Activation of endothelial nitric oxide synthase by midkine and uses therefor in effecting vasodilation

• US 8,288,343 B2
• Filed: 03/28/2008
• Issued: 10/16/2012
• Est. Priority Date: 03/30/2007
• Status: Active Grant

• Current Assignee: Cellmid Limited
• Original Assignee: Nagoya University
• Inventors: Kadomatsu, Kenji, Muramatsu, Takashi, Ishiguro, Hisaaki, Takenaka, Hiroharu, Sumida, Arihiro, Horiba, Mitsuru, Kodama, Itsuo
• Primary Examiner(s): Shafer, Shulamith H
• Application Number:
  US12/593,277
• Publication Number:
  US 20100197577A1
• Time in Patent Office: 1,663 Days
• Field of Search: None
• US Class Current: 514/16.4
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators

Abstract

The object is to find a nitric oxide synthase activator, a method for the administration of the activator, and the amount of the activator to be administered. Disclosed is a nitric oxide synthase activator comprising a midkine family protein or a midkine derivative as an active ingredient. Specifically disclosed is a nitric oxide synthase activator which is intended to be administered through the blood, a coronary artery or a vein and which comprises a midkine family protein or a midkine derivative as an active ingredient.

Claims

1. A method to activate nitric oxide synthase (eNOS) which method comprises contacting a vascular endothelial cell expressing said eNOS with a composition comprising a human midkine protein as an active ingredient.

2. The method of claim 1 wherein said eNOS is contained in a subject in need of activation of said eNOS and said contacting comprises administering said composition to the subject.

6. The method of claim 2 wherein said composition is administered in an amount of 50 ng/kg to 100 μ

g/kg.

3. A method to stimulate vasodilation in a subject in need of said stimulation of vasodilation which method comprises administering to the coronary artery of a subject in need of such stimulated vasodilation a composition comprising a human midkine protein as an active ingredient.

4. The method of claim 3 wherein said subject has an ischemia disorder or muscle cell dysfunction after ischemia perfusion.

5. The method of claim 3 wherein said administering is to the coronary artery of the subject comprises delivery of the human midkine protein via the lumen of a percutaneous transluminal coronary angioplasty (PTCA) device into a coronary artery of the subject.

7. The method of claim 3 wherein said composition is administered in an amount of 50 ng/kg to 100 μ

g/kg.