High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing.     

药物性牙龈肥大发病机制的研究进展

药物性牙龈肥大(DIGO)主要由长期服用苯妥英钠、环孢素A、硝苯地平引起,不仅影响牙面的清洁与美观和牙齿正常生理功能,而且可能造成患者心理上的障碍。然而,DIGO发病机制复杂,无法明确,导致治疗较为棘手。许多学者对其进行了多方面的研究,提出许多观点与假设,包括胶原生成与降解失衡机制、炎症等。该文从分子机制与药物具体机制两方面总结了近几年对DIGO发病的研究,并对DIGO未来的研究方向进行探讨,希望能够对DIGO的预防与临床治疗有所帮助。     

Utility of implantable cardioverter defibrillator electrograms to estimate repolarization alternans preceding a tachyarrhythmic event

Electrical alternans is a pattern of variation in the shape of the ECG waveform that appears on an every-other-beat basis. In humans, alternation in ventricular repolarization, namely, repolarization alternans, has been associated with increased vulnerability to ventricular tachycardia/ventricular fibrillation and sudden cardiac death. This study investigates the utility of implantable cardioverter defibrillator electrograms to estimate repolarization alternans preceding a tachyarrhythmic event. It is demonstrated that microvolt-level repolarization alternans is present prior to an arrhythmic event, and one can record low-amplitude-noise signals that can be used to obtain reliable estimates of repolarization alternans. This study eventually may lead to new methods that would prevent the onset of malignant tachyarrhythmias.     

Accelerated idioventricular rhythm detected during elective surgery in a healthy man.

Accelerated idioventricular rhythm (AIVR) is found most commonly in the presence of underlying heart disease. It is characterized by acceleration of a latent pacemaker that normally depolarizes slowly. We describe a 30-year-old man who was found to have episodes of accelerated idioventricular rhythm (AIVR) on cardiac monitoring during elective orthopedic surgery. Noninvasive evaluation including two-dimensional echocardiography was unremarkable. No late potentials were detected on a signal-averaged electrocardiogram. During an exercise tolerance test, AIVR was suppressed as heart rate increased. A 24-h Holter monitor revealed that the AIVR rate was consistently 73-76 beats/min, which appeared whenever the sinus rate slowed to this level. The patient has been asymptomatic, and the rhythm has persisted at least through a 5-month follow-up period.     

参仙升脉口服液辅助治疗缓慢性心律失常疗效观察

摘 要 目的: 观察参仙升脉口服液辅助治疗缓慢性心律失常的疗效和安全性。方法：缓慢性心律失常患者80例按就诊顺序分为两组。对照组患者采用常规治疗,观察组患者在对照组基础上加用参仙升脉口服液20 ml,po bid。两组均治疗4周。比较两组治疗前后24 h动态心电图变化、临床疗效及药品不良反应。结果：观察组临床总有效率为92.5%,明显高于对照组的70.0%（P＜0.05）。观察组患者治疗后24 h动态心电图检查结果明显优于对照组（P＜0.05）。治疗中两组患者均未出现明显不良反应。结论：常规治疗基础上加服参仙升脉口服液可有效提高缓慢性心律失常的临床疗效,安全性好,具有推广应用价值。     

Lead I R‐wave amplitude to distinguish ventricular arrhythmias with lead V3 transition originating from the left versus right ventricular outflow tract

BackgroundThe electrophysiology algorithm for localizing left or right origins of outflow tract ventricular arrhythmias (OT‐VAs) with lead V₃ transition still needs further investigation in clinical practice.HypothesisLead I R‐wave amplitude is effective in distinguishing the left or right origin of OT‐VAs with lead V₃ transition.MethodsWe measured lead I R‐wave amplitude in 82 OT‐VA patients with lead V₃ transition and a positive complex in lead I who underwent successful catheter ablation from the right ventricular outflow tract (RVOT) and left ventricular outflow tract (LVOT). The optimal R‐wave threshold was identified, compared with the V₂S/V₃R index, transitional zone (TZ) index, and V₂ transition ratio, and validated in a prospective cohort study.ResultsLead I R‐wave amplitude for LVOT origins was significantly higher than that for RVOT origins (0.55 ± 0.13 vs. 0.32 ± 0.15 mV; p < .001). The area under the curve (AUC) for lead I R‐wave amplitude as assessed by receiver operating characteristic (ROC) analysis was 0.926, with a cutoff value of ≥0.45 predicting LVOT origin with 92.9% sensitivity and 88.2% specificity, superior to the V₂S/V₃R index, TZ index, and V₂ transition ratio. VAs in the LVOT group mainly originated from the right coronary cusp (RCC) and left and right coronary cusp junction (L‐RCC). In the prospective study, lead I R‐wave amplitude identified the LVOT origin with 92.3% accuracy.ConclusionLead I R‐wave amplitude provides a useful and simple criterion to identify RCC or L‐RCC origin in OT‐VAs with lead V₃ transition.