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It remains to be elucidated whether Ca2+ antagonists induce pharmacological preconditioning to protect the heart against ischemia/reperfusion injury. The aim of this study was to determine whether and how pretreatment with a Ca2+ antagonist, azelnidipine, could protect cardiomyocytes against hypoxia/reoxygenation (H/R) injury in vitro. Using HL-1 cardiomyocytes, we studied effects of azelnidipine on NO synthase (NOS) expression, NO production, cell death and apoptosis during H/R. Action potential durations (APDs) were determined by the whole-cell patch-clamp technique. Azelnidipine enhanced endothelial NOS phosphorylation and NO production in HL-1 cells under normoxia, which was abolished by a heat shock protein 90 inhibitor, geldanamycin, and an antioxidant, N-acetylcysteine. Pretreatment with azelnidipine reduced cell death and shortened APDs during H/R. These effects of azelnidipine were diminished by a NOS inhibitor, L-NAME, but were influenced by neither a T-type Ca2+ channel inhibitor, NiCl2, nor a N-type Ca2+ channel inhibitor, ω-conotoxin. The azelnidipine-induced reduction in cell death was not significantly enhanced by either additional azelnidipine treatment during H/R or increasing extracellular Ca2+ concentrations. RNA sequence (RNA-seq) data indicated that azelnidipine-induced attenuation of cell death, which depended on enhanced NO production, did not involve any significant modifications of gene expression responsible for the NO/cGMP/PKG pathway. We conclude that pretreatment with azelnidipine protects HL-1 cardiomyocytes against H/R injury via NO-dependent APD shortening and L-type Ca2+ channel blockade independently of effects on gene expression. [ABSTRACT FROM AUTHOR]

Purpose: Azelnidipine, a BCS class II antihypertensive medication, is known for its low solubility and high permeability. In order to enhance its properties, generic GRAS (Generally Recognized as Safe) molecules were utilized in combination with crystal engineering to create novel cocrystal forms of azelnidipine. Methods: By varying the ratios (1:1, 1:2, and 2:1) and utilizing succinic acid and nicotinic acid as building blocks, pharmaceutical cocrystals of azelnidipine were successfully developed. A solvent ultrasonic technique was employed to synthesize these cocrystals, which were then subjected to various analytical techniques such as X-ray diffraction, differential scanning calorimetry, NMR, MASS, and FT-IR to confirm their purity, synthesize cocrystals, and evaluate their stability over a six-month period. X-ray crystal data revealed the characteristics of hydrogen bonding and interactions between the drug and co-formers, while differential scanning calorimetry highlighted differences in thermal behaviour and cocrystal formation. Results: Upon testing solubility and dissolution rate, it was observed that all cocrystals exhibited faster dissolution and higher equilibrium solubility compared to the parent medication. Among the cocrystals, those formed with succinic acid were found to be the most soluble form of azelnidipine. Conclusion: Overall, the development of pharmaceutical cocrystals of azelnidipine has shown promising results in enhancing the drug's solubility and dissolution rate, potentially leading to improved therapeutic outcomes. [ABSTRACT FROM AUTHOR]

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N‐doped CDs (N‐CDs) were synthesized through a single‐step hydrothermal process, using citric acid and urea as precursor materials. The prepared N‐CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N‐CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV–vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N‐CDs and AZEL, leading to fluorescence quenching of N‐CDs as a result of ground‐state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10–200 μg/ml (R2 = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL. [ABSTRACT FROM AUTHOR]

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.

An accurate, precise and simple stability indicating ultraviolet spectroscopic technique was developed to quantify azelnidipine and chlorthalidone, simultaneously was bulk and in combination by absorbance correction method. Ethanol (99.9 %) is used as the solvent in the method. The detection wavelength was found to be 275 nm for chlorthalidone, and 345 nm for azelnidipine. The methodology was validated concerning sensitivity, linearity, reproducibility, accuracy, ruggedness and robustness. Beer-Lamberts law was obeyed in the concentration from 3.2-80 μg mL-1 in case of azelnidipine and 5-125 μg mL-1 in case of chlorthalidone. Detection limits were obtained as 1.74 μg mL-1 for azelnidipine and 2.376 μg mL-1 for chlorthalidone. For azelnidipine, quantification limit was 5.272 μg mL-1, while for chlorthalidone it was 7.2 μg mL-1. Accelerated stability studies were carried out. Azelnidipine and chlorthalidone showed different degradation characteristics under acid, alkali, humidity, heats, and oxidized environment. [ABSTRACT FROM AUTHOR]

