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Azelnidipine is a novel dihydropyridine calcium channel antagonist and Metoprolol succinate is a beta blocker, this combination was approved by CDSCO for Phase III clinical trial in April 2021. This combination is utilized to achieve a better outcome in the treatment of stage 2 hypertension. The present research includes an HPLC and Absorbance Correction UV method for the determination in synthetic mixture.The HPLC chromatography was performed using a gradient technique on a reversed-phase C18 column with mobile phase based and optimized depending on the polarity of the molecules. The Unesphere C18 column Agela Tech., (250 mm x 4.6 mm i.d, 5 μm,) as stationary phase and Acetonitrile: Phosphate Buffer pH 3.5 (40:60%v/v) as mobile phase with UV detection at 275 nm at 1 ml/min for gradient elution was used to achieve chromatographic separation over the linearity 10.0 - 30.0 μg/mL and 50.0–150.0 μg/mL with r2 0.9995 and 0.9993 for Azelnidipine and Metoprolol succinate respectively. The retention time was found to be 6.367 and 2.308 min for Azelnidipine and Metoprolol succinate respectively.% RSD of intraday precision of AZL and MET was found to be 0.01 – 0.03% and 0.01 – 0.03%, respectively. Interday presion was found to be 0.02 – 0.06% and 0.02 – 0.05%, respectively which are indicated that the method is precise.% recovery for AZL and MET by this method was found in the range of 99.85 - 100.76% and 99.23 - 99.89%, respectively. The system suitability test parameters theoretical plates were found to be 7042.56 (AZL) and 2231.74 (MET) and tailing factor was found to be 1.47 (AZL) and 1.52 (MET).The Absorbance Correction UV method was developed validated at 313 nm (λmax of Azelnidipine) and 275.40 nm (λmax of Metoprolol succinate) in methanol: distilled water (20:80, v/v) for estimation of AZL and MET respectively and show linearity 5.0 - 25.0 μg/mL and 25.0 - 125.0 μg/mL with r2 0.9998 and 0.9991 for Azelnidipine and Metoprolol succinate respectively.% RSD of intraday precision of AZL and MET was found to be 0.46 – 0.64% and 0.42 – 0.71%, respectively and for interday precision was found to be 0.40 – 0.65% and 0.22 – 0.75%, respectively.% recovery for AZL and MET by this method was found in the range of 100.50 - 100.77% and 100.30 - 100.78%, respectively. The value of% RSD within the limit indicated that the method is accurate and% recovery shows that there is no interference from the excipients.Both methods were validated as per ICH Q2(R1) guidelines. The analytical method validation parameters were found to be as per acceptance criteria. In terms of accuracy and precision, statistical testing employing an analysis of variance test did not find any significant differences between the two methods. The ICH Q2R1 recommendations extensive statistical validation of the two established methodologies, proving their effective use in the simultaneous study of the two medications in bulk and tablets made within the laboratory.The Analytical eco scale (AES), National environmental method index (NEMI), Green analytical procedure index (GAPI), and software-based Analytical greenness metric (AGREE) tools were used to assess the ecological impact of the new UV spectrophotometric technique and HPLC method. This assessment confirmed the method's environmental friendliness in terms of solvent usage, chemical compounds, energy consumption, and trash creation. Both methods can be used to successfully analyze Azelnidipine and Metoprolol succinate in combination dose form without interference from excipients. There were no spectral or chromatographic interferences from formulation excipients discovered. Because the proposed procedures are simple, quick, precise, and accurate, they were effectively used to determine Azelnidipine and Metoprolol succinate in their dose forms. To evaluate the greenness and whiteness of an analytical method, a reliable assessment of the health and environmental risk associated with chemical use is essential. An objective and useful way of risk assessment should consider all pertinent characteristics of substances utilized, the actual quantities required for method implementation, and the result of the assessment should be quantified using a standard unit.

Epidemiological and mechanistic studies suggest that some US Food and Drug Administration (FDA)-approved drugs can reduce the incidence of cancer and inhibit tumor growth. Therefore, investigating FDA-approved drugs for cancer chemoprevention is a promising strategy. In this study, we screened FDA-approved drugs and found that azelnidipine, a Ca channel blocker widely used in the treatment of hypertension, inhibits the growth of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. We identified that MEK1/2 were direct targets of azelnidipine through pull-down assay and cellular thermal shift assay. Azelnidipine could suppress kinase activity of MEK1/2 through in vitro kinase assay. Hypophosphorylation of ERK1/2 decreased the levels of Cyclin D1/CDK6 in ESCC cells after azelnidipine treatment. More importantly, azelnidipine, like trametinib, inhibited the growth of ESCC in vivo. In conclusion, azelnidipine, a novel dual MEK1/2 inhibitor, exerted antitumor effects against ESCC cell lines and patient-derived xenograft in ESCC.

