MXPA00007509A - Method of promoting erythropoiesis - Google Patents
Method of promoting erythropoiesisInfo
- Publication number
- MXPA00007509A MXPA00007509A MXPA/A/2000/007509A MXPA00007509A MXPA00007509A MX PA00007509 A MXPA00007509 A MX PA00007509A MX PA00007509 A MXPA00007509 A MX PA00007509A MX PA00007509 A MXPA00007509 A MX PA00007509A
- Authority
- MX
- Mexico
- Prior art keywords
- seq
- artificial sequence
- tyr
- group
- pro
- Prior art date
Links
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Abstract
The present invention provides methods, compounds, pharmaceutical compositions, and kits for the augmentation of erythropoiesis by potentiating erythropoietin-induced differentiation with angiotensinogen, angiotensin I (AI), AI analogues, AI fragments and analogues thereof, angiotensin II analogues, AII fragments or analogues thereof or AII AT2 type 2 receptor agonists as a therapeutic adjunct. The method is useful for the treatment of congenital or acquired aplastic or hypoplastic anemia associated with chronic renal failure, end-stage renal disease, renal transplantation, cancer, AIDS, chemotherapy, radiotherapy, bone marrow transplantation and chronic diseases.
Description
METHOD TO PROMOTE ERITROPOIESIS
FIELD OF THE INVENTION
The present invention relates to compounds, methods, compositions and equipment for the stimulation of erythropoiesis. More specifically, the present invention relates to methods, compositions and equipment employing effective amounts of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogs thereof, angiotensin II analogs, All fragments or analogs thereof. or receptor agonists of type 2 All AT2 to stimulate erythropoiesis.
BACKGROUND OF THE INVENTION
Maintaining an adequate supply of oxygen to body tissues is vital for survival. In the United States alone, several million people suffer from anemia secondary to renal failure, chronic inflammatory diseases and diseases (U.S. Patent No. 4,987,121, incorporated herein in its entirety, as a reference). Since a considerable degree of oxygen transport capacity in the blood is governed by the concentration of erythrocytes in the blood, proper regulation of erythropoiesis is also crucial.
Previous studies by Reissmann (Reissmann, KR, Blood 5: 372-80 (1950)) and Erslev (Erslev, A., Blood 8: 349-57 (1953)) clearly demonstrated the hypoxia-induced stimulation of the secretion of the erythropoietin When erythropoietin is secreted by the cells that produce erythropoietin in response to hypoxia, it travels through the blood to its target organ, the hematopoietic tissues. In humans, the main hematopoietic tissue is inside the liver before birth and in the bone marrow after birth. (Id) There, erythropoietin binds specifically to its receptor in the erythroid progenitor cells called activity-forming erythroid units (BFU-E) and colony-forming erythroid units (CFU-E) and stimulates said cells to proliferate and differentiate ( Spivak, JL, Int. J. Cell Cloning 4: 139-66 (1986)). The BFU-E are the initial erythroid progenitors and constitute approximately 0.01% of the nucleated cells of the bone marrow. The CFU-E are derived from the BFU-E, counting for approximately 0.1% of the medullary cells and respond much more to the erythropyethine than the BFU-E (Spivak, J. L., supra); Sawada, K., et al., J. Clin. Invest. 80: 357-66 (1987)).
The always present low levels of erythropoietin seem sufficient for a basal erythropoiesis level. Relatively small blood losses do not seem to stimulate increased production of erythropoietin (Kickier, T. S., et al., J. Am. Med. Assoc. 260: 65-7 (1988)). It is only after a considerable loss of blood, when the production of erythropoietin and the level of erythropoiesis increase.
It has been established that the majority of patients with renal insufficiency and anemia have serum erythropoietin levels below those that might be expected for the degree of anemia (Caro, J., et al., J. Lab. Clin. Med. 93: 449-58 (1979); Radtke, HW, et al., Blood 54: 877-84 (1979); Chandra, M., et al., J. Pediatr. 113: 1015-21 (1988)), although they can still respond to hypoxia with an increase in serum erythropoieitin levels (Radtke, HW, et al., Blood 54: 877-84 (1979); Chandra, M. et al., J Pediatr 113: 1015- 21 (1988)). However, this greatly increased response of erythropoietin contributes substantially to the pathogenesis of anemia (Eschbach, J. W., et al., Am J Kid Dis 11: 203-9 (1988)). As a result, patients suffering from chronic kidney disease and kidney disease in the terminal phase, or those who undergo a kidney transplant; they develop severe anemia and require regular blood transfusions (Royet, U.S. Patent No. 5,482,924).
The use of recombinant human erythropoietin has facilitated the treatment of such patients. However, treatment with recombinant erythropoietin is extremely expensive and methods that increase the effect of erythropoiesis will allow the use of smaller doses of erythropoietin and therefore, treatment costs will decrease. Additionally, the increase in the level of erythropoiesis will significantly improve the clinical benefits for the treatment of hypoplastic anemia, or acquired, or congenital aplastic, associated with a chronic renal failure, a kidney disease in the terminal phase, a kidney transplant , cancer, AIDS, chemotherapy, radiotherapy, bone marrow transplantation, chronic diseases.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds and methods for the enhancement of erythropoiesis by potentiating erythropoietin-induced differentiation with angiotensinogen, angiotensin I (Al), Al analogs, Al fragments and analogs thereof, angiotensin II analogues. , All or analogues thereof or receptor agonists of type 2 All AT2, as a therapeutic adjunct.
In another aspect, the present invention provides pharmaceutical compositions comprising angiotensinogen, angiotensin I (Al), Al analogs, Al fragments and analogs thereof, angiotensin II analogues, All or analogs thereof or type 2 All receptor agonists. AT2 together with erythropoietin and a pharmaceutically acceptable carrier thereof.
In a further aspect, the present invention provides equipment for promoting erythropoiesis, wherein the kits comprise an effective amount of angiotensinogen, Al, Al analogs, Al fragments and analogs thereof, All analogs, All fragments or analogs thereof or Type 2 All AT2 receptor agonists and instructions for the use of an effective amount of an active agent as a therapeutic adjunct to treatment with erythropyethine.
