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Journal of Physiological Investigation Jun 2024A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans....
Perturbations of Telmisartan Alone and in Combination with Ranolazineor Dapagliflozin on the Amplitude and Gating of Voltage-gated Na+ Current in Neuroblastoma Neuronal Cells.
A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na+ currents (INa) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa, while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient (INa(T)) and late (INa(L)) components of INa were differentially stimulated with effective EC50's of 16.9 and 3.1 μM, respectively. The research implies that TEL's impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved.
PubMed: 38857206
DOI: 10.4103/ejpi.EJPI-D-24-00018 -
The Journal of Toxicological Sciences 2024Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated...
Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.
Topics: Animals; Male; Machine Learning; Seizures; Heart Rate; 4-Aminopyridine; Kainic Acid; Convulsants; Ranolazine; Bupropion; Electrocardiography; Dose-Response Relationship, Drug; Autonomic Nervous System; Telemetry; Biomarkers
PubMed: 38692910
DOI: 10.2131/jts.49.231 -
The Canadian Journal of Cardiology Apr 2024Ranolazine is a piperazine derivative and is indicated for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or...
Ranolazine is a piperazine derivative and is indicated for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies. Visual hallucinations together with neurological symptoms have been described with ranolazine treatment. In this case report, we describe a case of an elderly diabetic patient with chronic angina pectoris who developed visual hallucinations during an acute worsening of kidney function after tolerating ranolazine well for six years. Regular monitoring of electrocardiograms, kidney function, and psychiatric and neurological adverse effects in elderly patients on ranolazine is advised.
PubMed: 38692432
DOI: 10.1016/j.cjca.2024.04.018 -
Frontiers in Pharmacology 2024Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late...
Hypertrophic cardiomyopathy (HCM) is a leading cause of lethal arrhythmias in the young. Although the arrhythmic substrate has been hypothesised to be amenable to late Na block with ranolazine, the specific mechanisms are not fully understood. Therefore, this study aimed to investigate the substrate mechanisms of safety and antiarrhythmic efficacy of ranolazine in HCM. Computational models of human tissue and ventricles were used to simulate the electrophysiological behaviour of diseased HCM myocardium for variable degrees of repolarisation impairment, validated against and clinical recordings. S1-S2 pacing protocols were used to quantify arrhythmic risk in scenarios of (i) untreated HCM-remodelled myocardium and (ii) myocardium treated with 3µM, 6µM and 10µM ranolazine, for variable repolarisation heterogeneity sizes and pacing rates. ECGs were derived from biventricular simulations to identify ECG biomarkers linked to antiarrhythmic effects. 10µM ranolazine given to models manifesting ventricular tachycardia (VT) at baseline led to a 40% reduction in number of VT episodes on pooled analysis of >40,000 re-entry inducibility simulations. Antiarrhythmic efficacy and safety were dependent on the degree of repolarisation impairment, with optimal benefit in models with maximum JT interval <370 ms. Ranolazine increased risk of VT only in models with severe-extreme repolarisation impairment. Ranolazine efficacy and safety may be critically dependent upon the degree of repolarisation impairment in HCM. For moderate repolarisation impairment, reductions in refractoriness heterogeneity by ranolazine may prevent conduction blocks and re-entry. With severe-extreme disease substrates, reductions of the refractory period can increase re-entry sustainability.
PubMed: 38659580
DOI: 10.3389/fphar.2024.1379236 -
Heliyon Mar 2024African Trypanosomiasis caused by trypanosome parasites continues to be a major neglected health problem, particularly in developing countries. Current treatments are...
African Trypanosomiasis caused by trypanosome parasites continues to be a major neglected health problem, particularly in developing countries. Current treatments are marked by serious side effects, low effectiveness, high toxicity, and drug resistance prompting the need to develop novel, safe, effective, and alternative antitrypanosomal compounds. is an ethnomedicinal plant used in West Africa to treat many ailments including protozoan diseases. In this study, we investigated the antitrypanosomal potential of stem bark extracts of through and approaches. extracts were tested for their antitrypanosomal activities against parasite using Alamar blue assay. In addition, the antioxidant and cytotoxic activities were determined. LC-ESI-QTOF-MS was used to identify potential bioactive compounds present in the extracts. Bioactive compounds identified were subjected to molecular docking studies against (TR) and Uridine Diphosphate Galactose 4'-Epimerase (UDP). The . extracts (methanol, hexane, chloroform, and ethyl acetate) exhibited potential anti-trypanosomal activities with IC values of 21.25 ± 0.755,4.35 ± 0.166,2.57 ± 0.153 and 22.92 ± 2.321 μg/mL respectively. Moreover, the methanolic crude extracts showed moderate cytotoxicity against HepG2 and PNT2 cells, with IC values of 68.0 ± 2.05 and 78.7 ± 2.63 μg/mL respectively. LC-MS analysis revealed the presence of 24 bioactive compounds with 5 being druglike. Risperidone, Ranolazine, Dihydro-7-Desacetyldeoxygedunin, 6 beta-Hydroxytriamcinolone acetonide, and Dimethylmatairesinol were identified as novel potential inhibitors of TR and UDP with binding affinities of -10.4, -7.9, -8.7, -8.4 and -7.1 kcal/mol respectively against TR and -10.8, -8.4, -8.4, -7.6 and -8.1 respectively against UDP. This study indicates that has potential antitrypanosomal properties and therefore may have the potential to be developed as a therapeutic intervention for treating African trypanosomiasis.
