JPS6121452B2 - - Google Patents
Info
- Publication number
- JPS6121452B2 JPS6121452B2 JP12603478A JP12603478A JPS6121452B2 JP S6121452 B2 JPS6121452 B2 JP S6121452B2 JP 12603478 A JP12603478 A JP 12603478A JP 12603478 A JP12603478 A JP 12603478A JP S6121452 B2 JPS6121452 B2 JP S6121452B2
- Authority
- JP
- Japan
- Prior art keywords
- tml
- anemia
- mice
- cyclophosphoamide
- antitumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000000203 mixture Substances 0.000 claims description 36
- 208000007502 anemia Diseases 0.000 claims description 34
- 230000000259 anti-tumor effect Effects 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 14
- 229960004528 vincristine Drugs 0.000 claims description 11
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 11
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 11
- MXNRLFUSFKVQSK-QMMMGPOBSA-O N(6),N(6),N(6)-trimethyl-L-lysine Chemical compound C[N+](C)(C)CCCC[C@H]([NH3+])C([O-])=O MXNRLFUSFKVQSK-QMMMGPOBSA-O 0.000 claims description 7
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 3
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 claims description 3
- 229960003048 vinblastine Drugs 0.000 claims description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 3
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 26
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007799 cork Substances 0.000 description 5
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- 210000004881 tumor cell Anatomy 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 229940000425 combination drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 4
- 229960002110 vincristine sulfate Drugs 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940066206 glutamate 500 mg Drugs 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 231100001018 bone marrow damage Toxicity 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- -1 hydrogen halides Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZSZKPSDIZALKKQ-UHFFFAOYSA-N O=P1OC=CC=C1 Chemical compound O=P1OC=CC=C1 ZSZKPSDIZALKKQ-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
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- 238000004163 cytometry Methods 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000000254 damaging effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 210000002149 gonad Anatomy 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- 210000005259 peripheral blood Anatomy 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
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- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
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INDUSTRIAL APPLICATION FIELD The present invention relates to a novel antitumor anemia composition. More specifically, the present invention provides the use of one or more known cytostatic embolic agents.
The present invention relates to an anti-tumor anemia composition in which side effects are reduced by combining N-trimethyllysine (hereinafter abbreviated as "TML") to an anti-tumor anemia agent or anti-tumor anemia agent. The parent pharmaceutical composition of the present invention has cellular embolic activity, the degree of which corresponds to or is higher than the amount of antineoplastic anemia agent present in said composition. On the other hand, the composition has the characteristics that there is almost no side effect of bone marrow damage seen with known cell embolization agents, and even if accidental damage occurs, recovery is quick. BACKGROUND OF THE INVENTION All cellular embolic agents or antineoplastic anemic agents known to have strong inhibitory effects on tumor cell proliferation have been used in bone marrow and other intensively proliferating tissues (such as the small intestinal mucosa and gonads). It is known that chemotherapy for malignant tumors using it is severely limited because it exhibits toxic side effects to cells. In particular, it severely damages the hematopoietic system (haemopoeticus) and the immune system, so this side effect often ultimately leads to the death of the patient. Problems to be Solved by the Invention An object of the present invention is to provide an anti-tumor anemia composition that reduces the toxicity of the anti-tumor anemia agent and accelerates recovery from damage caused by this toxicity. Means to Solve the Problem It has been found that the toxicity of anti-tumor anemia agents is significantly reduced when administered to living organisms in combination with TML. This finding is very surprising considering that TML has been shown to promote tumor growth [Szende et al., Neoplasma, 17, 4, 433-434]
(1970)]. The present invention is useful for tumor growth and other tissues, e.g.
