Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-01-26
1999-05-11
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514 45, A61K31/195;31/70
Patent
active
059028297
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of modulating the micro-circulation, particularly in patients who have undergone, or are due to undergo, elective surgery.
Disruption of the microvasculature is a key factor in mechanisms of inter alia hepatic, mesenteric and cardiac ischemia-reperfusion injury. Recent in vitro studies using a blood free, low-flow, reflow liver perfusion model have demonstrated that reperfusion injury can be reduced by improving the microcirculation. For example, perfused livers from rats pre-treated with a fish-oil diet showed a marked improvement in microcirculation and a significant reduction in hepatic damage. In addition, it is also known that adenosine, a known vasodilator and an essential component in Caroline Rinse solution, improves survival following liver transplantation.
The present invention provides inter alia, a medicament, pre-operative administration of which to patients due to undergo elective surgery has a prophylactic effect vis-a-vis hypoperfusion-reperfusion injury in numerous micro-circulatory systems.
According to the present invention there is provided the use of L-arginine, a precursor of L-arginine and/or physiologically acceptable salts thereof, in the preparation of a medicament or nutritional formulation for the amelioration of micro-circulatory hypo-perfusion, and/or the treatment or prophylaxis of hypoperfusion-reperfusion injury, in patients which have undergone elective surgery, characterized in that the medicament or nutritional formulation is pre-operatively administered to the patient.
Preferred precursors of L-arginine are either ornithine or glutamine, particularly preferred ornithine.
The present invention further provides a method for the amelioration of micro-circulatory hypo-perfusion, and/or the treatment or prophylaxis of hypoperfusion-reperfusion injury, in patients which have undergone elective surgery, characterized in that L-arginine, a precursor of L-arginine and/or physiologically acceptable salts thereof is pre-operatively administered to the patient.
L-arginine is the substrate for nitric oxide synthetase (NOS), the enzyme responsible for the production of nitric oxide, a highly unstable molecule which inter alia mediates smooth muscle relaxation in vascular tissue. Two forms of this enzyme are known to be present in vivo, an essentially endothelial cell located calcium/NADPH dependant--calmodulin sensitive constitutive form, and an essentially calcium independent form the production/activity of which is induced in response to, for example, endotoxin/cytokinin--mediated metabolic stress. The inducible form of nitric oxide synthetase is located in macrophages and like cells, such as Kupffer and microglial cells in the liver and nervous system respectively.
Endogenous nitric oxide production can also increase blood flow by reducing the number of blood elements adhering to the lumen of the vessel. In high doses, nitric oxide can be cytotoxic and cause oxidative injury.
According to the present invention there is also provided the use of (i) a nitric oxide donor, and/or (ii) a substrate of the nitric oxide synthetase, and/or (iii) a precursor of the said substrate, in the preparation of a medicament or nutritional formulation for the amelioration of micro-circulatory hypo-perfusion, and/or the treatment or prophylaxis of hypoperfusion-reperfusion injury, in patients which have undergone elective surgery, characterized in that the medicament or nutritional formulation is pre-operatively administered to the patient.
There is further provided a method for the amelioration of micro-circulatory hypo-perfusion, and/or the treatment or prophylaxis of hypoperfusion-reperfusion injury, in patients which have undergone elective surgery, characterized in that i) a nitric oxide donor, and/or (ii) a substrate of the nitric oxide synthetase, and/or (iii) a precursor of the said substrate is pre-operatively administered to the patient.
It is preferred that treatment is initiated at least one day prior to surgery and that the medicament or formulati
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Schneider Heinz
Thurman Ronald G.
Morris Michael P.
Novartis Nutrition AG
Weddington Kevin E.
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