IL37244A - Labelled diagnostic compositions containing polysaccharides - Google Patents
Labelled diagnostic compositions containing polysaccharidesInfo
- Publication number
- IL37244A IL37244A IL37244A IL3724471A IL37244A IL 37244 A IL37244 A IL 37244A IL 37244 A IL37244 A IL 37244A IL 3724471 A IL3724471 A IL 3724471A IL 37244 A IL37244 A IL 37244A
- Authority
- IL
- Israel
- Prior art keywords
- labelling agent
- molecular weight
- groups per
- sulfated
- diagnostically effective
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 110
- 229920001282 polysaccharide Polymers 0.000 title claims description 28
- 239000005017 polysaccharide Substances 0.000 title claims description 28
- 150000004676 glycans Chemical class 0.000 title claims 9
- 238000002372 labelling Methods 0.000 claims description 47
- 239000003795 chemical substances by application Substances 0.000 claims description 44
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 41
- 210000004877 mucosa Anatomy 0.000 claims description 36
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 34
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 claims description 33
- 230000002496 gastric effect Effects 0.000 claims description 25
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 25
- 229920000945 Amylopectin Polymers 0.000 claims description 24
- 229920001592 potato starch Polymers 0.000 claims description 21
- -1 alkali metal salt Chemical class 0.000 claims description 20
- 230000002159 abnormal effect Effects 0.000 claims description 19
- 229910052783 alkali metal Inorganic materials 0.000 claims description 16
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical group [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 claims description 15
- 229940056501 technetium 99m Drugs 0.000 claims description 15
- 238000001514 detection method Methods 0.000 claims description 14
- 230000005855 radiation Effects 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 11
- 159000000000 sodium salts Chemical class 0.000 claims description 11
- 238000003384 imaging method Methods 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 8
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical group [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 claims description 3
- 229940044173 iodine-125 Drugs 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000001483 monosaccharide substituent group Chemical group 0.000 claims 3
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical group N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims 2
- ZCYVEMRRCGMTRW-YPZZEJLDSA-N iodine-125 Chemical group [125I] ZCYVEMRRCGMTRW-YPZZEJLDSA-N 0.000 claims 2
- 239000000243 solution Substances 0.000 description 43
- LFORPQYIKMHOCK-UHFFFAOYSA-M sodium;3-methylbutyl sulfate Chemical compound [Na+].CC(C)CCOS([O-])(=O)=O LFORPQYIKMHOCK-UHFFFAOYSA-M 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 150000004804 polysaccharides Chemical class 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000975 dye Substances 0.000 description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 208000025865 Ulcer Diseases 0.000 description 11
- 229910052788 barium Inorganic materials 0.000 description 10
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 10
- 238000000502 dialysis Methods 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 231100000397 ulcer Toxicity 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 238000007792 addition Methods 0.000 description 8
- 235000010323 ascorbic acid Nutrition 0.000 description 8
- 229960005070 ascorbic acid Drugs 0.000 description 8
- 239000011668 ascorbic acid Substances 0.000 description 8
- 238000012800 visualization Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 210000002784 stomach Anatomy 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 229940032296 ferric chloride Drugs 0.000 description 6
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229920005654 Sephadex Polymers 0.000 description 4
- 239000012507 Sephadex™ Substances 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000007107 Stomach Ulcer Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 235000012054 meals Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 235000014441 Prunus serotina Nutrition 0.000 description 2
- 241001412173 Rubus canescens Species 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000007958 cherry flavor Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
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- 239000010514 hydrogenated cottonseed oil Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 230000031700 light absorption Effects 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
- SHXOKQKTZJXHHR-UHFFFAOYSA-N n,n-diethyl-5-iminobenzo[a]phenoxazin-9-amine;hydrochloride Chemical compound [Cl-].C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=[NH2+])C2=C1 SHXOKQKTZJXHHR-UHFFFAOYSA-N 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
- 238000011002 quantification Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960001479 tosylchloramide sodium Drugs 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PVPBBTJXIKFICP-UHFFFAOYSA-N (7-aminophenothiazin-3-ylidene)azanium;chloride Chemical compound [Cl-].C1=CC(=[NH2+])C=C2SC3=CC(N)=CC=C3N=C21 PVPBBTJXIKFICP-UHFFFAOYSA-N 0.000 description 1
- GESUXCLRERRNSQ-UHFFFAOYSA-N 1-benzhydrylnaphthalene Chemical class C1=CC=CC=C1C(C=1C2=CC=CC=C2C=CC=1)C1=CC=CC=C1 GESUXCLRERRNSQ-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- OALHHIHQOFIMEF-UHFFFAOYSA-N 3',6'-dihydroxy-2',4',5',7'-tetraiodo-3h-spiro[2-benzofuran-1,9'-xanthene]-3-one Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 OALHHIHQOFIMEF-UHFFFAOYSA-N 0.000 description 1
- DDGMDTGNGDOUPX-UHFFFAOYSA-N 7-methyliminophenothiazin-3-amine;hydrochloride Chemical compound [Cl-].C1=C(N)C=C2SC3=CC(=[NH+]C)C=CC3=NC2=C1 DDGMDTGNGDOUPX-UHFFFAOYSA-N 0.000 description 1
- VZCCTDLWCKUBGD-UHFFFAOYSA-N 8-[[4-(dimethylamino)phenyl]diazenyl]-10-phenylphenazin-10-ium-2-amine;chloride Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1N=NC1=CC=C(N=C2C(C=C(N)C=C2)=[N+]2C=3C=CC=CC=3)C2=C1 VZCCTDLWCKUBGD-UHFFFAOYSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- JUQPZRLQQYSMEQ-UHFFFAOYSA-N CI Basic red 9 Chemical compound [Cl-].C1=CC(N)=CC=C1C(C=1C=CC(N)=CC=1)=C1C=CC(=[NH2+])C=C1 JUQPZRLQQYSMEQ-UHFFFAOYSA-N 0.000 description 1