In another aspect, the invention provides an improved cell culture medium for promoting erythropoiesis, comprising the addition of an effective amount of the active agents of the invention to promote erythropoiesis.
The methods and equipment of the present invention are clinically useful as a therapeutic adjunct for increasing the production of red blood cells in the treatment of hypoplastic anemia, acquired or congenital aplastic.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the effect of 1GD on the formation of human activity-forming erythroid units, where: (they apply for all graphs)
io u g / m l 2 l .Oug / m l ^ o. i ug / m l ÜI O.O I ug / ml ÍTTTTTT O ug / m! X /
a = activity-forming erythroid units t = cultivation days Figure 2 is a graph showing the effect of 24B on the formation of erythroid-forming units of human activity. Figure 3 is a graph showing the effect of 2GD on the formation of human activity-forming erythroid units. Figure 4 is a graph showing the effect of 5GD on the formation of human activity-forming erythroid units. Figure 5 is a graph showing the effect of AII (1-7) on the formation of human activity-forming erythroid units. Figure 6 is a graph showing the effect of AII on the formation of erythroid units forming human activity.
DETAILED DESCRIPTION OF THE PREFERRED MODALITIES
All of the cited patents, patent applications and references are incorporated herein by reference in their entirety.
As defined throughout this document, "increased erythropoiesis" can occur by direct stimulation of erythroid production, by increasing the production of erythropoietin or by any other mechanism.
Unless otherwise indicated, the term "active agents" as used herein refers to the group of compounds comprising angiotensinogen, angiotensin I (AI), AI analogs, Al fragments and analogs thereof, angiotensin analogs. II, All or analogous fragments thereof and type 2 All AT receptor agonists.
The biological formation of angiotensin is initiated by the action of renin in the angiotensinogen of the substrate in the plasma (Circulation Research 60786-790 (1987); Clouston et al., Genomics 2; 240-248 (1988): Kageyama et al., Biochemistry 23; 3603-3609; Ohkubo et al., Proc. Nati, Acad. Sci. 80.2196-2200 (1983), all references are incorporated herein in their entirety). The substance thus formed is a decapeptide called angiotensin I (Al) which is converted to All by the conversion enzyme angiotensinase which removes the His-Leu C-terminal residues from Al (Asp-Arg-Val-Tyr-Ile-His-Pro -Phe-His-Leu [SEQ ID NO: 37]). All is a well-known pressor agent and is commercially available.
Angiotensin-converting enzyme (ACE) inhibitors have been shown to exacerbate anemia in patients with chronic kidney disease and end-stage renal disease (ESRD), as well as in renal transplant recipients (Cruz et al., Am. J Kidney Diseases 28; 535-540 (1996), incorporated herein by reference in its entirety). The inhibitors (ACE) apparently induce anemia by a decrease in the production of red blood cells (Id). Some existing data suggest that ACE inhibitors can reduce the production of red blood cells by inhibiting angiotensin-mediated erythropoietin synthesis. (Herikata et al., Clin.Nephrol., 26: 27-32 (1986); Gould et al., J. Lab. Clin. Med. 96: 523-534 (1980); Conlon et al., Transplantation 56: 217 -219 (1993)). However, other studies show that ACE inhibitors do not inhibit erythropoietin synthesis and suggest that angiotensin plays no role in erythropoiesis (Cruz et al., 1996, Anderson et al., Biology of the Neonate 71: 194- 197 (1997), Shand et al., J. Hum. Hypertension 9: 233-235 (1995), Julián et al., Int. 46: 1397-1403 (1994), Gastón et al., Transplant Proc. 25: 1029-1031 (1993) Islam et al., Transplant Int. 3: 222-225 (1990); Rostaing et al., Transplant Proc. 26: 280-281 (1994)). So it is not clear if All or any of the analogues and All fragments stimulate the production of erythropoietin.
A recent study suggests that activation of the AT1 receptor with angiotensin II improves erythroid proliferation stimulated by erythropoietin in vitro. (Mrug et al., J. Clin Invest .100 (9): 2310-2314 (1997).) Previous studies have indicated that a mild infusion of angiotensin II in dogs (Fisher et al., In Annals New York Academic of Sciences, pp. 308-317: 1968) and mice (Fisher et al., J. Pharmacol., and Exper. Therapeutics 157: 618-625,1967) led to an increased production of erythropoietin, although angiotensin II injections in mice and rats did not lead to such an increase (Mann et al., PSEBM 121: 1152-1154 (1966); Bilsel et al., PSEBM 114: 475-479 (1963).) Therefore, there is some evidence that the angiotensin II (All) stimulates erythropoiesis in vitro, although the in vivo data are not clear, however, there are no data to suggest that any of the analogues and All fragments also stimulate erythropoiesis, in vitro or in vivo. , there are data that suggest that the All AII (1-7) fragment acts through a receptor (s) that are (are) different from the AT1 and AT receptors 2 that modulate the All activity.
(Ferrario et al., J. Am. Soc. Nephrol., 9: 1716-1722 (1998), lyer et al., Hypertension 31: 699-705 (1998), Freeman et al., Hypertension 28: 104 (1996).; Ambuhl et al., Brain Res. Bull. 35: 289 (1994) .Therefore, the stimulatory effect of All through AT1 receptor activation reported by Mrug et al. (See above) gives no indication of the potential stimulatory effect of All (1-7).
The patent of E.U.A. No. 5,015,629 issued to DiZerega (the description thereof is incorporated herein by reference) describes a method for increasing the healing speed of a wounded tissue, comprising the application to such tissue of angiotensin II (All) in a amount that is sufficient for said increase. The application of All to wounded tissue significantly increases the healing rate of the wound, leading to faster re-epithelialization and tissue repair. The term "All" refers to an octapeptide present in humans and other species having the sequence Asp-Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 1]. It has also been described the use of analogs and fragments All, AT2 agonists, as well as analogs there and fragments there in the healing of wounds. (U.S. Patent No. 5,269,292; U.S. Patent No. 5,716,935; WO96 / 39164; incorporated herein by reference in its entirety).
