topiramate and Myocardial-Infarction

Increases in heart rate were seen during the clinical program for fixed-dose combination phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management; however, the effect on cardiovascular (CV) outcomes is uncertain.. The aim of the present study was to determine the extent to which the rates of major adverse CV events (MACE) in patients using PHEN and TPM (including fixed dose) differed from the MACE rates during unexposed periods.. Retrospective cohort study.. MarketScan, US insurance billing data.. Patients aged >18 years with ≥6 months of continuous enrollment in the database before taking PHEN and/or TPM or after stopping these medications.. PHEN and TPM, taken separately and together (including fixed dose).. MACE, a composite of hospitalization for acute myocardial infarction and stroke and in-hospital CV death.. Because the outcomes are rare and the duration of medication use was brief, few events occurred. The MACE rates among current users of PHEN/TPM, fixed-dose PHEN/TPM, and PHEN were lower than those among unexposed former users. In contrast, the rate of MACE among current users of TPM was greater than among unexposed former users [incidence rate ratio: PHEN/TPM, 0.57; 95% CI, 0.19 to 1.78; fixed-PHEN/TPM, 0.24; 95% CI, 0.03 to 1.70; PHEN, 0.56; 95% CI, 0.34 to 0.91; TPM, 1.58; 95% CI, 1.33 to 1.87).. Overall, the data indicated no increased risk of MACE for current PHEN/TPM users; however, the 95% CIs for the PHEN/TPM groups were broad, indicating that the data were compatible with a wide range of possible values.

Topics: Adolescent; Adult; Anti-Obesity Agents; Drug Combinations; Female; Heart Rate; Hospitalization; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Obesity; Phentermine; Retrospective Studies; Stroke; Topiramate; Weight Loss; Young Adult

Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI).. After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes.. Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future.

Topics: Animals; Anti-Inflammatory Agents; Antigens, Ly; Collagen; Disease Models, Animal; Fibrosis; Fructose; GABA Agonists; Heart Rupture, Post-Infarction; Heart Ventricles; Macrophages; Mice, Inbred C57BL; Monocytes; Myocardial Infarction; Myocarditis; Myocardium; Phenotype; Receptors, GABA; Receptors, GABA-A; Time Factors; Topiramate; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling