Mexiletine in the Prophylaxis of Ventricular Arrhythmias During Acute Myocardial Infarction

Campbell, R. W. F.; Achuff, S. C.; Pottage, A.; Murray, Alan; Prescott, Laurence F.; Julian, Desmond G.

doi:10.1097/00005344-197901000-00005

Cited by 52 publications

(8 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clinical therapeutic window is thus concerningly narrow. Unsurprisingly therefore, although initial clinical trials reported positive findings [31][32][33][34][35]37,39,59 mexiletine has not emerged as a drug for primary prevention of SCD 12 ; as with all antiarrhythmics its ADRs are perceived to outweigh benefit in this context 5,16 . Consequently, since this, the most useful drug has limited utility, there remains an important unmet clinical need for primary prevention.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Hesketh

Wilder

Ranadive

et al. 2020

Sci Rep

View full text Add to dashboard Cite

the 'translational therapeutic index' (tti) is a drug's ratio of nonclinical threshold dose (or concentration) for significant benefit versus threshold for adversity. In early nonclinical research, discovery and safety studies are normally undertaken separately. our aim was to evaluate a novel integrated approach for generating a tti for drugs intended for prevention of ischaemia-induced ventricular fibrillation (VF). We templated the current best available class 1b antiarrhythmic, mexiletine, using the rat Langendorff preparation. Mexiletine's beneficial effects on the incidence of VF caused by 120 min regional ischaemia were contrasted with its concurrent adverse effects (on several variables) in the same hearts, to generate a TTI. Mexiletine 0.1 and 0.5 µM had no adverse effects, but did not reduce VF incidence. Mexiletine 1 µM reduced VF incidence to 0% but had adverse effects on atrioventricular conduction and ventricular repolarization. Separate studies undertaken using an intraventricular balloon revealed no detrimental effects of mexiletine (1 and 5 µM) on mechanical function, or any benefit against reperfusion-related dysfunction. Mexiletine's TTI was found to be less than two, which accords with its clinical therapeutic index. Although non-cardiac adversity, identifiable from additional in vivo studies, may reduce the tti further, it cannot increase it. our experimental approach represents a useful early-stage integrated risk/benefit method that, when TTI is found to be low, would eliminate unsuitable class 1b drugs prior to next stage in vivo work, with mexiletine's tti defining the gold standard that would need to be bettered. Coronary heart disease and acute myocardial infarction (AMI) constitute the largest cause of death worldwide 1 with sudden cardiac death (SCD) responsible for approximately 50% of lethality 2,3. Most SCD is due to ischaemia-induced arrhythmias, particularly ventricular fibrillation (VF) and ventricular tachycardia 4. Currently available antiarrhythmic drugs have failed against SCD 5. The reason for this is that the benefit afforded by those drugs found to suppress SCD is offset by adverse drug reactions (ADRs); in some trials, mortality was actually increased 6-8 while in other trials attempts to minimise ADR risk by use of lower drug doses resulted in loss of effectiveness 9,10. Presently the class 1b antiarrhythmic, mexiletine, and the non-selective class III drug, amiodarone 11 , are the only antiarrhythmics prescribed for SCD outside the hospital setting, but even these drugs are not considered sufficiently efficacious for use in the larger lower-risk populations 5,12 leaving a huge and longstanding unmet therapeutic need 4. Since amiodarone is an anomalous example of a class (III) that is otherwise discounted as a solution to SCD owing to proarrhythmia 5,12 , this leaves only class 1b agents as an avenue for new drug development. An essential part of the process of any new drug development is to mitigate against ADRs during the nonclinical phase. In view of this, we and oth...

show abstract

Section: Discussionmentioning

confidence: 99%

Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Hesketh

Wilder

Ranadive

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…quinidine [19], proprano lol [20,21], lidocaine [22][23][24][25][26][27][28], disopyramidc [29. 30], mexiletine [31] and tocainide [32], but few have been conducted in patients in the earliest hours of infarction.…”