The analytical chemistry community has prioritized the implementation of green analytical methods in recent years to minimize the adverse effect on the environment and human beings. The combination of Azelnidipine (AZD) and Olmesartan medoxomil (OLM) was used to manage hypertension. Thus, the present study aimed to develop an RP-HPLC technique to determine AZD and OLM simultaneously by the combined framework of design of experiments and green analytical principles. A central composite design (CCD) was employed for method optimization, with ethanol, and flow rate was selected as critical variables. The effective separation was performed by Agilent Eclipse Plus (C18, 250 × 4.6 mm i.d, 5 μm) with a mobile phase comprising ethanol and 1% v/v aqueous acetic acid in the ratio of 49.5:50.5 I flowing at 1 mL/min, the detection wavelength at 250 nm. The retention time for AZD and OLM were 6.362 and 3.323, respectively. Linearity was perceived over the concentration ranges of 6.4–9.6 and 16–24 μg/mL for AZD and OLM, respectively. The green character of the proposed method showed excellent green results. This innovative eco-friendly, design of experiment technology was adequate for regular analysis of AZD and OLM in pharmaceutical dosage form without harming the environment. [ABSTRACT FROM AUTHOR]

The aim of the present investigation was to prepare an orodispersible tablet of Azelnidipine using superdisintegrant agents like croscarmellose sodium by direct compression method. These formulated tablets were evaluated for drug content, weight variation, friability, hardness, solubility study also, and drug excipient compatibility study. Based on data obtained from pre-compression and post-compression evaluation of batches as well as the factorial design model study f7 batch was selected as the optimized batch. Based on the result obtained from the dissolution profile study it was concluded that the formula responsible for Azelnidipine tablets gives the fastest disintegration as well as absorption of the drug as compared to the conventional marketed tablet dosage form. [ABSTRACT FROM AUTHOR]

A stability-indicating RP-HPLC method for the development of Telmisartan (TTN) and Azelnidipine (ADN) is analyzed in tablet dosage form. The quantification of TTN and ADN combination is done by Supel cosil C18 column (250 mm, 4.6 mm, & 5 µm). Isocratic mobile phase had mobile phase consists of 0.10M Na2SO4(pH 3.6) and acetonitrile (pH 3.6) as 55:45v/v. For this analysis flow rate is measured as 1.00 mL/minute. Wavelength is identified as 258nm to examine TTN and ADN. Stability for both these drugs under distinctive environments were performed. Injected volume is 10 µL. Run time is 8 minute. Retention time is 2.8 and 3.7 respectively. The responses were linear in the concentrate range as 37.4-110.3 for TTN and 2.24-10.51 µg/mL for ADN respectively. Percent comparative standard deviance to precision is 0.193% for TTN, 0.195% for ADN. Percent assay to accuracy for both these drugs are 98.76% and 99.04% respectively. LOD values for TTN and ADN were 0.020 µg/mL and 0.065 µg/mL and LOQ values for TTN and ADN were 0.009 µg/mL and 0.031 µg/mL. Robustness studies revealed that this method is robust by percent comparative standard deviance. This stability-indicating RP-HPLC procedure to both TTN, ADN analysis is more simple, highly sensitive, more precise, highly specific and robust, making it appropriate to the assessment of TTN and ADN in formulation. [ABSTRACT FROM AUTHOR]

The present study is aimed towards developing and validating novel RP-UPLC method for the estimation of Telmisartan and Azelnidipine in their pharmaceutical formulations and to carry out stability studies by forced degradation to ascertain the stability of selected drugs. A mobile phase system consisting of Phosphate buffer: Acetonitrile in the ratio of 70: 30 v/v is used in the method. The analysis of the drugs is accomplished using Acquity UPLC BEH C18 column (1.7 µm, 100 × 2.1 mm ID) at 240nm. The retention time of Telmisartan and Azelnidipine were found to be 2.946 and 5.635, respectively. The forced degradation studies revealed that the degradation of Telmisartan is observed slightly in alkali presence. From the results of the study for the selected drugs, the sample recoveries in all the formulations were within the limits, hence the proposed method can be conveniently adopted for the determination of Telmisartan and Azelnidipine in combined formulation. [ABSTRACT FROM AUTHOR]

Introduction: Azelnidipine is one of the newer Calcium Channel Blockers (CCB) approved in China, Japan, and India. Some studies have found that the blood pressure-lowering effect of azelnidipine is more than amlodipine, and others found the effect similar. Aim: This meta-analysis was conducted to evaluate the efficacy of azelnidipine in managing hypertensive patients by lowering Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Heart Rate (HR) as compared to amlodipine. Methods: PubMed/MEDLINE, Google Scholar, PROQUEST, and International Clinical Trial Registry Platform (ICTRP) were searched for published articles to evaluate the clinical efficacy of azelnidipine in the management of hypertension patients. Data were extracted from the selected 11 randomized clinical trials (RCTs). The risk of bias 2 (RoB2) tool was used for the quality assessment of the included studies, and the random-effects model was used to estimate the effect size. Results: There were no statistically significant differences in the reduction of SBP (Mean Difference, MD: − 1.07; 95% CI: − 4.10, 1.95, p-value: 0.49) and DBP (MD: 0.27; 95% CI: − 2.66, 3.20, p-value: 0.86) between both the drugs. In terms of HR reduction, there was a statistically significant difference (MD: − 3.63; 95% CI: − 5.27, − 2.00, p-value: < 0.0001) between both drugs. Egger's test excluded any publication bias for the included studies (p = 0.21). Meta-regression excluded the effect of the duration of treatment on outcome parameters. Conclusion: Though no significant difference between azelnidipine and amlodipine was found, in terms of reduction in SBP and DBP, azelnidipine reduced heart rate significantly compared to amlodipine. PROSPERO Registration: CRD42023390361. [ABSTRACT FROM AUTHOR]

