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WO1999045945A1 - Methodes ameliorees de radiotherapie - Google Patents

Methodes ameliorees de radiotherapie Download PDF

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Publication number
WO1999045945A1
WO1999045945A1 PCT/US1999/005194 US9905194W WO9945945A1 WO 1999045945 A1 WO1999045945 A1 WO 1999045945A1 US 9905194 W US9905194 W US 9905194W WO 9945945 A1 WO9945945 A1 WO 9945945A1
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seq
group
tyr
ala
active agent
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PCT/US1999/005194
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English (en)
Inventor
Kathleen E. Rodgers
Gere Dizerega
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University Of Southern California
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Application filed by University Of Southern California filed Critical University Of Southern California
Priority to EP99911273A priority Critical patent/EP1061937A1/fr
Priority to JP2000535359A priority patent/JP3728400B2/ja
Priority to CA002323237A priority patent/CA2323237C/fr
Priority to AU29957/99A priority patent/AU744799B2/en
Publication of WO1999045945A1 publication Critical patent/WO1999045945A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/085—Angiotensins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/14—Angiotensins: Related peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0644—Platelets; Megakaryocytes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/32—Angiotensins [AT], angiotensinogen

Definitions

  • Radiation therapy is currently one of the most useful methods of treating cancerous tumors.
  • radiation therapy damages normal tissue surrounding the tumor (U.S. Patent No. 5,599,712, incorporated by reference herein in its entirety).
  • This damage can include fibrosis, remodeling of the extracellular matrix, vascular damage, aberrant angiogenesis, pneumonitis, atherogenesis, osteonecrosis, mucositis, immunosuppression and functional impairment (U.S. Patent No. 5,616,561, incorporated by reference herein in its entirety).
  • techniques have been developed to minimize radiation-induced damage to surrounding normal tissues by limiting radiation to the lowest level effective for cancer treatment. Since there is a direct relationship between the amount of radiation and the effectiveness of the treatment, this method compromises the overall effectiveness of the treatment.
  • Platelets for such procedures are obtained by plateletpheresis from normal donors.
  • platelets for transfusion have a relatively short shelf-life and also expose the patients to considerable risk of exposure to dangerous viruses, such as the human immunodeficiency virus (HIN).
  • HIN human immunodeficiency virus
  • the administration of hematopoietic growth factors may reduce short-term side effects induced by radiation, but has been hypothesized to cause long-term hematopoietic damage (Masse et al., 1998; Watanabe et al., 1996).
  • Bone marrow contains pluripotent stem cells that are capable of reconstituting the entire hematopoietic system. Bone marrow transplantation has been used to treat various intractable hematopoietic diseases including leukemia and severe aplastic anemia. (U.S. Patent No. 5,186,931, incorporated by reference herein in its entirety.) Typically, a bone marrow transplant patient is subjected to irradiation to reduce the leukocyte count to zero, followed by transplantation of bone marrow cells which function by producing a sufficient number of normal leukocytes. However, various complications, such as death, infectious diseases, graft versus host disease, radiation nephritis, and interstitial pneumonia frequently occur during the time period between transplantation and the return to normal white blood cell levels after transplantation.
  • the present invention provides methods and kits for mitigating radiation induced tissue damage, improving the effectiveness of radiation therapy, to support bone marrow transplantation, and promoting megakaryocyte production and mobilization and platelet production, each method comprising the administration of angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof or All AT 2 type 2 receptor agonists to a patient in need thereof.
  • an improved cell culture medium and kits are provided for the production of megakaryocytes and platelets wherein the improvement comprises addition to the cell culture medium of an effective amount of angiotensinogen, Al, Al analogues, Al fragments and analogues thereof, All, All analogues, All fragments or analogues thereof or All AT? type 2 receptor agonists.
  • Figure 1 is a graph showing the effect of All treatment two days prior to exposure on post-irradiation mouse mortality.
  • Figure 2 is a graph showing the effect of All treatment on the day of exposure on post-irradiation mouse mortality.
  • Figure 3 is a graph showing the effect of All treatment two days following exposure on post-irradiation mouse mortality.
  • Figure 4 is a graph showing the effect of All treatment two days prior to exposure on white blood cell number after irradiation.
  • Figure 5 is a graph showing the effect of All treatment on the day of exposure on white blood cell number after irradiation.
  • Figure 6 is a graph showing the effect of All treatment two days following exposure on white blood cell number after irradiation.
  • Figure 7 is a graph showing the effect of All treatment two days prior to exposure on megakaryocyte number after irradiation.
  • Figure 8 is a graph showing the effect of All treatment on the day of exposure on megakaryocyte number after irradiation.
  • Figure 9 is a graph showing the effect of All treatment two days following exposure on megakaryocyte percentage after irradiation.
  • Figure 10 is a graph showing the effect of All treatment two days prior to exposure on monocyte number after irradiation.
  • Figure 11 is a graph showing the effect of All treatment on the day of exposure on monocyte number after irradiation.
  • Figure 12 is a graph showing the effect of All treatment two days following exposure on monocyte number after irradiation.
  • Figure 13 is a graph showing the effect of All treatment two days prior to exposure on neutrophil number after irradiation.
