The purpose of this investigation was to determine if exogenous estrogen could attenuate the ventricular arrhythmias caused by myocardial ischemia and reperfusion. Conjugated equine estrogen, administered as an intravenous bolus injection (100 micrograms) to anesthetized, instrumented beagles of both genders, significantly attenuated the incidence of ventricular arrhythmias during a 20-min period of ischemia (2 +/- 1 vs. 19 +/- 16% ectopy) and in the first 5 min of reperfusion (15 +/- 9 vs. 69 +/- 20% ectopy). By 15-20 min of ischemia, ventricular salvos and nonsustained ventricular tachycardia were frequently observed in nontreated dogs. One dog in this group fibrillated during ischemia. In contrast, estrogen-treated dogs exhibited only an occasional ventricular premature beat during the same period of ischemia. When compared with baseline values, the percent ectopy during ischemia in estrogen-treated dogs was insignificant. During reperfusion, nontreated dogs displayed severe, life-threatening arrhythmias such as sustained ventricular tachycardia. In two of these dogs ventricular tachycardia deteriorated to ventricular fibrillation. In comparison, estrogen-treated dogs displayed only innocuous ventricular arrhythmias during reperfusion, i.e., ventricular premature beats, ventricular salvos, and ventricular bigeminy. In addition to the effect of estrogen on arrhythmias, there was a gradual increase in coronary blood flow on reperfusion in estrogen-treated dogs. This effect of estrogen was preceded by a significantly higher coronary perfusion pressure during ischemia (31 +/- 2 vs. 18 +/- 4 mmHg, P < 0.05). In conclusion, our findings suggest that antiarrhythmic effects of estrogen treatment might stabilize ventricular rhythmicity during ischemia and reperfusion.
BackgroundThis analysis updates on the previously reported serious treatment emergent adverse event (TEAE) profile of cladribine tablets (CT) 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) following integration of final data from the PREMIERE registry and post-approval safety data from worldwide sources.MethodsThe monotherapy oral cohort (CT3.5, N=923, patient-years [PY]=3936.69; placebo, N=641, PY=2421.47) was derived from the CLARITY, CLARITY Extension and ORACLE-MS trials plus the PREMIERE registry. Adjusted adverse event incidences-per-100PY (Adj-AE-per-100PY) were calculated, cumulative to end of PREMIERE (October 2018).ResultsPatient characteristics were balanced between groups. Adj-AE-per-100PY for ≥1 serious TEAE were:3.80 (CT3.5), 3.05 (placebo); for serious lymphopenia (preferred term [PT]): 0.10 (CT3.5), 0 (placebo); for serious infections and infestations (system organ class): 0.60 (CT3.5), 0.42 (placebo); for serious herpes zoster (PT): 0.05 (CT3.5), 0 (placebo); and malignant tumours: 0.26 (CT3.5), 0.12 (placebo). Post-approval sources reported 1622 AEs in the Periodic Benefit-Risk Evaluation Report (275 were serious); none repre- sented a new safety signal.ConclusionsNo new major safety findings for cladribine tablets were identified in this finalised integrated dataset containing final data from the PREMIERE registry. Findings are consistent with previously published integrated safety analyses. No new safety signals were identified from post-approval safety data. CLARITY:NCT00213135. CLARITY Extension:NCT00641537. ORACLE-MS:NCT00725985. PREMIERE:NCT01013350g.giovannoni@qmul.ac.uk
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