NL8602140A - METHOD FOR PREVENTING A HYPOTENSIVE SHOCK AND LOCALIZED BONE RESORPTION CAUSED BY BACTERIAL ENDOTOXINS. - Google Patents
METHOD FOR PREVENTING A HYPOTENSIVE SHOCK AND LOCALIZED BONE RESORPTION CAUSED BY BACTERIAL ENDOTOXINS. Download PDFInfo
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- NL8602140A NL8602140A NL8602140A NL8602140A NL8602140A NL 8602140 A NL8602140 A NL 8602140A NL 8602140 A NL8602140 A NL 8602140A NL 8602140 A NL8602140 A NL 8602140A NL 8602140 A NL8602140 A NL 8602140A
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- Netherlands
- Prior art keywords
- endotoxin
- peroxy
- diphosphate compound
- compound
- peroxy diphosphate
- Prior art date
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- 239000002158 endotoxin Substances 0.000 title claims description 63
- 238000000034 method Methods 0.000 title claims description 18
- 208000006386 Bone Resorption Diseases 0.000 title claims description 10
- 230000024279 bone resorption Effects 0.000 title claims description 10
- 208000001953 Hypotension Diseases 0.000 title claims description 6
- 208000021822 hypotensive Diseases 0.000 title claims description 6
- 230000001077 hypotensive effect Effects 0.000 title claims description 6
- 230000035939 shock Effects 0.000 title claims description 6
- -1 peroxy diphosphate compound Chemical class 0.000 claims description 27
- 239000001177 diphosphate Substances 0.000 claims description 21
- 235000011180 diphosphates Nutrition 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 231100000252 nontoxic Toxicity 0.000 claims description 7
- 230000003000 nontoxic effect Effects 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001417 5'-guanylyl group Chemical group C=12N=C(N([H])[H])N([H])C(=O)C=1N=C([H])N2[C@@]1([H])[C@@](O[H])([H])[C@@](O[H])([H])[C@](C(OP(=O)(O[H])[*])([H])[H])([H])O1 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 125000001572 5'-adenylyl group Chemical group C=12N=C([H])N=C(N([H])[H])C=1N=C([H])N2[C@@]1([H])[C@@](O[H])([H])[C@@](O[H])([H])[C@](C(OP(=O)(O[H])[*])([H])[H])([H])O1 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 230000000415 inactivating effect Effects 0.000 claims description 2
- 230000002779 inactivation Effects 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000002510 pyrogen Substances 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 229910052718 tin Inorganic materials 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 239000011135 tin Substances 0.000 claims 1
- 210000002966 serum Anatomy 0.000 description 17
- 230000035605 chemotaxis Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 239000001301 oxygen Substances 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- 210000000988 bone and bone Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 238000011282 treatment Methods 0.000 description 7
- 241000700159 Rattus Species 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 4
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 210000000214 mouth Anatomy 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 2
- 102000013563 Acid Phosphatase Human genes 0.000 description 2
- 108010051457 Acid Phosphatase Proteins 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
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- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000003200 peritoneal cavity Anatomy 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 241000606750 Actinobacillus Species 0.000 description 1
- 208000002679 Alveolar Bone Loss Diseases 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- ULBTUVJTXULMLP-UHFFFAOYSA-N butyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCC ULBTUVJTXULMLP-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001767 cationic compounds Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000005482 chemotactic factor Substances 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 230000007893 endotoxin activity Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- OKISBDHRUPZLOC-UHFFFAOYSA-N gallin Chemical compound OC(=O)C1=CC=CC=C1C1C2=CC=C(O)C(O)=C2OC2=C(O)C(O)=CC=C21 OKISBDHRUPZLOC-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000011268 leukocyte chemotaxis Effects 0.000 description 1
- 238000012454 limulus amebocyte lysate test Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000011587 new zealand white rabbit Methods 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
- 230000009965 odorless effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002895 organic esters Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000004971 peroxyphosphoric acids Chemical class 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920002432 poly(vinyl methyl ether) polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 229910052712 strontium Inorganic materials 0.000 description 1
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 210000000623 ulna Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
* ί; VO 8326* ί; VO 8326
Werkwijze voor het verhinderen van een hypotensieve shock en gelokaliseerde botresorptie veroorzaakt door bacteriêle endotoxinen.A method of preventing hypotensive shock and localized bone resorption caused by bacterial endotoxins.
