Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Improving prediction of torsadogenic risk in the CiPA in silico model by appropriately accounting for clinical exposure.

Any adverse event is reliant on three properties: the appropriate pharmacology to trigger the event, the appropriate exposure of compound, and intrinsic patient factors. Each alone is necessary but insufficient to predict the event. The Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative attempts to predict the risk of torsade de pointes (TdP) by focusing on an in-silico model with thresholds determined at modest multiples of the therapeutic exposure for the parent molecule. This emphasizes the pharmacologic properties necessary for TdP but does not account for situations where clinical exposure may be higher, or where hERG potassium channel active metabolites are involved. Could accounting for clinical worst-case scenarios and metabolites, as is already standard practice in thorough QTc studies, improve the prediction algorithm? Terfenadine, a drug classed as "Intermediate" risk by CiPA, was assessed differently in the in-silico model validation. The clinical concentration of terfenadine used for the model was the exposure in the presence of metabolic inhibition representing a 14 to 40-fold increase in exposure compared to the therapeutic plasma concentration. However, several other "Intermediate" risk compounds are also known to be sensitive to metabolic inhibition and/or to have therapeutically active major metabolites, some of which are known to block hERG. Risperidone and astemizole are relevant examples. If only parent exposure is used to calculate a therapeutic window, risperidone has a relatively large multiple between clinical exposure and the hERG potency. Using this exposure of risperidone, the drug borders the "Intermediate" and "Low/No" risk categories for the CiPA in-silico model's TdP metric. The desmethyl metabolite of astemizole likely contributes significantly to the effects on cardiac repolarization, being equipotent on hERG but circulating at much higher levels than parent. Recalculating the TdP metric and margin values for terfenadine, risperidone and astemizole using the unbound concentration normally associated with treatment and a clinical worst case changes the qNet metric to higher risk values and illustrates the potential benefit to the algorithm of consistently using a clinical high exposure scenario accounting for all "hERG-active species". This exercise suggests repeating the model qualification accounting for clinical exposures and metabolites under 'stressed' scenarios would improve prediction of the TdP risk.

Possibility as an anti-cancer drug of astemizole: Evaluation of arrhythmogenicity by the chronic atrioventricular block canine model.

Since astemizole in an oral dose of 50 mg/kg/day was recently reported to exert anti-cancer effect in mice, we evaluated its proarrhythmic potential using the atrioventricular block dogs in order to clarify its cardiac safety profile. An oral dose of 3 mg/kg prolonged the QT interval without affecting the QTc (n = 4), whereas that of 30 mg/kg increased the short-term variability of repolarization and induced premature ventricular contractions in each animal, resulting in the onset of torsade de pointes in 1 animal (n = 4). Thus, proarrhythmic dose of astemizole would be lower than anti-cancer one, limiting its re-profiling as an anti-cancer drug.

Surface-patterned SU-8 cantilever arrays for preliminary screening of cardiac toxicity.

Arrays of a µgrooved SU-8 cantilever were utilized to analyze changes in the contraction force and beating frequency of cardiomyocytes in vitro. The longitudinally patterned µgrooves facilitates alignment of cardiomyocytes on top of the SU-8 cantilever, which increases the contraction force of cardiomyocytes by a factor of about 2.5. The bending displacement of the SU-8 cantilever was precisely measured in nanoscale using a laser-based measurement system combined with a motorized xyz stage. The cantilever displacement due to contraction of the cardiomyocytes showed the maximum on day 8 after their cultivation. Following preliminary experiments, Isoproterenol, Verapamil, and Astemizole were used to investigate the effect of drug toxicity on the physiology of cardiomyocytes. The experimental results indicated that 1 µM of Isoproterenol treatment increased contraction force and beating frequencies of cardiomyocytes by 30% and 200%, respectively, whereas 500 nM of Verapamil treatment decreased contraction force and beating frequencies of cardiomyocytes by 56% and 42%, respectively. A concentration of less than 5 nM of the hERG channel suppression drug Astemizole did not change the contraction forces in the displacement but slightly decreased the beating frequencies. However, irregular or abnormal heartbeats were observed at Astemizole concentrations of 5 nM and higher. We experimentally conformed that the proposed SU-8 cantilever arrays combined with the laser-based measurement systems has the great potential for a high-throughput drug toxicity screening system in future.

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome.

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type.

On-chip constructive cell-network study (II): on-chip quasi-in vivo cardiac toxicity assay for ventricular tachycardia/fibrillation measurement using ring-shaped closed circuit microelectrode with lined-up cardiomyocyte cell network.