Section: Discussionmentioning

confidence: 99%

Antiarrhythmic Effect of Tiapamil in Patients with Acute Myocardial Infarction

Dubner¹,

Gimeno²,

Elencwajg³

et al. 1982

Cardiology

View full text Add to dashboard Cite

The efficacy of intravenously administered tiapamil in treating premature ventricular contractions (PVCs) in the acute phase of acute myocardial infarction was evaluated in 20 patients using 24-hour continuous ECG monitoring (Holier). All patients presented frequent and/or complex ventricular arrhythmias (Lown classification II-V). Tiapamil reduced the number of PVCs to a statistically highly significant degree (p < 0.01), i.e. 82-85% in the 4th hour of treatment. The number of PVCs increased again after therapy was discontinued. Where supraventricular ectopic beats were present in addition to PVCs, tiapamil reduced them by 93% in the 3rd and 4th hours of treatment. These results suggest that tiapamil could be an effective antiarrhythmic agent in acute myocardial infarction.

show abstract

“…594 Three studies were neutral with respect to tocainide and disopyramide (LOE 1), 582 mexilitine (LOE 1), 579 and tocainamide (LOE 1). 585 One study showed harm with amiodarone (LOE 1) 584 and 1 trial (LOE 1) 591 showed harm with a variety of drugs, including ␤-blockers.…”

Section: Consensus On Sciencementioning

confidence: 99%

Part 9: Acute Coronary Syndromes

Bossaert

O’Connor²,

Arntz³

et al. 2010

Circulation

103

View full text Add to dashboard Cite

These experts reviewed 25 topics related to the acute initial management of acute coronary syndrome (ACS), which was further categorized as unstable angina, non-ST-elevation MI (UA/NSTEMI) and ST-elevation MI (STEMI). Topics were identified based on previous recommendations, emerging science, and clinical importance, using an iterative writing process involving all Task Force members. The Task Force reviewed the evidence specifically related to diagnosis and treatment of ACS in the out-ofhospital setting and the first hours of care in the in-hospital setting, typically in the emergency department (ED). The evidence review took place over several years, with ongoing refinement of recommendations being made as new evidence was published. The purpose of the review was to generate current, evidence-based treatment recommendations for healthcare providers who serve as the initial point of contact for patients with signs and symptoms suggestive of ACS.The following is a summary of the most important changes in recommendations for diagnosis and treatment of ACS since the last ILCOR review in 2005. 1,2• The history and physical examination, initial ECG, and initial serum biomarkers, even when used in combination, cannot be used to reliably exclude ACS in the prehospital and ED settings.• In contrast, chest pain observation protocols are useful in identifying patients with suspected ACS and patients who require admission or may be referred for provocative testing for coronary artery disease (CAD) to identify reversible ischemia. Such strategies also reduce cost by reducing unnecessary hospital admissions and improve patient safety through more accurate identification of NSTEMI and STEMI.• The acquisition of a prehospital 12-lead ECG is essential for identification of STEMI patients before hospital arrival and should be used in conjunction with pre-arrival hospital notification and concurrent activation of the catheter laboratory.• Nonphysicians can be trained to independently interpret 12-lead ECGs for the purpose of identifying patients with STEMI, provided that appropriate and reliable STEMI criteria are used. This skill is of particular value in the prehospital setting where paramedics may independently identify STEMI, thus mitigating over-reliance on ECG transmission.• Computer-assisted ECG interpretation can be used to increase diagnostic accuracy of STEMI diagnosis when used alone or in combination with ECG interpretation by a trained healthcare provider.• STEMI systems of care can be implemented to improve the time to treatment. The following measures have been shown to reduce the time to primary percutaneous coronary intervention (PPCI): institutional commitment, use of a team-based approach, arranging single-call activation of the catheterization laboratory by the emergency physician or prehospital provider, requiring the catheterization laboratory to be ready in 20 minutes, having an experienced cardiologist always available, and providing real-time data feedback.• Intravenous (IV) ␤-blockers should not be give...

show abstract

Mexiletine in the Prophylaxis of Ventricular Arrhythmias During Acute Myocardial Infarction

Cited by 52 publications

References 0 publications

Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Characterisation of mexiletine’s translational therapeutic index for suppression of ischaemia-induced ventricular fibrillation in the rat isolated heart

Antiarrhythmic Effect of Tiapamil in Patients with Acute Myocardial Infarction

Part 9: Acute Coronary Syndromes

Contact Info

Product

Resources

About