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- BFMYDTVEBKDAKJ-UHFFFAOYSA-L disodium;(2',7'-dibromo-3',6'-dioxido-3-oxospiro[2-benzofuran-1,9'-xanthene]-4'-yl)mercury;hydrate Chemical compound O.[Na+].[Na+].O1C(=O)C2=CC=CC=C2C21C1=CC(Br)=C([O-])C([Hg])=C1OC1=C2C=C(Br)C([O-])=C1 BFMYDTVEBKDAKJ-UHFFFAOYSA-L 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- KBQHZAAAGSGFKK-VENIDDJXSA-N dysprosium-157 Chemical compound [157Dy] KBQHZAAAGSGFKK-VENIDDJXSA-N 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- IDAQSADEMXDTKN-UHFFFAOYSA-L ethyl green Chemical compound [Cl-].[Br-].C1=CC([N+](C)(C)CC)=CC=C1C(C=1C=CC(=CC=1)N(C)C)=C1C=CC(=[N+](C)C)C=C1 IDAQSADEMXDTKN-UHFFFAOYSA-L 0.000 description 1
- 239000001761 ethyl methyl cellulose Substances 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 229940044631 ferric chloride hexahydrate Drugs 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 229910001448 ferrous ion Inorganic materials 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000989 food dye Substances 0.000 description 1
- 229940006110 gallium-67 Drugs 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000010749 gastric carcinoma Diseases 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- PCHJSUWPFVWCPO-OUBTZVSYSA-N gold-198 Chemical compound [198Au] PCHJSUWPFVWCPO-OUBTZVSYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- XMBWDFGMSWQBCA-BKFZFHPZSA-N iodane Chemical compound [132IH] XMBWDFGMSWQBCA-BKFZFHPZSA-N 0.000 description 1
- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940107698 malachite green Drugs 0.000 description 1
- FDZZZRQASAIRJF-UHFFFAOYSA-M malachite green Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC=CC=1)=C1C=CC(=[N+](C)C)C=C1 FDZZZRQASAIRJF-UHFFFAOYSA-M 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- QSHDDOUJBYECFT-AHCXROLUSA-N mercury-197 Chemical compound [197Hg] QSHDDOUJBYECFT-AHCXROLUSA-N 0.000 description 1
- QSHDDOUJBYECFT-NJFSPNSNSA-N mercury-203 Chemical compound [203Hg] QSHDDOUJBYECFT-NJFSPNSNSA-N 0.000 description 1
- 230000003458 metachromatic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- YYGBVRCTHASBKD-UHFFFAOYSA-M methylene green Chemical compound [Cl-].C1=CC(N(C)C)=C([N+]([O-])=O)C2=[S+]C3=CC(N(C)C)=CC=C3N=C21 YYGBVRCTHASBKD-UHFFFAOYSA-M 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical group 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CXZRDVVUVDYSCQ-UHFFFAOYSA-M pyronin B Chemical compound [Cl-].C1=CC(=[N+](CC)CC)C=C2OC3=CC(N(CC)CC)=CC=C3C=C21 CXZRDVVUVDYSCQ-UHFFFAOYSA-M 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- KZUNJOHGWZRPMI-AKLPVKDBSA-N samarium-153 Chemical compound [153Sm] KZUNJOHGWZRPMI-AKLPVKDBSA-N 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YCUVUDODLRLVIC-VPHDGDOJSA-N sudan black b Chemical compound C1=CC(=C23)NC(C)(C)NC2=CC=CC3=C1\N=N\C(C1=CC=CC=C11)=CC=C1\N=N\C1=CC=CC=C1 YCUVUDODLRLVIC-VPHDGDOJSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical compound [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229940117972 triolein Drugs 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- JEVGKYBUANQAKG-UHFFFAOYSA-N victoria blue R Chemical compound [Cl-].C12=CC=CC=C2C(=[NH+]CC)C=CC1=C(C=1C=CC(=CC=1)N(C)C)C1=CC=C(N(C)C)C=C1 JEVGKYBUANQAKG-UHFFFAOYSA-N 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- NAWDYIZEMPQZHO-AHCXROLUSA-N ytterbium-169 Chemical compound [169Yb] NAWDYIZEMPQZHO-AHCXROLUSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1282—Devices used in vivo and carrying the radioactive therapeutic or diagnostic agent, therapeutic or in vivo diagnostic kits, stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Heart & Thoracic Surgery (AREA)
- Dispersion Chemistry (AREA)
- Biodiversity & Conservation Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
37244/2 o* *aan finals'? o»aaieb Ο'ΤΪΟΠ Labelled diagnostic compositions containing polysacbarides \ G.D. 3MKLB & CO LABELLED COMPOSITIONS The detection and accurate measurement of abnormal mucosa (i..e_. mucous membrane), in mammals, especially humans, can be an invaluable aid to the medical practitioner in the diagnosis of a great number of disorders associated with the presence of such abnormal mucosa. Illustrative of such disorders are gastric and duodenal ulcers, carcinoma, benign lesions comprehending those with diffuse mucosal changes frequently interpreted as gastritis, oesophagitis, pre-ulcer, ulcerated colitis and similar pathological conditions. In the past, the most common method employed for the diagnosis of ulcers and stomach carcinoma was barium radiology including the familiar barium meal followed by X-ray examination.
Unfortunately the barium method suffers from several drawbacks including the well known dangers of X-ray examination, and inaccuracy and inconvenience in usage. For example, the barium method is not susceptible of visualizing ulcers unless gross changes have occured in the mucosa and the ulcerated area is susceptible of planar visualization. Consequently, it is difficult to detect gastric ulcers because it is frequently impossible to assess the dimensional aspects of the depth and angles of the abnormal area upon barium radiological examination. Conversely, in certain subjects it has been found that barium radiology has shown abnormally deep rugal folds, particularly on the greater curvature of the body of the stomach, supposedly indicative of gastric ulcers, whereas the presence of ulceration could be confidently excluded from the areas sus ected u on a ro riate fibrosco ic examination, particularly utilizing as a diagnostic aid the labelled composition of this invention. In the case of X-ray examination of the type employed in the barium meal method, i.e. where the radiological source of energy is outside the subject, in contradistinction to the source being within the subject as hereafter described, there is the ever present danger of excess radiation which can be harmful to both the radiological technician and the subject, being particularly acute in the case of pregnant patients.
The object of this invention is to provide a safe, simplified, highly accurate, and convenient method for the detection in mammals of abnormal mucosa, particularly of the gastrointestinal variety, as well as a labelled composition suitable for use in this method. According to this method, a labelled polysaccharide composition, which binds strongly and differentially to mucosa, is administered to the mammal and timely subsequent examination of the mammal by a suitable visualizing technique provides definitive detection and quantification of abnormal mucosa present in the tested area.
Polysaccharides suitable for the formulation of the composition of this invention are anionic polysaccharides having a high charge density, conveniently of the order of 0.97 X 10~6 to 0.50 X 10"6 ZOI A°)3 (negative charge per Angstrom3) which characteristically bind differentially to mucosa and include sulfated and phosphorylated polysaccharides having a molecular weight of at least 1,000,000.
Among such sulfated polysaccharides are sulfated starch, sulfated mequite £um, sulfated psyllium seed, sulfated amylopectin, sulfated cellulose, sulfated amylose and rides having specifically desirable application in this invention are those containing one to two sulfate groups per monosaccharide unit, for example per glucose unit in the case of starch, starch fractions, and particularly corn and potato amylopectin. It has been observed that polysaccharides lacking a high charge density lack the ability of the polysaccharide component of the instant composition to differentially and strongly bind to mucosa, particularly without causing deleterious side effects to the subject, for example degraded carrageenin. Particularly preferred sulfated polysaccharides for use in this invention are the alkali metal, and especially sodium, salts of sulfated potato starch amylopectin, said alkali metal salts possessing about 1-1.8 sulfate groups per glucose unit and characterized also by a molecular weight of about 1-30 X 10?. (The expression "molecular weight" as used in this application refers to weight average molecular weight.) A very preferred polysaccharide is the sodium salt of sulfated potato starch amylopectin possessing substan-tially 1.6 sulfate groups per glucose unit and characterized by a molecular weight of about 6.3 10?, which material is known by the non-proprietary name "sodium amylosulfate" . The preparation of the aforementioned alkali metal salts of sulfated potato starch amylopectin and in particular sodium amylosulfate, are described in United States Patent No. 3,271,388, issued September 6, 1966. The latter sulfated polysaccharides are preferred components of the labelled composition of this invention because of their superior binding properties which promote not only their uniform binding with the labelling si n to mucosa which most importantly enables the resultant labelled composition of this invention to be characterized by this same advantageous binding property permitting optimal physiological and diagnostic results. Physiologically, for example, the labelled composition of this invention is not only safe, in view of its low toxicity and negligible absorption from the gastrointestinal tract, but simultaneously provides therapeutic treatment for the abnormal area as well as amazingly accurate visualization of the abnormality.
The choice of an appropriate labelling agent for use in the Instant composition is dependent upon numerous factors which affect the diagnostic effectiveness and physiological suitability of the labelling agent and the ultimate composition. Moreover, each of these critical factors must be coordinated with the selection of polysaccharide and visualizing instrument which is to be employed. Consequently, considering the magnitude and complexity of choices available, the safe, simplified, highly accurate and convenient labelled composition provided by this invention is most unexpected against the background of known materials which have been employed for such purposes previously. Throughout this application the expression "diagnostically effective" as applied to the labelling agent of the instant composition shall refer to that combination of properties, discussed with particularity hereinafter with respect to both the dye and the radionuclide labelling agents, which enable the agent, as well as the composition in which it is incorporated, to permit definitive detection and quantification of mucosal of the abnormality by the imaging instrument employed.
The expression "physiologically suitable" as applied to the labelling agent of the instant composition refers to those properties discussed with particularity hereinafter with respect to both the dye and radionuclide labelling agents, which enable the agent, as well as the composition in which it is incorporated to produce a diagnos-tically effective response while assuring patient and technician safety. It has been found that in view of their respective properties, certain radionuclides and certain dyes can meet the stringent requirements of "diagnostically effective" and "physiologically suitable" and consequently constitute the appropriate labelling agents of the instant composition.
Specifically, in the selection of an appropriate dye for use in this invention from the standpoint of diagnostic effectiveness, one must ascertain that they exhibit strong light absorption and a capacity to provide the desired contrast. Suitably such properties are present in materials having at least 1/10 the light absorption as does methylene blue. As a measure of its absorption, it is noted that methylene blue has a molecular extinction coefficient of 80 , 000 at 658 millimicrons in water. In assessing physiological suitability, appropriate dyes are those which have been found to substantially lack toxicity in mammals at diagnostic doses, i.e. doses sufficient to permit visualization of the abnormality upon endoscopic examination, and which chemically combine with the selected polysaccharide to form a uniformly stained com-position. Such dyes include basic aniline dyes, including le viol t dieth l- phenosafranin, etc.), pyronins (e.g., acridine red 3B, pyronin B, etc.), oxazins (e.£., brilliant cresyl blue, cresyl fast violet, nile blue[sulfate] ) , basic azo dyes (e.g., Janus green, indazole blue, Bismarck brown, etc.), triphenyl- and diphenylnaphthylmethanes (e.g. , malachite green, pararosaniline chloride, pararosaniline acetate, methyl violet, ethyl green, Victoria blue, etc.), phthalocyanines (e.g., alcian blue, luxol fast blue, etc.), and preferably the thiazins (e.g., thionin, azure A, B and C, methylene green, toluidine blue and especially methylene blue). Other polysaccharide staining dyes can also be used including fluorochrome stains such as the fluoresceins, fat stains such as sudan black B, the tetrazoles (e.g., blue tetrazolium) , and food dyes such as P.D. and C. #1 (food and drug color no. 1). As indicated, the thiazins are the preferred dyes for the dye labelling component of the instant diagnostic composition, with methylene blue being most preferred, in view of their suitable extinction coefficient, which is both strong as well as providing the desired contrast, and their substantial lack of toxicity. A very preferred embodiment of this invention comprises the labelled composition containing preferably no greater than 2Ϊ, but conveniently within the range of about 0.01 to 5.0Ϊ, by weight of methylene blue and preferably no less than 90% by weight of sodium amylosulfate. Said very preferred embodiment is especially advantageous as a diagnostic reagent in comparison with methylene blue used alone because of the former's superior binding qualities. That is, the intensity of color in the stained area is greater and persists longer than methylene blue ψ The choice of an appropriate radionuclide for use as an instant labelling agent is likewise dependent upon its ability to be diagnostically effective and physiologically suitable. With respect to a radionuclide, the term "physiologically suitable" comprehends the properties of: (1) short half life, (2) essentially pure gamma emission and no substantial emission of beta-particles, and (3) chemical compatibility with the selected polysaccharide such that negligible absorption of the resultant composi-tion occurs from the gastrointestinal tract. The importance of a short half life, that is one no greater than 60 days and more preferably of considerably low magnitude such as 2-24 hours, stems from the fact that the radiation dose to the patient should be an intense burst of high energy in order to maximize effectiveness and safety, since high energy radiation is better tolerated by mammals than low energy radiation. The use of essentially pure gamma emittor provides an additional safety factor because it has been observed that radiation damage is frequently the result of the absorption of beta emissions, rather than gamma emissions. Generally gamma energy of .03-2 Mev is desirable for an optimal and safe result. Among those characteristics maximizing the diagnostic effectiveness of a radionuclide labelling agent is its chemical ability to bind irreversibly to the polysaccharide carrier. Such property is essential to an effective diagnostic aid since less than essentially quantitative and irreversible combination would provide: (1) an aggregate of label in the composition which would not permit accurate visualization of the abnormality, or (2) loosely bound or unbound radio ψ in the loss of the material throughout the body of the mammal being studied and, perhaps, necessitate the administration of an unusually high dosage of labelled composition in order to achieve any useful visual result. For obvious reasons of safety an unusually high radiation dosage is to be avoided. A significant factor which must be considered in the selection of a diagnostically effective radionuclide for use in the instant labelled composition is its ability to be visualized on existing instru-mentation. Many types of radiation imaging equipment provide varying tolerances of isotope energy, most commonly in the range of 20-2000 Kev, though this wide range is not necessarily available on any one instrument currently marketed. Among possible radionuclides for use in this invention are iodine-131, iodine-125, iodine-123, indium-Ill, indium-113m, iodine-132, indium-llUm, ytterbium-169 , gallium-67, dysprosium-157, mercury-203, mercury-197, gold-198, bismuth-204, chromium-51 and most preferred, in view of its short half life, ideal lack of beta emission and ability to be imaged on both rectilinear scanners and scintillation cameras, is technetium-99m. Additional radionuclides, which because of unusually long half life, failure to be adequately imaged on present detectors, etc. are less desirable, though nevertheless of potential usefulness as advances in radiation imaging instrumentation may provide better energy resolution enabling use of lower dosages of radionuclides, include selenium-75, gallium-68, cobalt-57, samarium-153, and lutetium-177.
The dye labelled compositions can be manufac-tured by mixing the dye with the selected polysaccharide resulting product to enhance its purity. Alternatively other conventional methods of staining carbohydrate materials may be employed.
The radionuclide labelled compositions of this invention can be prepared by methods analagous to those used for the labelling of proteins, such as albumin, and fats such as triolein, as well as other radiolabeled carbohydrate materials known in the art. As as illustration of such a procedure the preferred polysaccharide material of this invention, sodium amylosulfate, was combined with 25i_SO(jium iodide in a suitable solvent such as acetone, in the optional presence of an oxidizing agent, such as (N-chloro-p_-toluenesulfonamido) sodium. After stirring and cooling, the resultant composition is optionally dialyzed against water to provide greater purity of the 125i_SO(jium amylosulfate composition product thereof. The technetium-99m labelled compositions of this invention are most conveniently prepared by utilization of a reducing agent such as ascorbic acid, a source of stannous ion, illustratively stannous chloride, or most preferably a source of ferrous ion, such as ferric chloride and ascorbic acid or ferrous chloride. The most preferred procedure entails the addition of a few drops of 99m hydrochloric acid to a saline solution of ^ Tc-sodium pertechnetate, followed by the addition of a reducing agent such as ferric chloride coupled with ascorbic acid. The mixture is thereafter permitted to stand for several minutes, after which time upon adjustment of pH, the desired sulfated polysaccharide, such as sodium amylosulfate, is added to the reaction mixture, and 99m labelled sodium amylosulfate. Any unbound technetium- 99m may be removed by passing a solution of the product through an ion exchange or gel filtration column.
As indicated above, the selection of radionuclide labelling agent for incorporation in the composition of this invention is dependent upon the visualizing instrument which is to be used for the detection of abnormal mucosa. several Described hereinafter are throo oommon types of radiation imaging devices currently in use, each of which can be used with at least one or more of .the instant radionuclide labelled compositions. Specifically, the technetium-99m labelled compositions of this invention are detectable on all of the instruments discussed hereinafter and consequently these radionuclide labelled polysaccharides are particularly preferred embodiments of this invention. Two basic types of radiation imaging devices are rectilinear instruments or scanners, whose detecting heads move back and forth over the scanning area; and scintillation cameras, produce a unitary which are characterized by their wnlquo ability to -view all image of the object under study at all tlmoo any given moment.
With respect to the rectilinear scanner, the concentration of radionuclide in the target organ is outlined by a corresponding pattern of dots. Various black and white printout systems are often employed. However, systems in which the color of the printout changes with the count rate may be of particular value when scanning areas of gradual change in concentration. A typical rectilinear scanner is Nuclear-Chicago Corporation's PHO/DOT® Isotope Scanner, which automatically produces a 8uporb display of the loca-tion and concentration of isotope-labelled compositions corded on X-ray film by a photorecording system (photoscans) and is also printed on paper by a dot recording system (dotscans). The PHO/DOT has the ability to visualize isotopes within the energy range of 20-2000 Kev.
The scintillation camera, commonly known as the in its basic embodiment Anger camera, is described/in U.S. Patent No. 3 , 011 , 057 . Such camera devices have the feature of viewing at least a substantial portion of the object under study at any one time, thus significantly reducing examination time in comparison to rectilinear scanners. A typical scintillation camera, Nuclear-Chicago Corporation's PHO/GAMMA® Scintillation Camera, includes an image or detector head containing a sodium iodide thallium activated scintillation crystal and a matrix of photomultiplier tubes; inter-changeable collimators (multiaperture or pinhole); and image data computation, display and control modules. The distribution of radionuclides is often imaged on Polaroid® film (scintiphotos). The PHO/GAMMA instrument has the ability to visualize isotopes within the energy range 6f 50-680 Kev.
Very recent improvements of the scintillation camera are those having tomographic Imaging capabilities. These involve various additions to the basic Anger camera system such as those described in Canadian Patent Nos . 872386 and 872387 , in German Offenlegungsschrift No. 2011164 and in an article by G. Muehllehner, "A Tomographic Scintillation Camera", Physics in Medicine and Biology, Vol. 16 , No. 1 , pp. 87-96 ( 1971 ) . Nuclear-Chicago Corporation's PHO/GAMMA Tomocameratm Accesory comprises System consists of the conventional PHO/GAMMA Scintilla ? a floating-top radiographic table and an associated operating control module, and has the ability to image data from four distinct parallel anatomical planes in a single displa .
