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Patent US5910484 - Treatment of ischemic cardiac malfunction - Google Patents
The present invention is based on the unexpected discoveries that hypothalamic inhibitory factor (HIF) has a positive inotropic effect in a whole organ preparation, such as an isolated perfused heart, and that HIF, to a greater extent than ouabain, dilates the coronary arteries in the isolated perfused...http://www.google.com/patents/US5910484?utm_source=gb-gplus-sharePatent US5910484 - Treatment of ischemic cardiac malfunction
Publication number US5910484 A
Application number US 08/866,712
Also published as DE69827126D1, DE69827126T2, EP0983071A1, EP0983071B1, US6265383, WO1998053832A1
Publication number 08866712, 866712, US 5910484 A, US 5910484A, US-A-5910484, US5910484 A, US5910484A
Inventors Garner T. Haupert, Jr.
Patent Citations (8), Non-Patent Citations (62), Referenced by (63), Classifications (6), Legal Events (4)
US 5910484 A
Guinea pigs were anesthetized with 65-100 mg pentobarbital in the peritoneal cavity followed by anticoagulation using 200 units of heparin via femoral vein. Sternotomy was performed, the beating heart removed and placed in a bowl containing room temperature saline. The aorta was trimmed and cannulated onto the perfusion apparatus. Retrograde perfusion of Kreb's solution (37° C.) at 70 mm Hg bubbled with 95% 02/5% CO2 from a 3 liter reservoir was begun within one minute of cardiectomy. A micro flexible temperature probe was inserted in the open pulmonary artery allowing coronary effluent to drain. The left atrial appendage was incised, the left ventricle vented, and a water-filled balloon-tipped catheter inserted into the left ventricle chamber. Left ventricular systolic pressure (LVP), left ventricular end diastolic pressure (LVEDP), maximal rate of rise of left ventricular pressure (dP/dT), and aortic root pressure (AOP) were recorded on a precalibrated multichannel dynograph. Coronary flow (CF) is measured by timed volumetric collection. The heart was paced (HR) at 272 BPM by way of electrodes attached to the right atrium. After 30 minutes of perfusion, coronary flow was then diverted into a recirculating perfusion circuit primed with 60 cc of Kreb's solution.
HIF has been previously shown to produce positive inotropic effects in isolated, spontaneously beating myocytes in culture, with greater potency and a different toxic profile from ouabain (Hallaq, H. and Haupert, G., Jr., Proc. Natl. Acad. Sci., USA, 86:10080-10084 (1989)). As shown herein, HIF also produces a positive inotropic effect in an intact, whole organ preparation. 20 μg HIF was prepared to homogeneity as confirmed by mass spectral measurement, for infusion into an isolated, perfused guinea pig heart preparation according to the Langendorf methodology (Hendren, W. G., et al., J. Thor. Cardiovasc. Surg., 94:614-625 (1987)). This methodology allows continuous measurement of left ventricular pressure generation, the first derivative of the pressure measurement (dP/dT), end diastolic pressure and coronary flow. Pilot studies with ouabain were carried out to determine the minimal consistently effective dose to produce an enhanced inotropic effect. For both ouabain and HIF, this amount was 4 μg of pure inhibitor administered to a perfusion volume of 60 ml Krebs-Heinsleit buffer (final concentration 1×10-7 M). Coded samples were prepared of HIF, ouabain and placebo (vehicle), and administered randomly to the preparation. The one conducting the experiments was blinded to the samples.
TABLE 1__________________________________________________________________________Effects of HIF, ouabain and placebo on performance and perfusioncharacteristics inisolated, perfused guinea pig heart (LVP, left ventricular pressure;dP/dt, rate ofdevelopment of pressure)   LVP post dPdt  dP/dt post                            End Dia                                EDP post  coronary                                                CF postGROUPSLVP   intervention         %  mmHg.sec-1                  intervention                        %   pressure                                intervention                                      %   flow cc/min                                                intervention                                                      %__________________________________________________________________________ouabain73.82   90.44 *         22.5            2326  2856 *                        22.7                            7.66                                8.01  4.6 25.84 27.77*                                                      7.5n = 9placebo67.17   68.29 1.7            2104  2088  -0.7                            7.77                                9.19  18.2                                          25.89 25.09 -3.1n = 8HIF  70.54   89.91 *         27.4            2292  2884 *                        25.8                            7.6 7.77  2.1 24.37 27.82*                                                      14.1n = 9__________________________________________________________________________  P<0.01 intervention vs placebo *P<0.01 pre intervention vs post intervention
EP0433074A1 * Dec 13, 1990 Jun 19, 1991 The General Hospital Corporation Method for treating cardiac malfunction
WO1992004047A1 * Aug 21, 1991 Mar 19, 1992 University Of Maryland At Baltimore Methods of treating, diagnosing and monitoring therapies from levels of human oubain-like factor and antibody thereof
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US6265383 * Jun 7, 1999 Jul 24, 2001 The General Hospital Corporation Treatment of ischemic cardiac malfunction
US6846646 Dec 24, 1998 Jan 25, 2005 The General Hospital Corporation Methods for screening HIF like ouabain-resistant Na+-K+-ATPase agents
US7396658 Mar 16, 2004 Jul 8, 2008 The General Hospital Corporation Methods for screening HIF like ouabain-resistant Na+—K+-ATPase agents
US20040248080 * Mar 16, 2004 Dec 9, 2004 The General Hospital Corporation Methods for screening HIF like ouabain-resistant Na+-K+-ATPase agents
International Classification A61P9/10, A61K31/70, A61K31/704
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