  • Figure 14 is a graph showing the effect of All treatment on the day of exposure on neutrophil number after irradiation.
  • Figure 15 is a graph showing the effect of All treatment two days following exposure on neutrophil number after irradiation.
  • Figure 16 is a graph showing the effect of All treatment two days prior to exposure on lymphocyte number after irradiation.
  • Figure 17 is a graph showing the effect of All treatment on the day of exposure on lymphocyte number after irradiation.
  • Figure 18 is a graph showing the effect of All treatment two days following exposure on lymphocyte number after irradiation.
  • Figure 19 is a graph showing is a graph showing the effect of All analogues and fragments treatment on white blood cell number after irradiation.
  • Figure 20 is a graph showing is a graph showing the effect of I analogues and fragments treatment on platelet number after irradiation.
  • Figure 21 is a graph showing the effect of All on mouse survival receiving bone marrow transplantation after lethal irradiation.
  • Figure 22 is a graph showing the effect of All analogues and fragments treatment on white blood cell number after irradiation.
  • Figure 23 is a graph showing the effect of All on white blood cell number in the blood of mice receiving bone marrow transplantation after lethal irradiation.
  • Figure 24 is a graph showing the effect of All on white blood cell number in the blood of mice receiving bone marrow transplantation after lethal irradiation..
  • the present invention fulfills the needs for improved therapeutic methods to mitigate radiation induced tissue damage, to improve the effectiveness of radiation therapy, to support bone marrow transplantation, and to promote megakaryocyte production and mobilization and platelet production.
  • tissue damage refers not only to reduction of damage, but also encompasses recovery of tissue from damage.
  • tissue refers to any tissue type, and also includes hematopoietic stem and progenitor cells, white blood cells and platelets.
  • megakaryocyte mobilization refers to the movement of a megakaryocyte precursor cell from the bone marrow into the periphery.
  • the phrase "improved platelet production” or “improved megakaryocyte production,” means that the number of platelets or megakaryocytes is significantly elevated above the normal range of platelets or megakaryocytes in the particular mammal involved.
  • the elevation of platelet or megakaryocyte counts may occur in a time-dependent manner, and may be cyclical, increasing and then constant or decreasing, or constant, etc.
  • active agents refers to the group of compounds comprising angiotensinogen, angiotensin I (Al), Al analogues, Al fragments and analogues thereof, angiotensin II (All), All analogues, All fragments or analogues thereof and All AT type 2 receptor agonists.
  • MI in an amount which is sufficient for said increase.
  • the application of MI to wound tissue significantly increases the rate of wound healing, leading to a more rapid re-epithelialization and tissue repair.
  • the term MI refers to an octapeptide present in humans and other species having the sequence Asp-Mg-Val-Tyr-Ile-His-
  • angiotensin I M
  • MI angiotensin I
  • MI is a known pressor agent and is commercially available. The use of MI analogues and fragments,
  • AT2 agonists as well as AIII and AIII analogues and fragments in wound healing has also been described.
  • MI increases mitogenesis and chemotaxis in cultured cells that are involved in wound repair, and also increases their release of growth factors and extracellular matrices
  • diZerega U.S. Patent No. 5,015,629; Dzau et. al., J. Mol. Cell. Cardiol. 21 :S7 (Supp III) 1989; Berk et. al., Hypertension 13:305-14 (1989); Kawahara, et al., BBRC 150:52-9 (1988); Naftilan, et al, J. Clin. Invest. 83: 1419-23 (1989); Taubman et al, J. Biol.
  • MI was shown to be angiogenic in rabbit corneal eye and chick chorioallantoic membrane models (Fernandez, et al., J. Lab. Clin. Med. 105:141 (1985); LeNoble, et al., Eur. J. Pharmacol. 195:305-6 (1991). Therefore, MI may accelerate wound repair through increased neovascularization, growth factor release, reepithelialization and/or production of extracellular matrix.
  • MI has also been implicated in both cell growth and differentiation (Meffert et al., Mol. and Cellul. Endocrin. 122:59 (1996)).
  • Two main classes of All receptors, ATi and AT 2 have been identified (Meffert, 1996).
  • the growth-promoting effects of MI have been attributed to mediation by the ATI receptor, while some evidence suggests that the AT2 receptor may be involved in mediation of the cell differentiation effects of MI (Bedecs et al., Biochem. J. 325:449 (1997)).
  • MI(l-7) (All residues 1-7) or other fragments of All to evaluate their activity. MI(l-7) elicits some, but not the full range of effects elicited by AIL Pfeilschifter, et al, Eur. J. Pharmacol. 225:57-62 (1992); Jaiswal, et al., Hypertension 19(Supp. II):II-49-II-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 a., Br. J. Pharmacol. 111 :652-654 (1994).
  • angiotensinogen angiotensin I (Al)
  • Al angiotensin I
  • Al Al analogues
  • MI analogues All fragments or analogues thereof or All AT 2 type 2 receptor agonists
  • angiotensinogen angiotensin I (Al)
  • M analogues Al fragments and analogues thereof
  • All, All analogues, MI fragments or analogues thereof or All AT 2 type 2 receptor agonists would be effective in reducing radiation-induced human tissue damage or in treating patients in need of radiation therapy.
