Targeting ELK-1 transcription factor and mechanosensitive MDM4 receptor using an HCN channel blocker alleviates lung fibrosis.

BackgroundThe PREVENT-MINS trial investigated whether perioperative heart rate reduction with ivabradine could prevent myocardial injury after noncardiac surgery (MINS). Although ivabradine modestly reduced heart rate, it did not reduce the incidence of MINS in the intention-to-treat analysis. This per-protocol analysis of the PREVENT-MINS trial, with a post-hoc biomarker substudy, evaluated whether perioperative iva bradine modifies postoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations, a marker of perioperative cardiovascular risk.MethodsThis analysis included 2008 participants who received ≥ 1 dose of study drug, underwent surgery, and had NT-proBNP and troponin measured (ivabradine: n = 1,001; placebo: n = 1,007). Postoperative NT-proBNP levels and changes from baseline (ΔNT-proBNP) were compared by treatment allocation. Clinical outcomes and safety endpoints from the parent trial were evaluated. Analysis of covariance (ANCOVA) assessed ivabradine’s effect on postoperative NT-proBNP after adjustment for baseline values and clinical covariates.ResultsMINS occurred in 17.7% of ivabradine-treated vs. 15.7% of placebo patients (RR 1.13; 95% CI: 0.93–1.37; P = 0.23). Median postoperative NT-proBNP was higher with ivabradine than with placebo (418.0 vs. 333.5 pg mL–1; P < 0.001), as were ΔNT-proBNP values (215.1 vs. 154.0 pg mL–1; P < 0.001). After adjustment for baseline and relevant clinical covariates, ivabradine was independently associated with an approximately 82% increase in postoperative NT-proBNP (Δlog = 0.59 ± 0.19; 95% CI: 26–164).ConclusionsIvabradine did not reduce the incidence of MINS and was associated with greater postoperative NT-proBNP release. Perioperative heart rate reduction with ivabradine may elevate markers of cardiac stress without measurable clinical benefit.

Development of Ivabradine Hydrochloride Nanosuspension Containing Gel for Transdermal Delivery: In Vitro and Ex Vivo Characterization

Introduction: Ivabradine (IVAB) is an effective heart-rate lowering drug used in patients with heart failure. However, its potential protective effect in the context of doxorubicin (DOXO)-induced cardiomyopathy, a serious complication of anthracycline chemotherapy, remain poorly understood. Aims: 1) To assess the effects of IVAB on cardiac remodeling in a murine model of DOXO-induced cardiomyopathy, and 2) to investigate its potential interaction with the renin-angiotensin system, as the cardioprotective effects of IVAB may extend beyond heart rate reduction. Methods: C57BLC/6 female mice (n=36) were allocated into 2 groups: control (n=4) and treatment by DOXO (n=32). DOXO administration (4 mg/kg/week, intraperitoneal injections) was performed over 5 weeks and followed by a 10 weeks gavage treatment with either water (H 2 O), IVAB (10 mg/kg/day), or metoprolol (METO) (100 mg/kg/day). Heart function was assessed by echocardiography every two weeks over a 16-week period. At the end of the study, fibrosis levels and angiotensin II type 1 receptor (AT 1 R) expression in the heart and kidneys were evaluated using picrosirius red (PSR) staining and in vitro 125 I-[Sar 1 , Ile 8 ]-Angiotensin II autoradiography, respectively. Statistical analyses were conducted using One-Way ANOVA and paired t-tests. Results: After completion of DOXO injections, all mice demonstrated a lower cardiac function versus baseline (-19%, p&lt;0.0001) and higher heart rate (+5%, p&lt;0.05). During treatment, only IVAB reduced heart rate (-9%, p&lt;0.0001) and improved the cardiac function (+8%, p&lt;0.05) when compared to H 2 O group. One week after treatment completion, 1) cardiac function in IVAB group was decreased (-8%, p&lt;0.01) when compared to end of treatment; and was similar to the other groups; 2) there was no difference in cardiac mass between groups; 3) cardiac fibrosis was increased in METO (+40%, p&lt;0.05) when compared to control; 4) renal fibrosis was increased in all DOXO-groups vs controls (H 2 O +47%, p=0.055; IVAB +90%, p&lt;0.001 and METO +47%, p=0.058); and 5) renal AT 1 Rs were reduced (-47%, p&lt;0.01) only in the DOXO-H 2 O group, while treatment with IVAB and METO preserved these levels at values comparable to controls. Conclusions: Improved cardiac function by IVAB is not due to reduced fibrosis, despite sustained normal renal AT 1 R expression. This may explain the rapid relapse in cardiac dysfunction once the drug is stopped.