BACKGROUNDS: Conventional in vitro approach using human ether-a-go-go related gene (hERG) assay has been considered worldwide as the first screening assay for cardiac repolarization safety. However, it does not always oredict the potential QT prolongation risk or pro-arrhythmic risk correctly. For adaptable preclinical strategiesto evaluate global cardiac safety, an on-chip quasi-in vivo cardiac toxicity assay for lethal arrhythmia (ventricular tachyarrhythmia) measurement using ring-shaped closed circuit microelectrode chip has been developed. RESULTS: The ventricular electrocardiogram (ECG)-like field potential data, which includes both the repolarization and the conductance abnormality, was acquired from the self-convolutied extracellular field potentials (FPs) of a lined-up cardiomyocyte network on a circle-shaped microelectrode in an agarose microchamber. When Astemisol applied to the closed-loop cardiomyocyte network, self-convoluted FP profile of normal beating changed into an early afterdepolarization (EAD) like waveform, and then showed ventricular tachyarrhythmias and ventricular fibrilations (VT/Vf). QT-prolongation-like self-convoluted FP duration prolongation and its fluctuation increase was also observed according to the increase of Astemizole concentration. CONCLUSIONS: The results indicate that the convoluted FPs of the quasi-in vivo cell network assay includes both of the repolarization data and the conductance abnormality of cardiomyocyte networks has the strong potential to prediction lethal arrhythmia.

QT prolongation and safety in the Indian population.

The QT interval in electrocardiogram (ECG) reflects the total duration of ventricular myocardial depolarization and repolarization. It has been well recognized that many condition may cause QT interval prolongation. Unfortunately, numbers of cardiac and non-cardiac drug prolong the QT interval and cause a distinctive polymorphic ventricular tachycardia termed torsade de pointes (TdP). TdP can degenerate into ventricular fibrillation, which leads to sudden cardiac death. Recently various regulatory and clinical bodies of Europe, USA, Canada and Australia have made their focus on the drugs that induce prolongation of QT interval. Committee for Proprietary Medicinal Products (CPMP) of the European Agency issued a document entitled 'Points to Consider: The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products' [1, 2]. In addition, USFDA adopted the guideline 'Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-anti arrhythmic drugs' [3]. These documents and guidelines are primarily concern with development of novel agents and the new use or new dose of already approved drugs. The scope of this guideline is to study the effect of drugs on QT prolongation and give idea of evaluation of drug's effects on QT prolongation. Today more than 50 available drugs (both old and new) have been identify, which prolong the QT interval [1]. Several drugs have been withdrawn from many countries on this basis but many of these drugs are still available in Indian market and potentially creating life-threatening arrhythmias. This article will focus on recommendation of study on the normal limits of QT interval in Indian population and preparation of the database, which can be helpful in withdrawal of drugs from the market that produces QT prolongation.

A clinical drug library screen identifies astemizole as an antimalarial agent.

The high cost and protracted time line of new drug discovery are major roadblocks to creating therapies for neglected diseases. To accelerate drug discovery we created a library of 2,687 existing drugs and screened for inhibitors of the human malaria parasite Plasmodium falciparum. The antihistamine astemizole and its principal human metabolite are promising new inhibitors of chloroquine-sensitive and multidrug-resistant parasites, and they show efficacy in two mouse models of malaria.

Estimation of potency of HERG channel blockers: impact of voltage protocol and temperature.

INTRODUCTION: The HERG channel is widely used for the assessment of proarrhythmic risk for new drugs. HERG channel blockers obstruct channel functions through various mechanisms, which usually show time dependence, voltage dependence, and state dependence. The voltage protocol and temperature may affect the estimation of drug potency, but limited information is available in this regard. The purpose of this study was to evaluate the influence of voltage protocol and temperature on predicting the potency of HERG channel blockers, and to determine electrophysiological approaches for new drugs screening studies. METHOD: Whole-cell patch-clamp electrophysiology was carried out by utilizing different voltage step protocols to examine the potency of compounds known to preferentially block the channel in the closed (ketoconazole and BeKm-1), open, and/or inactivated states (E-4031, astemizole, and terfenadine) in HEK293 cells transfected with HERG cDNA at room temperature and near-physiological temperature. RESULTS: Drug potency determined using different voltage protocols varied dependent on the mechanisms of drug actions. For most compounds, the IC(50) values obtained with a long pulse step protocol at room temperature were close to those determined with the voltage protocols designed to disclose their intrinsic potency. Relative to room temperature, the potency of E-4031, terfenadine, and ketoconazole was not changed at approximately 35 degrees C, but potency of astemizole was reduced. DISCUSSION: The long pulse step protocol with room temperature can be selected for HERG channel safety screening studies. Alternative voltage protocols or temperatures should be considered if HERG study results are not consistent with other cardiac safety assessments.