  • M analogues Al fragments and analogues thereof, angiotensin II (MI), MI analogues, MI fragments or analogues thereof or All AT 2 type 2 receptor agonists to stimulate the production and mobilization of megakaryocytes, or to stimulate the production of platelets.
  • MI angiotensin II
  • MI fragments or analogues thereof All AT 2 type 2 receptor agonists to stimulate the production and mobilization of megakaryocytes, or to stimulate the production of platelets.
  • a peptide agonist selective for the AT2 receptor (All has 100 times higher affinity for AT2 than ATI) is p-amino ⁇ henylalanine6-MI ["(p-NH 2 -Phe)6-MI)"], Asp-Mg-Val-Tyr-Ile-Xaa-Pro-Phe [SEQ ID NO.36] wherein Xaa is p-NH 2 -Phe
  • the active Al, M analogues, M fragments and analogues thereof, MI analogues, fragments of All and analogues thereof of particular interest in accordance with the present invention are characterized as comprising a sequence consisting of at least three contiguous amino acids of groups R -R in the sequence of general formula I
  • R ⁇ is suitably selected from Asp, Glu, Asn, Acpc (1- aminocyclopentane carboxylic acid), Ma, Me 2 Gly, Pro, Bet, Glu(NH 2 ), Gly,
  • R B is suitably selected from Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;
  • R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He.
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer, Ala, and azaTyr;
  • R 5 is selected from the group consisting of He, Ala, Leu, norLeu, Val
  • R° is His, Arg or 6-NH 2 -Phe
  • R 7 is Pro or Ala
  • R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr, excluding sequences including R as a terminal Tyr group.
  • Compounds falling within the category of AT2 agonists useful in the practice of the invention include the MI analogues set forth above subject to the restriction that R 6 is p-NH 2 -Phe.
  • various nonpeptidic agents e.g., peptidomimetics
  • having the requisite AT2 agonist activity are further contemplated for use in accordance with the present invention.
  • R A and R B are Asp- Arg, Asp-Lys, Glu-
  • Arg and Glu-Lys include the following: All, Mil or MI(2-8), Arg-Nal-Tyr-He-His-Pro-Phe [SEQ ID ⁇ O:2];
  • MI(3-8) also known as desl-AIII or MN, Nal-Tyr-Ile-His-Pro-Phe [SEQ ID ⁇ O:3]; AII(l-7), Asp-Arg-Nal-Tyr-Ile-His-Pro [SEQ ID NO:4]; MI(2-7).
  • Still another preferred embodiment encompassed within the scope of the invention is a peptide having the sequence Asp-Arg-Pro-Tyr-
  • a class of particularly preferred compounds in accordance with the present invention consists of those with the following general structure: Rl -Arg-R2-R3-R4-His-Pro-R5 wherein Rl is selected from the group consisting of H and Asp; R2 is selected from the group consisting of Val and Pro;
  • R3 is selected from the group consisting of Tyr and Tyr(PO 3 ) 2 ;
  • R4 is selected from the group consisting of Ala, He, Leu, and norLeu;
  • R5 is Phe, He, or is absent.
  • SEQ ID NOJ SEQ ID NO:4, SEQ ID NO: 18, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:38
  • R 2 is selected from the group consisting of H, Arg, Lys, Ala, Orn, Ser(Ac), Sar, D-Arg and D-Lys;
  • R 3 is selected from the group consisting of Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr;
  • R 4 is selected from the group consisting of Tyr, Tyr(PO 3 ) 2 , Thr, Ser, homoSer and azaTyr;
  • R ⁇ is selected from the group consisting of He, Ala, Leu, norLeu, Val and Gly;
  • R 6 is His, Arg or 6-NH 2 -Phe;
  • R 7 is Pro or Ala; and R 8 is selected from the group consisting of Phe, Phe(Br), He and Tyr.
  • a particularly preferred subclass of the compounds of general formula II has the formula
  • R 2 , R 3 and R 5 are as previously defined. Particularly preferred is angiotensin III of the formula Arg-Val-Tyr-Ile-His-Pro-Phe [SEQ ID NO:2]. Other
  • preferred compounds include peptides having the structures Arg-Nal-Tyr-Gly-His- Pro-Phe [SEQ ID ⁇ O:17] and Arg-Nal-Tyr-Ala-His-Pro-Phe [SEQ ID NO:18].
  • the fragment MI(4-8) was ineffective in repeated tests; this is believed to be due to the exposed tyrosine on the N-terminus.
  • R 2 Appropriate side chains on the amino acid in position R 2 may contribute to affinity of the compounds for target receptors and/or play an important role in the conformation of the peptide. For this reason, Arg and Lys are particularly preferred as R 2 .
  • R 3 may be involved in the formation of linear or nonlinear hydrogen bonds with R 5 (in the gamma turn model) or R 6 (in the beta turn model). R 3 would also participate in the first turn in a beta antiparallel structure (which has also been proposed as a possible structure). In contrast to other positions in general formula I, it appears that beta and gamma branching are equally effective in this position. Moreover, a single hydrogen bond may be sufficient to maintain a relatively stable conformation. Accordingly, R 3 may suitably be selected from Val, Ala, Leu, norLeu, He, Gly, Pro, Aib, Acpc and Tyr. In another preferred embodiment, R is Lys.
