Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
2000-10-03
2004-01-13
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S002600, C514S012200, C424S602000, C423S308000
Reexamination Certificate
active
06676947
ABSTRACT:
The invention relates to use of erythropoietin (Epo) in low doses for production of pharmaceutical preparations for treatment of haemochromatoses and pharmaceutical combination preparations containing erythropoietin (Epo) and calcium compounds and/or phosphate compounds. These combination preparations are used particularly for treatment of primary haemochromatoses (inherited disturbances through excess of iron).
More than ⅔ (about 70%) of newly-formed bone-marrow parent cells in the organism participate in metabolism of iron and bone into erythrocytes and osteoblasts or osteoclasts. These processes (erythropoiesis and bone formation) are controlled by the two differentiating hormones, i.e. erythropoietin (Epo) and parathyroid hormone (PTH), the normal PTH concentration in the serum (between 10 and 60 ng/l ) resulting in normal formation of osteoblasts and osteoclasts whereas normal concentrations of Epo, between 6 and 25 U/l, result in normal formation of erythrocytes.
Erythopoiesis in particular is vitally important, since 45% of newly-formed bone-marrow parent cells develop into erythrocytes. For this reason all parameters (iron resorption, iron incorporation, Epo, folate, vitamin B12) of the iron metabolism are extremely closely regulated.
As is known, Epo is a glycoprotein which is formed in the kidneys and can also be synthesised and stimulates blood formation (erythropoiesis) “humorally”, i.e. by way of the bloodstream.
It is known to treat anaemia, particularly anaemia of haemodialysis patients caused by transfusion (renal anaemia) with recombinant human erythropoietin (rhEpo). Anaemia in chronic illness is the second most frequent form of anaemia throughout the world.
Reduced production of new erythrocytes is an important factor in anaemia when caused by reduced erythropoiesis in the bone or disturbances in iron re-utilisation. The daily iron requirement for normal erythropoiesis is 25 mg. Iron deficiency anaemia, which is the most frequent form of hypochromic anaemia, is regulated by addition of iron. Administration in combination with rhEpo is used in therapy in order to obtain a significant increase in the number of erythrocytes.
In clinical chemistry, disturbances in iron metabolism are diagnosed by determining the concentration of serum ferritin. The total body iron is about 3.5 g in men and 2.5 g in women. Iron occurs in active metabolism and in storage compartments. The active pool in a man on average contains 2100 mg in the haemoglobin, 200 mg in the myoglobin, 150 mg in enzymes in the tissue (haem and non-haem) and 3 mg in the iron transport compartment. Iron in the form of ferritin (700 mg) and haemosiderin (300 mg) is stored in tissue between the cells.
The total resorption mechanism for iron has not yet been fully explained (Gunshin et al., Nature 388, 482-488, 1997), but probably occurs via the protein divalent cation transporter (“DCT1”). Regulation is critically influenced by the small-intestine mucosa cells. In the case of the mucosa, the critical signal seems to be the total iron content of the body. It has been shown that the serum ferritin concentration is inversely related to the quantity of absorbed iron.
The iron is delivered by the intestinal mucosa cells to the transferrin. This iron transport protein has two iron-bonding sites. It is synthesised in the liver. There is therefore a mechanism whereby iron can be taken from cells (e.g. small-intestine mucosa or macrophages) and delivered to specific membrane receptors of erythroblasts, placenta cells or liver cells. Through endocytosis, the transferrin-iron-receptor complex arrives at the erythrocyte precursor cells, where the iron is delivered to the mitochondria, where haem is formed from iron and protoporphyrin.
Iron not needed for erythropoiesis is conveyed by transferrin to two kinds of storage pools. The most important store is ferritin. This is a heterogeneous family of proteins surrounding an iron nucleus. It is soluble and is the active storage form in the liver (hepacytes), bone marrow, spleen (macrophages), erythrocytes and in the serum (about 100 ng/ml). The tissue ferritin pool is very labile and quickly available when iron is needed. The circulating serum ferritin comes from the reticulo-endothelial system (RES) and the concentration in circulation varies in parallel with the total body iron (each ng/ml corresponds to 8 mg of iron supply).