Objective: The current work intended to build a robust, precise, accurate, and specific HPLC method for the measurement of Ivabradine in tablet dosage form and in bulk, using an advanced analytical techniques. Materials and Methods: Both perception and head part examination were used to control the basic bounds. In this investigation, an enhanced fluid chromatography method that may be used for the evaluation of Ivabradine HCL was developed through the use of the Quality by Design approach. The method was developed using the C18 segment and a portable stage that contained 0.1 M potassium dihydrogen orthophosphate and acetonitrile in the ratio 35:65 at a flow rate of 1.0 ml/min. A PDA indicator at 288 nm was used to finish the discovery process. Results: Under these perfect conditions, the baseline drug separation may be completed in less than 3.0 minutes with good resolution. The discovery procedure was completed by using a PDA indicator at 288 nm. The improved test settings were validated by adhering to ICH Q2 (R1) guidelines. Conclusion: The methods that were suggested have been found to be effective and explicit, making them suitable for regular examination of the structure of tablets containing ivabradine hydrochloride.

Objective: To investigate the effects of ivabradine tablets combined with milrinone on arterial blood flow and cTnI in patients with acute myocardial infarction (AMI) combined with heart failure (HF). Methods: A randomised double-blind, placebo-parallel controlled clinical study protocol was adopted to select 78 patients with AMI combined with HF who attended the cardiology care unit of our hospital from January 2022 to January 2024, and randomly divided them into 2 groups of 39 patients each. Both groups were given conventional treatment, with Bmilrinone combined with placebo for oral administration in the control group and milrinone combined with ivabradine hydrochloride tablets for oral administration in the observation group. Compare the clinical efficacy and the occurrence of adverse reactions between the two groups. Compare the arterial blood flow indexes [cardiac index (CI), left ventricular ejection fraction (LVEF), global end-diastolic volume index (GEDVI), systemic vascular resistance index (SVRI), early diastolic/late diastolic LV valvular flow velocity (E/A ratio)], cardiac enzymology indexes [cardiac troponin I (cTnI), troponin T (cTnT)], and cardiac enzymes [cardiac troponin I (cTnI), troponin T (cTnT)] in the 2 groups before and after treatment, lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB)], circulating endocrine hormone levels [renin activity (PRA), angiotensin II (Ang II), aldosterone (Ald)] and quality of life scoring indexes [Seattle Angina Scale (SAQ), Pittsburgh Sleep Quality Index (PSQI)]. Results: After treatment, the total clinical effectiveness rate of the observation group (87.18%) was significantly higher than that of the control group (66.67%) (P &lt; 0.05). The CI, LVEF, E/A ratio and SAQ scores of the observation group were significantly higher than those of the control group, and the scores of GEDVI, SVRI, cTnI, cTnT, LDH, CK-MB, PRA, Ang II, Ald and PSQI were significantly lower than those of the control group, which were significantly different (P &lt; 0.05). There was no significant difference in the comparison of the incidence of adverse reactions between the 2 groups (P &gt; 0.05) The incidence of adverse reactions in the 2 groups was not significantly different (P &gt; 0.05). Conclusion: Ivabradine tablets combined with milrinone in the treatment of AMI combined with HF patients with significant efficacy, can effectively reduce myocardial injury, stabilise arterial haemodynamics, improve the cardiac function of the patients, and does not increase the adverse effects of drugs.