  • R 4 conformational analyses have suggested that the side chain in this position (as well as in R 3 and R 5 ) contribute to a hydrophobic cluster believed to be essential for occupation and stimulation of receptors.
  • R is preferably selected from Tyr, Thr, Tyr (PO 3 ) , homoSer, Ser and azaTyr.
  • Tyr is particularly preferred as it may form a hydrogen bond with the receptor site capable of accepting a hydrogen from the phenolic hydroxyl (Regoli, et al. (1974), supra).
  • R 4 is Ala.
  • R 5 is suitable in position R 5 , it is preferred that the amino acid in this position be selected from He, Ma, Leu, norLeu, Gly and Nal.
  • R° is His, Arg or 6- ⁇ H 2 -Phe.
  • conformational models suggest that His may participate in hydrogen bond formation (in the beta model) or in the second turn of the antiparallel structure by influencing the orientation of R 7 .
  • R 7 should be Pro in order to provide the most desirable orientation of R 8 .
  • both a hydrophobic ring and an anionic carboxyl terminal appear to be particularly useful in binding of the analogues of interest to receptors; therefore, Tyr and especially Phe are preferred for purposes of the present invention.
  • Analogues of particular interest include the following: TABLE 2 Angiotensin II Analogues
  • Analogue 4 Glu-Mg-Val-Tyr-Ile-His-Pro-Phe SEQ ID NO: 22
  • Analogue 5 Asp-Lys-Val-Tyr-Ile-His-Pro-Phe SEQ ID NO: 23
  • Analogue 16 Asp-Arg-Val-Tyr-norLeu-His-Pro-Phe SEQ ID NO: 34
  • Analogue 17 Asp-Arg-Val-homoSer-Tyr-Ile-His-Pro-Phe SEQ ID NO: 35
  • polypeptides of the instant invention may be synthesized by methods such as those set forth in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, 2nd ed., Pierce Chemical Co., Rockford, 111. (1984) and J. Meienhofer, Hormonal Proteins and Peptides, Vol. 2, Academic Press, New York, (1973) for solid phase synthesis and E. Schroder and K. Lubke, The Peptides, Vol. 1, Academic Press, New York, (1965) for solution synthesis.
  • the disclosures of the foregoing treatises are incorporated by reference herein.
  • these methods involve the sequential addition of protected amino acids to a growing peptide chain (U.S. Patent No. 5,693,616, herein incorporated by reference in its entirety). Normally, either the amino or carboxyl group of the first amino acid and any reactive side chain group are protected. This protected amino acid is then either attached to an inert solid support, or utilized in solution, and the next amino acid in the sequence, also suitably protected, is added under conditions amenable to formation of the amide linkage. After all the desired amino acids have been linked in the proper sequence, protecting groups and any solid support are removed to afford the crude polypeptide. The polypeptide is desalted and purified, preferably chromatographically, to yield the final product.
  • the present invention provides methods and kits for the mitigation of tissue damage due to radiation exposure comprising the administration of angiotensinogen, angiotensin I (M), M analogues, M fragments and analogues thereof, angiotensin II (MI), MI analogues, All fragments or analogues thereof or MI AT 2 type 2 receptor agonists (the "active agents").
  • the present invention provides improved methods and kits for treating a patient afflicted with a neoplastic disease state that is being treated with ionizing or nonionizing radiation, the improvement comprising conjunctive therapy whereby an effective radioprotective amount of the active agents is provided.
  • the present invention provides improved methods and kits for treating a patient in need of radiation therapy, the improvement comprising the administration of the active agents in conjunction with the radiation therapy.
  • the invention is appropriate for use with any type of ionizing radiation exposure such as therapeutic or accidental X-ray, gamma ray, or beta particle exposure.
  • ionizing radiation exposure suitable for treatment with the methods and kits of the present invention include, but are not limited to, clinical radiation therapy, medical diagnostics using radioactive tracers, exposure to naturally occurring ionizing radiation sources such as uranium and radon, wartime exposure, and accidental exposures including occupational exposure at nuclear power facilities, and medical and research institutions.
  • Examples of nonionizing radiation exposure suitable for treatment with the methods and kits of the present invention include, but are not limited to, ultraviolet light, X-rays, microwaves, radio-frequency waves, and electromagnetic radiation.
  • any tissue susceptible to radiation-induced tissue damage can gain protection by use of the active agents of the invention.
  • breast tissue is an excellent candidate for receiving the benefit of the subject invention.
  • Radiation- induced tissue damage can be a fatal side effect of over-exposure to radiation therapy.
  • the fibrotic reaction common in normal breast tissue surrounding the cancerous tumor being treated with radiation therapy undermines the cosmetic advantages of radiation therapy over surgical treatment. This disadvantage will lead many patients to elect a less effective or more dangerous treatment after radiation therapy.