To sum up, in iron metabolism
all cells of the RES are stores of ferritin and haemosiderin,
Hb-synthesising, iron-consuming parent cells are converted by Epo into erythrocytes and
iron is transported by transferrin from the store to the erythrocytes in process of formation and back from dead erythrocytes into the store.
In bone metabolism, on analogy with iron metabolism
the bone stores hydroxyl apatite crystals (and collagen) and the osteoclast “labilises” the hydroxyl apatite by breaking it down to a basic skeleton.
If no disturbance occurs, the basic skeleton is used for synthesis.
parent cells which synthesise hydroxyl apatite (and collagen) and consume calcium and phosphate are converted by PTH (+IGF 1+2) into osteoblasts and
calcium and phosphate are transported from the store to the osteoblasts in process of formation and back to the store after synthesis of hydroxyl apatite.
As early as 1983, S. G. Massry (Kidney International 24, (16) 204-207) and also F. N. Hutchison and J. Jones (AJKD Vol. 29, No. 5, May 1997) described how in cases of hyperparathyroidism, i.e. at very high PTH concentrations, erythropoiesis is suppressed. In other words a high concentration of PTH (>>60 ng/l) slows down the formation of Epo in the organism, thus inevitably reducing the formation of erythrocytes.
PTH is therefore an important regulator in the human organism, since both iron metabolism and bone metabolism are regulated by PTH. PTH of course regulates resorption of calcium, phosphate, magnesium and iron.
However, the following weak points may occur in iron and bone metabolism:
insufficient differentiation of the parent cells by Epo or PTH,
“labilisation” of the form of storage (iron nucleus in ferritin or hydroxyl apatite in collagen by osteoclast) or
insufficient transport of iron to erythrocytes or hydroxyl apatite (calcium and phosphate) to the osteoblasts.
Treatment is possible for disturbances of erythropoiesis in the case of renal anaemia or iron deficiency anaemia but no successful treatment has been found for haemochromatoses. Bloodletting is the only method at present.
Haemochromatoses are iron storage diseases resulting from an excess of iron in the organism, particularly in the parenchymatous organs, associated with increased iron absorption and massive deposition of iron in the form of haemosiderin in numerous organisms and in the monocyte-macrophage system. A distinction is made between primary (idiopathic) haemochromatoses and secondary (erythropoietic) haemochromatoses. Secondary haemochromatoses are disturbances in blood formation resulting in haemosiderosis (inherited excess of iron in the organism). Primary (idiopathic) haemochromatoses appear in the form of liver cirrhosis (pigment cirrhosis), bronze discoloration of the skin and failure of endocrine and exocrine glands (hypogonadism, insulin-dependent diabetes mellitus or “bronze diabetes”), cardiac insufficiency, and hair loss.
The object of the invention therefore is to provide pharmaceutical preparations suitable for treatment of haemochromatoses and containing optimum proportions of active substances.
It has unexpectedly been found that erythropoietin preparations in low dosage are suitable for treatment of haemochromatoses.
The invention therefore relates to use of Epo for producing pharmaceutical preparations for treatment of haemochromatoses.
According to the invention the preparations contain 500 to 5000 U of Epo and are preferably used for treatment of patients with secondary haemochromatoses.
The erythropoietin preparations according to the invention can be active substances comparable in physiological effect with human erythropoietin. According to the i
Gottschalk René
Lehmann Paul
Carlson Karen Cochrane
Johnston George W.
Liu Samuel W.
Parise John P.
Roche Diagnostics GmbH
LandOfFree
Use of erythropoietin for the treatment of haemochromatoses does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of erythropoietin for the treatment of haemochromatoses, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of erythropoietin for the treatment of haemochromatoses will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3203848