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Cureus Apr 2023An Emergency Use Authorization (EUA) was issued by the FDA on December 22, 2021 for the investigational antiviral drug nirmatrelvir copackaged with the HIV-1 protease...
An Emergency Use Authorization (EUA) was issued by the FDA on December 22, 2021 for the investigational antiviral drug nirmatrelvir copackaged with the HIV-1 protease inhibitor ritonavir (Paxlovid - Pfizer) for outpatient treatment of mild to moderate COVID-19 in children 12 years and old that are high risk of severe disease. Due to the effects, Paxlovid has on liver metabolism it has a copious amount of drug-to-drug interactions. Here we present a rare case of a patient that was given Paxlovid and continued to take her Ranolazine at home. She presented to the emergency department obtunded and after an initial workup, it was determined to be secondary to ranolazine toxicity. She eventually recovered over 54 hours and returned to her baseline.
PubMed: 37153311
DOI: 10.7759/cureus.37153 -
Philosophical Transactions of the Royal... Jun 2023Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was...
Atrial fibrillation (AF) is frequently associated with β-adrenergic stimulation, especially in patients with structural heart diseases. The objective of this study was to determine the synergism of late sodium current (late ) and Ca/calmodulin-dependent protein kinase (CaMKII)-mediated arrhythmogenic activities in β-adrenergic overactivation-associated AF. Monophasic action potential, conduction properties, protein phosphorylation, ion currents and cellular trigger activities were measured from rabbit-isolated hearts, atrial tissue and atrial myocytes, respectively. Isoproterenol (ISO, 1-15 nM) increased atrial conduction inhomogeneity index, phospho-Na1.5 and phospho-CaMKII protein levels and late by 108%, 65%, 135% and 87%, respectively, and induced triggered activities and episodes of AF in all hearts studied ( < 0.05). Sea anemone toxin II (ATX-II, 2 nM) was insufficient to induce any atrial arrhythmias, whereas the propensities of AF were greater in hearts treated with a combination of ATX-II and ISO. Ranolazine, eleclazine and KN-93 abolished ISO-induced AF, attenuated the phosphorylation of Na1.5 and CaMKII, and reversed the increase of late ( < 0.05) in a synergistic mode. Overall, late in association with the activation of CaMKII potentiates β-adrenergic stimulation-induced AF and the inhibition of both late and CaMKII exerted synergistic anti-arrhythmic effects to suppress atrial arrhythmic activities associated with catecholaminergic activation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
Topics: Animals; Rabbits; Atrial Fibrillation; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Adrenergic Agents; Sodium; Heart Atria; Action Potentials; Calcium
PubMed: 37122215
DOI: 10.1098/rstb.2022.0163 -
European Review For Medical and... Apr 2023The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells.
OBJECTIVE
The aim of this study was to evaluate the effectiveness of ranolazine on hypoxia-inducible factor-1α (HIF-1α) and oxidative stress in H9c2 cardiomyocyte cells.
MATERIALS AND METHODS
We have assessed the effects of increasing concentrations of methotrexate (MTX) and ranolazine on proliferation of H9c2 rat cardiomyocyte cells by MTT assay. Malondialdehyde (MDA) protein oxidation [advanced oxidation protein products (AOPPs)], lipid hydroperoxide (LOOH) and xanthine oxidase (XO) activity as oxidative stress markers and HIF-1α levels increased and total thiol (T-SH), catalase (CAT) activity and total antioxidant capacity (TAC) antioxidant capacity markers decreased in MTX-treated cells compared to control cells.
RESULTS
Oxidative stress markers decreased, and antioxidant capacity markers increased in cells treated with ranolazine alone compared to control cells. For all parameters, we showed that the levels of oxidant, antioxidant markers and HIF-1α in cells treated with MTX and ranolazine together reached the level of the control group, and ranolazine reversed the oxidative damage caused by MTX.
CONCLUSIONS
The cell viability increased the levels of oxidant and prooxidant markers and decreased the levels of antioxidant markers decreased in H9c2 cardiomyocytes induced by oxidative stress. These results suggest that ranolazine may protect the cardiomyocytes from MTX-induced oxidative damage. The effects of ranolazine could result from its antioxidant properties.
Topics: Ranolazine; Anti-Inflammatory Agents; Antioxidants; Myocytes, Cardiac; Cardiovascular Agents; Oxidative Stress; Animals; Rats
PubMed: 37070896
DOI: 10.26355/eurrev_202304_31927 -
JACC. Cardiovascular Imaging Apr 2023Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to... (Review)
Review
Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials.
Topics: Humans; Quality of Life; Predictive Value of Tests; Myocardial Ischemia; Coronary Artery Disease; Positron-Emission Tomography; Coronary Angiography; Perfusion; Coronary Circulation; Myocardial Perfusion Imaging
PubMed: 36881418
DOI: 10.1016/j.jcmg.2022.12.015 -
European Cardiology Feb 2023This article evaluates the efficacy of using ranolazine to improve diastolic performance and exercise capacity in heart failure with preserved ejection fraction. A... (Review)
Review
This article evaluates the efficacy of using ranolazine to improve diastolic performance and exercise capacity in heart failure with preserved ejection fraction. A comprehensive literature review found eight trials where there are no significant difference in peak O2 (p=0.09) and exercise duration (p=0.18) between ranolazine and placebo. The ranolazine group had significantly higher and better diastolic parameters compared to placebo, with a mean difference of 0.45 (95% CI [27.18-39.50]). There were no significant differences for haemodynamic parameters (blood pressure and heart rate) and electrocardiography (QT interval) between ranolazine and placebo. The review found that ranolazine has good wefficacy to improve diastolic performance among heart failure with preserved ejection fraction patients and it does not affect blood pressure, heart rate and rate of ventricular repolarisation (shortening of the QT interval).