Childhood muscle-related cancer rhabdomyosarcoma is a rare disease with a 50-year unmet clinical need for the patients presented with advanced disease. The rarity of ∼350 cases per year in North America generally diminishes the viability of large-scale, pharmaceutical industry driven drug development efforts for rhabdomyosarcoma. In this study, we performed a large-scale screen of 640,000 compounds to identify the dihydropyridine (DHP) class of anti-hypertensives as a priority compound hit. A structure-activity relationship was uncovered with increasing cell growth inhibition as side chain length increases at the ortho and para positions of the parent DHP molecule. Growth inhibition was consistent across n = 21 rhabdomyosarcoma cell line models. Anti-tumor activity in vitro was paralleled by studies in vivo. The unexpected finding was that the action of DHPs appears to be other than on the DHP receptor (i.e. , L-type voltage-gated calcium channel). These findings provide the basis of a medicinal chemistry program to develop dihydropyridine derivatives that retain anti-rhabdomyosarcoma activity without anti-hypertensive effects. • 640,000 compounds were screened for potential hits, leads or therapeutic agents for treating rhabdomyosarcoma. • The dihydropyridine (DHP) class of anti-hypertensives were found to be priority compound hits. • The DHP drug azelnidipine was selected as a lead compound for consistent anti-tumor cell activity. • Anti-tumor activity of azelnidipine in vitro was paralleled by studies in vivo. • The action of the DHP drugs was found to be other than on the DHP receptor (i.e. , L-type voltage-gated calcium channel). [ABSTRACT FROM AUTHOR]

Fixed-dose drug combinations promote compliance and optimize prescription schedules. Recently, the FDA approved a film-coated tablet containing azelnidipine (8 mg) and chlorthalidone (6.25 or 12.5 mg) for the treatment of hypertension. A novel gradient mode high-performance liquid chromatography (HPLC) technique was developed and rigorously validated to enable the routine analysis of a fixed-dose combination. Materials and Methods: The stationary phase employed in this study was a Phenomenex Luna C8 column (250 x 4.6 mm, 5 μm particle size). The mobile phase consisted of a mixture of acetonitrile and water, with the addition of 0.1 percent formic acid, employed in a gradient mode. A typical detection wavelength of 256 nm was utilized for both compounds. The validation of this method adhered to the performance parameters outlined in the ICH Q2 (R1) guidelines. Results: This method successfully analyzed azelnidipine (99.58% w/w) and chlorthalidone (100.25% w/w) in a synthetic mixture prepared from their respective commercial tablet formulations. This process was executed to ensure the absence of plagiarism in the revised text. Conclusion: Thus, the technique inferred is ideal for routine examination of fixed-dose tablet formulation. [ABSTRACT FROM AUTHOR]

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.

An efficient, perceptive, sensitive, accurate and economical RP-UPLC method with tunable UV detector has been developed for the simultaneous estimation of telmisartan and azelnidipine in bulk powders and their combined film-coated bilayer tablet dosage form. The proposed method employs Agilent Zorbax Stable Bond (SB) packing C8 (100 mm × 2.1 mm, 2 μm) column, a mobile phase consisting of 0.01 N potassium dihydrogen orthophosphate (pH 4.8) and acetonitrile in 70:30 v/v ratio pumped at a flow rate of 0.3 mL/min, and the UV detector tuned to 257 nm wavelength, which reliably separates all analytes with good resolution. Telmisartan and azelnidipine were eluted from the column at 0.675 and 1.601 min, respectively. Linearity of the telmisartan and azelnidipine determination was observed in the range of 20 – 120 μg/mL and 2 – 12 μg/mL, respectively. Computed values of the validation parameters confidently show that the method is specific, accurate and precise with high sensitivity. Exploration of the analytes under various forced degradation conditions with the help of the proposed method confirms stability-indicating character of the method. The developed method has high efficiency in separating telmisartan and azelnidipine and ensures their stability-indicating assay with good sensitivity and specificity, thus being adapted to the pharmaceutical industry applications. [ABSTRACT FROM AUTHOR]

