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Postepy Dermatologii I Alergologii Jun 2014Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and... (Review)
Review
Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and stimulates mucous glands in the nasal cavity. Antihistamines are the basis of symptomatic treatment in the majority of allergic diseases, especially allergic rhinitis, allergic conjunctivitis, urticaria and anaphylaxis. The cardiotoxic effects of the two withdrawn drugs, terfenadine and astemizole, were manifested by prolonged QT intervals and triggering torsades de pointes (TdP) caused by blockade of the 'rapid' I Kr potassium channels. These phenomena, however, are not a class effect. This review deals with a new generation of antihistamine drugs in the context of QT interval prolongation risk.
PubMed: 25097491
DOI: 10.5114/pdia.2014.43191 -
Indian Journal of Pharmacology 2016Allergic rhinitis (AR) is a global health problem. Almost 10%-25% of population worldwide is affected by AR. Oral/intranasal H1-antihistamine, decongestants, leukotriene... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparison of efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine in patients of allergic rhinitis: A randomized, double-blind clinical trial.
OBJECTIVES
Allergic rhinitis (AR) is a global health problem. Almost 10%-25% of population worldwide is affected by AR. Oral/intranasal H1-antihistamine, decongestants, leukotriene receptor antagonists, and intranasal corticosteroids are the pillars in the management of AR. The combination therapy of montelukast with antihistaminic provides enhancing and complimentary effects, thereby reducing the symptoms effectively, but there are scanty data regarding the comparisons of combinations. Therefore, we aimed to compare the efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine combination in patients of AR.
MATERIALS AND METHODS
Seventy patients with AR participated in a prospective, randomized, double-blind, parallel, active-controlled, comparative 4-week trial. The patients between the age group of 18-65 years of either gender having moderate-severe intermittent or mild persistent AR were included in the study. The study inclusion criteria required the patients with total nasal symptom score (TNSS) of 5 or higher. The patients were randomly divided into two treatment groups with montelukast-levocetirizine (10 mg and 5 mg) in one group and montelukast-fexofenadine (10 mg and 120 mg) in another group. TNSS parameter was the main effectiveness parameter.
RESULTS
Evaluation of TNSS revealed significant difference ( < 0.05) when compared from baseline to 4 week in both groups. The mean change of TNSS, i.e., 9.46 was significant ( < 0.05) in montelukast-fexofenadine group. The cost-effectiveness ratio was less in montelukast-levocetirizine group than in montelukast-fexofenadine group.
CONCLUSION
The decrease in TNSS was more in montelukast-fexofenadine group, but the cost-effectiveness is more with montelukast-levocetirizine combination.
Topics: Acetates; Anti-Allergic Agents; Anti-Asthmatic Agents; Cetirizine; Cost-Benefit Analysis; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Quinolines; Rhinitis, Allergic; Sulfides; Terfenadine; Treatment Outcome
PubMed: 28066101
DOI: 10.4103/0253-7613.194854 -
British Journal of Clinical Pharmacology Aug 1998The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the... (Comparative Study)
Comparative Study Review
The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
Topics: Administration, Oral; Beverages; Biological Availability; Calcium Channel Blockers; Citrus; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Felodipine; Food-Drug Interactions; Humans; Intestine, Small; Mixed Function Oxygenases; Pharmacokinetics
PubMed: 9723817
DOI: 10.1046/j.1365-2125.1998.00764.x -
Biomedicine & Pharmacotherapy =... Apr 2022Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of...
Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications - dexrazoxane, metoprolol, carvedilol and valsartan - are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.
Topics: Animals; Cardiomyopathies; Cardiotoxicity; Carvedilol; Doxorubicin; Zebrafish
PubMed: 35158142
DOI: 10.1016/j.biopha.2022.112695 -
Clinical Cardiology Sep 1993The polymorphic ventricular tachycardia torsade de pointes can occur in the congenital long QT syndromes or as a consequence of therapy with QT-prolonging drugs. The... (Review)
Review
The polymorphic ventricular tachycardia torsade de pointes can occur in the congenital long QT syndromes or as a consequence of therapy with QT-prolonging drugs. The latter can include not only antiarrhythmic drugs such as quinidine, but also a number of drugs which are not usually considered to have major cardiovascular effects: these include nonsedating antihistamines, such as terfenadine; antibiotics such as erythromycin; and neuroleptics such as thioridazine. The electrocardiographic hallmark of both the congenital and acquired forms of the long QT syndrome is marked QT(U) lability, particularly as a function of heart rate. The underlying mechanism is thought to be triggered activity arising as a consequence of early afterdepolarizations. An understanding of the basic mechanism has led to an understanding of the effective forms of therapy, which include maneuvers to include the heart rate (pacing, isoproterenol) as well as maneuvers which may not necessarily alter the QT interval but may prevent the arrhythmia (magnesium, beta blockers). Intensive study of the clinical features and basic mechanisms underlying torsade de pointes has led to the definition of a new mechanism for cardiac arrhythmias; understanding such mechanisms may ultimately lead to the development of safer antiarrhythmic therapy.