This study aimed to investigate the potential role of cesium chloride (CsCl), ivabradine (IVA), and isoproterenol (ISO) on the sensory transmission of bladder afferents to graded urinary bladder distension (UBD). We specifically selected these drugs to target the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels to determine their role in afferent encoding. The bladders of C57BL/6 female mice were harvested with attached pelvic nerves in continuity, and the stimulus-response function (SRF) of bladder afferents to stepped bladder distension (20, 40, 60, 80 cmH2O) was recorded by single-fiber recordings. Their changes in SRF to bath application of CsCl, IVA, and ISO were then evaluated. The presence of HCN on bladder afferent endings was assessed through immunohistological staining on bladder sections from mice with genetically labeled bladder afferents. IVA and ISO did not significantly reduce afferent responses to UBD, whereas CsCl increased afferent responses. Bladder afferents in the pelvic nerve pathway were categorized into low-firing (LF, < 10 Hz) and high-firing (HF, > 10 Hz) groups. SRF in both the LF and HF groups showed similar trends with no significant changes in response to IVA and ISO. CsCl increased SRF only in the HF group but not in the LF group. Immunohistological staining revealed that HCN1 does not extensively co-localize with afferent endings, showing only sporadic presence. Our targeted pharmacological studies with single-fiber recordings and immunohistological staining collectively suggest that HCN channels do not play a significant role in bladder afferent sensory transmission.

A simple, accurate, and precise RP-HPLC method was developed and validated for the simultaneous estimation of Carvedilol (CDL) and Ivabradine (IVD) in bulk and pharmaceutical dosage forms. The chromatographic separation was achieved using a C18 column with a mobile phase consisting of a suitable buffer and acetonitrile in an optimized ratio. The method exhibited excellent linearity in the concentration range of 1–5 µg/ml for both CDL and IVD with correlation coefficients (r²) of 0.9996 for each drug. System suitability parameters, such as retention time, tailing factor, and number of theoretical plates, were within acceptable limits, ensuring efficient system performance. The recovery study confirmed the accuracy of the method, with percent recoveries ranging between 97.13% and 98.72% for both drugs. The method also demonstrated excellent repeatability, day-to-day precision, analyst-to-analyst reproducibility, and robustness, with %RSD values consistently below 1.5%. Furthermore, forced degradation studies confirmed the stability-indicating nature of the method. This validated method can be effectively applied for routine quality control and stability testing of CDL and IVD in pharmaceutical formulations.

This study explores the molecular pathways through which Ivabradine (IVN) exerts protective effects against Cyclophosphamide (CP)-induced hepatotoxicity, aiming to identify the underlying mechanisms involved. Animals were assigned at random into four groups (10 rats in each group): Group 1 was administered 1 mL of distilled water orally for 10 consecutive days, along with a single intraperitoneal injection of 0.9% saline on the seventh day. Group 2 received distilled water for 10 days and a single CP injection (200 mg/kg, IP) on day 7. Groups 3 and 4 were administered IVN at either 5 or 10 mg/kg orally each day for 10 consecutive days, plus CP on day 7. Rats were euthanized for biochemical, histological, immunostaining, qRT-PCR, and western blot assessments. Rats treated with CP exhibited notable elevations in liver enzymes (ALT, AST) along with decreased levels of antioxidant indicators (HO-1, Nrf2, GSH). Concentrations of MPO, MDA, and iNOS, along with IL-1β, TNF-α, and IL-6, were markedly elevated (p < 0.01). Immunostaining showed elevated NF-kB p65 and caspase-9, aligning with observed liver histopathology. Conversely, IVN administration reduced hepatic enzymes and alleviated tissue alterations. It provided antioxidant defense by correcting redox imbalance and lowering inflammation through targeting the p38MAPK/NF-κB p65 axis and the JAK1-STAT3 pathway(p < 0.01). IVN also prevented CP-induced PI3K-Akt suppression and reduced caspase-related apoptotic activity. The current findings indicate that IVN could represent a valuable treatment option to mitigate CP-induced liver injury via its antioxidant, anti-inflammatory, and apoptosis- suppressing properties, thereby supporting the need for further exploration in future studies.

