GB2144128A - The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it - Google Patents
The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it Download PDFInfo
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- GB2144128A GB2144128A GB08320576A GB8320576A GB2144128A GB 2144128 A GB2144128 A GB 2144128A GB 08320576 A GB08320576 A GB 08320576A GB 8320576 A GB8320576 A GB 8320576A GB 2144128 A GB2144128 A GB 2144128A
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- Prior art keywords
- eisenin
- carcinostatic
- effect
- tripeptide
- glu
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- VIPNGHPLCAMVEB-UHFFFAOYSA-N 2-[[5-amino-5-oxo-2-[(5-oxopyrrolidine-2-carbonyl)amino]pentanoyl]amino]propanoic acid Chemical compound OC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)C1CCC(=O)N1 VIPNGHPLCAMVEB-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 108010044108 eisenin Proteins 0.000 title claims abstract description 38
- 230000003327 cancerostatic effect Effects 0.000 title claims abstract description 15
- 230000002434 immunopotentiative effect Effects 0.000 title claims abstract description 6
- 239000000203 mixture Substances 0.000 title description 2
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 241000024188 Andala Species 0.000 claims abstract description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract description 5
- 235000004279 alanine Nutrition 0.000 claims abstract description 5
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 4
- 241000243681 Eisenia bicyclis Species 0.000 claims abstract description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract 2
- 235000013922 glutamic acid Nutrition 0.000 claims abstract 2
- 239000004220 glutamic acid Substances 0.000 claims abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 241000230129 Eisenia <Phaeophyceae> Species 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229940102223 injectable solution Drugs 0.000 claims 1
- 241001474374 Blennius Species 0.000 abstract description 3
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 abstract 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 16
- 230000000694 effects Effects 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 6
- 230000001464 adherent effect Effects 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 210000001072 colon Anatomy 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000008055 phosphate buffer solution Substances 0.000 description 4
- 208000006313 Delayed Hypersensitivity Diseases 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 3
- 238000011047 acute toxicity test Methods 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- 230000034994 death Effects 0.000 description 3
- 231100000517 death Toxicity 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 210000004989 spleen cell Anatomy 0.000 description 3
- 241001494479 Pecora Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000001900 immune effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000011640 AKR mouse Methods 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OHJMTUPIZMNBFR-UHFFFAOYSA-N biuret Chemical compound NC(=O)NC(N)=O OHJMTUPIZMNBFR-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000003200 peritoneal cavity Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 208000008732 thymoma Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07K5/0825—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Glp-amino acid; Derivatives thereof
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The tripeptide Eisenin of the general formula L-Pyroglu-L-Glu-I-Ala wherein Pyroglu, Glu and Ala represent pyroglutamic acid, glutamic acid and alanine respectively, found in the seaweed Eisenia bicyclis and obtainable synthetically is a carcinostatic agent having an immunopotentiating carcinostatic effect.
Description
SPECIFICATION
The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it
This invention relates to a carcinostatic agent having an immunopotentiating carcinostatic effect.
According to one aspect of this invention, there is provided the tripeptide Eisenia of the general formula:
L-Pyroglu-L-Glu-L-Aia wherein Pyroglyu, Gly and Ala represent pyroglumatic acid, glumatic acid and alanine respectively, for use in a method for the treatment of cancer as a carcinostatic agent having an im munopotentiating carcinostatic effect.
The peptide of this invention is obtainable by extraction from the seaweed Eisenia bicyclis, and hence is generally formed herein Elsenin, or by synthesis, and acts as a carcinostatic agent having an immunopotentiating carcinostatic effect.
It has recently been found possible to synthesize Eisenin, although previously it was only extracted from the seaweed Eisenia bicyclia. Eisenin forms colourless long needles having a silkthread gloss, shows a positive Biuret reaction, some shrinkage at a melting point of 1 80or and decomposes on melting at 225-226"C, and yields an aqueous solution which is acidic.
It has now been found that Eisenin, whether of natural or synthetic origin, possesses an antitumour effect which is not a direct effect but which is manifested in such a way that the nonspecific immunological ability of the vital body is increased. Eisenin is easy to synthesise because it has a simple tripeptide structure. Furthermore, since Eisenin is crystalline, it may be formed into fine powder, and since it is water soluble, it may be processed into various pharmaceutical forms, preferably in dosage unit form, such as injectable solutine, tablets, ointments and suppositories using pharmaceutically acceptable carriers and excipients commonly employed in pharmaceutical practice.