The instant compositions can be combined with pharmaceutically acceptable carriers suitable for the administration of such a diagnostic aid. Obviously, the chemical properties of the particular labelling agent chosen for use in the composition will, in practice, limit the type of carriers with which it can be combined. For example, the instant technetium-99m composition, because of the short half life of technetium-99m, can most conveniently be used as a liquid of relatively few ingredients, since compounding time for complicated formulations would reduce the usefulness and practicality of the end product. The term "pharmaceutically acceptable carrier" as used herein in reference to the compositions of this invention means a solid or a liquid composed of a single substance or a number of substances which may be solids, liquids or a combination of solids and liquids each of which is less toxic than an equal weight of the active ingredient present in the composition when measured in the same mammalian host using the same method and conditions of administration. The concentration of the active ingredient in the composi-tion is not critical, but for economy of preparation, when a dye is the labelling component, the concentration should be at least 0.5Ϊ by weight and preferably 1-80 . An illustration of a suitable radionuclide composition is that containing 80-1500 mg. of sodium amylosulfate (250-500 mg. being the more preferred range), and 0.1 to 10 mCi τ (more preferably In the amount of 2 milllCuries ) . These compositions can be administered either orally or parenterally. For oral administration, tablets, lozenges, capsules, dragees, pills and powders are suitable, while aqueous and non-aqueous solutions or suspensions are appropriate for both oral (e.g_. in the case of radionuclide labelling agents via a stomach tube) and parenteral (e.g. rectal) administration. Acceptable pharmaceutical carriers are exemplified by chewable tablets, sugars such as lactose or sucrose, starches such as corn starch or potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose or cellulose acetate phthalate, talc, calcium phosphates such as dicalclum phosphate or tricalcium phosphate, sodium sulfate, calcium sulfate, polyvinyl alcohol, acacia, stearic acid, alkaline earth metal stearates such as magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma, water, agar, alginic acid, benzyl alcohol, isotonic saline and phosphate buffer solution as well as other non-toxic compatible substances used in pharmaceutical formulations. Some typical formulations as well as the method of preparation thereof, are presented below.
Formulation I Liquid Composition Containing 2% Methylene Blue: Sodium Amylosulfate Amount Ingredient (Cone. 250 mg 5 ml. ) (Cone. 500 mg./5 ml. ) Composition of methylene 250 mg. 500 mg. blue with sodium amylosulfate (in a ratio of preferably 2:100, respectively) f To the composition of methylene blue with sodium amylosulfate was added slowly, with stirring, 100 ml. of distilled water. To this slurry was added, with stirring, sufficient distilled water to bring the mixture to the volume of 1 liter and stirring was continued until solution was complete. The solution was then poured into amber bottles of the desired quantity, for example, five milliliter portions, sampled and assayed.
Formulation II Chewable Tablet Composition Containing 2% Methylene Blue: Sodium Amylosulfate Amount Ingredient Per Tablet Per Batch of 1000 Composition of methylene blue 500 mg. 500 g. with sodium amylosulfate (in a ratio of preferably 2:100, respectively) Dextrose USP, anhydrous 1.66 g. 1660 g.
Polyvinylpyrrolidone 67. ^ mg. 67.4 g .
Hydrogenated cottonseed oil 22.6 mg. 22.6 g.
Flavor (e_.£. , Florasynth en- 1.76 mg. I.76 g. trapped black cherry flavor) 00 Grams of the composition of sodium amylosulfate with 2% methylene blue (powder form) was blended with I66O grams of dextrose, and 67.^ grams polyvinylpyrrolidone in a large bowl for 5 minutes. That mixture was thereafter comminuted at high speed, remixed, granulated with 300 ml. of ethanol, and dried for four hours at 60°C. After oscillation through a #12 screen, followed by the addition of 22.6 grams of hydrogenated cottonseed oil and 1.76 grams of Florasynth entrapped black cherry flavor, the mixture was blended for 5 minutes and a sample was taken for assaying. Thereafter 7 The method of this invention for the detecting in mam-mals of abnormal mucosa, particularly of the gastrointestinal variety, comprises the administration of a diagnostic dose of the instant novel diagnostic composition. The term "diagnos-tic dose" is defined as the amount of active ingredient that will adequately adhere to the mucosa and effect labelling thereof sufficient to permit detection upon examination, endoscopically in the case of dye labelling agents and by radiation imaging devices in the instance of radionuclide labelling agents. This dose will vary with the particular labelling agent chosen, the type and location of the particular disorder being diagnosed, the route of administration, the particular polysaccharide used, and the subject's physical characteristics, e.g. body weight and physiological state such as hypersecretory. A typical diagnostic dosage for a subject of about 22 to about 136 kg. body weight for the composition of sodium amylosulfate with up to 2 % methylene blue is 100 to 500 milligrams, administered about 1/4 hour prior to endoscopic examination for gastric ulcer. For a subject of identical weight and disorder, 2 millicuries of technetium-99m combined with 250 mg. of sodium amylosulfate, administered 1-2 hours prior to examination with a radiation imaging device, would be a typical diagnostic dosage.
Application of the instant method to the diagnosis of abnormal gastric mucosa, particularly ulcers, has been found to be especially effective when the preferred dye labelled composition of this invention, i.e. sodium amylosulfate with no greater that 2 % by weight methylene blue, is administered to the patient fifteen minutes prior to hollow tubular instrument designed to pass into the stomach by way of the mouth and esophagus and fitted with optical and lighting equipment that permits visual inspection of the stomach) to which a camera suitable for color photo-graphy has been affixed. As will be apparent to those skilled in endoscopic identification, the light source for the gastroscope may be visible or ultraviolet lighting dependent upon the particular dye employed in the composition. In a very preferred embodiment of this invention, methylene blue, which may be viewed by visible light, serves as the dye.
In one clinical illustration of this very preferred method and diagnostic aid of this invention, a human subject, previously known to possess an ulcer as diagnosed by barium radiology, was administered 5 ml. of an aqueous solution containing 250 mg. of the composition comprising 23» methylene blue with sodium amylosulfate . Fifteen minutes later, gastroscopic examination of the patient accompanied by color photography of the area in question revealed the ulcer. The visualization of the ulcer, both to the naked eye and in the color photographs, was marked by sharpness of color, namely bright blue, at the edges of the ulcer crater, while the crater was differentially deprived of such color. Moreover, the shape and character of the ulcer as well as an indication of depth was apparent upon inspection. Thus, in contrast and preference to X-ray pictures produced via the barium meal method, wherein the crater itself is often poorly defined or distorted, the shape and character of the ulcer or other abnormality in the mucosa is easily detected and quantified. Hence the useful in detecting aberations of gastric mucosa since the characteristics of the stomach (its asymmetry, flabbiness and variability in shape and motility) make it difficult to examine by radiological techniques employing a source of radioenergy outside the subject, such as the barium meal method. Most effective and desirable results, are obtained when the radioenergy source is placed within the subject, as with the instant compositions wherein the labelling agent is a radionuclide, most preferably technetium-99ni, as illustrated in Examples 3. to 11 described hereinafter.