When TML, which is known to accelerate bone marrow proliferation, is administered in combination with an antineoplastic anemia agent, cellular embolic activity is substantially unchanged or enhanced; based on the finding that the toxicity of Many natural, semi-synthetic or synthetic antineoplastic anemia agents can be used in the compositions of the invention. Representative examples of these drugs are shown below. naturally occurring ones such as vinblastine, vincristine and lyurosine; and 1,4-di-(2-methylsulfophenyloxyelamino)-1,4-didesoxyerythrite dimethylsulfonate (hereinafter referred to as this compound). teeth
(abbreviated as ``ritosulfanum''), 2[bis-(2-chloroethyl)]
-amino]-tetrahydro-2H-1,3,2-
Synthetic anti-tumor anemia agents such as oxaphosphorine-2-oxide (cyclophosphoamide) and N-formyllieurosine represented by the following formula. The above compounds are merely examples and are not intended to limit the range of known antineoplastic anemia agents that may be used in the compositions of the present invention. In carrying out the pharmaceutical composition according to the present invention,
It is common to use antineoplastic anemia agents in the form of their pharmaceutically acceptable salts. The salt can be an acid addition salt or a quaternary salt. The salt form provides good and rapid absorption and provides a stable form of the free base, which is sensitive to heat and light and prone to decomposition, such as diindole alkaloids. Although TML can be used in either racemic or optically active form, according to our experiments,
L-TML was found to be the most effective.
TML is advantageously used in the form of a pharmaceutically acceptable acid addition salt. Said acid addition salts may be acid salts containing asymmetric or organic acids, such as hydrogen halides such as hydrogen chloride, hydrogen bromide, or hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, maleic acid, fumaric acid, citric acid. , malic acid, tartaric acid, ascorbic acid, aspartic acid, glutamic acid, etc. Preferably, the hydrochloride, monofumarate, acetate or ascorbic acid addition salt of the TML is used. Monoglutamate of TML (TML.Glu) can be used with particular advantage. Salts of TML formed with one or more molecules of fumaric acid, aspartic acid or glutamic acid are new, and the preparation method is described in Japanese Patent Publication No. 58340/1983. In order to demonstrate the pharmaceutically useful properties of the compositions of the invention, the adverse effects of various anti-tumor anemia agents on blood tests were compared with that of compositions in which TML was also present. The weight of each test was 25g.
CBA of 35 female mice was carried out as follows: 7 groups of 5 mice each (group a)
Divided into g). The following treatments were administered to the above individual groups: a. No treatment; b. One dose of 30 mg/Kg of ritosulfanam; c. 30 mg/Kg of ritosulfanum and 20 mg/Kg of TML.
Kg combination once administered; d cyclophosphoamide 50 mg/Kg once administered; e cyclophosphoamide 50 mg/Kg and TML20
mg/Kg combination once administered; f Vincristine 2mg/Kg once administered; g Biwacristine 2mg/Kg and TML 20mg/Kg
The previous season's drug was administered intraperitoneally. In some cases
TML was used in its hydrochloride form. The mg/Kg value indicates the number of mg per kg of the test animal's body weight. The day before the treatment (indicated by 0 in the table below) and the subsequent 8 days, the mice were subjected to differential identification and quantitative peripheral blood cytometry after 16 hours of food deprivation at the same time once a day. The results obtained are shown in Tables 1 to 3 below.
and shown in FIGS. 1 to 6. Table 1 and Figures 1 and 2 show the results obtained with litosulfanum;
Table 2 and Figures 3 and 4 relate to treatment with cyclophosphoamide, and Table 3 and Figures 5 and 6 relate to treatment with cyclophosphoamide.
The figure shows the results of treatment with vincristine. In the figure, the dotted line I shows the changes in blood cell count of mice treated with various anti-tumor anemia agents alone, and the solid line shows the results obtained with the combination of various anti-tumor anemia agents and TML. Changes in the number of red blood cells (RBC) during the 8-day experiment are shown in figures 1, 3 and 5 in millions, and changes in the number of white blood cells (WBC) are shown in figures 2 and 5 in units of thousands. 4 and 6
Shown in the figure.
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ãã§ããã[Table] From Tables 1 to 3 and Figures 1 to 6, the following unexpected benefits of the composition of the present invention were clearly observed: reductions are observed, but their magnitude always remains below the amount of reduction induced when known antineoplastic anemia agents are administered alone. Furthermore, regeneration can be observed on the 3rd or 4th day after treatment.