This invention therefore provides, in a second aspect, a pharmaceutical composition, which comprises the tripeptide Eisenin of the general formula
L-Pyroglu-l-Glu-L-Ala wherein Pyroglu, Glu and Ala represent pyroglumatic acid, glumatic acid and alanine respectively, in association with a pharmacologically acceptable carrier.
For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made by way of illustration only to the accompanying drawings, wherein.
Figure 1 is a graph showing the anti-tumour effect of the tripeptide Eisenin against the isologous allogenic tumor;
Figure 2 is a graph showing the life prolonging effect of the same;
Figure 3 is a graph showing the anti-tumor effect where the T-cells do not participate;
Figure 4 is a graph showing the life prolonging effect of the same; and
Figure 5 is a graph showing the anti-tumor effect of Eisenin against the isologous xenogenic tumor.
These figures will be referred to in the description of the results of tests carried out on animals using Eisenin which will now be reported. In the figures and in the tables which follow, the legends Eisenin Treated and Nontreated mean Eisenin administered and not administered respectively.
(1) Animal Experiments
The animals used as experimental subjects were Balb/C mice and nude mice, and the tumors used were induced by means of Colon (Balb/C Colon cancer) and Sarcoma 1 80.
a. 1 ,000,000 Colon 26 cells were transplanted subscutaneously into Balb/C mice. Eisenin was intraperitoneally administered to the mice at a rate of 5 mg per animal three times every other day. The weight of the tumor taken from the dead mice and the survival rate were determined. The results thereof are set forth in Fig. 1 and Fig. 2.
b. 1,000,000 Colon 26 cells were transplanted subcutaneously into nude mice, Eisenin was intraperitoneally administered to the mice at a rate of 5 mg per animal twice very other day, and the weight of the tumor on death and the survival rate were examined. The results are set forth in Fig. 3 and Fig. 4.
c. 1,000,000 Sarcoma 1 8 cells were transplanted subcutaneously into Balb/C mice, Eisenin was intraperitoneally and orally administered to the mice at a rate of 5 mg per animal three times every other day and the weight of the tumor on death was examined. The results are set forth in Table 5.
d. 106 Sheep red blood cells (S R bc) were intravenously injected into Balb/C mice. Four days later, 108 sheep red cells and phosphate buffer solution (PBS) were subcutaneously injected into the sole of the left foot and at the same time the phosphate buffer solution (PBS) alone was subcutaneousiy injected into the sole of the right foot. A further two days later, the thicknesses of both feet were measured to examine the delayed hyper-sensitivity. The results are set forth in
Table 1.
Table 1 Delayed Hyper-sensitivity
Group 1 T (+). E (+) Group 2 T (+). E (-) Group 3 T (-). E (-) Group 4 T (-). E (+) L R L-R ###x100 L R L-R ###x100 L R L-R ###x100 L R L-R ###x100 1.59 1.57 0.02 1 1.91 1.69 0.22 13 1.90 1.85 0.05 3 2.09 1.86 0.23 12 1.56 1.54 0.02 1 1.83 1.83 0 0 1.95 1.85 0.10 5 2.18 1.98 0.20 10 1.87 1.68 0.19 11 1.91 1.80 0.11 6 2.08 1.92 0.16 8 1.84 1.86 0.02 0 1.95 1.49 0.46 31 1.86 1.67 0.19 11 1.89 1.78 0.11 6 1.93 1.81 0.12 7 1.75 1.67 0.08 5 1.78 1.69 0.09 5 1.91 1.82 0.09 5 0.87 1.72 0.15 9 1.54 1.57 0.03 0 1.96 1.72 0.24 14 2.01 1.78 0.23 13 1.93 1.61 0.32 20 1.58 1.54 0.04 3 1.71 1.52 0.19 13 1.97 1.91 0.06 3 1.87 1.88 0.01 0 1.90 1.65 0.25 15 1.82 1.69 0.13 8 1.99 1.80 0.19 11 1.93 1.87 0.06 3 - - - - 1.83 1.87 0.04 0 1.92 1.82 0.10 5 - - - - - - - 1.77 1.77 0 0 1.92 1.75 0.17 10 - - - Average 8 Average 7 Average 7 Average 8 Notes: 1. T(+) means tumor transplanted; T(-) means tumor not transplanted.
