The effect of the thioether-bridged, stabilized Angiotensin-(1-7) analogue cyclic ang-(1-7) on cardiac remodeling and endothelial function in rats with myocardial infarction.

Modulation of renin-angiotensin system (RAS) by angiotensin-(1-7) (Ang-(1-7)) is an attractive approach to combat the detrimental consequences of myocardial infarction (MI). However Ang-(1-7) has limited clinical potential due to its unfavorable pharmacokinetic profile. We investigated effects of a stabilized, thioether-bridged analogue of Ang-(1-7) called cyclic Ang-(1-7) in rat model of myocardial infarction. Rats underwent coronary ligation or sham surgery. Two weeks thereafter infusion with 0.24 or 2.4 µg/kg/h cAng-(1-7) or saline was started for 8 weeks. Thereafter, cardiac morphometric and hemodynamic variables as wells as aortic endothelial function were measured. The average infarct size was 13.8% and was not changed by cAng-(1-7) treatment. MI increased heart weight and myocyte size, which was restored by cAng-(1-7) to sham levels. In addition, cAng-(1-7) lowered left ventricular end-diastolic pressure and improved endothelial function. The results suggest that cAng-(1-7) is a promising new agent in treatment of myocardial infarction and warrant further research.

Use of hydrophobins in formulation of water insoluble drugs for oral administration.

The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs. Bioavailability of two of these drugs, nifedipine and cyclosporine A (CyA), was tested when administered as a SC3-based suspension. SC3 (in a 1:2 (w/w) drug:SC3 ratio) or 100% PEG400 increased the bioavailability of nifedipine to a similar degree (6+/-2- and 4+/-3-fold, respectively) compared to nifedipine powder without additives. Moreover, SC3 (in a 7:1 (w/w) drug:hydrophobin ratio) was as effective as a 20-fold diluted Neoral formulation by increasing bioavailability of CyA 2.3+/-0.3-fold compared to CyA in water. Interestingly, using SC3 in the CyA formulation resulted in a slower uptake (p<0.001 in T(max)) of the drug, with a lower peak concentration (C(max) 1.8 mg ml(-1)) at a later time point (T(max) 9+/-2 h) compared to Neoral (C(max) 2.2 mg ml(-1); T(max) 3.2+/-0.2). Consequently, SC3 will result in a more constant, longer lasting drug level in the body. Taken together, hydrophobins are attractive candidates to formulate hydrophobic drugs.