  • the present invention is also particularly suitable for those patients in need of repeated or high doses of radiation therapy. For some cancer patients, hematopoietic toxicity frequently limits the opportunity for radiation dose escalation (Watanabe et al., British J. Haematol.
  • Skin exposure is particularly common in accidental radiation exposure. It is an excellent candidate for the inventive therapy, especially as the compounds of the invention can be administered topically.
  • Other tissues that are susceptible to radiation-induced damage following accidental or therapeutic ionizing or nonionizing radiation exposure include, but are not limited to: liver, lung, gastrointestinal tract, kidneys, testes, salivary gland, mucosa and brain.
  • the present invention provides improved methods and kits for supporting bone marrow transplantation comprising the administration of the active agents to a patient in need thereof.
  • auxiliary agents including, but not limited to interleukin (IL)-3, D - 1, IL-4, 11-5, granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), anticancer agents, antiviral agents, and antibiotics.
  • kits for mitigating radiation induced tissue damage and improving the efficacy of radiation therapy comprising an effective amount of the active agents of the invention for mitigating radiation induced tissue damage or improving the efficacy of radiation therapy, and instructions for using the amount effective of active agent as a therapeutic.
  • the kit further comprises a pharmaceutically acceptable carrier, such as those adjuvants described above.
  • the kit further comprises a means for delivery of the active agent to a patient.
  • Such devices include, but are not limited to syringes, matrical or micellar solutions, bandages, wound dressings, aerosol sprays, lipid foams, transdermal patches, topical administrative agents, polyethylene glycol polymers, carboxymethyl cellulose preparations, crystalloid preparations (e.g., saline, Ringer ' s lactate solution, phosphate-buffered saline, etc.), viscoelastics, polyethylene glycols. and polypropylene glycols.
  • the means for delivery may either contain the effective amount of angiotensinogen, M, M analogues, M fragments and analogues thereof, MI, MI analogues, MI fragments or analogues thereof or MI AT 2 type 2 receptor
  • 22 agonists may be separate from the compounds, which are then applied to the means for delivery at the time of use.
  • the methods and kits of the present invention by mitigating radiation induced tissue damage and improving the efficacy of radiation therapy and bone marrow transplantation, significantly enhance the utility of presently available treatments both for radiation-induced tissue damage and for clinical radiation therapy.
  • megakaryocytes are isolated from bone marrow as described in U.S. Patent No. 5,178,856, incorporated by reference herein in its entirety. Briefly, marrow is flushed from a subject's femur with Iscove's modification of Dulbecco's medium (IMDM) supplemented with Nutridoma-SP (Boehringer Mannheim, Indianapolis, Ind.), a serum-free medium supplement. For culture studies, a single cell suspension is made by repetitive expulsion through progressively smaller needles.
  • IMDM Dulbecco's medium
  • a monocellular suspension is made by gentle filtration through a 100 micron nylon mesh.
  • adherent cells are removed to enrich the numbers of megakaryocytes or their progenitor cells. Up to 2 x 10 6 cells/ml are placed in growth
  • the cells are expanded for a period of between 2 and 21 days and cellular proliferation is assessed at various time points during this time period. Subsequent medium changes are performed as needed.
  • megakaryocyte production and mobilization and platelet production are assessed by the extent of megakaryocyte ploidization by flow
  • subjects are irradiated as above and active agent is injected subcutaneously before, at the time of, and after irradiation.
  • Blood samples are taken at various times after administration of the active agent to monitor the number of white blood cells, megakaryocytes and platelets.
  • subjects are treated with total body irradiation and active agent is administered subcutaneously (10 ⁇ g./kg/day or 100 ⁇ g/Tcg/day) at various times before and after irradiation.
  • the number of white blood cells, megakaryocytes and platelets is preferably determined by counting with a hemacytometer followed by differential morphologic analysis.
  • hematopoietic precursor cells are isolated from bone marrow, peripheral blood or umbilical cord blood and cultured under appropriate growth conditions, in the presence of the active agents. Megakaryocyte production is assessed at various time points during culture by differential morphologic analysis.
  • hematopoietic precursor cells are isolated from bone marrow aspirates from the posterior iliac crest (Caplan and Haynesworth, U.S. Patent No. 5,486,359).
  • CD34 + hematopoietic precursor cells are isolated from the aspirate by attaching a biotinylated monoclonal antibody specific for CD34 (available
  • the isolated cells are suspended in culture medium and incubated in the presence of, preferably, between about OJ ng/ml and about 10 mg/ml of the active agents of the invention.
  • the cells are expanded for a period of between 8 and 21 days and megakaryocyte production is assessed via phase microscopy to detect increased size and polyploidization at various points during this time period.
  • a method of increasing megakaryocyte production and mobilization and platelet production by exposure to the active agents is disclosed, either in the presence or absence of other growth factors and cytokines.
  • growth factors and cytokines include, but are not limited to thrombopoietin, lymphokines, interleukins - 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, granulocyte colony-stimulating factor, granulocyte/macrophage colony stimulating factor, macrophage colony-stimulating factor, tumor necrosis factor, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, and stem cell factor.
  • megakaryocytes and/or platelets that have been cultured in the presence of the active agents are used for autologous transplantation, to reconstitute a depleted hematopoietic system.
