Objectives: Endoxifen is a protein kinase C inhibitor. The objective of the present phase III study was to demonstrate the safety and efficacy of endoxifen in treating bipolar I disorder (BPD I) patients. Methods:A multicenter, double-blind, active-controlled study was conducted using a daily dose of 8 mg endoxifen compared to 1000 mg divalproex, the current standard treatment, in patients with BPD I acute manic episodes with/without How to cite this article: Ahmad A, Sheikh S, Khan MA, et al.Endoxifen: A new, protein kinase C inhibitor to treat acute and mixed mania associated with bipolar I disorder. Bipolar

In children with congenital cardiac anomalies, isoproterenol has been used to simulate exercise. To determine if these states are comparable, 28 children with pulmonary valvar stenosis were studied by cardiac catheterization at rest, during supine submaximal exercise, and during isoproterenol infusion. Similar heart rates were obtained during exercise (142/min) and isoproterenol infusion (139/min). Cardiac index, right ventricular systolic pressure and oxygen consumption were measured during each physiologic state. The change in pulmonary valve area from rest was calculated. At similar heart rates, cardiac index was significantly greater with exercise than with isoproterenol and right ventricular systolic pressure was similar in the two states. Thus, the calculated pulmonary valve area was significantly smaller with the pharmacologically induced stress. The study indicates that several of the hemodynamic effects of isoproterenol are not comparable to those produced by exercise in patients with pulmonary valvar stenosis.

Sixty-four children with pulmonary stenosis were studied by cardiac catheterization both at rest and on exercise. Whereas milder degrees of stenosis were associated with normal right ventricular function, more severe stenosis was associated with fixed stroke index and elevated RVEDP, and suboptimal response of cardiac index. These changes result from altered right ventricular compliance. In several the compliance abnormality was related to myocardial hypertrophy, whereas in four patients it was most likely caused by myocardial fibrosis.

We reviewed Ghosh et al. 1 letter based on our active-controlled, double-blind, and randomized trial 2 that demonstrated the therapeutic benefit of Endoxifen in patients with bipolar I disorder. The author's reservations about the sample size estimation, statistical analysis, and missing data handling on the published article are unfounded. The clinical study design, conduct, and analysis were done under required regulatory and Good Clinical Practice guidelines. The non-inferiority margin was chosen based on consideration of our prior study. 3

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