Endotoxinen zijn complexe macromoleculen die lipide, koolhydraat en proteïne bevatten* Zij worden in hoofdzaak aangetroffen op het oppervlak van gram-negatieve organismen en gewoonlijk aangeduid als lipopolysacchariden. Deze macromoleculen zijn voor de gastheer giftig 5 en kunnen dodelijk zijn. Zij kunnen bijvoorbeeld een ernstige hypotensieve shock veroorzaken en tevens een veelvoud van toxische reacties in het lichaam te voorschijn roepen, zoals botresorptie. In de mond zijn de endotoxinen als hoofdfactor betrokken bij de ontsteking van tandvlees en gelokaliseerd botverlies, zoals alveolair botverlies.Endotoxins are complex macromolecules containing lipid, carbohydrate and protein. * They are mainly found on the surface of gram-negative organisms and are commonly referred to as lipopolysaccharides. These macromolecules are toxic to the host and can be fatal. For example, they can cause severe hypotensive shock and also evoke a variety of toxic reactions in the body, such as bone resorption. In the mouth, endotoxins as the main factor are involved in gum inflammation and localized bone loss, such as alveolar bone loss.
10 Theoretisch zouden verbindingen die zuurstof afgeven endotoxinen kunnen inactiveren- Vanwege de snelheid waarmee vele zuurstof-afgevende verbindingen zuurstof afgeven hebben zij echter in het algemeen weinig effect op de bestrijding van endotoxinegroei. Verbindingen die zuurstof langzamer zouden afgeven kunnen het endotoxine-effect bestrijden. Hun 15 effectiviteit wordt echter in het algemeen beperkt doordat de omstandigheden van zuurstofafgifte niet overeenkomen met de omstandigheden die in het lichaam overheersen.Theoretically, oxygen-releasing compounds may inactivate endotoxins. However, because of the rate at which many oxygen-releasing compounds release oxygen, they generally have little effect in fighting endotoxin growth. Compounds that would release oxygen more slowly can combat the endotoxin effect. However, their effectiveness is generally limited by the fact that the oxygen delivery conditions do not correspond to those prevailing in the body.
Zoals beschreven in de Amerikaanse octrooiaanvrage 726545, ingediend 24 april 1985, van aanvraagster hebben warmbloedige zoogdieren, 20 zoals knaagdieren tot en met mensen, alkalisch fosfatase of zuur fos-fatase in hun lichamen. Peroxydifosfaatverbindingen bezitten de eigenschap langzaam zuurstof af te geven. De hoeveelheid zuurstof die zij afgeven is één-tiende van de hoeveelheid die door waterstofperoxyde wordt afgegeven. Slechts ongeveer 50% van hun actieve zuurstof wordt in 25 20 uur bij 25°C in aanwezigheid van alkalisch fosfatase of zuur fos fatase afgegeven.As described in the applicant's US patent application 726545, filed April 24, 1985, warm-blooded mammals, such as rodents to humans, have alkaline phosphatase or acid phosphatase in their bodies. Peroxy diphosphate compounds have the property of slowly releasing oxygen. The amount of oxygen they release is one-tenth of the amount released by hydrogen peroxide. Only about 50% of their active oxygen is released at 25 ° C in the presence of alkaline phosphatase or acid phosphatase in 25 hours.
Peroxydifosfaatverbindingen (PDP) geven waterstofperoxyde langzaam in aanwezigheid van fosfatase-enzymen volgens de vergelijking van het reactieschema A van het formuleblad af, waarin X een niet-giftig 30 farmaceutisch aanvaardbaar kation is of een organische estereenheid completeert. Fosfatase voor het afbreken van het peroxydifosfaat is in speeksel alsmede in plasma, darmvloeistoffen en witte bloedcellen aanwezig.Peroxy diphosphate compounds (PDP) slowly release hydrogen peroxide in the presence of phosphatase enzymes according to the equation of the reaction scheme A of the formula sheet, wherein X is a non-toxic pharmaceutically acceptable cation or completes an organic ester unit. Phosphatase for breaking down the peroxy diphosphate is present in saliva as well as in plasma, intestinal fluids and white blood cells.
