Rationale
While much progress has been made in the resolution of the cellular hierarchy underlying cardiogenesis, our understanding of chamber-specific myocardium differentiation remains incomplete.
Objective
To better understand ventricular myocardium differentiation, we targeted the ventricle-specific gene, Irx4, in mouse embryonic stem cells to generate a reporter cell line.
Methods and Results
Using an antibiotic-selection approach, we purified Irx4+ cells in vitro from differentiating embryoid bodies. The isolated Irx4+ cells proved to be highly proliferative and presented Cxcr4, Pdgfr-alpha, Flk1 and Flt1 on the cell surface. Single Irx4+ ventricular progenitor cells (VPC) exhibited cardiovascular potency, generating endothelial cells, smooth muscle cells and ventricular myocytes in vitro. The ventricular specificity of the Irx4+ population was further demonstrated in vivo as VPCs injected into the cardiac crescent subsequently produced Mlc2v+ myocytes that exclusively contributed to the nascent ventricle at E9.5. These findings support the existence of a newly identified ventricular myocardial progenitor.
Conclusions
This is the first report of a multipotent cardiac progenitor that contributes progeny specific to the ventricular myocardium.
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Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.
Aim: To determine the potential impact of high-intensity statins on the risk of major vascular event (MVE), all-cause mortality, coronary heart disease (CHD) death and death by other cardiac causes.
Recently, dry powder inhalation (DPI) powders coated with nanometre-thin layers of biodegradable polymers, prepared using pulse laser deposition (PLD), have been evaluated as a slow-release formulation for DPI use, with the goal of improving pulmonary selectivity. This paper describes evaluation of the chemical stability of one potential polymer, poly lactic acid (PLA), during the ablation process, the resulting respirable properties and potential cytotoxicity of coated glucocorticoid powders, and the resulting sustained-release characteristics of PLA-coated glucocorticoids creating using PLD. Triamcinolone acetonide (TA) and budesonide (BUD) were used as two model glucocorticoids to determine pulmonary targeting (PT) in-vivo. The chemical stability of PLA was determined at various laser energy densities. The respirable fraction and the cytotoxicity of the micronized particles of TA and BUD, coated using optimum laser energy density, were determined. In-vitro dissolution profiles were generated for the coated/uncoated formulations and an ex-vivo receptor binding assay was used to determine PT in rats. Increasing laser energy density led to decreases in molecular weight and film density, and increases in degradation products, roughness and thickness of the film. The mean dissolution time of coated formulations of BUD was longer (4 h) than with the less lipophilic TA (2 h). This correlated well with a more pronounced pulmonary selectivity observed for coated BUD ex-vivo. Stability and the physical properties of the film correlated with the laser energy density. We observed a direct relationship between the dissolution rate of the uncoated and coated formulation and the degree of PT; however, physiochemical properties of the drug (e.g. lipophilicity) may also contribute to the improved PT.
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