A selective agonist peptide has been identified for the AT2 receptor (the All has 100 times higher affinity for AT2 than for AT1). This peptide is p-aminophenylalanine6-AII ["p-NH2-Phe) 6-AII)"], Asp-Arg-Val-Tyr-lle-Xaa-Pro-Phe [SEQ ID NO.36] wherein Xaa is p-NH2-Phe (Speth and Kim, BBrc 169: 997-1006 (1990)). This peptide gave binding characteristics comparable to the AT2 antagonists in the experimental models tested (Catalioto, et al., Eur. J. Pharmacol., 256: 93-97 (1994); Bryson, et al., Eur. J. Pharmacol. 225: 119-127 (1992)). Many studies have focused on the All (1-7) (residues All 1-7) or other All fragments to evaluate their activity. The All (1-7) causes in some proportion, but not in the whole range; the effects caused by the All. Pfeilschifter, et al., Eur. J. Pharmacol. 225: 57-62 (1992); Jaiswal, et al., Hypertension 19 (Supp.ll): - 49-ll-55 (1992); Edwards and Stack, J. Pharmacol. Exper. Ther. 266: 506-510 (1993); Jaiswal, et al., J. Pharmacol. Exper. Ther. 265: 664-673 (1991); Jaiswal, et. Al., Hypertension 17: 1115-1120 (1991); Portsi, et al., Br. J. Pharmacol. 111: 652-654 (1994).
The active analogs All, All fragments and analogues thereof of particular interest according to the present invention are characterized in that they comprise a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of the formula wherein X is H or one to three peptide groups, RA is appropriately selected from Asp, Glu, Asn, Acpc (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc, RB is appropriately selected from Arg, Lys, Ala, Orn, Ser ( Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, Lys, norLeu, He, Gly, Pro, Aib, Acpc and Tyr; R4 is selected from the group consisting of Tyr, Tyr (PO3) 2, Thr, Ser, Ala, homoSer and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, noreLeu, Val and Gly;
R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr, excluding sequences that include R4 as a terminal group Tyr. Compounds that fall within the category of AT2 agonists useful in the practice of the invention include the All analogs previously determined, subject to the restriction that R6 is p-NH2-Phe. Particularly preferred combinations for RA and RB are Asp-Arg,
Asp-Lys, Glu-Arg and Glu-Lys. Particularly preferred embodiments of this class include the following: There, Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 2]; AII (3-8), also known as des1 -AIII or AlV, Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 3]; AII (1-7), Asp-Ar-Val-Tyr-lle-His-Pro [SEQ ID NO: 4]; AII (2-7). Arg-Val-Tyr-lle-His-Pro [SEQ ID NO: 5]; AII (3-7), Val-Tyr-lle-His-Pro [SEQ ID NO: 6]; At 1 (5-8), lle-His-Pro-Phe- [SEQ ID NO: 7]; AII (1-6), Asp-Arg-Val-Tyr-lle-His- [SEQ ID NO: 8]; AII (1-5), Asp-Arg-Val-Tyr-lle- [SEQ ID NO: 9]; AII (1-4), Asp-Arg-Val-Tyr- [SEQ ID NO: 10] and AII (1-3), Asp-Arg-Val- [SEQ ID NO: 11]. Other preferred embodiments include: Arg-norLeu-Tyr-lle-His-Pro-Phe [SEQ ID NO: 12] and Arg-Val-Tyr-norLeu-His-Pro-Phe [SEQ ID NO: 13]. Another preferred embodiment within the scope of the invention is a peptide having the sequence Asp-Arg-Pro-Tyr-lle-His-Pro-Phe [SEQ ID NO: 31]. AII (6-8), His-Pro-Phe- [SEQ ID NO: 14] and AII (4-8), Tyr-lle-His-Pro-Phe- [SEQ ID NO: 15] were also tested and found that it is not effective.
An additional class of particularly preferred compounds according to the present invention consists of those with the following general structure: ASP-ARG-R1 -R2-R3-R4-PRO-R5 wherein R1 is selected from the group consisting of Val, Pro and Lys; R2 is selected from the group consisting of Tyr, Tyr (PO3) 2 and Ala; R3 is selected from the group consisting of He, Val, Leu, norLeu and Ala; R4 is selected from the group consisting of His and Arg and R5 is Phe or is absent and wherein the active agent is not All. Preferred embodiments of this class in the invention include SEQ ID NO: 4, SEQ ID NO: 19, DEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40. Particularly preferred embodiments of this class include SEQ ID NO: 4, SEQ ID NO: 31, SEQ ID NO: 38 and SEQ ID NO: 3.
Another class of compounds of particular interest according to the present invention are those of the general formula II.
R2-R3-R4-R5-R6-R7-R8 in which R2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, Lie, Gly, Pro, Aib, Acpc and Tyr; R4 is selected from the group consisting of Tyr, Try (PO3) 2, Thr, Ser, homoSer and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6es His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), lie and Tyr.
A particularly preferred subclass of the compounds of the general formula II has the formula R2-R3-Tyr-R5-His-Pro-Phe- [SEQ ID NO: 16] wherein R2, R3 and R5 are as previously defined. Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-lle-His-Pro-Phe [SEQ ID NO: 2]. Other preferred compounds include the peptides having the structures Arg-Val-Tyr-Gly-His-Pro-Phe [SEQ ID NO: 17] and Arg-Val-Tyr-Ala-His-Pro-Phe- [SEQ ID NO. : 18]. The All (4-8) fragment was ineffective in repeated tests; it is believed that it is due to the tyrosine exposed in the term N.
The standard three-letter abbreviations for amino acid residues are used in the formulas above. In the absence of a contrary indication, the L form is used. Other residues are abbreviated as follows: TABLE 1 Abbreviation for Amino Acids
It has been suggested that the All and its analogues adopt either a gamma turn or a beta turn (Regoli, et al., Pharmacologi Reviews 26:69 (1974).) In general, the neutral back strands in position R3, R5 are considered. and R7 can be involved in the maintenance of the appropriate distance between the active groups in positions R4, R6 and R8 basically responsible for the binding to the receptors and / or intrinsic activity.The hydrophobic side chains in positions R3, R5 and R8 can play also an important role in the total conformation of the peptide and / or contribute to the formation of a hypothetical hydrophobic chamber.