8602140 Τ ΐ -2-8602140 Τ ΐ -2-
Opgemerkt is dat bacterieel endotoxine tevens reageert met intact PDP. Deze reactie vindt onafhankelijk van de aanwezigheid van fosfatasen plaats; dat wil zeggen dat deze buiten het lichaam van een warmbloedig dier ook plaatsvindt. Het is echter zeer belangrijk dat 5 zelfs in aanwezigheid van fosfatase de reactie ook plaatsvindt wanneer warmbloedige zoogdieren volgens de onderhavige uitvinding worden behandeld met PDP. Het is gewenst te voorzien in een voorschrift waardoor de behandeling voortgaat tot de endotoxinen zijn geïnactiveerd.It has been noted that bacterial endotoxin also reacts with intact PDP. This reaction takes place independently of the presence of phosphatases; that is, it takes place outside the body of a warm-blooded animal. However, it is very important that even in the presence of phosphatase, the reaction also occurs when warm-blooded mammals of the present invention are treated with PDP. It is desirable to provide a prescription by which treatment continues until the endotoxins are inactivated.
Het is een doel van deze uitvinding endotoxinen te inactiveren 10 en daardoor hun toxische effecten zoals ontsteking, botresorptie en hypotensieve shock te belemmeren.It is an object of this invention to inactivate endotoxins and thereby hinder their toxic effects such as inflammation, bone resorption and hypotensive shock.
Andere doeleinden van deze uitvinding zullen duidelijk worden uit een beschouwing van de volgende toelichting.Other objects of this invention will become apparent from a consideration of the following explanation.
Volgens bepaalde doeleinden heeft de uitvinding betrekking op 15 een werkwijze voor het belemmeren van hypotensieve shock en gelokaliseerde botresorptie veroorzaakt door bacteriële endotoxinen bestaande uit het invoeren van een niet-giftig wateroplosbaar farmaceutisch aanvaardbare peroxydifosfaatverbinding in contact met endotoxinen om in-activering van genoemd bacterieel endotoxine te veroorzaken.According to certain objectives, the invention relates to a method of inhibiting hypotensive shock and localized bone resorption caused by bacterial endotoxins consisting of introducing a non-toxic water-soluble pharmaceutically acceptable peroxydiphosphate compound in contact with endotoxins to inactivate said bacterial endotoxin. cause.
20 Een procedure voor het aantonen van de inactivering van endo toxine betreft het overwinnen van de inductie van de Vorming van een factor die chemotactisch ten opzichte van polymorfonucleaire leuco-cyten is, hierna genaamd "PMN". Een dergelijke factor wordt bepaald volgens de Boyden chemotaxismethode, waarbij witte bloedcellen van een 25 konijn worden aangetrokken (chemotaxis) door in hét gebied opgewekte endotoxine geïnduceerde factor. In de boydenmethode vindt, wanneer een bacterieel endotoxine lipopolysaccharide met een serum uit een zoogdier wordt geïncubeerd, het volgende plaats: geïncubeerd bijA procedure for demonstrating the inactivation of endotoxin involves overcoming the induction of the formation of a factor that is chemotactic with respect to polymorphonuclear leucocytes, hereinafter referred to as "PMN". Such a factor is determined according to the Boyden chemotaxis method, in which rabbit white blood cells are attracted (chemotaxis) by endotoxin induced factor in the region. In the boyden method, when a bacterial endotoxin lipopolysaccharide is incubated with a mammalian serum, the following occurs: incubated at
30 Serum en endotoxine 1 .....' chemotactische factoren voor PMN30 Serum and endotoxin 1 ..... chemotactic factors for PMN
lichaamstemperatuur gedurende 1 uurbody temperature for 1 hour
Het chemotaxisverschijnsel is bestudeerd met behulp van Boyden-kamers als beschreven door Cates et al, "Modified Boyden Chamber Method 35 for Measuring PMN Chemotaxis" in Leukocyte Chemotaxis, Methods,The chemotaxis phenomenon has been studied using Boyden chambers as described by Cates et al, "Modified Boyden Chamber Method 35 for Measuring PMN Chemotaxis" in Leukocyte Chemotaxis, Methods,
Physiology and Clinical Application, uitgegeven door Gallin en Quie, 3502146 £ ¾ -3-Physiology and Clinical Application, published by Gallin and Quie, 3502146 £ ¾ -3-
Raven Press, N.Y., 1978, biz. 67-71. Wanneer endotoxine chemotaxis zoals in de onderhavige uitvinding induceert, kan het percentage remming worden gekwantificeerd met de Boyden chemotaxisproef.Raven Press, N.Y., 1978, biz. 67-71. When endotoxin induces chemotaxis as in the present invention, the percent inhibition can be quantified with the Boyden chemotaxis assay.