2. E(+) means Eisenin treated; E(-) means Eisenin non-treated.
3. L means the thickness of the left foot (mm);
R means the thickness of the right foot (mm).
(2) In Vitro Assay a. Sensitivity Test
Colon 26 was tissue cultured, and brought into contact with Eisenin at various concentrations for 3 days. Tritium-thymidine, tritium-uridine and tritium-leucine were added to the cuiture medium and the inclusion of these compounds into the cells was examined to determine the inhibition index. Examination of the influence of Eisenin on the syntheses of DNA, RNA and protein traced through these labelled culture supplements yielded results which are set forth in
Table 2.
Table 2 Sensitivity Test
Concentration of Eisenin 1.0 0.1 0.01 0.001 0.0001 Control (mg/ml) Counts per 140430 190120 207474 220010 231236 218622 Minute ln l the Case of 171170 203872 229569 213816 219336 1 220775 Thymidlne* 163554 201151 240628 221170 224786 245962 (CPM) 176167 223845 246273 213017 233612 226495 'Average 170297 198381 238823 218332 229878 221964 1.1. (X) 23 11 8 2 0 I 27088 32774 37043 39415 32836 32553 Counts per Minute in 20903 25271 33211 31675 29585 31801 the Case of 19954 24222 31498 28671 24135 ! 30304 (CPM) 22463 26786 34408 1 33161 1 29958 1 27653 Average 21107 25426 33039 31169 1 30793 , 31553 1.1. (%) 33 19 0 O 2 1 2 I Counts per 6826 13311 12285 13620 12952 14674 Minute in the Case of 6150 12566 11020 14230 11936 11382 Leucine * - 8076 12097 13379 11808 12690 (CPM) 6587 7076 11318 11355 10952 i 14350 Average 6521 11318 14478 13743 12232 13905 1.1. (eh) 53 19 17 1 12 Notes: (1) Inhibition Index (I.I.) is calculated from the
following equation, and.where 1.1. exceeds 75%,
it is judged effective.
CPM (Control) - CPM (Drug)
I.I.= x100 CPM (Control)
(2) measurement was made on a scintillation counter
* tritium labelled b. Cytotoxicity Test 1 5 Mg of Eisenin were intraperitoneally administered to Balb/C mice and starch was administered to a control group. Both test and control mice had implanted, as target cells, BW 5174 (thymoma of AKR mouse) cells. The spleen cells and the intraperitonel cells of sacrificed mice were respectively divided into the adherent cells and the non-adherent cells, and cytoxicity was examined in each case. The results are set forth in Table 3.
Table 3 Cytotoxicity Test
Eisenin Control Ainistered Group SDleer. 24 23 Spleen Cells Total 24E 23E Non-adherent Cells (Natural Killer) Adherent Cells (Macrophage) 10 10 ntaperitoneal Cells Total 24E -BE Total 24E -8E Non-adherent Cells 32% 2% (Natural Killer) t Adherent Cells (Macrophage) 17% -5% Notes: (1) Percent Cytotoxicity (%) in Table 3 is based on
the following equation:
(2) Measurement is made by 51Cr release assay.
(3) Acute Toxicity Test
9 Balb/C mice (average body weight 20 g) were subjected to intraperitoneal administeration of Eisenin. The results obtained are set forth in Table 4.