Abstract Background Azelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported. Case presentation In the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment. Conclusions Azelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Mohammad Yasin Karami,1,2 Nasrin Mansournia,1 Neda Bagherian,3 Alireza Makarem,4 Nader MoeinVaziri,5 Sahar Borna,6 Amir Hossein Pourdavood,7 Iman Shamohammadi4 1Metabolic Disease Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran; 2Breast Disease Research Center, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 3Department of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 4Department of Urology, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 5Department of Surgery, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; 6Student Research Committee, Faculty of Medicine, Sari University of Medical Sciences, Sari, Iran; 7Department of Surgery, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, IranCorrespondence: Neda BagherianDepartment of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, IranTel +98 9177021044Email bagheriannn@gmail.comObjective: To evaluate the effects of azelnidipine-carboxyl methyl cellulose (AZL-CMC) gel and carboxyl methyl cellulose 2% gel (CMC) on the healing of full-thickness skin wounds of diabetic rats.Methods: Fifteen Sprague Dawley male rats were studied. The rats were divided into three groups: AZL-CMC gel-treated, CMC 2% gel-treated, and control group. Wounds were assessed by wound area measurement every 3 days and histopathology samples were collected at 4, 7 and 12 days post wounding to evaluate the healing process using stereological study. Mann–Whitney U-test repeated measurement and non-parametric one-way analysis of variance (ANOVA) were used to analyze the data using SPSS, version 18.Results: Numerical density of the fibroblasts of the AZL-CMC gel treated group was 59.17±2.69 (×104/mm3) and higher than the control 22.64±1.34 (×104/mm3) and CMC 2%-treated groups 40.80±5.27 (×104/mm3), respectively, PConclusion: The healing of AZL-CMC gel-treated wound was better than the control wounds, grossly. Wound healing processes and wound closure in the intervention group began sooner and was completed more quickly. The quantitative and qualitative parameters showed the significant wound healing effect of the AZL-CMC gel-treated group.Keywords: wound healing, azelnidipine, streptozotocin, diabetic, rat

Reduced bioavailability of azelnidipine is related to its poor aqueous solubility and extensive first-pass metabolism, which hinder its efficacy. These problems were addressed by implementing (1) a liquisol technique for promoting the dissolution rate in a controlled-release manner and (2) a core-in-cup bucco-adhesive drug delivery system as an alternative to the oral route. A 33 factorial design was used to study the effects of polymer type (sodium carboxymethyl cellulose (CMC Na), chitosan, or Carbomer P940) concentration (5, 10 or 15 %) and preparation technique (simple mix, liquisol or wet granulation) on the dissolution and mucoadhesion of core-in-cup azelnidipine buccoadhesive tablets. Tablet micromeritics, swelling index, mucoadhesive strength and in vitro release were characterized. Statistical analyses of these factors show ed significant effects on the studied responses, where F#16 prepared by the liquisol technique and containing 15 % CMC Na was chosen with an overall desirability of 0.953.

Flaviviruses, represented by Zika and dengue virus (ZIKV and DENV), are widely present around the world and cause various diseases with serious consequences. However, no antiviral drugs have been clinically approved for use against them. Azelnidipine (ALP) is a dihydropyridine calcium channel blocker and has been approved for use as an antihypertensive drug. In the present study, ALP was found to show potent anti-flavivirus activities in vitro and in vivo. ALP effectively prevented the cytopathic effect induced by ZIKV and DENV and inhibited the production of viral RNA and viral protein in a dose-dependent manner. Moreover, treatment with 0.3 mg/kg of ALP protected 88.89% of mice from lethal challenge. Furthermore, using the time-of-drug-addition assay, the enzymatic inhibition assay, the molecular docking, and the surface plasmon resonance assay, we revealed that ALP acted at the replication stage of the viral infection cycle by targeting the viral RNA-dependent RNA polymerase. These findings highlight the potential for the use of ALP as an antiviral agent to combat flavivirus infections.