Endotoxine-materiaal kan in het lichaam van een warmbloedig dier 5 worden geïntroduceerd via zijn aanwezigheid in de oppervlakken van gram-negatieve microörganismen, zoals Actinobacillus actinomycetemcomitens (A.a.), Escherichia coli (E. coli), Bacteroides melanenogenicus (B. mei) en Salmonella typhi (S. typhi).Endotoxin material can be introduced into the body of a warm-blooded animal through its presence in the surfaces of gram-negative microorganisms, such as Actinobacillus actinomycetemcomitens (Aa), Escherichia coli (E. coli), Bacteroides melanenogenicus (B. mei) and Salmonella typhi (S. typhi).
Oraal endotoxine geïsoleerd uit A. a. is toxisch ten opzichte 10 van alveolair bot. Niet-oraal endotoxine gezuiverd uit E. coli kan dodelijk voor de gastheer blijken te zijn.Oral endotoxin isolated from A. a. Is toxic to alveolar bone. Non-oral endotoxin purified from E. coli can prove deadly to the host.
Andere bekende procedures voor het remmen van endotoxine-vorming worden uitgevoerd met behulp van resorptie in een botkweek-medium; een kuikenembryo-lethaliteitsproef is tevens bruikbaar.Other known procedures for inhibiting endotoxin formation are performed using resorption in a bone culture medium; a chick embryo lethality test is also useful.
15 De toxische reactie wordt effectief geremd door endotoxine in situ in een warmbloedige gastheer te behandelen met een remmend-effectieve hoeveelheid van een niet-giftige, wateroplosbare farmaceutisch aanvaardbare peroxydifosfaatverbinding. Het peroxydifosfaat reageert met het endotoxine in het lichaam als een intact molecuul, onder 20 inactivering van de peroxydifosfaatverbinding. Aangezien het endotoxine wordt geïnactiveerd is het duidelijk dat endotoxine met het peroxydifosfaat in reactie treedt.The toxic reaction is effectively inhibited by treating endotoxin in situ in a warm-blooded host with an inhibitively effective amount of a non-toxic, water-soluble pharmaceutically acceptable peroxy diphosphate compound. The peroxy diphosphate reacts with the endotoxin in the body as an intact molecule, inactivating the peroxy diphosphate compound. Since the endotoxin is inactivated, it is clear that endotoxin reacts with the peroxy diphosphate.
In het algemeen is ongeveer 0,1-7% peroxydisfosfaatverbinding in een farmaceutische drager, zoals in oplossing, effectief in een 25 doseringsvoorschrift van ongeveer 0,2-14 mg per kg lichaamsgewicht.Generally, about 0.1-7% peroxydisphosphate compound in a pharmaceutical carrier, such as in solution, is effective in a dosage regimen of about 0.2-14 mg per kg of body weight.
De effectiviteit van de renaming kan men aantonen door het verminderde endotoxine-effect en dit wordt gekwantificeerd op basis van geremde chemotaxis ten opzichte van PMN.The effectiveness of the renaming can be demonstrated by the reduced endotoxin effect and this is quantified on the basis of inhibited chemotaxis compared to PMN.