The following examples are given for the purpose of illustrating the preparation of the instant diagnostic composition according to the present invention. It will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In the following examples, temperatures are given in degrees Centigrade (°C). 1 EXAMPLE 1 A 1% aqueous solution of sodium amylosulfate (i.e. » the sodium salt of sulfated potato starch amylopectin, possessing substantially 1.6 sulfate groups per glucose unit, characterized by a molecular weight of about 6.3 X 10? and having been prepared according to the method described in Example 4 of U.S. Patent No. 3,271,388) was placed inside a dialysis bag, and the bag was then placed inside a container having a 0.5$ solution of methylene blue (U.S. P.) in water. The ratio of methylene blue solid, in the outer compartment, to sodium amylosulfate solid, in the inner compartment, was 2/100. The two solutions were allowed to equilibrate for 24 hours, after which time practically all the methylene blue had diffused into the dialysis bag con-taining the sodium amylosulfate solution. At the end of this time, the dialysis bag was removed from the exhausted methylene blue outer solution and placed in a large container of hydrochloric acid at pH 2, where it was dialyzed for 24 hours. No detectable methylene blue was removed by 2 hour dialysis against the acid solution, proving the irreversible binding of methylene blue to sodium amylosulfate under acid conditions analogous to that of gastric juice. At the end of the acid dialysis period, the contents of the dialysis bag were neutralized to a pH of 7.4 with sodium hydroxide and lyophilized.
Alternatively, upon completion of the 24 hour equilibration described above, the dialysis bag containing the sodium amylosulfate-methylene blue solution was removed from the exhausted methylene blue outer solution and was adjusted to a pH of 7.8 with sodium hydroxide and the solution f was thereafter lyophilized for 72 hours. The lyophilized material was first extracted with ethanol and then with redistilled acetone, followed by filtration. The resultant filtercake was dried in vacuo for 48 hours to provide a composition, identical with that prepared in the preceding paragraph containing 2 % methylene blue with about 93Ϊ sodium amylosul ate, which composition is characterized by ultraviolet absorption maxima at about 2*»6 , 285 and 575 millimicrons. It will be observed that the methylene blue component individually displays ultraviolet absorption maxima at about 609 and 667 millimicrons. Thus by comparison with the maxima described above for the prepared composition, this metachromatic behavior is evidence that the composition consists of a unique composition of matter distinguishable from its component, methylene blue.
EXAMPLE 2 A 0 . 1? solution of methylene blue in water was pumped slowly, over a S hour period, at a rate of 0 .1 ml/min., into a rapidly stirred 1 .0 percent solution of the alkali metal salt of sulfated potato starch amylopectin possessing 1-1 .8 sulfate groups per glucose unit and being characterized also by a molecular weight of 1-30 X 1θ7 in water. After the solutions were combined, the dyed salt solution was dialyzed against acid, then against water, and finally lyophilized and purified as described in the above example to provide a composition containing 2% methylene blue and an alkali metal salt of sulfated potato starch amylopectin possessing 1-1 . 8 sulfate groups per glucose unit and being characterized also by a molecular weight of 1-30 X 107 .
EXAMPLE 3 To a suspension of 503 mg. of sodium amylosulfate in 10 ml. of acetone was added a solution of 1 mCi of carrier-free 125i -sodium iodide in 10 ml. of acetone. To that mixture was then added 10 ul. of an aqueous solution of Chloramine-T, i.e. (N-chloro-p_-toluenesulfonamido) sodium [concentration ■ 2 mg./ml.], and the resultant mixture was stirred at 60°C. for about two hours, then allowed to cool to room temperature over a period of one hour. The mix-ture was diluted with approximately 0 ml. of water and then dial zed against three 5.5 liter portions of water during a period of four days, using cellulose dialyzer tubing. The contents of the tubing were then lyophilized, affording approximately 0.^5 g. of 125i-sodium amylosulfate composition having a specific activity of 18.9 pCi/g.
A solution containing the ^l-sodium amylosulfate product described above in 50 ml. of water was administered intragastrically to a 7.8 kg. female dog (Beagle). After waiting five minutes, the stomach region was visualized by means of a Nuclear-Chicago Corporation PHO/DOT Isotope Scanner. The dot and photo scans demonstrated the binding effect of 125i_SO(jium amylosulfate to the muscosa observed.
EXAMPLE H To a suspension of 503 mg. of sodium amylosulfate in 10 ml. of acetone was added a solution of 1 mCi of carrier-free 125i-sodium iodide in 10 ml. of acetone. That mixture was stirred at 60°C. for about two hours, then allowed to cool to room temperature over a period of one hour. The resultant mixture was trans- ferred to dialysis tubing with approximately 2 ml. of acetone and 60 ml. of water and then dialyzed against 5.5 liters of water for about two hours. The contents of the tubing were lyophilized. There were obtained approximately 409 mg. of 12^l-sodium amylosulfate composition having a specific activity of 18.0 yCi/g, EXAMPLE 5 501.5 Mg. of sodium amylosulfate, 5.1 ml. of water containing 1 mCi of carrier-free ^^I-sodium iodide, and an aqueous solution of 4.4 x lO""11 millimoles of Cloramine-T were combined and the required amount of water needed to bring the total amount of water to 50 ml. was added. The resulting mixture, containing amylosulfate, was administered intragastrically to a 7.8 kg. dog (Beagle) and the stomach region was visualized by means of a Nuclear-Chicago Corporation PHO/GAMMA Scintillation Camera. Scintiphotos were taken over a period of 2-1/2 hours. Binding to the gastrointestinal mucosa was observed throughout the length of the visual-ization period.
EXAMPLE 6 A solution of 3.69 mCi of carrier-free 99mTc-sodium pertechnetate in 2 ml. of saline (obtained by elution from a 99Mo-9 mTc generator) was acidified with 3 drops of 2 N aqueous hydrochloric acid solution. To that solution were added 10 mg. of ferric chloride hexahydrate, followed by 8 mg. of ascorbic acid. The acidity of the resulting solution was adjusted to approximately pH 5 by addition of 14 drops of IN aqueous sodium f then added and the mixture was stirred for about five minutes. At the end of that time, the mixture was passed through a small Sephadex chromatographic column in order to remove free technetium. The first 25 ml. of eluate were discarded and the next 50 ml. were collected. The latter eluate contained 99mTc_sodium amylosulfate with an activity, corrected to zero time, of 0.0426 mCi/ml. (total radioactivity ■ 2.1 mCi). 43 Ml. of that solution (radioactivity » 1.8 mCi) were administered to a 7.8 kg. dog (Beagle) for gastrointestinal visualization using a Nuclear-Chicago Corporation PHO/GAMMA Scintillation Camera. Scintiphotos were taken beginning at about 4 minutes after administration and continuing for three and one-half hours. Binding to the gastrointestinal mucosa was observed throughout the length of the visualization period.