  • the cells Prior to transplantation, the cells are rinsed to remove all traces of culture fluid, resuspended in an appropriate medium and then pelleted and rinsed several times. After the final rinse, the cells are resuspended at between 0.7 x 10 6 and 50 x 10 6 cells per ml in an appropriate medium and reinfiised into a subject through intravenous infusions.
  • the active agents are used to increase in vivo megakaryocyte production and mobilization and platelet production.
  • the active agents may be administered by any suitable route, including orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pha ⁇ naceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the active agents of all aspects of the present invention may be administered by any suitable route, including orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • parenteral as used herein includes, subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intratendinous, intraspinal, intracranial, intrathoracic, infusion techniques or intraperitoneally.
  • the active agents of the invention may be made up in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions, or emulsions).
  • the compounds of the invention may be applied in a variety of solutions.
  • Suitable solutions for use in accordance with the invention are sterile, dissolve sufficient amounts of the peptide, and are not harmful for the proposed application.
  • the compounds of the present invention are very stable but are hydrolyzed by strong acids and bases.
  • the compounds of the present invention are soluble in organic solvents and in aqueous solutions at pH 5-8.
  • the active agents may be subjected to conventional pharmaceutical operations such as sterilization and or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
  • the active agents are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
  • the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, carboxymethyl cellulose colloidal solutions, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the carrier or diluent may include time delay material, 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 (e.g., liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
  • the dosage regimen for mitigating radiation-induced tissue damage and improving the efficacy of radiation therapy with the active agents is based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely by a physician using standard methods. Dosage levels of the order of between OJ ng/kg and 10 mg/kg body weight of the active agents are useful for all methods of use disclosed herein.
  • the treatment regime will also vary depending on the disease being treated, based on a variety of factors, including the type of injury, the age, weight, sex, medical condition of the individual, the severity of the condition, the route of administration, and the particular compound employed.
  • the active agents are administered to an oncology patient for up to 30 days prior to a course of radiation therapy and for up to 60 days post-radiation exposure.
  • the therapy is administered for 1 to 6 times per day at dosages as described above.
  • the compounds of the invention can be administered either prior to, simultaneously with, or subsequent to radiation exposure.
  • the active agent is administered subcutaneously.
  • a suitable subcutaneous dose of active ingredient of active agent is preferably between about 0J ng.kg and about 10 mg/kg administered twice daily for a time sufficient to mitigate radiation-induced tissue damage, to provide a radioprotective effect for a radiation therapy patient afflicted with a neoplastic disease, to effectively treat a patient in need of radiation therapy, to support bone marrow transplantation and to promote megakaryocyte production and mobilization and platelet production.
  • the concentration of active agent is between about 100 ng/kg body weight and about 10.0 mg/kg body weight, In a most preferred embodiment, the concentration of active agent is between about 10 ⁇ g/kg body weight and about 10.0 mg/kg body weight.
  • This dosage regimen maximizes the therapeutic benefits of the subject invention while minimizing the amount of agonist or peptide needed. Such an application minimizes costs as well as possible deleterious side effects.
  • the active ingredient may comprise from 0.0001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0J%> to 1% of the fo ⁇ nulation.
  • the active agent is administered topically. Suitable topical doses and active ingredient concentration in the formulation are as described for subcutaneous administration.
  • the active agent is selected from the group consisting of SEQ ID NO. 1, SEQ ID NO:2, SEQ ID NO:
  • SEQ ID NO:9 SEQ ID NOJ0, SEQ ID NOJ 1, SEQ ID NOJ2, SEQ ID NOJ3,
  • 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,
  • administration of the active agent is localized to the area affected by the tissue- damaging radiation.
  • an improved cell culture medium for megakaryocyte and platelet production, wherein the improvement comprises addition to the cell culture medium of an effective amount of between about OJ ng and 10 mg ml of the active agents of the invention.
  • Any cell culture media that can support megakaryocyte and platelet production can be used with the present invention.
  • Such cell culture media include, but are not limited to Basal Media Eagle, Dulbecco's Modified Eagle Medium, Iscove's Modified Dulbecco's Medium, McCoy's Medium, Minimum Essential Medium, F-10 Nutrient Mixtures, Opti- MEM® Reduced-Serum Medium, RPMI Medium, and Macrophage-SFM Medium or combinations thereof.
  • the improved cell culture medium can be supplied in either a concentrated (ie: 10X) or non-concentrated form, and may be supplied as either a liquid, a powder, or a lyophilizate.
  • the cell culture may be either chemically defined, or may contain a serum supplement.
  • Culture media is commercially available from many sources, such as GIBCO BRL (Gaithersburg, MD) and Sigma (St. Louis, MO)
  • kits for megakaryocyte and platelet production wherein the kits comprise an amount effective for megakaryocyte and platelet production of the active agents of the invention, and instructions for its use as a cell culture media supplement.
  • kits further comprise cell culture growth medium. Any cell culture media that can support megakaryocyte and platelet
  • the cell culture medium can be supplied in either a concentrated (ie: 10X) or non-concentrated form, and may be supplied as either a liquid, a powder, or a lyophilizate.