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Antipsychotic Agents; Dogs; Electrocardiography; Erythromycin; Heart Rate; Histamine Antagonists; Humans; Long QT Syndrome; Torsades de Pointes
PubMed: 7902224
DOI: 10.1002/clc.4960160910 -
Trends in Cardiovascular Medicine Oct 2017While it is well known that mutation of several different ion channels can cause congenital long QT syndrome, block of I is widely thought to be responsible for most... (Review)
Review
While it is well known that mutation of several different ion channels can cause congenital long QT syndrome, block of I is widely thought to be responsible for most cases of drug-induced acquired long QT syndrome (aLQTS). In this article, we review evidence supporting another cause of aLQTS due to inhibition of phosphoinositide 3-kinase (PI3K) signaling. Inhibition of PI3K affects multiple plateau currents, reducing I, I, and I while increasing the persistent sodium current (I). The effects of PI3K inhibitors develop slowly, requiring hours to days to reach steady state. Dofetilide and terfenadine, an antihistamine on which much of the original I hypothesis was based, are among the many drugs that inhibit the PI3K pathway. Reduced PI3K signaling may also play a role in aLQTS associated with diabetes. Drug safety testing to identify aLQTS risk may be improved by examining PI3K-dependent effects that develop over time.
Topics: Action Potentials; Animals; Heart Conduction System; Heart Rate; Humans; Long QT Syndrome; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Potassium Channel Blockers; Protein Kinase Inhibitors; Risk Factors; Sodium Channel Blockers
PubMed: 28687226
DOI: 10.1016/j.tcm.2017.05.005 -
Chinese Medicine Nov 2021Cardiomyopathy is a kind of cardiovascular diseases, which makes it more difficult for the heart to pump blood to other parts of the body, eventually leading to heart...
BACKGROUND
Cardiomyopathy is a kind of cardiovascular diseases, which makes it more difficult for the heart to pump blood to other parts of the body, eventually leading to heart failure. Naoxintong (NXT), as a traditional Chinese Medicine (TCM) preparation, is widely used in the treatment of cardiovascular diseases, including cardiomyopathy, while its underlying mechanism has not been fully elucidated. The purpose of this study is to investigate the therapeutic effect of NXT on cardiomyopathy and its molecular mechanism in zebrafish model.
METHODS
The zebrafish cardiomyopathy model was established using terfenadine (TFD) and treated with NXT. The therapeutic effect of NXT on cardiomyopathy was evaluated by measuring the heart rate, the distance between the sinus venosus and bulbus arteriosus (SV-BA), the pericardial area, and the blood flow velocity of zebrafish. Then, the zebrafish hearts were isolated and collected; transcriptome analysis of NXT on cardiomyopathy was investigated. Moreover, the heg1 mutant of zebrafish congenital cardiomyopathy model was used to further validate the therapeutic effect of NXT on cardiomyopathy. Additionally, UPLC analysis combined with the zebrafish model investigation was performed to identify the bioactive components of NXT.
RESULTS
In the TFD-induced zebrafish cardiomyopathy model, NXT treatment could significantly restore the cardiovascular malformations caused by cardiac dysfunction. Transcriptome and bioinformatics analyses of the TFD and TFD + NXT treated zebrafish developing hearts revealed that the differentially expressed genes were highly enriched in biological processes such as cardiac muscle contraction and heart development. As a cardiac development protein associated with cardiomyopathy, HEG1 had been identified as one of the important targets of NXT in the treatment of cardiomyopathy. The cardiovascular abnormalities of zebrafish heg1 mutant could be recovered significantly from NXT treatment, including the expanded atrial cavity and blood stagnation. qRT-PCR analysis further showed that NXT could restore cardiomyopathy phenotype in zebrafish through HEG1-CCM signaling. Among the seven components identified in NXT, paeoniflorin (PF) and salvianolic acid B (Sal B) were considered to be the main bioactive ones with myocardial protection.
CONCLUSION
NXT presented myocardial protective effect and could restore myocardial injury and cardiac dysfunction in zebrafish; the action mechanism was involved in HEG1-CCM signaling.
PubMed: 34775978
DOI: 10.1186/s13020-021-00532-0 -
British Journal of Pharmacology Sep 2019A second-generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the...
BACKGROUND AND PURPOSE
A second-generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the activity of G-protein-gated inwardly rectifying K (GIRK) channels, which regulate the excitability of neurons and cardiomyocytes. To clarify the underlying mechanism(s), we examined the effects of several antihistamines on GIRK channels and identified the structural determinant for the inhibition.
EXPERIMENTAL APPROACH
Electrophysiological recordings were made in Xenopus oocytes and rat atrial myocytes to analyse the effects of antihistamines on various GIRK subunits (K 3.x). Mutagenesis analyses identified the residues critical for inhibition by terfenadine and the regulation of ion selectivity. The potential docking site of terfenadine was analysed by molecular docking.
KEY RESULTS
GIRK channels containing K 3.1 subunits heterologously expressed in oocytes and native GIRK channels in atrial myocytes were inhibited by terfenadine and other non-sedating antihistamines. In K 3.1 subunits, mutation of Phe137, located in the centre of the pore helix, to the corresponding Ser in K 3.2 subunits reduced the inhibition by terfenadine. Introduction of an amino acid with a large side chain in K 3.2 subunits at Ser148 increased the inhibition. When this residue was mutated to a non-polar amino acid, the channel became permeable to Na . Phosphoinositide-mediated activity was also decreased by terfenadine.
CONCLUSION AND IMPLICATIONS
The Phe137 residue in K 3.1 subunits is critical for inhibition by terfenadine. This study provides novel insights into the regulation of GIRK channels by the pore helix and information for drug design.
Topics: Animals; Dose-Response Relationship, Drug; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Histamine Antagonists; Male; Molecular Docking Simulation; Mutation; Myocytes, Cardiac; Oocytes; Rats; Rats, Wistar; Structure-Activity Relationship; Xenopus laevis
PubMed: 31116876
DOI: 10.1111/bph.14717