EXAMPLE 7 A solution of 3.4 mCi of carrier-free 99mTc_ sodium pertechnetate in 2 ml. of saline (obtained by elution from a ^^ o- 99mTc generator) was stirred with 500 mg. of sodium amylosulfate in 50 ml. of water for 5 minutes. The resultant mixture was poured into dialysis tubing and dialyzed against three 5.5 liter portions of water during a period of about five and one-half hours.
There was thus obtained 25 ml. of a 99mTc-sodium amylosulfate composition having a total radioactivity, corrected to zero time, of about 0.12 mCi.
EXAMPLE 8 A solution of 3.4 mCi of carrier-free "mTc- elution from a ^Mo- 99mTc generator) was stirred while adding 3 drops of 2 N aqueous hydrochloric acid solution. There were then added, with stirring, 10 mg. of ferric chloride, followed by 8.5 mg. of ascorbic acid. The acidity of the resulting solution was adjusted to pH 4.5-5.5 with 1 N aqueous sodium hydroxide solution. 503 Mg. of sodium amylosulfate were added and stirring was continued for about 30 minutes. The resultant solution was transferred to dialysis tubing and dialyzed against three 4 liter portions of water during a period of about five and one-half hours. There were obtained 28 ml. of a 99mTc_sodjLum amylosulfate composition having a total radioactivity, corrected to zero time, of 1.24 mCi.
EXAMPLE 9 A solution of 3.86 mCi of carrier-free "mTc-sodium pertechnetate in 2 ml. of saline (obtained by elution from a 99 o-^m c generator) was acidified with 3 drops of 2 N aqueous hydrochloric acid solution. To that solution were added 17.5 mg. of ferric chloride, followed by 16 mg. of ascorbic acid. The acidity of the resulting solution was adjusted to pH 4.5-5.5 by the addition of approximately 14 drops of 1 N aqueous sodium hydroxide solution. 500 Mg. of sodium amylosulfate were then added and the mixture was stirred for about one hour. At the end of that time, the mixture was passed through a small Sephadex column. The first 20-30 ml. eluted from the column were discarded. The next 50 ml. which were eluted were collected. There were thus obtained 50 ml, of a ^"Tc-sodium amylosulfate composition having a total radioactivity, corrected to zero time, of EXAMPLE 10 A solution of 3.86 mCi of carrier-free 99mTc_ sodium pertechnetate in 2 ml. of saline (obtained by elution from a 99M0- 99mTc generator) was acidified with 3 drops of 2 N aqueous hydrochloric acid solution. To that solution were added 17.5 mg. of ferric chloride, followed by 16 mg. of ascorbic acid. The acidity of the resulting solution was adjusted to pH 4.5-5.5 by the addition of approximately l^ drops of 1 N aqueous sodium hydroxide solution. 500 Mg. of the sodium salt of sulfated potato starch amylopectin possessing 1.8 sulfate groups per glucose unit and being characterized also by a molecular weight of 12.5 10? were then added and the mixture was stirred for about one hour. At the end of that time, the mixture was passed through a small Sephadex column. The first 25 ml. eluted from the column were discarded. The next 50 ml. which were eluted were collected. There were thus obtained 50 ml. of a composition containing the sodium salt of sulfated potato starch amylopectin possessing 1.8 sulfate groups per glucose unit and being characterized by a molecular weight of 12.5 X 1θ7, labelled with technetium-99m.
EXAMPLE 11 A solution of 3.69 mCi of carrier-free "mTc-sodium pertechnetate in 2 ml. of saline (obtained by elution from a ^ o- 99mTc generator) was acidified with 3 drops of 2 N aqueous hydrochloric acid solution. To that solution were added 10 mg. of ferric chloride, followed by 8 mg. of ascorbic acid. The acidity of the resulting solution was adjusted to approximately pH 5 by the addition of 14 drops of 1 N aqueous sodium hydroxide solution. 500 Mg. of the alkali metal salt of sulfated potato starch amylopectin possessing 1-1.8 sulfate groups per glucose unit and being characterized also by a molecu-lar weight of 1-30 X 10? were then added and the mixture was stirred for about five minutes. At the end of that time, the mixture was passed through a small Sephadex column. The first 25 ml. of eluate were discarded and the next 0 ml. were collected. The latter eluate contain-ed the aforementioned alkali metal salt of sulfated potato starch amylopectin, labelled with technetium-99m.
Claims (35)
1. A composition useful in the detection of abnormal gastrointestinal mucosa which comprises a sulfated polysaccharide, which differentially binds to the gastrointestinal mucosa, and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per plexed monosaccharide unit, com&4ne«h-wlth a diagnostically effective, physiologically suitable labelling agent.
2. The composition according to Claim 1 wherein the polysaccharide is a sulfated amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per glucose unit.
3. The composition according to Claim 1 wherein the polysaccharide is a sulfated potato starch amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per glucose unit.
4. A composition useful in the detection of abnormal gastrointestinal mucosa which comprises an alkali metal salt of sulfated potato starch amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a molecular weight of about 1-30 X 10-7 and a sulfate content of about 1-1.8 sulfate groups per glucose unit, combined with a diagnostically effective, physiologically suitable labelling agent.
5. The composition according to Claim wherein the alkali metal salt is the sodium salt possessing about 1.6 sulfate groups per glucose unit and characterized also by a molecular weight of about 6.3 X 10?.
6. A composition according to Claim 4 wherein the alkali metal salt is the sodium salt possessing about 1.8 sulfate groups per glucose unit and characterized also by a molecular weight of about 12.5 X 10?.
7. A composition according to Claim 1 or 4 wherein the diagnostically effective, physiologically suitable labelling agent is a dye.
8. The composition according to Claim 1 or 4 wherein the diagnostically effective, physiologically suit able labelling agent is a thiazin dye.
9. The composition according to Claim 1 or Ί wherein the diagnostically effective, physiologically suit able labelling agent is the dye, methylene blue.