Formulation and Assessment of Novel Ivabradine Hydrochloride Microspheres Using Synthetic Polymers

Quantitative spectrophotometric determination of ivabradine hydrochloride in pharmaceutical formulations based on redox reaction using cerric(IV) ammonium sulphate

Introduction: Blood pressure-lowering medications can reduce or even reverse left ventricular (LV) hypertrophy and myocardial fibrosis induced by chronically elevated blood pressure. However, in patients with resistant hypertension (HPT), high blood pressure often remains unresponsive to anti-hypertensive treatment. Therefore, the search for novel therapeutic strategies that would help preserve or restore myocardial properties and, hence, LV function even under the effect of persistently elevated blood pressure has remained of significant importance. Hypothesis: Considering that a competitive mineralocorticoid receptor antagonist spironolactone (SL) could alleviate HPT-induced myocardial fibrosis, whereas a treatment with a heart rate-lowering drug ivabradine (IVA) was shown to mitigate the scale of concentric hypertrophy and LV dysfunction, it has been hypothesized that a combination of these two compounds might benefit myocardial properties and cardiac function even in the presence of chronically elevated blood pressure. Methods: Twenty male, 7-week-old Dahl salt-sensitive (DSS) rats were placed on a high-salt diet (8% NaCl) for 7 weeks to induce chronic, self-sustaining HPT. Then all HPT rats were switched back to a normal-salt diet (0.3% NaCl) and randomized in two experimental groups to receive ether a combined treatment (HPT-T) with IVA (10 mg/kg/day) and SL (20 mg/kg/day) or the vehicle only (HPT-V) for 8 weeks via intraperitoneal ALZET osmotic pumps. Ten age-matched male DSS rats fed a normal-salt diet only were used as control. Heart rate and peripheral blood pressure were evaluated every week in conscious rats for the duration of the study using a CODA tail-cuff plethysmography system. At the end of an experimental period, osmotic pumps were removed to terminate the treatment, and 1 week later, central (aortic) and cardiac hemodynamic parameters were assessed in isoflurane-anesthetized rats using a Millar micro-tip pressure catheter attached to a PowerLab data acquisition system. Subsequently, rats were euthanized, and their hearts were excised, weighed and processed to paraffin for histology and quantitative morphology. Statistical analysis was performed using Prism 6 software. Results: During 8 weeks of treatment, mean arterial pressure (MAP) had remained persistently elevated in both groups of HPT rats by ~27% (P≤0.001) compared to control, whereas heart rate had been solely reduced in HPT-T rats by ~38% (P≤0.001) and ~27% (P≤0.001) compared to HPT-V and control rats, respectively. After cessation of treatment, heart rate became similar in all rats, while the level of MAP remained significantly higher in HPT groups. The assessment of aortic (central) and cardiac hemodynamics revealed a marked reduction in central MAP (149.4±4.3 vs. 167.5±3.3 mmHg, P≤0.01) and peak systolic LV pressure (169.8±6.5 vs. 187.2±5.4 mmHg, P≤0.01) in rats from HPT-T group compared to HPT-V rats. Surprisingly, a decrease in central blood pressure detected in HPT-T animals coincided with an evident decline in LV contractility. The morphologic examination of the hearts revealed that chronic HPT did induce relatively comparable scale of LV hypertrophy (P≤0.001) and myocardial fibrosis (P≤0.01) in two HPT groups. However, in contrast to HPT-V group, the rats in HPT-T group showed a marked increase in myocardial density of CD68-positive monocytes/macrophages (228.8±12.5 vs 62.4±7.1 cells/mm 2 , P≤0.0001). Conclusion: Our findings demonstrate that a cotreatment of chronically HPT rats with IVA and SL did not improve myocardial tissue properties but led to a sustained decrease in LV and central blood pressure that was corresponded with myocardial inflammation and reduction in LV contractility. Supported by Camden Health Research Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Duchenne muscular dystrophy (DMD), a severe muscle disease caused by mutations in the gene encoding for the intracellular protein dystrophin, is associated with impaired cardiac function and arrhythmias. A causative factor for complications in the dystrophic heart is abnormal calcium (Ca) handling in ventricular cardiomyocytes, and restoration of normal Ca homeostasis has emerged as therapeutic strategy. Here, we used a rodent model of DMD, the dystrophin-deficient DMDmdx rat, to test the following hypothesis: chronic administration of ivabradine (IVA), a drug clinically approved for the treatment of heart failure, improves Ca handling in dystrophic ventricular cardiomyocytes and thereby enhances contractile performance in the dystrophic heart. Intracellular Ca measurements revealed that 4-months administration of IVA to DMDmdx rats significantly improves Ca handling properties in dystrophic ventricular cardiomyocytes. In particular, IVA treatment increased electrically-evoked Ca transients and speeded their decay. This suggested enhanced sarcoplasmic reticulum Ca release and faster removal of Ca from the cytosol. Chronic IVA administration also enhanced the sarcoplasmic reticulum Ca load. Transthoracic echocardiography revealed a significant improvement of cardiac systolic function in IVA-treated DMDmdx rats. Thus, left ventricular ejection fraction and fractional shortening were enhanced, and end-systolic as well as end-diastolic diameters were diminished by the drug. Finally, chronic IVA administration neither significantly attenuated cardiac fibrosis and apoptosis, nor was vascular function improved by the drug. Collectively our findings suggest that long-term IVA administration enhances contractile function in the dystrophic heart by improvement of Ca handling in ventricular cardiomyocytes. Chronic IVA administration may be beneficial for DMD patients.