The prevalence of hypertension and comorbidities such as metabolic syndrome, diabetes mellitus, and chronic kidney disease in India is alarmingly high. Amlodipine, an older-generation calcium channel blocker (CCB), is currently the gold standard for hypertension management in India. However, it has several disadvantages, including reflex tachycardia and pedal edema. Therefore, an effective antihypertensive agent that does not cause these adverse effects and provides end-organ protection is required for the holistic management of hypertension in the country. Azelnidipine is a new-generation CCB that has recently been approved for the treatment of hypertension in India. This review provides an overview of the utility of azelnidipine for hypertension control, including comparisons with traditional CCBs such as amlodipine. It discusses the key antihypertensive effects of azelnidipine as well as its advantages in the prevention of tachycardia and associated complications. In addition, this review highlights the extensive cardio- and renoprotective activities of azelnidipine, including its effects on systolic and diastolic function and urinary albumin excretion. Overall, this substantial body of evidence supports the use of azelnidipine for the treatment of hypertension, especially in India. It suggests that the adoption of azelnidipine as the new gold standard CCB could help India battle its hypertension epidemic. [ABSTRACT FROM AUTHOR]

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.

This study was performed to evaluate the neuroprotective effect of Azelnidipine in cerebral ischemia/reperfusion and to envisage its mechanisms. Twenty-eight adult male Sprague-Dawley rats weighing 200-300 g were randomized into 4 groups (7 rats in each group). Sham (neck dissection without bilateral common carotid artery occlusion), control (30 minutes of bilateral common carotid artery occlusion and reperfusion for 1 hour), vehicle (identical volume of 0.3% carboxymethylcellulose (CMC) orally every day then bilateral common artery occlusion and reperfusion), and Azelnipine-treated rats (7 days of Azelnidipine pretreatment 3 mg/kg/day followed by bilateral common carotid artery occlusion and reperfusion). In addition to brain infarct volume and histopathological assessment, the brain tissues were harvested to evaluate cerebral IL-6, IL-10, TNF-α, ICAM-1, NF-κB p65, and total antioxidant capacity levels. Cerebral levels of IL-6, IL-10, TNF-α, NF-κB p65, and ICAM-1, besides cerebral infarct volume, were significantly elevated in control and vehicle related to sham groups, while total antioxidant capacity was markedly reduced. Azelnidipine treatment resulted in remarkable upregulation of total antioxidant capacity; meanwhile, IL-6, TNF-α, NF-κB p65, and ICAM-1 showed a considerable reduction. Cerebral IL-10 levels were not affected by Azelnidipine pretreatment. Histologically, control and vehicle rats showed severe ischemic injury, which was greatly reversed by Azelnidipine treatment. The current study disclosed that Azelnidipine could markedly reduce cerebral infarct volume and ameliorate histopathological damage in male rats exposed to cerebral ischemia/reperfusion. The neuroprotective effects of Azelnidipine probably stemmed from its anti-inflammatory and antioxidative properties. Azelnidipine had no effect on cerebral IL-10 levels. [ABSTRACT FROM AUTHOR]

A new simple, accurate and precise HPLC method has been developed and validated for estimation of Azelnidipine in its formulation. In RP-HPLC method, a C8 column and methanol: water (85:15), pH adjusted to 3.0 using orthophosphoric acid were used at a flow rate of 1.0 mL/min and detected at 257 nm. The retention time for Azelnidipine was found to be 9.1 min. The developed method was validated for linearity, precision, accuracy, specificity, LOD and LOQ as per ICH guidelines. Linearity was observed in the range of 0.5-25 μg/mL for Azelnidipine and correlation coefficient was found to be 0.9949. LOD and LOQ for Azelnidipine were found to be 0.15 μg/mL and 0.5 μg/mL respectively. The % recovery was found to be 99.8%. The method was applied for estimation of Azelnidipine in its formulation. The assay result was found to be 99.6% of percentage label claim of Azelnidipine. [ABSTRACT FROM AUTHOR]