Suitable side chains at the amino acid at the R 2 position can contribute to the affinity of the compounds for the target receptors and / or play an important role in the formation of the peptide. For this reason, Arg and Lys are particularly preferred as R2. For the purposes of the present invention, it is considered that R3 may be involved in the formation of linear or non-linear hydrogen bonds with R5 (in the gamma-turn model) or R6 (in the beta-turn model). R3 also participates in the first turn in an antiparallel beta structure (which has also been proposed as a possible structure). In contrast to the other positions of the general formula I, it is apparent that the beta and gamma branches are equally effective in this position. In addition, a simple hydrogen bond may be sufficient to maintain a relatively stable conformation. Accordingly, R3 can be appropriately selected from Val, Ala; Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr. In addition, it has surprisingly been found that Lys is appropriate in R3 (see Examples).
With respect to R4, conformational analyzes have suggested that the side chain in this position (as well as in R3 and R5) contribute to a hydrophobic grouping considered essential for the occupation and stimulation of the receptors. Therefore, R4 is preferably selected from Tyr, Thr, Tyr (PO3) 2, homoSer, Ser and azaTyr. In addition, it has surprisingly been found that Ala is appropriate in the R4 position (see Examples). In this position, Tyr is particularly preferred since it can form a hydrogen bond with the receptor site capable of accepting a phenolic hydroxyl hydrogen (Regoli, et al. (1974), supra). In the R5 position, an amino acid with an alicyclic or aliphatic β chain is particularly desirable. Therefore, while Gly is suitable in the R5 position, it is preferred that the amino acid in this position be selected from He, Ala, Leu, norLeu, Gly and Val.
In Al and All analogs, fragments and analogs of the fragments of particular interest according to the present invention, R6 is His, Arg or 6-NH2-Phe. The unique properties of the imidazole ring of histidine (eg, ionization at a physiological pH, the ability to act as a proton donor or acceptor, the aromatic character) are considered to contribute to its particular utility as R6. For example, conformational models suggest that His can participate in hydrogen bond formation (in the j efa model) or in the second antiparallel structure spin by the influence of the R7 orientation. Similarly, it is currently considered that R7 can be Pro in order to provide the most desirable orientation of R8. In the R8 position, a hydrophobic ring and an anionic carboxyl radical appear to be particularly useful in binding the analogs of interest to the receptors; therefore, Tyr and especially Phe are preferred for the purposes of the present invention.
Analogs of particular interest include the following:
TABLE 2 Angiotensin II analogs
The polypeptides of the present invention can be synthesized by a variety of methods such as those set forth in J.M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd. Ed., Pier Chemical Co., Rockford, Ill. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroeder and K. Lubke, The Peptides, Vol. 1, Academic Press, New York, (1965) for solution synthesis. The discussion of the previous treaties is incorporated in this document as a reference.
In general, these methods involve the sequential addition of protected amino acids to an increasing peptide chain (U.S. Patent No. 5,693,616, herein incorporated in its entirety, by reference). Normally, the amino or carboxyl group of the first amino acid and any reactive group of the side chain are protected. This protected amino acid is attached to an inert solid support or is used in solution and the next amino acid in the sequence, also suitably protected; it is added under sensitive conditions for the formation of the amide bond. After all the desired amino acids have been linked in the proper sequence, the protecting groups and any solid support are removed to produce the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to give the final product.
In one aspect, the present invention provides methods for increasing erythropoiesis by potentiating erythropoietin-induced differentiation with angiotensin I (Al), Al analogs, fragments and analogs thereof, angiotensin II analogues, fragments or All analogues thereof or All 2 AT2 type 2 receptor agonists (ie, "active agents") as a therapeutic adjunct for treatment with erythropoietin. The methods and equipment of the present invention are clinically useful as a therapeutic adjunct for increasing the production of red blood cells in the treatment of hypoplastic anemia, acquired or congenital aplastic.
The use of erythropoietin to promote erythropoiesis is well known in the art, as exemplified in Royet et al., U.S. Patent. No. 5,482,924; Goldberg et al., Patent of E.U.A. No. 5,188,828; Vanee et al., Patent of E.U.A. No. 5,541, 158 and Baertschi et al., U.S. Patent. No. 4,987,121, all of them are incorporated in their entirety in this document, as references. The dose regimen of erythropoietin can vary widely, but can be determined routinely by a physician using standard methods. The dose levels of the order of between about 1 EPO unit / kg and about 5,000 EPO units / kg body weight are useful for all the methods of use described herein.
In one embodiment, the effects of the active agents on the growth of the erythroid progenitors in vitro were analyzed, using the colony formation test. The test consists of growing erythroid progenitor cells in a semi-solid medium (methylcellulose) for two weeks (Yu et al., U.S. Patent No. 5,032,507). The conditioned medium consisting of lymphocytes treated with phytohaemagglutinin (PHA-LCM) supplemented with erythropyethine and preferably, between about 0.1 ng / ml and about 10 mmg / ml of the active agents.
The growth of BFU-E conditioned erythroid precursors (activity-forming erythroid units) was monitored by identifying and counting the colonies under an inverted microscope, as well as by labeling with dyes from the colonies (Yu et al., Patent of US No. 5,032,507). The number of mixed colonies represents the number of initial progenitor cells (containing an erythroid cell, as well as one or more cells of the lineage).
In another embodiment, erythropoiesis was increased ex vivo by obtaining a sample of bone marrow cells, as is known in the art, by enhancing erythropoietin-induced differentiation with the active agents of the invention and infusion of the treated cells in the patient's back.