Carivalan® pharmaceutical formulation, which includes carvedilol and ivabradine hydrochloride, is commonly prescribed for alleviating pain associated with angina. Solid contact ion-selective electrodes with wide range of applications have been developed for analysis of these two active ingredients. Those types of electrodes have common drawbacks. Aside from development of aqueous layer, the incorporated ion exchanger in plasticized membrane is usually unable to differentiate in sensing between two similarly charged lipophilic organic ions. These flaws impeded simultaneous quantification of carvedilol and ivabradine hydrochloride in their dosage form. First, attempts were made to stabilize possible signals by synthesizing hydrophobic multiwall carbon nanotubes-based carbon paste. Precipitation polymerization was used to create molecular imprinted polymers (MIPs) for each drug. MIPs’ graved cavities serve as artificial host-tailored receptors that are able to recognize and bind to individual drugs. Carvedilol MIP-based sensor showed Nernstian slope of 55.30 mV/decade while the corresponding value for ivabradine one was 55.50 mV/decade. The respective LODs were 7.0 × 10− 8 M and 6.0 × 10− 7 M. Interference from excipients of pharmaceutical formulation, common plasma ions, and possible oxidation byproducts was not witnessed, permitting direct and simultaneous measurement of carvedilol and ivabradine in their tablet solution and spiked human plasma. Furthermore, the proposed technique was compared favorably with the official titrimetric and reported spectrophotometric methods for analyzing carvedilol and ivabradine, respectively.

Introduction: Unlike conventional angina treatment medicines, newer antianginals such as Ivabradine hydrochloride and Trimetazidine dihydrochloride displayed therapeutic potential without negative effects. However, IBH and TMZ both have shorter half-life and require multiple dosing. Literature study revealed that bilayer tablet of combination is not available. Hence, the objective of present research was to formulate and evaluate bilayer floating gastroretentive tablets with IBH immediate and TMZ floating release layer. Materials and Methods: Simple direct compression method and floating technique was employed. IBH and TMZ layer developed separately. IBH layer prepared using Avicel-112, Klucel EXF ultra, and Vivasol/Crosscarmelose sodium while TMZ layer developed using Kollidon SR, Benecel K 200 M, and Sodium bicarbonate. Best trials combined for the preparation of bilayer tablet. Tablets evaluated for pre-compression and post-compression parameters, floating time, floating lag time (FLT), total floating time swelling index, and matrix integrity. Results: Melting point, differential scanning calorimetry, and ultraviolet absorbance confirmed the identity and purity of drug. Fourier transform infrared spectrum of active pharmaceutical ingredient and drug mixture with excipients demonstrated the compatibility. IR layer trial I-4 showed passable flow with 3 s of disintegration time in distilled water and 100% drug release within 5 min. Floating layer trial T-8 showed fair flow characteristic, 15 s FLT, &gt;24 h of total floating time and controlled the drug release more than 12 h without burst effect. Discussion: Preformulation study result revealed that the both the drug are pure form and compatible. For immediate release layer, Vivasol (Crosscarmelose) showed best disintegration and combination HPMC K200 M and Kollidon SR polymer with sodium carbonate provided controlled release with low FLT and high total floating time. Conclusion: Based on research findings, it can be concluded that bilayer gastroretentive tablets successfully formulated with IBH as IR layer and TMZ as floating layer. Combination of polymer needed for drug release control with tablet floatability. Hydrophilic polymer Benecel K200 M forms matrix channel which entrap sodium bicarbonate bubbles and tablet become buyant while Kollidon SR and stearic acid contributes in retardation of drug release.