Simple Summary: Novel pharmacological approaches are needed to improve treatments of advanced cancers, despite the considerable benefit of immunotherapy. New drugs are searched for to complement the activity of monoclonal antibodies targeted to the PD-1/PD-L1 immune checkpoint. Here, we have identified and discussed known drugs which could reinforce immunotherapy based on their capacity to modulate this major checkpoint. The repositioning of these drugs, in particular liothyronine, azelnidipine, niclosamide, and albendazole, may represent an alternative approach to improve cancer treatments, compared to the de novo drug design strategy. The repurposing of a few other established drugs to promote cancer immunotherapy is also presented. Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Azelnidipine is a dihydropyridine used as a calcium channel blocker. The main aim of this study was to develop a validated bio-analytical method (as per US-FDA and EMA guidelines) for in vivo pharmacokinetic and bioequivalence study of azelnidipine in human plasma by LC-MS/MS, API-4000. In this method, the drug was ionized in negative mode and gave adequate response because this drug was highly sensitive and had high electron affinity due to the presence of the electron-withdrawing the nitro group in the structure of azelnidipine. The deprotonated precursor ions [M-H] - at mz-1 581.2 and consistent fragment ion selected was mz-1 491.0. For internal standard, the deprotonated precursor ions [M-H] - at mz-1 269.0 (highest peak) was observed in Q1 MS and characteristic product ions or fragment ions found in Q3 MS were at mz-1 169.8. For plasma extraction, the liquid-liquid extraction technique was used. The calibration concentrated points of azelnidipine were 0.15 to 10.00 ng mL-1 including LLOQ 0.15 ng mL-1, LQC 0.46 ng mL-1, MQC 3.75 ng mL-1 and HQC 7.50 ng mL-1. The LOD value was 0.07 ng mL-1. The result of matrix effect of internal standard (tolbutamide) ranges between 93.51% - 98.68% and 91.94% - 95.07% for azelnidipine, recovery result after extraction of plasma of azelnidipine was 90.73% to 100.46% and for IS it was 95.95% to 98.82%. After administration of film-coated azelnidipine 8mg of test drug at 2.92±0.77h. Cmax obtained was 5.98±1.93ng mL-1 whereas for reference drug it was 6.18±1.96ng mL-1 Cmax at 3.03±0.98h. This method was validated as per regulatory guidelines and is highly selective, specific, highly sensitive and reproducible with low ionic suppression and high recovery, High throughput screening method was successfully applied to in vivo pharmacokinetic and bioequivalence study of azelnidipine. [ABSTRACT FROM AUTHOR]

Introduction: The renoprotective effects of dihydropyridine calcium channel blockers (CCBs) have been established as non-inferior to other classes of antihypertensive drugs. Studying their effect on renal outcome parameters, specifically for amlodipine as monotherapy, in real-world settings can further help in expanding its usage among Indian patients. This study was performed to assess the effects of amlodipine and other dihydropyridine CCBs (cilnidipine, benidipine and azelnidipine) on renal parameters and effectiveness in blood pressure reduction in Indian patients. Methods: The retrospective data of adult patients (> 18 years) with essential hypertensive who were prescribed amlodipine (n = 92), cilnidipine (n = 91), benidipine (n = 70) or azelnidipine (n = 71) as monotherapy were analyzed. The renal outcomes, serum creatinine, estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), microalbumin, urine albumin-to-creatinine ratio (UACR), sodium and potassium levels, and mean changes in BP were analyzed from baseline to 12 months. Appropriate statistical methods were used to determine the significance (p value < 0.05). Results: From baseline to the end of the study, mean serum creatinine changed from 0.98 ± 0.17 to 1.07 ± 0.28 mg/dL with amlodipine, 0.97 ± 0.18 to 1.13 ± 0.50 mg/dL with cilnidipine, 0.98 ± 0.30 to 0.97 ± 0.27 mg/dL wi th benidipine, and 0.99 ± 0.23 to 0.98 ± 0.25 mg/dL with azelnidipine (p = 0.01). The mean microalbumin and UACR were reduced from baseline to the end of the study (p = 0.06 and p > 0.05). No significant changes were observed in BUN, sodium or potassium levels. Overall, for all CCBs, the mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were reduced from baseline to the end of the study (p = 0.002). At the end of the study, the average dose of amlodipine was 7.25 mg, and the average reduction in SBP and DBP per mg dose was 1.54 and 0.57 mmHg. The corresponding numbers for the other CCBs were as follows: cilnidipine, 14.28 mg, 0.26 and 0.01; benidipine, 5.71 mg, 0.41 and 0.11; azelnidipine, 15.88 mg, 0.13 and 0.06. Conclusion: Amlodipine and other CCBs demonstrated good efficacy and similar effects on renal parameters from baseline to end of study. Amlodipine also showed higher potency by demonstrating greater BP reduction at a lower dose. Thus, amlodipine can remain a preferred choice among CCBs, even with the advent of the newer CCBs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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

Objectives: In the work presented here, the degradation behavior of azelnidipine under diverse forced degradation conditions was studied. A stability-indicating liquid chromatographic method was established which could separate and resolve azelnidipine from its degradation products. Further, chemical kinetics under acidic and alkaline conditions were studied, and validation studies were performed. Materials and Methods: Using reversed-phase chromatography, azelnidipine and its formed degradants were resolved using phosphate buffer (pH 3.0) and methanol in a mixture of 10:90% v/v as a mobile phase at a flow rate of 1.0 mL/min. All eluents were detected at a wavelength of 256 nm. Results: Azelnidipine was degraded under acid, alkali, wet heat, and oxidized environment. The pH-dependent rate of hydrolysis of azelnidipine was studied under acidic and alkaline conditions and chemical kinetics were determined. Further, the oxidative degradation product of azelnidipine was synthesized and characterized as 3-(1-benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-6-methyl-4-(3-nitrophenyl) pyridine-3,5-dicarboxylate (dehydro-AZD). Conclusion: The susceptibility of azelnidipine to hydrolysis was attributed to the presence of ester at 3 and 5 positions of 1,4 dihydropyridine. Further, under oxidative conditions, the aromatization of 1,4 dihydropyrinine resulted in dehydro-AZD. Azelnidipine followed the first-order reaction under acid and alkali hydrolysis, and was more susceptible to degradation under acidic conditions. The synthesized and confirmed dehydro-AZD was found as one of the metabolites and impurities of azelnidipine. The evaluated validation parameters ascertained the practicality of the method for the quantification of azelnidipine tablets. [ABSTRACT FROM AUTHOR]

