CHD. In addition, the combination therapy regulated hs-cTnT and CK-MB levels, which may suggest a better patient prognosis.

Protective Effect of Nicorandil on Contrast-Induced Acute Kidney Injury After Emergency Percutaneous Coronary Intervention.

Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2 µmol/L in serum creatinine (Scr) from baseline within 72 h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72 h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.