Typerende niet-giftige, wateroplosbare farmaceutisch aanvaard-30 bare peroxydifosfaatverbindingen zijn de alkalimetaalzouten (b.v.Typical non-toxic, water-soluble pharmaceutically acceptable peroxydiphosphate compounds are the alkali metal salts (e.g.
lithium, natrium en kalium) van aardalkalimetaalzouten (b.v. magnesium, calcium en strontium) en zink, tin en kwaternaire ammoniumzouten, alsmede C, alkyl-, adenylyl-, guanylyl-, cytosylyl- en thylmylylesters.lithium, sodium and potassium) of alkaline earth metal salts (e.g. magnesium, calcium and strontium) and zinc, tin and quaternary ammonium salts, as well as C, alkyl, adenylyl, guanylyl, cytosylyl and thylmylyl esters.
Alkalimetaal-, in het bijzonder kaliumzout heeft onder de anorganische 35 kationen de voorkeur. Het tetrakaliumperoxydifosfaat is een stabiele, geurloze, fijnverdeelde, vrijvloeiende, witte niet-hygroscopische kris- 8802140 -4- > μ ·' 'v tallijne vaste stof met een molecuulgewicht van 346,35 en een actief zuurstofgehalte van 4,6%.Alkali metal, especially potassium salt, is preferred among the inorganic cations. The tetrapotassium peroxide diphosphate is a stable, odorless, finely divided, free-flowing, white, non-hygroscopic crystalline 8802140 -4-> μ · 'v talline solid with a molecular weight of 346.35 and an active oxygen content of 4.6%.
Tetrakaliumperoxydifosfaat is voor 47-51% wateroplosbaar bij 0-61°C maar onoplosbaar in een gewoon oplosmiddel, zoals acetonitril, 5 alcoholen, ethers, ketonen, dimethylformamide, dimethylsulfoxyde en dergelijke. Een 2%'s waterige oplossing heeft een pH van ongeveer 9,6 en een verzadigde oplossing daarvan een pH van ongeveer 10,9. Een 10%'s oplossing in water bij 25°C toonde geen actief zuurstofverlies na 4 maanden; en bij 50°C toonde een 10%'s oplossing een actief zuurstof-10 verlies van 3% in 6 maanden.Tetrapotassium peroxide diphosphate is 47-51% water soluble at 0-61 ° C but insoluble in a common solvent such as acetonitrile, alcohols, ethers, ketones, dimethylformamide, dimethyl sulfoxide and the like. A 2% aqueous solution has a pH of about 9.6 and a saturated solution thereof has a pH of about 10.9. A 10% aqueous solution at 25 ° C showed no active oxygen loss after 4 months; and at 50 ° C, a 10% solution showed an active oxygen loss of 3% in 6 months.
Van de organische verbindingen hebben die welke hydrofobe eigenschappen leveren, zoals ^2.-12 alkylgroepen en die welke de snelle opname van peroxydifosfaateenheid door de cellen vergemakkelijken, zoals ade-nylyl-, guanylyl-, cytosylyl-, en thylmylylesters de voorkeur.Of the organic compounds, those that provide hydrophobic properties, such as ^ 2 -12 alkyl groups, and those that facilitate the rapid uptake of peroxydiphosphate unit by the cells, such as adeylyl, guanylyl, cytosylyl, and thylmylyl esters are preferred.
15 Men kan de peroxydifosfaatverbinding oraal of systemisch toe dienen voor het remmen van endotoxinen in de mondholte of andere delen van het lichaam.The peroxy diphosphate compound can be administered orally or systemically to inhibit endotoxins in the oral cavity or other parts of the body.