In a preferred embodiment, bone marrow cells are isolated from peripheral blood samples via standard techniques (U.S. Patent Nos. 4,987,121, 5,104,653, incorporated herein by reference, in their entirety). 2 x 10 6 bone marrow cells were seeded in culture dishes in an appropriate medium, such as modified Dulbecco's medium (IMDM) supplemented with (final concentration): horse serum (15%), fetal calf serum (5%) ), hydrocortisone (0.4 mg / ml), saturated transferrin Fe, penicillin 100 u / ml and streptomycin (0.1 mg / ml) (royet at al., U.S. Patent No. 5,482,924). An adherent cell monolayer was formed. After 15 days, the non-adherent cells were removed and fresh bone marrow cells were re-seeded in the presence of 0.1 U / ml of erythropoietin (EPO) and preferably, between about 0.1 ng / ml and about 10 mg / ml of the cells. active agents of the invention. The cells expanded for a period of between 2 and 21 days with subsequent media changes, as required. Prior to reinfusion in the subject, the cells were examined microscopically to verify the absence of contamination. The cells were rinsed to remove any trace of culture fluid, resuspended in an appropriate medium and agglomerated to be rinsed several times. After final rinsing, the cells were resuspended at approximately 0.7 x 106 and 50 x 106 cells per ml in an appropriate medium and reinfused in a subject. Erythropoiesis was monitored by counting red blood cells or hemoglobin concentration at time intervals (Yu et al., U.S. Patent No. 5,032,507, incorporated herein by reference, in its entirety).
To be used in the increase of erythropoiesis in vivo, the active agents can be administered by any appropriate route, including formulations in oral, parenteral, spray inhalation, rectal, transdermal or topical unit doses; containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The parenteral term used herein includes subcutaneous, intravenous, intra-arterial, intramuscular, intra-stent, intratendinous, intraspinal, intracranial, intrathoracic, infusion or intraperitoneal techniques.
Transdermal means include, but are not limited to, transdermal patches used to release the active agents at the treatment site. Transdermal formulations can be prepared by incorporating the active agent into a thixotropic or gelatinous carrier including, but not limited to, a cellulosic medium, for example, methyl cellulose or hydroxyethyl cellulose, the resulting formulation is subsequently packaged in a transdermal device adapted to ensure Direct contact with the skin of a carrier.
The active agents can be manufactured in solid form (including granules, powders or suppositories) or in liquid form (for example solutions, suspensions or emulsions). The active agents may be subject to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, stabilizers, etc.
While the active agents can be administered as a single active pharmaceutical agent, they can also be used in combination with one or more other compounds. When administered as a combination, the active agent (s) and the compound (s) can be formulated as separate combinations that are given at the same time or at different times, or the active agent (s) (s) and the compound (s) can be given as a single composition.
For administration, the active agents are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The active agents can be mixed with lactose, sucrose, starch powder, cellulose esters or alkanoic acids, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate. , polyvinylpyrrolidone and / or polyvinyl alcohol and formed into tablets or encapsulated by conventional administration. Alternatively, the compounds of this invention can be dissolved in a saline solution, water, polyethylene glycol, propylene glycol, colloidal solutions of carboxymethyl cellulose, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, gum tragacanth and / or several stabilizers. Other adjuvants in the form of administration are well known in the pharmaceutical art. The carrier or diluent may include time retarding materials, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (eg, liniments, lotions, ointments, creams or pastes) and drops suitable for administration to the eyes, nose or ears
The dose regimen to increase erythropoiesis with active agents is based on a variety of factors, including the type of injury, age, weight, sex, the individual's medical condition, the severity of the condition, the route of administration and compound employed in particular. Therefore, the dosage regimen can vary widely, but can be determined routinely by the physician using standard methods. The dose levels in the order of between 0.1 ng / kg and 10 mg / kg of the active agents per body weight are useful for all the methods described herein.
The treatment regimen will vary depending on the disease to be treated, based on a variety of factors including the type of injury, age, weight, sex, the individual's medical condition, the severity of the condition, the route of administration and the compound employed in particular.
In a preferred embodiment of the present invention, the active agents are administered intravenously. An appropriate dose of the active agents is preferably between about 0.1 ng / kg and about 10 mg / kg administered twice a day. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise amounts as high as 10% w / w, but preferably not more than 5% w / w and more preferably from 0.1% to 1% of the formulation.
In another aspect, the present invention provides a novel peptide with erythropoiesis promoting activity, consisting of the peptide with the Asp-Arg-Lys-Tyr-lle-His-Pro-Phe sequence (SEQ ID NO: 39).
A further object of the present invention is to provide pharmaceutical compositions comprising the active agents as an ingredient for use in the method of the invention. The compositions comprise the active agents together with the erythropoietin and a pharmaceutically acceptable carrier this term includes any carrier which does not interfere with the effectiveness of the biological activity of the active agents and erythropoietin and which is not toxic to the host to which it is administered. The dosage and administration of the pharmaceutical compositions will vary depending on the disease to be treated, based on a variety of factors including the type of injury, age, weight, sex, medical condition of the individual, severity of the condition , the route of administration and the compound employed in particular, as mentioned above. Therefore, the dose regimen can vary widely, but can be determined routinely by the physician using standard methods.
In a further aspect, the present invention provides equipment that promotes erythropoiesis, wherein the equipment comprises an effective amount of the active agent and instructions for using said effective amount of active agent as a therapeutic adjunct. In a preferred embodiment, the kit further comprises a pharmaceutically acceptable carrier, such as the adjuvants described above. In another preferred embodiment, the kit further comprises means for releasing the active agent to a mammal. Such devices include, but are not limited to matrix or micellar solutions, polyethylene, glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (eg, saline, Ringer's lactate solution, phosphate-stabilized saline, etc.), viscoelastic , polyethylene glycols and polypropylene glycols.
In a further preferred embodiment, the kits also comprise an amount of erythropoietin effective to accelerate erythropoiesis.
In another aspect of the present invention, an improved cell culture medium is provided for the promotion of erythropoiesis, wherein the improvement comprises adding to the cell culture medium an effective amount of the active agents of the invention. Any cell culture media that can withstand erythropoiesis can be used with the present invention. Such cell culture media include, but are not limited to Basal Media Eagle, Modified Dulbecco's Eagle Medium, Iscove Modified Dulbecco's Medium, Minimum Essential Medium, F-10 Nutrient Blends, Opti-MEM ™ Medium-Serum Reduced Medium and RPMI or combinations thereof.