PubMed: 36844933
DOI: 10.15420/ecr.2022.10 -
Basic & Clinical Pharmacology &... May 2023Atrial arrhythmias are a hallmark of heart diseases. The antiarrhythmic drug ranolazine with multichannel blocker properties is a promising agent to treat atrial...
Atrial arrhythmias are a hallmark of heart diseases. The antiarrhythmic drug ranolazine with multichannel blocker properties is a promising agent to treat atrial arrhythmias. We therefore used the rat model of monocrotaline-induced pulmonary-hypertension to assess whether ranolazine can reduce the incidence of ex vivo atrial arrhythmias in isolated right atrium. Four-week-old Wistar rats were injected with 50 mg/kg of monocrotaline, and isolated right atrium function was studied 14 days later. The heart developed right atrium and right ventricular hypertrophy, and the ECG showed an increased P wave duration and QT interval, which are markers of the disease. Moreover, monocrotaline injection caused enhanced chronotropism and faster kinetics of contraction and relaxation in isolated right atrium. Additionally, in a concentration-dependent manner, ranolazine showed chronotropic and ionotropic effects upon isolated right atrium, with higher potency in the control when compared with experimental model. Using a burst pacing protocol, the isolated right atrium from the monocrotaline-treated animals was more susceptible to develop arrhythmias, and ranolazine was able to attenuate the phenotype. Thus, we concluded that the rat model of monocrotaline-induced pulmonary-hypertension develops right atrium remodelling, which increased the susceptibility to present ex vivo atrial arrhythmias, and the antiarrhythmic drug ranolazine ameliorated the phenotype.
Topics: Rats; Animals; Ranolazine; Anti-Arrhythmia Agents; Hypertension, Pulmonary; Monocrotaline; Atrial Fibrillation; Rats, Wistar; Heart Atria; Disease Models, Animal
PubMed: 36799082
DOI: 10.1111/bcpt.13845 -
Purinergic Signalling Sep 2023Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four...
Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.
Topics: Mice; Animals; Adenosine; Hypothermia; Nimodipine; Receptors, Purinergic P1; Dipyridamole
PubMed: 36781825
DOI: 10.1007/s11302-023-09924-3 -
International Journal of Molecular... Jan 2023KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na-Ca exchanging process. This compound was demonstrated to prevent...
KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na-Ca exchanging process. This compound was demonstrated to prevent intracellular Na-dependent Ca uptake in intact cells; however, it is much less effective at preventing extracellular Na-dependent Ca efflux. Therefore, whether or how this compound may produce any perturbations on other types of ionic currents, particularly on voltage-gated Na current (), needs to be further studied. In this study, the whole-cell current recordings demonstrated that upon abrupt depolarization in pituitary GH cells, the exposure to KB-R7943 concentration-dependently depressed the transient () or late component () of with an IC value of 11 or 0.9 μM, respectively. Likewise, the dissociation constant for the KB-R7943-mediated block of on the basis of a minimum reaction scheme was estimated to be 0.97 μM. The presence of benzamil or amiloride could suppress the magnitude. The instantaneous window Na current () activated by abrupt ascending ramp voltage (V) was suppressed by adding KB-R7943; however, subsequent addition of deltamethrin or tefluthrin (Tef) effectively reversed KB-R7943-inhibted . With prolonged duration of depolarizing pulses, the amplitude became exponentially decreased; moreover, KB-R7943 diminished magnitude. The resurgent Na current () evoked by a repolarizing V was also suppressed by adding this compound; moreover, subsequent addition of ranolazine or Tef further diminished or reversed, respectively, its reduction in magnitude. The persistent Na current () activated by sinusoidal voltage waveform became enhanced by Tef; however, subsequent application of KB-R7943 counteracted Tef-stimulated . The docking prediction reflected that there seem to be molecular interactions of this molecule with the hNa1.2 or hNa1.7 channels. Collectively, this study highlights evidence showing that KB-R7943 has the propensity to perturb the magnitude and gating kinetics of (e.g., , , , , and ) and that the Na channels appear to be important targets for the in vivo actions of KB-R7943 or other relevant compounds.
Topics: Thiourea; Sodium-Calcium Exchanger
PubMed: 36675319
DOI: 10.3390/ijms24021805 -
Biological & Pharmaceutical Bulletin 2023The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the...
The negative inotropic effects of nine Vaughan Williams class I antiarrhythmic drugs were examined in guinea pig ventricular tissue preparations. The drugs decreased the contractile force of papillary muscles with different potencies: the potency order was propafenone > aprindine > cibenzoline > flecainide > ranolazine > disopyramide > pilsicainide > mexiletine > GS-458967. The potency of drugs correlated with the reported IC values to block the L-type Ca channel rather than the Na channel. The effects of drugs were roughly the same when examined under a high extracellular K solution, which inactivates the Na channel. Furthermore, the attenuation of the extracellular Ca-induced positive inotropy was strong with propafenone, moderate with cibenzoline, and weak with pilsicainide. These results indicate that the negative inotropic effects of class I antiarrhythmic drugs can be largely explained by their blockade of the L-type Ca channel.
Topics: Guinea Pigs; Animals; Anti-Arrhythmia Agents; Propafenone; Myocardium; Lidocaine; Papillary Muscles
PubMed: 36596522
DOI: 10.1248/bpb.b22-00644