Farmaceutische dragers die geschikt zijn voor orale inneming zijn beklede tabletten samengesteld uit materiaal dat bestand is tegen 20 afbraak door maagzuur bij de maag pH (ongeveer 1-3) aangezien peroxy-difosfaat door dergelijke maagzuren zal worden geïnactiveerd. In plaats daarvan worden de dragers, met daarin aanwezig getabletteerde korrels van het peroxyfifosforzuurzout vaste materiaal opgelost door lichaamsvloeistoffen die een hogere pH hebben (ongeveer 5,5-10) en het peroxy-25 difosfaat niet inactiveren, waardoor dit onderworpen blijft aan de enzymatische werking van fosfatase dat bij mensen of andere warmbloedige dieren aanwezig is. Een gewenste tabletbekledingsoplossing is samengesteld uit een vetzuurester, zoals N-butylstearaat (typerend ongeveer 40-50, bij voorkeur ongeveer 45 gew.dln), was zoals carnaubawas (type-30 rend ongeveer 15-25, bij voorkeur ongeveer 20 gew.dln), vetzuur zoals stearinezuur (typerend ongeveer 20-30 gew.dln, bij voorkeur 25 gew.dln) en celluloseëster zoals celluloseacetaatftalaat (typerend ongeveer 5-15, bij voorkeur ongeveer 10 gew.dln) en organisch oplosmiddel (typerend ongeveer 400-900 din). Andere gewenste bekledingsmaterialen omvatten 35 schellak en copolymeren van malexnezuuranhydride en ethylenische verbindingen, zoals polyvinylmethylether. Dergelijke bekledingen zijn onder- 8602140 -5- scheiden van tabletten die in de mondholte worden afgebroken waarin het tabletmateriaal typerend ongeveer 80—90 gew.din mannitol en ongeveer 30-40 gew.dln magnesiumstearaat bevat.Pharmaceutical carriers suitable for oral ingestion are coated tablets composed of material resistant to gastric acid degradation at gastric pH (about 1-3) since peroxy diphosphate will be inactivated by such gastric acids. Instead, the carriers, containing tableted granules of the peroxyphosphoric acid salt solid contained therein, are dissolved by body fluids having a higher pH (about 5.5-10) and do not inactivate the peroxy-diphosphate, leaving it subject to the enzymatic action of phosphatase present in humans or other warm-blooded animals. A desired tablet coating solution is composed of a fatty acid ester, such as N-butyl stearate (typically about 40-50, preferably about 45 parts by weight), such as carnauba wax (type about 15-25, preferably about 20 parts by weight) fatty acid such as stearic acid (typically about 20-30 parts by weight, preferably 25 parts by weight) and cellulose ester such as cellulose acetate phthalate (typically about 5-15, preferably about 10 parts by weight) and organic solvent (typically about 400-900 parts) ). Other desired coating materials include shellac and copolymers of maleic anhydride and ethylenic compounds, such as polyvinyl methyl ether. Such coatings have been separated from tablets that decompose in the oral cavity in which the tablet material typically contains about 80-90 parts by weight mannitol and about 30-40 parts by weight magnesium stearate.
Getabletteerde korrels van het peroxydifosfaatzout worden ge-5 vormd door ongeveer 30-50 gew.dln van het peroxydifosfaatzout te mengen met ongeveer 45-65 gew.dln van een vaste polyhydroxysuiker, zoals manni-trol en te bevochtigen met ongeveer 20-35 gew.dln van de polyhydroxy-suikerverbindingsoplossing, zoals sorbitol, op grootte te sorteren, te mengen met ongeveer 20—35 gew.dln van een bindmiddel, zoals magnesium— 10 stearaat en de korrels samen te persen tot tabletten met een tabletpers-machine. De getabletteerde korrels worden bekleed door een schuim van een oplossing van het bekledingsmateriaal daarop te versproeien en te drogen onder verwijdering van het oplosmiddel. Dergelijke tabletten verschillen van tandtabletten die typerend bestaan uit samengeperste 15 korrels zonder een speciale beschermende bekleding.Tableted granules of the peroxy diphosphate salt are formed by mixing about 30-50 parts by weight of the peroxy diphosphate salt with about 45-65 parts by weight of a solid polyhydroxy sugar, such as mannitrol, and wetting with about 20-35% by weight. Sort parts of the polyhydroxy sugar compound solution, such as sorbitol, by mixing with about 20-35 parts by weight of a binder, such as magnesium stearate, and compressing the granules into tablets using a tablet press machine. The tableted granules are coated by spraying a foam of a solution of the coating material thereon and drying while removing the solvent. Such tablets differ from dental tablets, which typically consist of compressed granules without a special protective coating.