PubMed: 38545221
DOI: 10.1016/j.heliyon.2024.e28025 -
International Journal of Molecular... Mar 2024While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart... (Review)
Review
While essential hypertension (HTN) is very prevalent, pulmonary arterial hypertension (PAH) is very rare in the general population. However, due to progressive heart failure, prognoses and survival rates are much worse in PAH. Patients with PAH are at a higher risk of developing supraventricular arrhythmias and malignant ventricular arrhythmias. The latter underlie sudden cardiac death regardless of the mechanical cardiac dysfunction. Systemic chronic inflammation and oxidative stress are causal factors that increase the risk of the occurrence of cardiac arrhythmias in hypertension. These stressful factors contribute to endothelial dysfunction and arterial pressure overload, resulting in the development of cardiac pro-arrhythmic conditions, including myocardial structural, ion channel and connexin43 (Cx43) channel remodeling and their dysfunction. Myocardial fibrosis appears to be a crucial proarrhythmic substrate linked with myocardial electrical instability due to the downregulation and abnormal topology of electrical coupling protein Cx43. Furthermore, these conditions promote ventricular mechanical dysfunction and heart failure. The treatment algorithm in HTN is superior to PAH, likely due to the paucity of comprehensive pathomechanisms and causal factors for a multitargeted approach in PAH. The intention of this review is to provide information regarding the role of Cx43 in the development of cardiac arrhythmias in hypertensive heart disease. Furthermore, information on the progress of therapy in terms of its cardioprotective and potentially antiarrhythmic effects is included. Specifically, the benefits of sodium glucose co-transporter inhibitors (SGLT2i), as well as sotatercept, pirfenidone, ranolazine, nintedanib, mirabegron and melatonin are discussed. Discovering novel therapeutic and antiarrhythmic strategies may be challenging for further research. Undoubtedly, such research should include protection of the heart from inflammation and oxidative stress, as these are primary pro-arrhythmic factors that jeopardize cardiac Cx43 homeostasis, the integrity of intercalated disk and extracellular matrix, and, thereby, heart function.
Topics: Humans; Connexin 43; Pulmonary Arterial Hypertension; Arrhythmias, Cardiac; Anti-Arrhythmia Agents; Cardiac Conduction System Disease; Familial Primary Pulmonary Hypertension; Hypertension; Heart Failure; Inflammation
PubMed: 38542257
DOI: 10.3390/ijms25063275 -
Journal of Clinical Medicine Mar 2024: Although ranolazine has been available for years as a second-line treatment to reduce angina attacks in patients with stable angina pectoris, real-world data on the...
: Although ranolazine has been available for years as a second-line treatment to reduce angina attacks in patients with stable angina pectoris, real-world data on the effectiveness, tolerability, and safety of ranolazine are limited. : A non-interventional, prospective study was conducted to assess the effectiveness and safety of ranolazine. Patients eligible for enrolment had a baseline assessment between one and fourteen days after initiating ranolazine for the first time and a follow-up visit three months later. The primary endpoints comprised the weekly frequency of angina attacks, total adverse events, and ranolazine discontinuation rate. The secondary endpoints included the use of short-acting nitrates, changes on the Canadian Cardiovascular Society (CCS) angina classification score and quality of life scale score (QoL). : In total, 1101 patients were enrolled at 214 sites. Mean weekly angina attacks were reduced from 3.6 ± 2.9 to 0.4 ± 0.9 ( < 0.0001) and the mean weekly consumption of short-acting nitrates decreased by 1.7 ± 2.2 ( < 0.0001). CCS class and QoL were also improved ( < 0.0001). Adverse events were reported by 11 (1%) patients in total, while 2 of them (0.2%) were characterised as serious. Treatment was discontinued for various reasons in 23 patients (2.1%) after the follow-up period. Ranolazine treatment was equally effective in all subgroups tested, with larger benefits observed in patients with more frequent angina and CCS angina class III and IV. Up-titration of ranolazine during the study improved the outcomes. : Ranolazine was well tolerated and effectively reduced angina attacks, with simultaneous improvement of the CCS class and QoL score in patients with stable angina.