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.

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N-doped CDs (N-CDs) were synthesized through a single-step hydrothermal process, using citric acid and urea as precursor materials. The prepared N-CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N-CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV-vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N-CDs and AZEL, leading to fluorescence quenching of N-CDs as a result of ground-state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10-200 μg/ml (R 2  = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL., (© 2024 John Wiley & Sons Ltd.)

In this study, a physiologically based pharmacokinetic (PBPK) model of the cytochrome P450 3A (CYP3A) substrate azelnidipine was developed using in vitro and clinical data to predict the effects of azole antifungals on azelnidipine pharmacokinetics. Modeling and simulations were conducted using the Simcyp™ PBPK simulator. The azelnidipine model consisted of a full PBPK model and a first-order absorption model. CYP3A was assumed as the only azelnidipine elimination route, and CYP3A clearance was optimized using the pharmacokinetic profile of single-dose 5-mg azelnidipine in healthy participants. The model reproduced the results of a clinical drug-drug interaction study and met validation criteria. PBPK model simulations using azole antifungals (itraconazole, voriconazole, posaconazole, fluconazole, fosfluconazole) and azelnidipine or midazolam (CYP3A index substrate) were performed. Increases in the simulated area under the plasma concentration-time curve from time zero extrapolated to infinity with inhibitors were comparable between azelnidipine (range, 2.11-6.47) and midazolam (range, 2.26-9.22), demonstrating that azelnidipine is a sensitive CYP3A substrate. Increased azelnidipine plasma concentrations are expected when co-administered with azole antifungals, potentially affecting azelnidipine safety. These findings support the avoidance of azole antifungals in patients taking azelnidipine and demonstrate the utility of PBPK modeling to inform appropriate drug use., (© 2024 Published by Elsevier Ltd on behalf of The Japanese Society for the Study of Xenobiotics.)

A novel simple, rapid, sensitive and stability-indicating RP-HPLC method was developed and validated for the determination of azelnidipine (ALDP) and its impurities 1 and 2. Resolution of drug, its potential impurities and degradation products were achieved by RP-HPLC on was performed on Prontosil ODS C18 column (250 mm x 4.6 mm, 5µ) using a mobile phase consisting of methanol and 0.1M sodium acetate 40: 60 (v/v) at a flow rate of 1 ml/min and 231 nm of UV detector. Validation of the method was performed along with formulation analysis and forced degradation studies. The calibration curves of ALDP were linear over a concentration range of 50-300 µg/mL. The method was rapid with a retention time of the impurity 2, impurity and ALDP observed at 3.60, 5.15 and 6.90 min, respectively. The method was applied for the impurities determination in drug tablets and for degradation products determination in a stability study of ALDP. The impurity content in the tablets was quantified as 0.1% of total drug. The method can also be used for rapid and accurate quantification of ALDP in its tablets during stability testing. [ABSTRACT FROM AUTHOR]

Background: Iron overload can cause DNA oxidation which increase TGF β1, type 1 fibrilarprotein and myocardium fibrosis. Myocardium fibrosis is the main cause of death on the state of iron overload. The iron influx towards the cell during iron overload is still unknown, some research suggested LTCC acts as iron influx. This research aims to investigate the role of azelnidipine as type L calcium channel blocker, lowering TGF β1, collagen and myocardium fibrosis. Method: The research subjects consisted of 25 male Balb-C mice(8 weeks, 30-40mg) divided into 5 groups. Group 1 (NaCl+S) 0,3 cc Na Cl 0,9% (I.P) and drug solvent (Aquabidest, CMC and Nipagin) orally. Group 2Fe+S) 0.3 cc 1,5 mg Fe+sucrose (Venofer®) (I.P) and drug solvent (Aquabidest, CMC and Nipagin) orally. Group 3 (Fe+Dfx) 1,5 mg Fe+sucrose (Venofer®) (I.P) and deferasirox 20 mg/kg body weight/day orally, group 4 (Fe+Azl) 1,5 mg Fe+sucrose (Venofer®) (I.P) and azelnidipine 14 mg/day orally and group 5 (Fe+Dfx-Azl) 1,5 mg Fe+sucrose (Venofer®) (I.P) and mixture of deferasirox 20 mg/kg body weight/day and azelnidipine 14 mg/day orally. Fe-sucorse was diluted with NaCl 0.9 %. Intraperitoneal injection were administered intermittently for 60 days of treatment. Result: The highest Expression of TGF β, collagen I and fibrosis area fractions are in group Fe+S. The result of Post Hoc test between 2 treatment groups indicated that there were no difference in TGF β expression between groups NaCl+S with Fe+Dfx (P>0.05), Fe+Dzl (P>0.05). There are no significant in collagen expression between groups NaCl+S with Fe+Dfx (P > 0.05),Fe+Dzl (P>0.05). Conclusion: Azelnidipine, LTCC have roles on the influx of iron into the myocardium, lowering TGF β, collagen Iexpressionsand myocardium fibrosis. [ABSTRACT FROM AUTHOR]