  • the cell culture may be either chemically defined, or may contain a serum supplement.
  • the kit further comprises a sterile container, which can comprise either a sealed container, such as a cell culture flask, a roller bottle, or a centrifuge tube, or a non-sealed container, such as a cell culture plate or microtiter plate (Nunc; Naperville, IL).
  • the kit further comprises an antibiotic supplement for inclusion in the reconstituted cell growth medium.
  • appropriate antibiotic supplements include, but are not limited to actimonycin D, Fungizone®, kanamycin, neomycin, nystatin, penicillin, streptomycin, or combinations thereof (GIBCO).
  • mice Female C57B1/6 mice (Jackson Labs, Bar Harbor, Maine) were irradiated with 600 cGy total body irradiation. Subcutaneous injection with either MI (10 ⁇ g/kg/day or 100 ⁇ g/kg/day) or saline (placebo) was initiated two days before (-day
  • mice were anaesthetized with Metofane (Pittman-Moore Animal Health, NZ) and bled via the retro-orbital sinus. Red blood cells were lysed with 0.3%) acetic acid and the number of white blood cells was determined by counting with a hemacytometer.
  • Metofane Pantman-Moore Animal Health, NZ
  • Example 2 Effect of All and All Analogs/Fragments on WBC and platelet numbers After Irradiation The animals were irradiated and treated as in Example 1 , however, treatment started on day 0 only with one subcutaneous injection of either 10 ⁇ g/Tcg or 100 ⁇ g/Ttg daily until the study was terminated. Analogues and fragments of MI (see Table 3) were assessed for their effect on WBC recovery and platelet number after irradiation. The data are shown in Figures 20 and 21 and show that the peptides increase the production of both of these blood elements.
  • mice Male, 6-8 weeks old were irradiated with 600 cGy total body irradiation. Starting on the day of irradiation, the mice received either saline (0J ml) or 20 ⁇ g/ml angiotensin II (0J ml, 100 ⁇ g/kg) subcutaneously for fourteen days. At the end of this period, the bone marrow was harvested from the femur by flushing and the number of viable nucleated cells determined by counting under a light microscope on a hemacytometer in the presence of trypan blue.
  • donor bone marrow cells were then injected intravenously into recipient mice (female C57B1/6, 6-8 weeks old) that had been lethally irradiated (900 cGy total body irradiation) at two. concentrations: 1 x 10 6 or 1 x 10 s cells per mouse. After injection, the recipient mice received either saline or 100 ⁇ g/kg MI subcutaneously until death or termination.
  • the study design in its entirety is as follows:
  • mice The survival of the mice and the number of circulating white blood cells were measured as a function of time post-bone marrow transplantation.
  • the data are presented in Figures 22-24, and demonstrate that MI treatment increased both survival and white blood cell number in mice receiving bone marrow transplantation after irradiation. The greatest benefit was conferred by treatment of both the donor bone marrow cells and the recipient mice with MI.
  • the methods and kits of the present invention by mitigating radiation induced tissue damage and improving the efficacy of radiation therapy, significantly enhance the utility of presently available treatments both for radiation-induced tissue damage and for clinical radiation therapy, as well as bone marrow transplantation by increasing the survival rate of patients and accelerating the reconstitution of the patient's hematopoietic system.
  • the present invention will greatly augment clinical cancer treatments and bone marrow transplantation and other conditions that lead to decreased megakaryocyte production and mobilization and platelet production.
  • the method of the present invention also increases the potential utility of megakaryocytes as vehicles for gene therapy in hematopoietic disorders, by providing a more efficient means to rapidly expand transfected megakaryocytes. It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compounds, compositions, methods, procedures or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope of the appended claims.

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Abstract

La présente invention concerne des méthodes et trousses destinées à atténuer les dégâts causés aux tissus par un rayonnement, à améliorer l'efficacité de la radiothérapie, à faciliter une greffe de moelle osseuse et à favoriser la production et la mobilisation de mégacaryocytes et la production de plaquettes; chaque méthode consiste à administrer une quantité effective d'angiotensinogène, d'angiotensine I (AI), d'analogues d'AI, de fragments d'AI et de leurs analogues, d'angiotensine II (AII), d'analogues d'AII, de fragments d'AII ou de leurs analogues ou d'agonistes de récepteur d'AII AT2 de type 2.