Table 4 Acute Toxicity Test
No. of Deaths Dosage of 6 7/9 Eisenin (g/kg) 3 1/9 The results of the assays described above may be summarised thus. Table 1 and Table 2 show that in the case of such an isologous allogenic tumor as Colon 26 administered to Balb/C mice, a significant difference between the Eisenin treated group and the Eisenin non-treated group is observed thus indicating an anti-tumor effect for Eisenin; further, as shown in Figs. 3 and 4, similar results have been obtained in the case of the nude mice free from T cells; moreover a similar anti-tumor effect is recognized in the case of such isologuous xenogenic tumor as Sarcoma 180 against Balb/C mice as shown in Fig. 5.On the contrary, as can be seen from the results of the delayed hyper-sensitivity test on Balb/C mice shown in Table 1, there is hardly any difference between the average values for the four groups of combinations corresponding to the presence and absence of tumor transplantation and the presence and absence of treatment with Eisenin. Hence Eisenin has no effect on activation of immunological actions in which T cells participate. The sensitivity test results shown in Table 2, show that the inhibition index (I.l.) is low which indicates no inhibition effect by Eisenin; this means that
Eisenin has no direct effect on tumor cells. In addition, in the results of the cytotoxicity test shown in Table 3, although there is no significant difference in the case of the spleen cells, there is a significant difference in the case of intraperitoneal cells, and as a result, it can be recognized that the immunity imparting effect of Eisenin is mainly due to the activation of the adherent cells and the non-adherent cells in the peritoneal cavity. Furthermore, the acute toxicity test shows the LD50 of Eisenin to be in the vicinity of 5 g/kg. The effective dosage as estimated from the various test results above is suitably about 1 5 mg per 20 g body weight, taking the average body weight of Balb/C mice used in the experiments to be 20 g, that is, about 75 mg/kg. It is believed to be appropriate to administer Eisenin to a subject in this amount in several doses.
Claims (6)
1. The tripeptide Eisenia of the general formula:
L-Pyroglu-L-Glu-L-Ala wherein Pyrogly, Glu and Ala represent pyroglumatic acid, glumatic acid and alanine respectively, for use in a method for the treatment of cancer as a carcinostatic agent having an immunopotentiating carcinostatic effect.
2. The carcinostatic agent of Claim 1 wherein the Eisenin is extracted from Eisenia bicyclis.
3. The carcionstatic agent of Claim 1 wherein the Eisenin is synthetically obtained.
4. A pharmaceutical composition, which comprises tripeptide Eisenin of the general formula
L-Pyroglu-L-Glu-L-Ala wherein Pyroglu, Glu and Ala represent pyroglytamic acid, glutamic acid and alanine respectively, in association with a pharmacologically acceptable carrier.
5. A pharmaceutical composition as claimed in Claim 4, which is made up into a sterile injectable solution.
6. A pharmaceutical composition as claimed in Claim 4, substantially as described herein.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08320576A GB2144128B (en) | 1983-07-29 | 1983-07-29 | The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08320576A GB2144128B (en) | 1983-07-29 | 1983-07-29 | The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8320576D0 GB8320576D0 (en) | 1983-09-01 |
| GB2144128A true GB2144128A (en) | 1985-02-27 |
| GB2144128B GB2144128B (en) | 1986-11-26 |
Family
ID=10546533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08320576A Expired GB2144128B (en) | 1983-07-29 | 1983-07-29 | The tripeptide eisenin and carcinostatic compositions having an immunopotentiating carcinostatic effect which contain it |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2144128B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5445817A (en) * | 1992-08-21 | 1995-08-29 | The United States Of America As Represented By The Department Of Health And Human Services | Pertussis toxin used as a carrier protein with non-charged saccharides in conjugate vaccines |
| US7335644B2 (en) * | 2003-03-31 | 2008-02-26 | Council Of Scientific And Industrial Research | Anti-hypertensive molecules and process for preparation thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1374379A (en) * | 1972-03-14 | 1974-11-20 | Takeda Chemical Industries Ltd | Process for producing polypeptides |
-
1983
- 1983-07-29 GB GB08320576A patent/GB2144128B/en not_active Expired
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1374379A (en) * | 1972-03-14 | 1974-11-20 | Takeda Chemical Industries Ltd | Process for producing polypeptides |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5445817A (en) * | 1992-08-21 | 1995-08-29 | The United States Of America As Represented By The Department Of Health And Human Services | Pertussis toxin used as a carrier protein with non-charged saccharides in conjugate vaccines |
| US7335644B2 (en) * | 2003-03-31 | 2008-02-26 | Council Of Scientific And Industrial Research | Anti-hypertensive molecules and process for preparation thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8320576D0 (en) | 1983-09-01 |
| GB2144128B (en) | 1986-11-26 |
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| PCNP | Patent ceased through non-payment of renewal fee |