The improved cell culture medium can be delivered in a concentrated (for example: 10X) or non-concentrated form and can be supplied as a liquid, a powder or a lyophilisate. The cell culture can be defined chemically or it can contain a serum supplement.
Culture media and serum supplements are commercially available from GIBCO BRL (Gaithersburg, MD) and Sigma (St. Louis, MO).
The present invention, by providing methods and pharmaceutical compositions to increase erythropoiesis will greatly increase the clinical benefits of the treatment of hypoplastic anemia, acquired or congenital aplastic, improvement of anemia associated with cancer, AIDS, chemotherapy, radiotherapy, transplantation of bone marrow and chronic diseases.
The present invention can be better understood with reference to the accompanying examples, which are intended for purposes of illustration and should not be considered as limiting the scope of the invention defined by the appended claims.
Example I. All and Analog All and the Fragment Effect in the Formation of the Erythroid Progenitor.
CD34 + cells were isolated from human spinal blood by immunomagnetic chromatography using an antibody cocktail (Stem Cell Technologies, Vancouver BC) consisting of the following surface cellular proteins: glycophorin A, CD56, CD66b, CD3, CD24, CD14, CD2, CD19 and CD16. Enriched cells were cultured at 37 ° C at 5% CO 2 and air for 6 days in a medium containing serum-free StemSpam (Stem Cell Technologies), 3 lU / ml human erythropoietin (EPO), 20 ng / ml factor stem cell, 20 ng / ml of interleukin 3 and 20 ng / ml of GM-CSF. The cells were harvested, counted and cultured in 96-well dishes at a denature of 50,000 cells per dish in the same medium containing from 0 to 10 μg / ml of All, All analogs or All fragments. The peptides tested and the graph showing the data received by said tests are listed in Table 3. After an additional 3 days in suspension culture (day 9), the cells were washed to remove the peptides and cultured to evaluate the formation from the colony. The culture medium contained 0.9% methyl cellulose in the Iscove MDM with 30% fetal calf serum, 1% bovine serum albumin, 10 μM 2-mercaptoethanol, 2mM L-glutamine, 10% medium. Conditioned Leukocyte 10% agar with 3 lU / ml EPO. On days 2,4,9 and 14 the number and size of the colonies was evaluated, as well as the number of E-BFUs formed (activity-forming erythroid units) as a measure of erythropoiesis.
TABLE 3. Designation of the tested peptides
Name Abbreviation Sequence Figure SEQ ID
1 GD Ala4-AII (1-7) DRVAIHP 1 SEQ ID NO.18
GSD 24B Pro3-AII DRPYIHPF 2 SEQ ID NO.31
2GD Pro3-AII (1-7) DRPYIHP 3 SEQ ID NO.38
5GD Lys3-AII (1-7) DRKYHP 4 SEQ ID NO.39
All (1-7) DRVYIHP 5 SEQ ID NO.4
All DRVYIHPF 6 SEQ ID NO. 1
The data from these experiments are presented in Figures 1-6 and show that each of the peptides tested increased the number of BFU-E formed relative to the control where no peptide was added. Each of the peptides also increased the size of the colonies evaluated (data not shown). Therefore, said data demonstrate that each of the tested peptides can be used to accelerate the formation of the erythroid progenitor and thereby promote erythropoiesis.
The methods and equipment of the present invention are clinically useful as a therapeutic adjunct for the increased production of red blood cells in the treatment of hypoplastic anemia, acquired or congenital aplastic.
The present invention is not limited by the particular preferred embodiments mentioned above. It will be apparent to those skilled in the art that various modifications can be made with respect to the preferred embodiments described without departing from the concept of the invention. Such modifications are considered within the scope of the present invention.
Claims (30)
1. A method for increasing erythropoiesis, comprising contacting erythroid progenitor cells with an effective amount to increase erythropoiesis of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1 -R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of the formula X-RA-RB-, wherein X is H or one to three Peptide groups RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc; RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (PO3) 2, Thr, Ser, Ala, homoSer and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal Tyr group and wherein the active agent is not All.
The method according to claim 1, wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO. : 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16 , SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO : 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39.
The method according to claim 1, wherein the concentration of active agent is between about 0.1 ng / kg and about 10.0 mg / kg.
A method for increasing erythropoiesis comprising contacting erythroid progenitor cells with an effective amount to increase erythropoiesis of an active agent comprising a sequence of the following general formula: ASP-ARG-R1 -R2-R3-R4-PRO- R5 wherein R1 is selected from the group consisting of Val, Pro and Lys; R2 is selected from the group consisting of Tyr, Tyr (PO3) 2 and Ala; R3 is selected from the group consisting of He, Val, Leu, norLeu and To; R4 is selected from the group consisting of His and Arg and R5 is Phe or is absent and wherein the active agent is not All.
The method according to claim 4, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 39.
The method according to claim 4, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 31, SEQ ID NO: 38 and SEQ ID NO: 39.
The method according to claim 4, wherein the concentration of active agent is between about 0.1 ng / kg and about 10.0 mg / kg.
A pharmaceutical composition comprising an effective amount for increasing the erythropoiesis of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R 1 -R 8 in the sequence of the general formula I R 1 -R 2 -R 3 -R 4 -R5-R6-R7-R8 in which R1 and R2 together form a group of the formula X-RA-RB-, wherein X is H or one to three groups of peptides RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc; RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (PO3) 2, Thr, Ser, Ala, homoSer and azaTyr; R5 is selected from the group consisting of lie, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal Tyr group and wherein the active agent is not All; an amount of erythropoietin effective to stimulate erythropoiesis and a pharmaceutically acceptable carrier.
The pharmaceutical composition according to claim 8, wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39.
The pharmaceutical composition according to claim 8, wherein the concentration of active agent is between about 0.1 ng / kg and about 10.0 mg / kg.
A pharmaceutical composition comprising an effective amount for increasing the erythropoiesis of an active agent comprising a sequence of the following general formula: ASP-ARG-R1 -R2-R3-R4-PRO-R5 wherein R1 is selected from the group consisting of Val, Pro and Lys; R2 is selected from the group consisting of Tyr, Tyr (PO3) 2 and Ala; R3 is selected from the group consisting of He, Val, Leu, norLeu and Ala; R4 is selected from the group consisting of His and Arg and R5 is Phe or is absent and wherein the active agent is not All. an amount of erythropoietin effective to stimulate erythropoiesis and a pharmaceutically acceptable carrier.