PCT/US1999/005194 1998-03-10 1999-03-08 Methodes ameliorees de radiotherapie WO1999045945A1 (fr)

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EP99911273A EP1061937A1 (fr) 1998-03-10 1999-03-08 Methodes ameliorees de radiotherapie
JP2000535359A JP3728400B2 (ja) 1998-03-10 1999-03-08 改良型放射線治療の諸方法
CA002323237A CA2323237C (fr) 1998-03-10 1999-03-08 Methodes ameliorees de radiotherapie
AU29957/99A AU744799B2 (en) 1998-03-10 1999-03-08 Improved radiation therapy methods

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US9009698P 1998-06-19 1998-06-19
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US9021698P 1998-06-22 1998-06-22
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US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
US7122523B2 (en) * 2001-05-01 2006-10-17 University Of Southern California Methods for inhibiting tumor cell proliferation
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US7786085B2 (en) 1999-05-10 2010-08-31 University Of Southern California Method for treating a patient undergoing chemotherapy
WO2012021578A1 (fr) * 2010-08-10 2012-02-16 University Of Southern California Utilisation de l'angiotensine-ii (1-7) en transplantation cellulaire et comme agent destiné à prévenir/traiter une infection par un norovirus
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
WO2013152291A1 (fr) * 2012-04-05 2013-10-10 University Of Southern California Technologie de thérapie cellulaire pour administrer des peptides radio-protecteurs
US8557958B1 (en) 2012-06-18 2013-10-15 Tarix Pharmaceuticals Ltd. Compositions and methods for treatment of diabetes
US8633158B1 (en) 2012-10-02 2014-01-21 Tarix Pharmaceuticals Ltd. Angiotensin in treating brain conditions
WO2014047506A1 (fr) * 2012-09-20 2014-03-27 Synedgen, Inc. Procédés pour le traitement ou la prévention de dommages résultant d'un rayonnement, d'un trauma ou d'un choc
US9272013B2 (en) 2010-03-26 2016-03-01 University Of Southern California Methods for treating combined radiation and thermal injury
US9333233B2 (en) 2014-02-25 2016-05-10 Tarix Pharmaceuticals Ltd. Methods and compositions for the delayed treatment of stroke
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer
US11717532B2 (en) 2010-04-06 2023-08-08 Synedgen, Inc. Methods and compositions for treating wounds utilizing chitosan compounds

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
US7786085B2 (en) 1999-05-10 2010-08-31 University Of Southern California Method for treating a patient undergoing chemotherapy
US7122523B2 (en) * 2001-05-01 2006-10-17 University Of Southern California Methods for inhibiting tumor cell proliferation
US7652054B2 (en) 2001-05-31 2010-01-26 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US8124638B2 (en) 2001-05-31 2012-02-28 Vicore Pharma Ab Tricyclic compounds useful as angiotensin II agonists
US9272013B2 (en) 2010-03-26 2016-03-01 University Of Southern California Methods for treating combined radiation and thermal injury
US11717532B2 (en) 2010-04-06 2023-08-08 Synedgen, Inc. Methods and compositions for treating wounds utilizing chitosan compounds
WO2012021578A1 (fr) * 2010-08-10 2012-02-16 University Of Southern California Utilisation de l'angiotensine-ii (1-7) en transplantation cellulaire et comme agent destiné à prévenir/traiter une infection par un norovirus
WO2012070936A1 (fr) 2010-11-23 2012-05-31 Lanthiopep B.V. Nouveaux agonistes du récepteur de l'angiotensine de type 2 (at2) et leurs utilisations
EP2455388A1 (fr) 2010-11-23 2012-05-23 LanthioPep B.V. Nouveaux agonistes du récepteur 2 (AT2) de type angiotensine et leurs utilisations
US9290540B2 (en) 2010-11-23 2016-03-22 Lanthio Pep B.V. Angiotensin Type 2 (AT2) receptor agonists and uses thereof
US10214563B2 (en) 2010-11-23 2019-02-26 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
US9707268B2 (en) 2010-11-23 2017-07-18 Lanthiopep B.V. Angiotensin type 2 (AT2) receptor agonists and uses thereof
WO2013152291A1 (fr) * 2012-04-05 2013-10-10 University Of Southern California Technologie de thérapie cellulaire pour administrer des peptides radio-protecteurs
US8557958B1 (en) 2012-06-18 2013-10-15 Tarix Pharmaceuticals Ltd. Compositions and methods for treatment of diabetes
WO2014047506A1 (fr) * 2012-09-20 2014-03-27 Synedgen, Inc. Procédés pour le traitement ou la prévention de dommages résultant d'un rayonnement, d'un trauma ou d'un choc
US10716803B2 (en) 2012-09-20 2020-07-21 Synedgen, Inc. Methods for treatment or prevention of damage resulting from radiation, trauma or shock
US10022393B2 (en) 2012-09-20 2018-07-17 Synedgen, Inc. Methods for treatment or prevention of damage resulting from radiation, trauma or shock
US8633158B1 (en) 2012-10-02 2014-01-21 Tarix Pharmaceuticals Ltd. Angiotensin in treating brain conditions
US9511055B2 (en) 2012-10-02 2016-12-06 Tarix Pharmaceuticals Ltd. Angiotensin in treating brain conditions
US9333233B2 (en) 2014-02-25 2016-05-10 Tarix Pharmaceuticals Ltd. Methods and compositions for the delayed treatment of stroke
WO2021023698A1 (fr) 2019-08-02 2021-02-11 Lanthiopep B.V Agonistes du récepteur de l'angiotensine 2 (at2) destinés à être utilisés dans le traitement du cancer

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CA2659664A1 (fr) 1999-09-16
EP1061937A1 (fr) 2000-12-27
JP2002506042A (ja) 2002-02-26
CA2323237C (fr) 2009-05-19
CA2323237A1 (fr) 1999-09-16
AU2995799A (en) 1999-09-27
CA2659664C (fr) 2013-05-07

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