Background: The optimal therapy in patients with heart failure preserved ejection fraction (HFpEF) and hypertension (HT) has not been revealed. The beta blocker (BB) and the renin angiotensin aldosterone system inhibitor (RAAS-I) are recommend as class IIa in patients with HFpEF. The calcium channel blocker (CCB), a major anti-hypertensive drugs in Japan, is also recommend as class IIa in patients with HFpEF. However, the difference between azelnidipine, an L type CCB, and cilnidipine, an N type CCB, is unclear. We investigated the difference between azelnidipine and cilnidipine in patients with HFpEF and HT. Methods: Twenty-five consecutive HFpEF patients treated with BB and RAAS-I from April 2013 to March 2015 were enrolled. Initially, cilnidipine was used, and then switched to azelnidipine. Age, gender, blood pressure (BP), heart rate (HR), blood tests, echocardiography, and cardiac-scintigraphy (123I-metaiodobenzylguanidine: MIBG) were measured before and after six months from azelnidipine administration. Results: There was no statistically significant difference in BP. B type natriuretic peptides were significantly reduced (pre-state: 195.4 ± 209.7 pg/ml and post-state: 140.7 ± 136.4 pg/ml, p = 0.050). In echocardiography, the TEI index tended to be decreased (pre-state: 0.47 ± 0.15 and post-state: 0.42 ± 0.08, p = 0.057). As for MIBG, there was no significant change in the heart/mediastinum ratio. However, the washout rate was significantly reduced (pre-state: 44.7 ± 12.2 and post-state: 40.7 ± 12.1, p = 0.011). In addition, there was no statistically significant change, although HR tended to decrease by switching to azelnidipine (pre-state: 62.7 ± 11.6 and post-state: 61.8 ± 16.5, p = 0.373). Conclusions: In patients with HT and HFpEF, azelnidipine improved the severity of HF and cardiac sympathetic nerve activity compared with cilnidipine.

Strategies boosting both innate and adaptive immunity have great application prospects in cancer immunotherapy. Antibodies dual blocking the innate checkpoint CD47 and adaptive checkpoint PD-L1 or TIGIT could achieve durable anti-tumor effects. However, a small molecule dual blockade of CD47/SIRPα and TIGIT/PVR pathways has not been investigated. Here, an elevated expression of CD47 and PVR was observed in tumor tissues and cell lines analyzed with the GEO datasets and by flow cytometry, respectively. Compounds approved by the FDA were screened with the software MOE by docking to the potential binding pockets of SIRPα and PVR identified with the corresponding structural analysis. The candidate compounds were screened by blocking and MST binding assays. Azelnidipine was found to dual block CD47/SIRPα and TIGIT/PVR pathways by co-targeting SIRPα and PVR. In vitro, azelnidipine could enhance the macrophage phagocytosis when co-cultured with tumor cells. In vivo, azelnidipine alone or combined with irradiation could significantly inhibit the growth of MC38 tumors. Azelnidipine also significantly inhibits the growth of CT26 tumors, by enhancing the infiltration and function of CD8+ T cell in tumor and systematic immune response in the tumor-draining lymph node and spleen in a CD8+ T cell dependent manner. Our research suggests that the anti-hypertensive drug azelnidipine could be repositioned for cancer immunotherapy.

Wound healing is a natural response to restore the injured tissue to normal. Wound healing is also complicated process involving different cellular, molecular and biochemical mechanisms and various types of cytokines and growth factors. Calcium channel blockers belong to cardiovascular medicine and administrated to treatment of hypertension, angina and cardiac arrhythmia because of vasodilatory effect. Calcium channel blockers is divided to dihydropyridine and non-dihydropyrine. The potential of both dihydropyridine and non-dihydropyrine calcium channel blockers in wound healing have been reported in different animal models and in vitro previously. Amlodipine, verapamil, diltiazem, nifedipine, and azelnidipine are calcium channel blockers that indicated wound healing property. The various mechanisms that involve in wound healing effect of calcium channel blockers are discussed in this article.

Abstract Background Numerous evidences suggest that diabetic heart is characterized by compromised ventricular contraction and prolonged relaxation attributable to multiple causative factors including calcium accumulation, oxidative stress and apoptosis. Therapeutic interventions to prevent calcium accumulation and oxidative stress could be therefore helpful in improving the cardiac function under diabetic condition. Methods This study was designed to examine the effect of long-acting calcium channel blocker (CCB), Azelnidipine (AZL) on contractile dysfunction, intracellular calcium (Ca2+) cycling proteins, stress-activated signaling molecules and apoptosis on cardiomyocytes in diabetes. Adult male Wistar rats were made diabetic by a single intraperitoneal (IP) injection of streptozotocin (STZ). Contractile functions were traced from live diabetic rats to isolated individual cardiomyocytes including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (± dL/dt) and intracellular Ca2+ fluorescence. Results Diabetic heart showed significantly depressed PS, ± dL/dt, prolonged TPS, TR90 and intracellular Ca2+ clearing and showed an elevated resting intracellular Ca2+. AZL itself exhibited little effect on myocyte mechanics but it significantly alleviated STZ-induced myocyte contractile dysfunction. Diabetes increased the levels of superoxide, enhanced expression of the cardiac damage markers like troponin I, p67phox NADPH oxidase subunit, restored the levels of the mitochondrial superoxide dismutase (Mn-SOD), calcium regulatory proteins RyR2 and SERCA2a, and suppressed the levels of the anti-apoptotic Bcl-2 protein. All of these STZ-induced alterations were reconciled by AZL treatment. Conclusion Collectively, the data suggest beneficial effect of AZL in diabetic cardiomyopathy via altering intracellular Ca2+ handling proteins and preventing apoptosis by its antioxidant property.