The pharmaceutical composition according to claim 11, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 38 and SEQ ID NO: 39.
The pharmaceutical composition according to claim 11, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 31, SEQ ID NO: 38 and SEQ ID NO: 39.
The pharmaceutical composition according to claim 11, wherein the concentration of active agent is between 0.1 ng / kg and about 10.0 mg / kg.
A kit for increasing erythropoiesis, comprising: (a) an amount effective to increase erythropoiesis of at least one active agent comprising a sequence consisting of at least three contiguous amino acids of the groups R1-R8 in the sequence of the general formula I R1-R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of the formula X-RA-RB-, wherein X is H or one to three groups of peptides RA is selected from Asp, Glu, Asn, Acpc, Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc; RB is selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, lie, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (PO3) 2, Thr, Ser, Ala, homoSer and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal Tyr group and wherein the active agent is not All and (b ) instructions for using the effective amount of active agent to increase erythropoiesis.
The kit according to claim 15, wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO : 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO.30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO : 38 and SEQ ID NO: 39.
17. The equipment according to claim 15, wherein the effective agent concentration is between about 0.1 ng / lm and about 10.0 mg / ml.
18. A device for increasing erythropoiesis comprising an effective amount for increasing erythropoiesis of an active agent comprising a sequence of the following general formula: ASP-ARG-R1 -R2-R3-R4-PRO-R5 wherein R1 is selected from group consisting of Val, Pro and Lys; R2 is selected from the group consisting of Tyr, Tyr (PO3) 2 and Ala; R3 is selected from the group consisting of He, Val, Leu, norLeu and To; R4 is selected from the group consisting of H and Arg and R5 is Phe or absent and wherein the active agent is not All and (b) instructions for using the effective amount of active agent to increase erythropoiesis.
19. The equipment according to claim 18, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO.31 , SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 38 SEQ ID NO: 39.
The kit according to claim 18, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 31, SEQ ID NO: 38 and SEQ ID NO: 39.
The equipment according to claim 18, wherein the concentration of active agent is between about 0.1 ng / ml and about 10.0 mg / ml.
An improved cell culture medium for the promotion of erythropoiesis, wherein the improvement comprises the addition to the cell culture medium of an effective amount to promote erythropoiesis of at least one active agent comprising a sequence consisting of at least three amino acids contiguous of the groups R1-R8 in the sequence of the general formula I R1 -R2-R3-R4-R5-R6-R7-R8 in which R1 and R2 together form a group of the formula X-RA-RB- , wherein X is H or one to three groups of AR peptides is appropriately selected from Asp, Glu, Asn, Acpc, (1-aminocyclopentane carboxylic acid), Ala, Me2Gly, Pro, Bet, Glu (NH2), Gly, Asp (NH2) and Suc; RB is appropriately selected from Arg, Lys, Ala, Orn, Ser (Ac), Sar, D-Arg and D-Lys; R3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc, Lys and Tyr; R4 is selected from the group consisting of Tyr, Tyr (PO3) 2, Thr, Ser, Ala, homoSer and azaTyr; R5 is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly; R6 is His, Arg or 6-NH2-Phe; R7 is Pro or Ala and R8 is selected from the group consisting of Phe, Phe (Br), He and Tyr, excluding sequences that include R4 as a terminal Tyr group and wherein the active agent is not All.
23. An improved cell culture medium according to claim 22, wherein the active agent is selected from the group consisting of angiotensinogen, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 , SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38 and SEQ ID NO: 39
24. The improved cell culture medium according to claim 22, wherein the concentration of active agent is between about 0.1 ng / ml and about 10.0 mg / ml.
25. An improved cell culture medium for the promotion of erythropoiesis, wherein the improvement comprises the addition to the cell culture medium of an effective amount to promote erythropoiesis of at least one active agent comprising a sequence of the following general formula: ASP -ARG-R1 -R2-R3-R4-PRO-R5 wherein R1 is selected from the group consisting of Val, Pro and Lys; R2 is selected from the group consisting of Tyr, Tyr (PO3) 2 and Ala; R3 is selected from the group consisting of He, Val, Leu, norLeu and Ala; R4 is selected from the group consisting of His and Arg and R5 is Phe or is absent and wherein the active agent is not All.
26. The improved cell culture medium according to claim 25, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 19, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 32 SEQ ID NO: 34, SEQ ID NO: 38 and SEQ ID NO: 39.
27. The improved cell culture medium according to claim 25, wherein the active agent is selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 31, SEQ ID NO: 38 and SEQ ID NO: 39.
28. A novel peptide with erythropoiesis-promoting activity, consisting of the Asp-Arg-Lys-Tyr-lle-His-Pro-Phe sequence [SEQ ID NO: 39].
