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  Pharmaceutical Patents  

 

Title:  Use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing diseases by inhibition of calcium
United States Patent: 
7,999,076
Issued: 
August 16, 2011
I
nventors:  Zal; Franck (Morlaix-Ploujean, FR), Rousselot; Morgane (Saint-Pol-de-Leon, FR)
Assignee:
Centre National De La Recherche (Paris, FR)
Appl. No.: 
12/223,185
Filed: 
January 23, 2007
PCT Filed: 
January 23, 2007
PCT No.: 
PCT/EP2007/050651
371(c)(1),(2),(4) Date:  August 15, 2008
PCT Pub. No.: 
WO2007/085596
PCT Pub. Date: 
August 02, 2007


 

Pharm Bus Intell & Healthcare Studies


Abstract

The present invention relates to the use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing diseases by inhibition of calcium. Advantageously, the extracellular hemoglobin is obtained from Annelids. In particular, the invention concerns the use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing cardiovascular diseases, such as hypertension, angina such as angina pectoris, Raynaud's disease, arteriopathy, tachycardia, vasospasm, ischemia, myocardial infarction, congestive heart failure, arrhythmia or cerebrovacular accident.

Description of the Invention

The present invention relates to the use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing diseases by inhibition of calcium. Advantageously, the extracellular hemoglobin is obtained from Annelids. In particular, the invention concerns the use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing cardiovascular diseases, such as hypertension, angina such as angina pectoris, Raynaud's disease, arteriopathy, tachycardia, vasospasm, ischemia, myocardial infarction, congestive heart failure, arrhythmia or cerebrovacular accident.

Worldwide, efficient treatments of cardiovascular diseases, such as hypertension, are at stake. In France, more than 14 million people suffer from hypertension. In the U.S.A., about 65 million American adults, nearly one in three, have high blood pressure. Once high blood pressure develops, it usually lasts a lifetime.

High blood pressure or hypertension is called "the silent killer" because it usually has no symptoms. Some people may not find out they have it until they have trouble with their heart, brain, or kidneys. In France, only 73% of the people actually know their condition. However, when high blood pressure is not found and treated, it can cause very serious troubles such as heart failure, heart attack, stroke, kidney failure, infarct, apoplexy, or cerebral ischemic attack.

In many people with high blood pressure, a single specific cause is not known. In some people, high blood pressure is the result of another medical problem or medication. In many cases, many people get high blood pressure as they get older. Over half of all Americans age 60 and older have high blood pressure. Besides, the chances of getting hypertension are also higher when people are overweight, do not eat a healthy diet (for instance people who eat too much salt or drink too much alcohol), do not get exercise, or smoke too much, or else when people have a family history of high blood pressure.

Blood pressure medicines work in different ways to lower blood pressure. Several types of medicines can be used to treat high blood pressure, such as diuretics, beta blockers, alpha blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, nervous system inhibitors, or vasodilators. In particular, calcium channel blockers keep calcium from entering the muscle cells of the heart and blood vessels. As a result, they relax blood vessels and increase the supply of blood and oxygen to the heart while reducing its workload. The blood pressure usually thus goes down.

But, often, two or more drugs are needed for the treatment of high blood pressure. Besides, common high blood pressure medicines are needed to be taken for a long time. And, even if medicines usually control blood pressure, they often cannot cure it.

Furthermore, usual high blood pressure medicines often cause some unwanted side effects, such as breathing difficulty, coughing, or wheezing, irregular or fast, pounding heartbeat, skin rash, slow heartbeat, swelling of ankles, feet, or lower legs, constipation, diarrhea, flushing and feeling of warmth, headache, unusual tiredness or weakness.

For instance, flunarizine, which is a calcium channel blocking agent, can cause drowsiness and increased appetite and/or weight gain. Bepridil and nifedipine can cause nausea and dizziness or lightheadedness.

Some side effects can be very serious. For instance, the main side effect of dantrolene, when chronically used or when overdosed, is hepatitis.