PubMed: 38541898
DOI: 10.3390/jcm13061672 -
British Journal of Cancer May 2024Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving... (Review)
Review
BACKGROUND
Multi-faceted evidence from a range of cancers suggests strongly that de novo expression of voltage-gated sodium channels (VGSCs) plays a significant role in driving cancer cell invasiveness. Under hypoxic conditions, common to growing tumours, VGSCs develop a persistent current (I) which can be blocked selectively by ranolazine.
METHODS
Several different carcinomas were examined. We used data from a range of experimental approaches relating to cellular invasiveness and metastasis. These were supplemented by survival data mined from cancer patients.
RESULTS
In vitro, ranolazine inhibited invasiveness of cancer cells especially under hypoxia. In vivo, ranolazine suppressed the metastatic abilities of breast and prostate cancers and melanoma. These data were supported by a major retrospective epidemiological study on breast, colon and prostate cancer patients. This showed that risk of dying from cancer was reduced by ca.60% among those taking ranolazine, even if this started 4 years after the diagnosis. Ranolazine was also shown to reduce the adverse effects of chemotherapy on heart and brain. Furthermore, its anti-cancer effectiveness could be boosted by co-administration with other drugs.
CONCLUSIONS
Ranolazine, alone or in combination with appropriate therapies, could be reformulated as a safe anti-metastatic drug offering many potential advantages over current systemic treatment modalities.
Topics: Ranolazine; Humans; Voltage-Gated Sodium Channels; Male; Antineoplastic Agents; Animals; Female; Neoplasm Metastasis; Neoplasms; Neoplasm Invasiveness; Voltage-Gated Sodium Channel Blockers
PubMed: 38424164
DOI: 10.1038/s41416-024-02622-w -
Quantitative Imaging in Medicine and... Feb 2024Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review...
Ranolazine for improving coronary microvascular function in patients with nonobstructive coronary artery disease: a systematic review and meta-analysis with a trial sequential analysis of randomized controlled trials.
BACKGROUND
Microvascular dysfunction in patients with nonobstructive coronary artery disease is increasingly being recognized as an important health issue. This systematic review and meta-analysis evaluated the effectiveness of ranolazine, an antianginal agent, in improving coronary microvascular function.
METHODS
We conducted a comprehensive literature search of the Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure, the Chinese BioMedical Literature Database, and gray literature databases until September 30, 2023. The included studies were randomized controlled trials (RCTs) published in the English or Chinese languages that screened for eligibility using two independent investigators. Risk of bias was evaluated with the Cochrane Collaboration tool. Subgroup and sensitivity analyses were used to identify sources of heterogeneity. Meta-analysis was performed using RevMan version 5.4 (Cochrane) and Stata version 16.0 (StataCorp).
RESULTS
From 1,470 citations, 8 RCTs involving 379 participants were included in this analysis. Our findings showed that ranolazine increased coronary flow reserve (CFR) over an 8 to 12-week follow-up period [standardized mean difference =1.16; 95% confidence interval (CI): 0.4-1.89; P=0.002]. Ranolazine increased the global myocardial perfusion reserve index (MPRI) [weighted mean difference (WMD) =0.18; 95% CI: 0.07-0.29; P=0.002] and the midsubendocardial MPRI (WMD =0.10; 95% CI: 0.02-0.19; P=0.02). Moreover, ranolazine improved 3 of the 5 Seattle Angina Questionnaire scores, namely, physical functioning (WMD =4.89; 95% CI: 0.14 to 9.64; P=0.04), angina stability (WMD =17.31; 95% CI: 7.13-27.49; P=0.0009), and quality of life (WMD =10.11; 95% CI: 3.57-16.65; P=0.0003). Trial sequential analysis showed that the meta-analysis of angina stability and quality of life scores had a sufficient sample size and statistical power.
CONCLUSIONS
Our analysis suggests that ranolazine is associated with improvements in CFR, myocardial perfusion, and the Seattle Angina Questionnaire scores in patients with nonobstructive coronary artery disease. However, further large-scale RCTs with long-term follow-up are recommended to validate these findings and provide a more comprehensive understanding of the effects of ranolazine on coronary microvascular function.
PubMed: 38415135
DOI: 10.21037/qims-23-1029