Objective: Ivabradine (IVBD) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that inhibits the pacemaker If current causing spontaneous depolarization in the sino-atrial node thereby regulating heart rate in patients with heart failure (HF). Previous reports state that IVB use is associated with an increase in risk of atrial fibrillation (AF). This study aims to determine the incidence of ivabradine-associated AF over 1 year in a real-world database of AF naïve patients with HF. Methods: Rates of incident AF were determined using Merative Health MarketScan® Commercial Claims and Medicare Supplemental Database. Using ICD codes and outpatient medication dispensing records, we extracted HF patients who filled a prescription for IVBD between 01/2015 and 12/2021. Patients with a prior diagnosis of AF before starting IVBD were excluded. The study endpoint was the first diagnosis of AF, defined by ICD 9 and 10 codes, after the index IVBD dispensing. The time to AF was projected using cumulative incidence calculation. We used Kaplan-Meier product limit estimator to calculate AF outcomes at 30, 90, 180, and 365 days from the index IVBD, where patients were censored at the end of enrollment or end of the one-year follow up. Results: The analytic cohort at first IVB dispensing included 498 patients with mean (SD) age of 52.27 (12.47). Analytic cohort was slightly more weighted by male with a proportion of 53.2%. The cumulative incidence of AF at 30, 90, 180 and 365 days after the IVB use was 4.91%, 12.16%, 19.24%, and 28.11%, respectively. (Figure) Conclusions: Cumulative incidence of AF after IVBD was higher than the published AF incidence among commercially insured HF patients. A comparative safety assessment is warranted to quantify the measure of association for the AF incidence and exposure to IVBD.

Abstract Background Doxorubicin (DOX) is a widely used chemotherapeutic agent, and cardiotoxicity is one of its well-known side effects, which is mediated by cardiac mitochondrial dysfunction. Ivabradine (IVA), a heart rate reduction drug, exerts benefits in various cardiac diseases as shown in both preclinical and clinical studies. However, its roles on DOX-induced cardiotoxicity have never been investigated. Purpose We determined whether IVA reduces DOX-induced cardiotoxicity by directly promoting mitochondrial function and maintaining mitochondrial dynamic balance. Methods H9C2 cells were divided into 4 groups: 1) Control, 2) DOX (10 μM, 25 h), 3) IVA (3 μM, 25 h), 4) Pretreatment with IVA (3 μM, 1 h), followed by DOX treatment (10 μM, 24 h). Then, cell viability and mitochondrial function were determined. In animal study, male Wistar rats were divided into 4 groups: 1) Control, 2) IVA (10 mg/kg/d, PO), 3) DOX (3 mg/kg/d, 6 doses, IP), 4) Co-treatment with IVA (10 mg/kg/d, PO) and DOX (3 mg/kg/d, 6 doses, IP) for 30 days. Then, heart rate, cardiac function, and cardiac mitochondrial dynamic proteins were determined. Result DOX reduced %cell viability of H9C2 cells via increasing cellular and mitochondrial oxidative stress, and reducing mitochondrial respiration (Figure 1A, B). Under DOX-induced cellular injury condition, pretreatment with IVA resulted in increasing %cell viability by 11%, decreasing cellular and mitochondrial oxidative stress; however, IVA did not affect mitochondrial respiration. Consistent with in vitro study, DOX induced cardiac dysfunction as indicated by reduced heart rate and ejection fraction, impaired mitochondrial function and mitochondrial dynamics balance (Figure 1C, D). Co-treatment with DOX and IVA had no further impact on heart rate. DOX-IVA attenuated cardiac mitochondrial dysfunction and mitochondrial dynamics imbalance, thus prevented cardiac dysfunction. Conclusion IVA effectively protected against DOX-induced cardiotoxicity through improvement of mitochondrial function, mitochondrial dynamics, and reduction of oxidative stress. These findings suggest the therapeutic potential of IVA in preventing Dox-induced cardiotoxicity.