There was thus a need for a new drug for treating cardiovascular diseases without having the side effects and the drawbacks of the commonly used drugs, such as the ones mentioned above.

The invention makes it possible to remedy these disadvantages and major drawbacks.

The inventors thus discovered that a high molecular weight extracellular hemoglobin, advantageously the extracellular hemoglobin obtained from Annelids, can be efficiently used as a calcium inhibitor, by chelation of calcium, and can be efficiently used for the treatment of cardiac diseases, vascular diseases, or neurological diseases, such as hypertension.

High molecular weight extracellular hemoglobins, in particular the extracellular hemoglobin obtained from Annelids, were already used as blood substitutes (WO 01/92320), but they were never used as calcium chelating agent or for treating cardiac diseases, vascular diseases, or neurological diseases, in particular cardiovascular diseases.

The present invention relates to the use of a high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing diseases by inhibition of calcium.

The extracellular hemoglobin used in the present invention is a giant biopolymer having a high molecular weight of between several hundred thousand Daltons and several million Daltons, advantageously between 0.1 and 10 million Daltons, more advantageously between 1 and 5 million Daltons, and most advantageously between 3 and 4 million Daltons. The hemoglobin is thus approximately 60 times bigger than intracellular hemoglobins of vertebrates.

The giant biopolymers of the present invention are made up of approximately 150 to 200 polypeptide chains belonging to 1 to 15 different types, some of the polypeptide chains are linked by covalent bonds. The polypeptide chains are generally grouped together in two categories. The first category, consisting approximately of 144 to 192 elements, groups together the "functional" polypeptide chains, carrying an active site and capable of reversibly binding oxygen; these are globin-type chains of masses between 15 and 18 kDa, which are very similar to the .alpha.- and .beta.-type chains of vertebrates. The second category, consisting approximately of 36 to 42 elements, groups together "structural" polypeptide chains, having masses between 22 and 27 kDa, having few or no active sites but allowing the assembling of the "twelfths" (assembling of trimers and monomers).

Advantageously according to the present invention, the extracellular hemoglobin contains free cystein residues on some of the globin chains.

The term "extracellular hemoglobin" refers to a hemoglobin not contained in the cells and dissolved in the blood.

Some of the globin chains of extracellular hemoglobin are stabilised between themselves, by covalent bonds, in particular intermolecular disulphide bridges, and the globin chains may be auto-stabilised by intramolecular disulphide bridges.

The expression "the globin chains of extracellular haemoglobin are stabilised between themselves, by covalent bonds" refers to the presence of interchain disulphide bonds between two or more globin chains.

The expression "the globin chains are auto-stabilized" refers to the presence of intrachain disulphide bonds on each globin chain.

According to an advantageous embodiment of the present invention, the extracellular hemoglobin is obtained from Annelids. These extracellular hemoglobin molecules are present in the three classes of Annelids: Polychaetes, Oligochaetes and Achaetes and even in the Vestimentifers.

Annelids have been extensively studied for their extracellular hemoglobin. The images obtained of extracellular hemoglobins of Arenicola have revealed hexagonal elements. Each hemoglobin molecule is made up of two superimposed hexagons, called a hexagonal bilayer, and each hexagon is itself made up of six elements in the form of a drop of water called a hollow globular structure or "twelfth". The native molecule is formed from twelve of these sub-units, of a molecular mass of approximately 250 kDa. There is particular interest in Arenicola marina, a polychaete annelid of the intertidal ecosystem. Moreover, the structure of its extracellular hemoglobin is already known.

According to an advantageous embodiment of the invention, the extracellular hemoglobin comprises structural chains conferring a hexagonal structure on the hemoglobin.

The classification to which reference is made when using the term Annelids is that described in Meglitsch P. A., Invertebrate Zoology, Oxford University Press, Oxford, p. 834, (1972)

Particularly advantageously according to the present invention, the extracellular hemoglobin invention is obtained from Polychaete Annelids, preferably from Arenicola marina.

According to another embodiment of the invention, the extracellular hemoglobin can also be obtained by recombinant expression (See protocol in WO 2005/037392).