The number of red blood cells then approaches the control value (in the case of cyclophosphoamide this value is already equal to the control value on the fourth day). 2 In the cases of cyclophosphoamide + TML and ritosulfanum + TML, the number of white blood cells decreased on the second day after treatment, but the recovery was relatively quick, and the number of white blood cells returned to normal values 8 days after treatment. reach 3. When administering the combination of biwacristine and TML, the decline in red and white blood cell counts is significantly less than in mice treated with vincristine alone. Research on blood cell counting is done using the methods shown below.
TML-monoglutamate was also performed; a. Each of 12 healthy CFLP female mice (LATI) (2 weeks old, weighing 20-22 g) received 30 mg/kg body weight of lithosulfanum.
It was administered once intraperitoneally. Half of these mice received TML-monoglutamate 100 mg/Kg (body weight)
was administered intraperitoneally. After administration, 2, 4, 7,
Differential blood cell count and quantitative blood cell count were performed on days 10 and 17. Each measurement was performed on three mice at 3:00 pm when the stomach was empty. The results obtained are shown in Table 4 below. It is clear that red blood cell numbers and white blood cell numbers are likewise advantageously influenced when treated with the combination according to the invention. The combination has virtually no effect on the lymphocyte:granulocyte ratio: b 10 healthy female mice with CFLP (LATI) aged 8 weeks (each weighing between 20 and 22
g) 300 mg of cyclophosphoamide per kg body weight was administered once intraperitoneally to each patient. Half of the mice were given cyclophosphoamide and
TML-monoglutamate was treated intraperitoneally at 100 mg/Kg body weight. Quantitative blood cell counts were performed on days 4 and 10 after treatment. The results obtained are listed in Table 4. It is clear that the number of red blood cells in the group treated with the combination is higher than in the control group treated with cyclophosphoamide alone.
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ãã[Table] Since the toxic effects of antineoplastic anemia agents, which are often fatal, are substantially due to bone marrow damaging effects, the degree of reduction in toxicity of the composition of the present invention can be compared with that of various antineoplastic anemia agents. Toxicity and LD5 values were compared. Three known antineoplastic anemia agents, namely ritosulfanum, cyclophosphoamide and vincristine, were each compared with corresponding combination compositions also containing TML-salts. The study was carried out on DBA female mice, each weighing 25 g. The test mice were divided into groups of five mice each, and each group was tested by administering the test compound or composition once intraperitoneally.
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ããTable: The number of surviving mice was recorded during the first 10 days and 30 days after treatment. The results obtained are shown in Table 5.
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åŸãããçµæãäžèšè¡šïŒã«ç€ºãã[Table] From the above data, when mice were treated with the combination of cyclophosphoamide + TML and vincristine + TML, the mortality rate of mice was substantially reduced and It is clear that mortality rates are also reduced. It can be seen that the composition of the present invention significantly suppresses the toxic side effects of cyclophosphoamide or vincristine. According to our experiments, ritosulfanum and
The combination drug consisting of TML did not reduce mortality or show any protective effect compared to ritosulfanam alone. The effect of the composition on tumor cell proliferation was also tested. The study was conducted as follows: 155 female CFLP mice were injected intraperitoneally with Ehrlichi's ascites carcinoma (10 6 cells per mouse). On the 10th day after treatment, the test mice were divided into groups and received the following treatments: a 30 mice received saline alone (control); b 25 mice received TML 20 mg/Kg once intraperitoneally; c Cyclophosphoamide 20 mg/Kg was administered intraperitoneally once to 25 mice; d Ritosulfanam 20 mg/Kg was administered once intraperitoneally to 25 mice; e Cyclophosphoamide 20 mg/Kg and TML 20 mg/kg were administered to 25 mice. Kg combination drug administered intraperitoneally once; f Ritosulfanum 20 mg/Kg and
A combination of TML 20 mg/Kg was administered intraperitoneally once. In the above list, the mg/Kg value indicates the number of mg of the test compound per kg of mouse body weight. Three mice were sacrificed daily for 4 consecutive days after treatment and the total number of tumor cells present was determined. The results obtained are shown in Table 6 below.