Angina pectoris refers to chest pain or discomfort resulting from insufficient oxygen delivery to the heart muscle, commonly caused by coronary artery disease. Ivabradine (IVB) also known to be effective in managing angina and reducing myocardial ischemia. This study focuses on the development and assessment of sublingual films prepared using various film-forming polymers, including HPMC E5 LV, HPMC E15 LV, HPMC 3 cps, HPMC 5 cps, and pullulan, through the solvent casting technique. Experimental batches containing different concentrations of film-forming polymers were developed and analyzed based on several parameters, such as film thickness, surface area, elongation percentage, disintegration time (in vitro), folding endurance, tensile strength, drug content uniformity, dissolution profile (in vitro), and permeability studies (in vitro). A batch F10 with pullulan 100 mg was found to produce satisfactory results. With the help of minitab software the sublingual films batches were optimized by using 32 factorial designs. The 9 factorial batches were formulated, evaluated and validated to prepare the optimized batch. The optimized batch sublingual films found to release 99.5 ± 0.6% of drug within 10 minutes and satisfactory physicochemical properties.

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Austrian Science Fund (FWF) Objective Ivabradine (IVA) is indicated in symptomatic treatment of chronic stable angina, heart failure, and also in those who are unable to tolerate or have contraindications to the use of beta-blockers. It has been showed IVA may have cardiovascular benefits in Duchenne muscular dystrophy (DMD) patients. This study was aimed to investigate the sustained impact of chronic ivabradine (IVA) administration on cardiac function and potential underlying mechanism using high throutput proteomic analysis. Methods DMDmdx male and Sprague–Dawley wt (Sprague–Dawley) male rats were randomly allocated to vehicle (n = 6) or IVA (n=6; 10 mg/kg/day via drinking water for four months). Transthoracic echocardiography and unbiased proteomic analysis were performed to assess cardiac function and left ventricular (LV) tissue, respectively. Protein-protein interactions were graphically represented, and cluster analysis with subsequent enrichment analyses was conducted. Results Chronic IVA treatment significantly enhanced the LV ejection fraction (p&amp;lt;0.05 compared to vehicle-treated DMDmdx rats). Proteomic data identified possible transcription factors (SPI1, IRF1, PPARA), consistent with previous studies. The reduction in copper metabolic changes associated with DMD can be attributed to the upregulation of Atox1 following IVA treatment. Mitochondrial dysfunction was effectively mitigated by IVA, as indicated by the different abundance of mitochondrial proteins. In addition, intercellular adhesion molecule 1 showed a reduction in the number of animals treated with ivabradine, indicating a further positive effect of the treatment. Conclusion In summary, this study demonstrated the beneficial effects of IVA in DMDmdx rat hearts. Cluster analysis of proteomic data revealed notable changes in cardiac metabolism, inflammation, and mitochondrial function. Ivabradine has emerged as a potential therapeutic approach to address these shifts, while proteomic pathway analysis may uncover new drugable targets to alleviate cardiomyopathy progression in DMD.Interaction of IvabradinProtein-protein interaction network

Ivabradine restores tonic cardiovascular autonomic control and reduces tachycardia, hypertension and left ventricular inflammation in post-weaning protein malnourished rats