Background: Currently, no drug has been approved for the management of postischemic neuronal damage. Existing studies show that calcium channel blockers have neuroprotective properties, while citicoline is involved in maintaining neuronal integrity. Purpose: This study was envisaged to investigate the effect of azelnidipine (novel calcium channel blocker) alone and in combination with citicoline (phosphatidyl-choline analogue) against ischemic brain damage in Wistar rats. Methods: Previously standardized bilateral common carotid artery occlusion model was used to induce cerebral ischemic injury in Wistar rats. Pretreatment with azelnidipine (1.5 mg/Kg and 3 mg/Kg; p.o.) or citicoline (250 mg/Kg; i.p.) was done every 24 h starting 7 days before the bilateral common carotid artery occlusion surgery. Pharmacological assessments (behavioral, biochemical, mitochondrial, molecular, and histological) were done after 48 h of the reperfusion period. Results: Azelnidipine and citicoline were found to protect the brain from progressive neuronal damage as seen by improved sensorimotor behavior (locomotion, rota rod, and beam balance performance) and reduced oxidative stress (decreased malondialdehyde (MDA), nitrite, increased glutathione (GSH), superoxide dismutase (SOD)). Impairment of mitochondrial enzyme system and increase in the infarct area were found to be arrested by individual treatments with azelnidipine and citicoline. These effects were further potentiated synergistically as the combination of citicoline and azelnidipine was found to decrease glutamate levels, caspase-3 activity and histological alterations as compared to their individual effects. Conclusion: Azelnidipine and citicoline synergistically decrease excitotoxic and oxidative damage against ischemic brain injury in Wistar rats and, therefore, propose a clinically relevant combination for the prevention of postischemic neuronal damage. [ABSTRACT FROM AUTHOR]

Hypertension shows circadian blood pressure rhythms (day–night pattern) that urge the delivery of antihypertensive drugs at the right time in the desired levels. Thus, a bilayered core-in-cup buccoadhesive tablet was formulated that immediately releases olmesartan, to give a burst effect, and controls azelnidipine release, to prolong its therapeutic effect. The main challenge was the poor bioavailability of azelnidipine due to its poor aqueous solubility and first-pass effect. Hence, liquisolid compact buccoadhesive tablets were prepared to enhance solubility, dissolution profiles, and bypass the oral route. Two factorial designs were conducted to study the type and concentration effect of the mucoadhesive polymers on the dissolution and mucoadhesion of olmesartan and azelnidipine. Characterization studies were conducted regarding drug content, surface pH, water uptake, mucoadhesive strength, in vitro release, and ex vivo permeability. The core-in-cup olmesartan/azelnidipine buccoadhesive tablet showed similar release profile to the statistically optimized formulae of each drug. In vitro dissolution study showed enhanced release of azelnidipine than the directly compressed tablets, to comply with the regulatory standards of controlled release systems. In vivo pharmacokinetic study of olmesartan and azelnidipine conducted on human volunteers against Rezaltas® 10/8 mg tablet showed percentage relative bioavailability of 106.12 and 470.82%, respectively. [ABSTRACT FROM AUTHOR]

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.

Objectives: A simple, accurate, and reliable high-performance thin-layer chromatographic technique has been developed and validated for the simultaneous quantitation of azelnidipine and chlorthalidone in bulk and synthetic mixtures., Material and Methods: The procedure was carried out using a precoated silica gel 60 F254 TLC plate with a mobile phase of chloroform, ethyl acetate, and methanol in the ratio of 6.5:3.5:0.6 (by volume). Thin-layer chromatographic densitometry at 240nm was used to quantify medicines chromatographically., Results: Over concentration ranges of 250.0 to 1000.0ng/band for chlorthalidone and 160.0 to 640.0ng/band for azelnidipine, the high-performance thin-layer chromatography technique was quantitated. This technique produced a tight and well-resolved band at retention factors of 0.67±0.02 and 0.24±0.02 for azelnidipine and chlorthalidone, respectively. Data from a linear regression study calibrating this method revealed a strong linear correlation between the two approaches, with regression coefficients of r2>0.99 for both. According to The International Conference for Harmonization of Technical Requirements for Pharmaceuticals for Human Use requirements, the procedures were validated for precision, robustness, accuracy, and specificity., Conclusion: The developed method was also used to simultaneously estimate azelnidipine and chlorthalidone in a synthetic mixture. The results were found to be in exemplary % assay with label claims., (Copyright © 2023 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

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.