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äžã«é©ããçµæç©ãã€ãã€ããTable: From the above data it is clear that the combination of TML and ritosulfanam reduces tumor cell numbers substantially more than ritosulfanam alone. On the other hand, in the case of the combination consisting of cyclophosphoamide and TML, a slight increase in the number of tumor cells could be observed, but this was however negligible. The above experiments have shown that the composition of the present invention reduces the undesirable side effects of anti-tumor anemia agents known in the art. The combination drug can eliminate or reduce bone marrow damage, and as a result, the dosage of anti-tumor anemia agent can be increased. The actual amount of antineoplastic anemia agent administered in the compositions of the present invention is highly dependent on the properties of the agent chosen. For example, the daily dosage of ritosulfanam is 20 to 40 mg per person, the amount of cyclophosphoamide is 10 to 100 mg per person, and the amount of vincristine is 0.1 to 10 mg, preferably 1 to 5 mg per person. TML is preferably used in the form of its hydrochloride or monoglutamate salt.
The most preferred compounds are L-N-trimethyllysine hydrochloride and monoglumate, the exact dosage of which depends on the method of administration, the condition of the patient being treated, the severity of the symptoms and other similar factors;
The dose is 5 to 50 mg, preferably 20 to 40 mg per person per day. The compositions of the invention are preferably formulated in two different forms: a potent unit dose containing the vehicle and a high dose of the antineoplastic agent, and a dilute composition containing the vehicle. N of the antitumor anemia agent in the composition of the present invention
-The ratio to trimethyllysine can vary between 1:1 and 1:100 depending on the dosage of the drug chosen. In the compositions containing vincristine, vinblastine and N-formyl-lyurosine, the ratio of said cellular embolic agent to N-trimethyllysine is between 1:10 and 1:100, and in other compositions it is between 1:10 and 1:100. Varies between :1 and 1:10. Examples Preferred specific examples of the composition of the present invention and the method for producing the same will be explained. However, these examples are not intended to limit the invention. Example 1 TML-glutamate 500mg, N,N-bis(2
-chloroethyl)-tetrahydro-2H-1,
3,2-oxazophosphorine-2-amine-2-
500 mg of oxide (cyclophosphoamide) and 200 mg of protein-free gelatin were dissolved in distilled water for injection. The solution was adjusted to 35.0 ml and then passed under sterile conditions to remove bacteria. Fill a 10g ampoule with 3.5ml of the obtained sterilizing solution, freeze the contents of this ampoule at -60â for 20 hours,
Freeze-drying at -45°C in vacuum (25mmHg) and subsequent drying at +20°C for 10 hours. The ampoule was sealed with a sterile rubber cork stopper and placed in an aluminum cap.
The composition thus prepared contained 50 mg of TML-glutamate, 50 mg of cyclophosphoamide, and 20 mg of gelatin, lyophilized, per dry ampule sealed with a rubber cork stopper. The contents of the ampoule were dissolved in sterile distilled water or isotonic sodium chloride or glucose solution to a total volume of 10 ml before use for injection. Example 2 TML-glutamate 500 mg, 1,4-di(2
-methylsulfonyloxyethylamino)-1,
4-Didesoxyerythrite dimethyl sulfonate (ritosulfanum) 300 mg and gelatin 400
mg was dissolved in distilled water for injection. The volume of this solution is
A volume of 10.0 ml was prepared and further processed as described in Example 1. However, each ampoule was filled with 1 ml portions for freeze-drying. The resulting composition contained 50 mg TML-glutamate, 30 mg ritosulfanum and 40 mg gelatin in lyophilized form per dry ampule sealed with a rubber cork stopper. Example 3 TML-glutamate 500 mg, vincristine sulfate 5 mg and gelatin 200 in distilled water for injection
mg and make the final volume of this solution 10.0ml
It was adjusted to Further operations as described in Example 2 were carried out.
This composition contains 50 mg TML-glutamate, 0.5 mg vincristine sulfate and 20 mg gelatin per dry ampule sealed with a rubber cork stopper.
contained in lyophilized form. Example 4 500 mg of TML-glutamate, 5 mg of vincristine sulfate, 80 mg of polyvinylpyrrolidone, and 365 mg of mannitrate were dissolved in distilled water for injection, and the final volume of the solution was adjusted to 10.0 ml. Further operations as described in Example 2 were carried out. This composition per dry bottle sealed with a rubber cork stopper.