Antihistamines.

Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of "classic" or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-the-counter medications. The history of the discontinued "second-generation" antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The "third-generation" nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses.

[Risk of drug interactions. Combinations of drugs associated with ventricular arrhythmias]. / Riesgo de interacciones medicamentosas. Combinaciones de medicamentos asociados a arritmia ventricular.

OBJECTIVE: To determine the frequency of concurrent use of cisapride, astemizole and terfenadine with macrolides and azole antimitotics, drug combinations that have been reported in the literature as producing a pharmacological interaction associated with potentially fatal ventricular arrhythmias. MATERIAL AND METHODS: A retrospective analysis of a total of 72,444 prescriptions generated by 611 physicians during a 6 months period for ambulatory patients, was performed. The database included a register of automatic alerts produced every time a predetermined drug combination was detected. RESULTS: 145 potentially risk situations were detected, with an incidence rate to 2.1 cases per 1,000 prescriptions, which increases to 6.2% when prescriptions for terfenadine, astemizole, and cisapride were included, with 12, 9 y 5%, respectively. Only 36 physicians (6%) wrote prescriptions producing alerts, and about half (45%) were pediatricians. The same physician prescribed both drugs in 31% of the cases. CONCLUSION: The use of drug combinations associated with a high risk of potentially fatal ventricular arrhythmias is relatively high in Mexico. An electronic online detecting system showed to be useful in preventing this kind of potential pharmacological interactions.

Cardiotoxicity of new antihistamines and cisapride.

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Second generation antihistamines in the treatment of seasonal allergic rhinitis due to Parietaria and cypress pollen.

Second generation antihistamines have been employed in the treatment of seasonal allergic rhinitis for many years. However, their effects on two distinctive Mediterranean allergic conditions, viz. Parietaria pollinosis and cypress pollinosis, have been scarcely investigated, so far. A comparative efficacy and side effect trial of astemizole and terfenadine in the treatment of seasonal allergic rhinitis due to either Parietaria or cypress pollen was carried out in 27 adult patients, according to a double-blind, double-dummy parallel-group design. Airborne pollen monitoring allowed comparison of symptom scores with pollen counts. Seven patients (26%) withdrew, due to poor symptom control. In contrast, in a subset of 15 patients who completed the trial, treatment led to a substantial and statistically significant decline in symptom severity in both the astemizole and the terfenadine study group. However, no statistically significant inter-group differences could be detected.

H1-receptor antagonists: safety issues.

Histamine is an important neurotransmitter. Old (first-generation) H1-receptor antagonists such as chlorpheniramine, diphenhydramine, or triprolidine produce histamine blockade at H1-receptors in the central nervous system (CNS) and frequently cause somnolence or other CNS adverse effects. New (second generation) H1-antagonists such as cetirizine, fexofenadine, and loratadine represent an advance in therapeutics; in manufacturers' recommended doses, they enter the CNS in smaller amounts, produce relatively little somnolence or other CNS adverse effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Two H1-antagonists, astemizole and terfenadine, have been found to prolong the QTc interval and, rarely, to cause cardiac dysrhythmias after overdose or under other specific conditions. This has led to withdrawal of regulatory approval for them. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use.

Second-generation antihistamines: the risk of ventricular arrhythmias.

Some second-generation antihistamines, notably terfenadine and astemizole, have been associated with prolongation of the QT interval and the development of torsades de pointes, a potentially fatal ventricular arrhythmia. This rare adverse event has been associated with greatly elevated blood levels of these agents, resulting from drug overdose, hepatic insufficiency (dysfunction), or interactions with other drugs that inhibit their metabolism. This paper reviews the data concerning the effects of selected second-generation antihistamines on cardiac conduction, particularly the QT interval, to evaluate whether ventricular arrhythmias are a class effect of these agents. Electrocardiographic studies indicate that terfenadine and astemizole, but not loratadine or cetirizine, prolong the QT interval in laboratory animals. In vitro studies demonstrate that terfenadine and astemizole block the cardiac K+ channels, leading to delayed ventricular repolarization and QT-interval prolongation; in contrast, neither loratadine nor its metabolite, desloratadine, significantly inhibits cardiac K+ channels at clinically achievable blood levels. Studies in human volunteers confirm the absence of electrocardiographic effects of azelastine, cetirizine, fexofenadine, and loratadine administered at several times the recommended dose or concomitantly with agents that inhibit their metabolism and elimination. In conclusion, the data indicate that the potential to cause ventricular arrhythmias is not a class effect of second-generation antihistamines and that loratadine, cetirizine, azelastine, and fexofenadine are not associated with torsades de pointes or other ventricular arrhythmias.