According to an advantageous embodiment of the invention, the extracellular hemoglobin is naturally polymerised, non-toxic, non-allergenic, and non-immunogenic.

The expression "non-toxic" means that the hemoglobin does not cause any pathological disorder of an immune-reaction, allergic or nephrotoxic type.

Besides, advantageously, the extracellular hemoglobin has no pathogenic agent, and does not lead to physiopathology in animals.

The expression "has no pathogenic agent" refers to the absence of identified microorganisms or viruses.

The absence of pathological disorders indirectly implies the absence of pathogens.

None of the side effects likely to be encountered with products of the prior art, in particular oedemas, problems of immunogenicity and nephrotoxicity do not exist within the framework of the present invention.

According to an advantageous embodiment of the invention, the extracellular hemoglobin is able to chelate to divalent ions, in particular to calcium, thus forming complexing compounds. The extracellular hemoglobin is thus advantageously a calcium chelator, enabling to bind to calcium.

The studies conducted by the inventors of the present invention with respect to properties of the extracellular hemoglobin self-assembly (in particular the Annelid extracellular hemoglobin self-assembly) revealed the importance of the divalent cations Ca.sup.2+ and Mg.sup.2+ in the maintenance of the quaternary structure of the hemoglobin at basic pH. The quaternary structure of the extracellular hemoglobin is stabilized at slightly basic pH, in particular at physiologic pH (pH between 7 and 8), by those divalent cations.

The divalent cations Ca.sup.2+ and Mg.sup.2+ allow the maintenance of the quaternary structure of the extracellular hemoglobin (in particular the Annelid extracellular hemoglobin). These ions prevent dissociation and slow dissociation kinetics of the extracellular hemoglobin at alkaline pH.

The extracellular hemoglobin, once administered under human physiological conditions, binds the calcium present in blood to maintain its quaternary structure. This instantaneous reaction leads to a reduction in the level of physiological calcium.

It can thus be concluded that the extracellular hemoglobin of the present invention is advantageously an equivalent to calcium inhibitors, by chelating and binding blood calcium. Today, calcium inhibitors refer to the drugs that inhibit the entrance of calcium into the cells by voltage-dependant calcium channels. The extracellular hemoglobin of the present invention advantageously has effects similar to calcium inhibitors, since the extracellular hemoglobin is a calcium chelating agent.

According to an embodiment of the invention, the extracellular hemoglobin advantageously has several effects: Cardiac Effects: for instance on the level of nodal tissue: slowing the action potential's slow diastolic depolarization in phase 0, or on the level of the myocardium: possibility of a negative inotropic effect Vascular effects: general vasodilatation, of coronary or cerebral predominance Effects on nonvascular smooth fibers: relaxation Neurological effects: reduction in excitability.

The present invention more particularly relates to the use of the high molecular weight extracellular hemoglobin for the manufacture of a medicament for treating and/or preventing cardiac diseases, vascular diseases, or neurological diseases, in particular cardiovascular diseases.

Advantageously, the medicament of the present invention is used for treating and/or preventing hypertension, angina such as angina pectoris, Raynaud's disease, arteriopathy, tachycardia, vasospasm, ischemia, myocardial infarction, congestive heart failure, arrhythmia or cerebrovacular accident.

The medicament of the present invention advantageously contains pharmacologically acceptable carriers or excipients.

According to another advantageous embodiment, the medicament of the present invention is intended for oral, topical, or parenteral administration, in particular for intravenous administration.

The medicament of the present invention can be administered in the form of tablets, capsules, solutions, liquids, . . .

According to another advantageous embodiment, the medicament of the present invention is intended for a usage dose of from a few mg/kg to a few g/kg, advantageously from 50 mg/kg to 2000 mg/kg.
 

Claim 1 of 9 Claims

1. A method for treating hypertension in a patient, comprising administering to said patient an effective amount of a high molecular weight extracellular hemoglobin having a molecular weight of between 0.1 and 10 million Daltons.

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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.
 

 

     
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