TML - 50mg glutamate, 0.5mg vincristine sulfate, 8mg polyvinylpyrrolidone
mg and mannite in lyophilized form. Example 5 50 mg of TML-monoglutamate, 50 mg of cyclophosphoamide, 1 mg of colloidal silicic acid, 1 mg of magnesium stearate, 2 mg of talc and 56 mg of potato starch were mixed in dry powder form to obtain a homogeneous mixture. The resulting 160 mg homogeneous powder mixture was then filled into hard gelatin capsules to create a composition suitable for oral administration.
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The accompanying drawings show changes in the numbers of red blood cells and white blood cells observed when mice were administered various antitumor anemia agents. Figures 1 and 2 show changes in the numbers of red blood cells and white blood cells when ritosulfanum was administered, respectively. Figures 3 and 4
Each of the figures shows similar results when cyclophosphoamide was administered to mice, and each of Figures 5 and 6 shows similar results with vincristine. In the figure, the dotted line shows the results obtained only from the antitumor anemia drug used, and the solid line shows the results obtained from the combination drug in which the drug was combined with TML.
Claims (1)
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çµæç©ã ïŒ æè «ç貧è¡å€ãšããŠãã³ã¯ãªã¹ãã³ããã³ã
ã©ã¹ãã³ãããã¯ïŒ®âãã«ãã«ãªãŠãŠãã·ã³ãå«
ãã§ãªãç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®çµæç©ã ïŒ æè «çæ§è²§è¡å€ã®ïŒ®ãâããªã¡ãã«ãªãžã³ã
ããã¯ãã®å¡©ã«å¯Ÿããå²åãïŒïŒ10åã³ïŒïŒ100
ã®éã«ããç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®çµæç©ã ïŒ åèšïŒ®ãâããªã¡ãã«ãªãžã³å¡©ãšããŠïŒ¬â
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ãªãç¹èš±è«æ±ã®ç¯å²ç¬¬ïŒé èšèŒã®çµæç©ã[Scope of Claims] 1. An antitumor anemia composition comprising a combination of at least one antitumor anemia agent and N-trimethyllysine or a pharmaceutically acceptable salt thereof. 2 N,N-bis(2-chloroethyl)-tetrahydro 2H-1,3,2 as an antitumor anemia agent
2. The composition according to claim 1, which comprises oxazophosphorine-2-amine-2-oxide (cyclophosphoamide). 3. The composition according to claim 1, comprising 1,4-di-(2-methylsulfonyloxyethylamino)-1,4-didesoxyerilide dimethylsulfonate (ritosulfanum) as an antitumor anemia agent. thing. 4. The composition according to claim 2 or 3, wherein the ratio of the antitumor anemia agent to N-trimethyllysine or its salt is between 1:1 and 1:10. 5. The composition according to claim 1, which comprises vincristine, vinblastine, or N-formyllieurosine as an antitumor anemia agent. 6 The ratio of antitumor anemia agent to N-trimethyllysine or its salt is 1:10 and 1:100.
A composition according to claim 5 between. 7 LâN as the N-trimethyllysine salt
The composition according to claim 1, comprising: -trimethyllysine monoglutamate.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HURI001649 | 1977-10-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5470429A JPS5470429A (en) | 1979-06-06 |
JPS6121452B2 true JPS6121452B2 (en) | 1986-05-27 |
Family
ID=11001126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12603478A Granted JPS5470429A (en) | 1977-10-13 | 1978-10-13 | Medical composition |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5470429A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63186750U (en) * | 1987-05-26 | 1988-11-30 | ||
JPH02162096A (en) * | 1988-12-15 | 1990-06-21 | Cmk Corp | Method and device for sticking pad for screen frame |
-
1978
- 1978-10-13 JP JP12603478A patent/JPS5470429A/en active Granted
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63186750U (en) * | 1987-05-26 | 1988-11-30 | ||
JPH02162096A (en) * | 1988-12-15 | 1990-06-21 | Cmk Corp | Method and device for sticking pad for screen frame |
Also Published As
Publication number | Publication date |
---|---|
JPS5470429A (en) | 1979-06-06 |
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