Deregulation of brain Ca2+ homeostasis is linked with oxidative stress, mitochondrial dysfunction, neurodegeneration, loss of synaptic plasticity, and cholinergic deficits. Earlier chronic administration of calcium channel blockers (L-type CCBs) has afforded relief in Alzheimer's disease (AD) symptoms. Azelnidipine (AZL) is a long duration L-type Ca2+ channel blocker recently included in anti-hypertensive therapy. The present study reveals the role of AZL in the management of ICV-STZ induced AD in rats. Wistar rats of either sex (aged 12–15 weeks and weight range 260–280 g) were divided into 6 groups in single blind fashion and stereotaxic surgery was performed. Streptozotocin (3 mg/kg) was injected (ICV) in five groups and one group was administered with ACSF. AZL was administered (1.5, 3 and 6 mg/kg; p.o.) to separate groups of ICV-STZ pre-treated rats for 14 successive days. Memory of rats was measured using elevated plus maze and novel object recognition task. After behavioral evaluation, the animals were sacrificed and whole brains were isolated for estimation of AChE activity, TBARS and GSH levels. ICV-STZ treatment increased the brain AChE activity, TBARS level, decreased GSH level, and thereby impaired the memory of rats. The Ca2+ antagonistic property of AZL attenuated the STZ induced derangement of biochemical parameters and resurrected the memory functions in rats. This study exhibited that long-term blockade of the L-type Ca2+ channels using azelnidipine mitigates AD type dementia owing to its neuroprotective and antioxidant properties. [ABSTRACT FROM AUTHOR]

Hypertension is the most common regulating risk factor for cardiovascular disease (CVD) and death; the increased risk associated wi th blood pressure (BP) elevation can be greatly reduced by treatment with antihypertensive drugs that lower both BP and related tar get organ damage. New Ca2+ channel antagonists have been recently developed, especially in the DHP compounds that have considerable higher vascular selectivity, slower onset and longer duration of hypotensive action. The antihypertensive effect of azelnidipine is primarily based on the inhibition of trans-membrane Ca2+ influx through the voltage-dependent channels of vascular smooth muscles. Ca2+ channels are categorized into several subtypes, including L-type, T-type, N-type, P/Q-type, and R-type Ca2+ channels depend on their electrophysiological properties. Clinical studies have demonstrated that azelnidipine markedly reduced heart rate and proteinuria in hypertensive patients by inhibiting sympathetic nerve activity. Azelnidipine has also been confirmed to have cardio-protective, neuroprotective, and anti-atherosclerotic properties, and has also been found to prevent insulin resistance. [ABSTRACT FROM AUTHOR]

Photo-exposure has a crucial effect on the natures of photosensitive pharmaceuticals in addition to their contents in medicines through the photodegradation. Generated photoproducts might be more bioactive and contribute to the expression of adverse side effects. This study aimed to clarify the photochemical behavior of medicines of azelnidipine, which is a member of dihydropyridine antihypertensive drugs, by the evaluation of its photostability and the determination of chemical structures of generated photoproducts. Calblock® tablets and its altered forms (powders and suspensions) were UV-irradiated by a black light. Residual amounts of active pharmaceutical ingredients (APIs) were monitored by high-performance liquid chromatography. The chemical structures of two photoproducts were determined by electrospray ionization tandem mass spectrometry. API of Calblock® tablets was photodegraded with the generation of several photoproducts. Its photodegradability was more significant when Calblock® tablets were crushed or suspended. Structural determination revealed that two photoproducts were benzophenone and a pyridine derivative. It was speculated that these photoproducts were generated by the elimination of diphenyl methylene radical and additional chemical reaction including oxidation and hydrolysis. Azelnidipine was photosensitive and its photodegradation in Calblock® tablets was promoted by the change of the dosage form. This difference might be derived from the light emission efficiency. This study suggests that API contents of Calblock® tablets might decrease when tablets or its altered forms are exposed to sunlight irradiation with the generation of benzophenone, which is a toxicological potent. • Photochemical behaviors of azelnidipine medicine and its altered forms are evaluated. • Azelnidipine in powders and suspensions are photodegraded by UV irradiation. • Main photoproduct of azelnidipine is benzophenone. • Another photoproduct of azelnidipine is a pyridine derivative. • Benzophenone is generated by the elimination of a diphenyl methylene moiety. [ABSTRACT FROM AUTHOR]