10. A composition useful in the detection of abnormal gastrointestinal mucosa which comprises an alkali metal salt of sulfated potato starch amylopectin, which is characterized by a molecular weight of 1-30 X 10? and a sulfate content of 1-1.8 sulfate groups per glucose unit combined with 2% by weight of the diagnostically effective physiologically suitable labelling agent, methylene blue.
11. A composition according to Claim 1 or 4 wherein the diagnostically effective, physiologically suit able labelling agent is a radionuclide.
12. A composition according to Claim 1 or 4 v.'herein the diagnostically effective, physiologically suit able labelling agent is iodine-125.
13. The composition according to Claim 1 or 4 wherein the diagnostlcally effective, physiologically suitable labelling agent is iodine-131.
14. The composition according to Claim 1 or wherein the diagnostlcally effective, physiologically suitable labelling agent is technetium-99m.
15. · A composition useful in the detection of abnormal gastrointestinal mucosa which comprises the sodium salt of sulfated potato starch amylopectin, which is characterized by a molecular weight of about 6.3 X 10? and a sulfate content of about 1.6 sulfate groups per plexed glucose unit, combined with the diagnostlcally effective, physiologically suitable labelling agent, technetium-99m.
16. The method of detecting abnormal gastrointestinal mucosa which comprises administering to a mammal a diagnostic dbse of a composition comprising a sulfated polysaccharide, which differentially binds to the gastrointestinal mucosa, and which is characterized by a molecular weight of at least one million and a sulfate content of substantially 1-2 sulfate groups per monosaccharide unit, plexed combined with a diagnostlcally effective, physiologically suitable labelling agent, followed by examination of the mucosa.
17. The method according to Claim 16 wherein the polysaccharide is an alkali metal salt of sulfated potato starch amylopectin, said salt possessing about 1-1.8 sulfate groups per glucose unit and characterized also by a molecular weight of about 1-30 X 10?.
18. The method according to Claims 16 or 17 wherein the diagnostlcally effective, physiologically suit- able labelling agent is methylene blue, which is visualized upon endoscopic examination of the mucosa.
19. The method according to Claims 16 or 17 wherein the diagnostically effective, physiologically suitable labelling agent is technetium-99m and the examination is conducted with a radiation imaging device.
20. The method of detecting abnormal gastrointestinal mucosa in mammals which comprises administering to the mammal a diagnostic dose of a composition comprising the sodium salt of sulfated potato starch amylopectin possessing 1.8 sulfate groups per glucose unit and charac- plexed terized also by a molecular weight of 6.3 X 10^, comb>jM»fr4 with the diagnostically effective, physiologically suitable labelling agent, technetium-99m, followed by examination with a radiation imaging device.
21. The process for the preparation of a composition useful in the detection of abnormal gastrointestinal plexirig mucosa which comprises comhin4n¾ a sulfated polysaccharide, which differentially binds to the gastrointestinal mucosa, and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per monosaccharide unit, with a diagnostically effective, physiologically suitable labelling agent.
22. The process according to Claim 21 wherein the polysaccharide is a sulfated amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per glucose unit.
23. The process according to Claim 21 wherein the polysaccharide is a sulfated potato starch amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a molecular weight of at least one million and a sulfate content of substantially one to two sulfate groups per glucose unit.
24. The process for the preparation of a composition useful in the detection of abnormal gastrointestinal mucosa which comprises combtnttrg an alkali metal salt of sulfated potato starch amylopectin which differentially binds to the gastrointestinal mucosa and which is characterized by a' molecular weight of about 1-30 X 1θ7 and a sulfate content of about 1-1.8 sulfate groups per glucose unit with a diagnostically effective, physiologically suitable labelling agent.
25. The process according to Claim 24 wherein the alkali metal salt is the sodium salt possessing about 1.6 sulfate groups per glucose unit and characterized also by a molecular weight of about 6.3 X 10^.
26. The process according to Claim 2 wherein the alkali metal salt is the sodium salt possessing about 1.8 sulfate groups per glucose unit and characterized also by 7 a molecular weight of about 12.5 X 10 ·
27. The process according to Claim 21 or 24 wherein the diagnostically effective, physiologically suitable labelling agent is a dye.
28. The process according to Claim 21 or 24 wherein the diagnostically effective, physiologically suitable labelling agent is a thiazin dye.
29. The process according to Claim 21 or 2*1 wherein the diagnostically effective, physiologically suitable labelling agent is the dye, methylene blue.
30. The process for the preparation of a composition useful in the detection of abnormal gastrointestinal plexirtg mucosa which comprises comfrifri-wg" an alkali metal salt of sulfated potato starch amylopectin, which is characterized by a molecular weight of 1-30 X 10? and a sulfate content of 1-1.8 sulfate groups per glucose unit, with 2% by weight of the diagnostically effective, physiologically suitable labelling agent, methylene blue.
31. ; The process according to Claim 21 or 24 wherein the diagnostically effective, physiologically suitable labelling agent is a radionuclide.
32. The process according to Claim 21 or 24 wherein the diagnostically effective, physiologically suitable labelling agent is iodine-125.
33. The process according to Claim 21 or 24 wherein the diagnostically effective, physiologically suitable labelling agent is iodine-131.
34. The process according to Claim 21 or24 wherein the diagnostically effective, physiologically suitable labelling agent is technetium-99m.
35. . The process for the preparation of a composition useful in the detection of abnormal gastrointestinal plerLrig mucosa which comprises comMntng the sodium salt of sulfated potato starch amylopectin, which is characterized by a molecular weight of about 6 . 3 X 10? and a sulfate content of about 1.6 sulfate groups per glucose unit, with the diagnostically effective, physiologically suitable labelling agent, technetium-99m.
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- 1971-07-06 ES ES392966A patent/ES392966A1/en not_active Expired
- 1971-07-06 NL NL7109318A patent/NL7109318A/xx unknown
- 1971-07-06 CH CH989571A patent/CH565559A5/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
SE399821B (en) | 1978-03-06 |
IE35439B1 (en) | 1976-02-18 |
NL7109318A (en) | 1972-01-10 |
BE769554A (en) | 1972-01-06 |
CA946741A (en) | 1974-05-07 |
IE35439L (en) | 1972-01-06 |
ES392966A1 (en) | 1975-04-16 |
DE2133005A1 (en) | 1972-01-20 |
IL37244A0 (en) | 1971-10-20 |
GB1355559A (en) | 1974-06-05 |
CH565559A5 (en) | 1975-08-29 |
ZA714438B (en) | 1972-08-30 |
FR2100869B1 (en) | 1974-09-06 |
FR2100869A1 (en) | 1972-03-24 |
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