29. A pharmaceutical composition comprising the peptide according to claim 28 and a pharmaceutically acceptable carrier.
30. The pharmaceutical composition according to claim 29, further comprising an amount of erythropoietin effective to stimulate erythropoiesis. SUMMARY The present invention provides methods, compounds, pharmaceutical compositions and equipment for the enhancement of erythropoiesis by potentiating the erythropyethin-induced differentiation with angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogs thereof, analogs of angiotensin II, All or analogous fragments thereof or type II All 2 receptor agonists as a therapeutic adjunct. The method is useful for the treatment of hypoplastic anemia, acquired or congenital aplastic associated with chronic renal disease, end-stage renal disease, kidney transplantation, cancer, AIDS, chemotherapy, radiotherapy, bone marrow transplantation and chronic diseases. List of Sequences < 110 > Kathleen Rodgers and gere diZerega < 120 > Method for hematopoietic promotion and Mesenchymal Cell Proliferation and Differentiation < 130 > 98,009-C < 140 > to be assigned < 141 > to be assigned < 160 > 39 < 170 > Patentln Ver. 2.0 < 210 > 1 < 2ll > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Angiotensin II < 400 > 1 Asp Arg Val Tyr lie His Pro Phe < 210 > 2 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII2-8 < 400 > 2 Arg Val Tyr lie His Pro Phe < 210 > 3 < 211 > 6 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence :. AII (3-8) < 400 > 3 Val Tyr His Pro Phe < 210 > 4 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (1-7) < 400 > 4 Asp Arg Val Tyr lie His Pro < 210 > 5 < 211 > 6 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (2-7) < 400 > 5 Arg Val Tyr lie His Pro fifteen < 210 > 6 < 211 > 5 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (3-7) < 400 > 6 Val Tyr He His Pro 1 5 < 210 > 7 < 211 > 4 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (5-8) < 400 > 7 lie His Pro Phe 1 < 210 > 8 < 211 > 6 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (1-6) < 400 > 8 Asp Arg Val Tyr He His fifteen < 210 > 9 < 211 > 5 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > < 400 > 9 Asp Arg Val Tyr He 1 5 < 210 > 10 < 211 > 4 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (1-4) < 400 > 10 Asp Arg Val Tyr 1 < 210 > eleven < 211 > 3 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (1-3) < 400 > eleven Asp Arg Val 1 < 210 > 12 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Xaa in position 2 is NIe < 222 > 2 < 223 > Description of the Artificial Sequence: Analogue AII < 400 > 12 Arg Xaa Tyr He His Pro Phe fifteen < 210 > 13 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Xaa in position 4 is NIe < 222 > 4 < 223 > Description of the Artificial Sequence: analogue AII < 400 > 13 Arg Val Tyr Xaa His Pro Phe 1 5 < 210 > 14 < 211 > 3 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (6-8) < 400 > 14 His Pro Phe 1 < 210 > fifteen < 211 > 5 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: AII (4-8) < 400 > fifteen Tyr He His Pro Phe 1 5 < 210 > 16 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Xaa in position 1 can be Hydrogen, Arg, Lys Ala, Orn, Ser (Acetylated), MeGly, D-Arg. or D-Lys; Xaa in position 2 can be be Val, Ala, Leu, NIe, He, Gly, Pro, Aib, Ac?, Or Tyr: Xaa in position 4 can be, eg, Ala, Leu, NIe, Val, or Gly < 222 > 1-4 < 223 > Description of the Artificial Sequence: Analogue AII class < 400 > 16 Xaa Xaa Tyr Xaa His Pro Phe 1 5 < 210 > 17 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: analogue AII < 400 > 17 Arg Val Tyr Gly His Pro Phe < 210 > 18 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII < 400 > 18 Arg Val Tyr Ala His Pro Phe 1 5 < 210 > 19 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII i < 400 > 19 Asp Arg Val Tyr Val His Pro Phe 1 '5 < 210 > twenty < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 2 < 400 > twenty Asn Arg Val Tyr Val His Pro Phe 1 5 < 210 > twenty-one < 211 > eleven < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Description of the Artificial Sequence: Analogue AII 3 < 400 > twenty-one Wing Pro Gly Asp Arg He Tyr Val His Pro Phe 1 5 10 < 210 > 22 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 4 < 400 > 22 Glu Arg Val Tyr He His Pro Phe 1 5 < 210 > 2. 3 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 5 < 400 > 2. 3 Asp Lys Val Tyr He His Pro Phe fifteen < 210 > 24 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AJÍ 6 < 400 > 24 Asp Arg Ala Tyr He His Pro Phe fifteen < 210 > 25 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 7 < 400 > 25 Asp Arg Val Thr He His Pro Phe fifteen < 210 > 26 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 8 < 400 > 26 Asp Arg Val Tyr Leu His Pro Phe 1 5 < 210 > 27 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 9 < 400 > 27 Asp Arg Val Tyr He Arg Pro Phe fifteen < 210 > 28 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 10 < 400 > 28 Asp Arg Val Tyr He His Wing Phe fifteen < 210 > 29 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 11 < 400 > 29 Asp Arg Val Tyr He His Pro Tyr fifteen < 210 > 30 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 12 < 400 > 30 Pro Arg Val Tyr He His Pro Phe fifteen < 210 > 31 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of the Artificial Sequence: Analogue AII 13 < 400 > 31 Asp Arg Pro Tyr He His Pro Phe fifteen < 210 > 32 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > PHOSPHORYLATION < 222 > 4 < 223 > Description of the Artificial Sequence: Analogue AII 14 < 400 > 32 Asp Arg Val Tyr He His Pro Phe fifteen < 210 > 33 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Xaa at position 3 is NIe < 222 > 3 < 223 > Description of the Artificial Sequence: Analogue AII 15 < 400 > 33 Asp Arg Xaa Tyr He His Pro Phe fifteen < 210 > 3. 4 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > Xaa at position 5 is NIe < 222 > 5 < 223 > Description of the Artificial Sequence: Analogue AII 16 < 400 > 3. 4 Asp Arg Val Tyr Xaa His Pro Phe 1 5 < 210 > 35 < 211 > 9 < 212 > PRT < 213 > Artificial Sequence < 220 > < 221 > homo Being < 222 > 4 < 223 > Description of the Artificial Sequence: Analogue AII 17 < 400 > 35 Asp Arg Val Ser Tyr He His Pro Phe fifteen < 210 > 36 < 211 > 8 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of Artificial Sequence: p-aminophenylalanine 6 AII < 400 > 36 Asp Arg Val Tyr He Xaa Pro Phe fifteen < 210 > 37 < 211 > 10 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of Artificial Sequence: angiotensin I < 400 > 37 Asp Arg Val Tyr He His Pro Phe His Leu 1 5 10 < 210 > 38 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of Artificial Sequence: 2GD: Pro3-AII (1-7) < 400 > 38 Asp Arg Prol Tyr He His Pro 1 5 < 210 > 39 < 211 > 7 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of Artificial Sequence: 5GD: Lys3 AII (1-7) < 400 > 39 Asp Arg Lys Tyr He His Pro
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60/111,535 | 1998-12-09 | ||
| US60/074,106 | 1998-12-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00007509A true MXPA00007509A (en) | 2001-07-03 |
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