Een effectieve toedieningsdosis van peroxydifosfaat met een voorgeschreven schema, wanneer de toediening door orale inneming plaatsvindt, is ongeveer 0,1-6 g per kg lichaamsgewicht per dag; wanneer de' toediening systemisch is, zoals intramusculaire, intraperitoneale of 20 intraveneuze injectie, is de dosering ongeveer 0,1-2 g per kg lichaamsgewicht per dag.An effective administration dose of peroxydiphosphate with a prescribed schedule, when administered by oral ingestion, is about 0.1-6 g per kg of body weight per day; when the administration is systemic, such as intramuscular, intraperitoneal or intravenous injection, the dose is about 0.1-2 g per kg body weight per day.
Fysiologisch aanvaardbare pyrogeenvrije oplosmiddelen zijn geschikte dragers ten gebruike op de in de techniek erkende wijze voor systemische toediening. Pekeloplossing gebufferd met fosfaat tot een 25 fysiologische pH van ongeveer 7-7,4 is de voorkeursdrager voor systemische toediening. Dergelijke oplosmiddelen dient men te onderscheiden van water-vochtighoudende dragers die typerend in tandpasta's worden toegepast. Een dergelijke oplossing wordt typerend bereid door gedeïoni-seerd gedestilleerd water te steriliseren, te controleren om niet-pyro-30 geniciteit te verzekeren onder toepassing van de Limulus amebocytlysaat (LAL) -proef beschreven door Tsuji et al in "Pharmaceutical Manufacturing" oktober 1984, blz. 35-41 en daaraan dan een fosfaatbuffer (pH ongeveer 8,5-10) gemaakt in pyrogeenvrij steriel water en ongeveer 1-100 mg peroxydifosfaatverbindingsderivaat en natriumchloride tot een concen-35 tratie van ongeveer 0,5-1,5 gew.% toe te voegen. Men kan de oplossing vóór gebruik in flesjes verpakken, nadat deze opnieuw is gesteriliseerd 8602140 -6- door passage door een micropoor filter. Als alternatieven kunnen andere oplossingen zoals Ringer's oplossing die 0,86 gew.% natriumchloride, 0,03 gew.% kaliumchloride en 0,033 gew.% calciumchloride bevat worden toegepast.Physiologically acceptable pyrogen-free solvents are suitable carriers for use in the art-recognized manner for systemic administration. Brine solution buffered with phosphate to a physiological pH of about 7-7.4 is the preferred vehicle for systemic administration. Such solvents should be distinguished from water-moisturizing carriers typically used in toothpastes. Such a solution is typically prepared by sterilizing deionized distilled water, checking to ensure non-pyrogenicity using the Limulus amebocyte lysate (LAL) test described by Tsuji et al in "Pharmaceutical Manufacturing" October 1984, pp. 35-41 and then a phosphate buffer (pH about 8.5-10) made in pyrogen-free sterile water and about 1-100 mg peroxydiphosphate compound derivative and sodium chloride to a concentration of about 0.5-1.5 wt. % to add. The solution can be packaged in vials before use after it has been re-sterilized by passage through a micropore filter. As alternatives, other solutions such as Ringer's solution containing 0.86 wt% sodium chloride, 0.03 wt% potassium chloride and 0.033 wt% calcium chloride can be used.
5 De volgende voorbeelden illustreren het vermogen van de peroxy- difosfaat (PDP) -verbinding chemotaxis geïnduceerd door endotoxine-geïnduceerde factor in serum en endotoxine giftigheid ten opzichte van bot te remmen.The following examples illustrate the ability of the peroxy diphosphate (PDP) compound chemotaxis induced by inhibiting serum endotoxin-induced factor and endotoxin toxicity to bone.
Voorbeeld IExample I
10 PMN worden verkregen uit de buikvliesholte van volwassen10 PMN are obtained from the peritoneal cavity of the adult
Nieuw Zeeland witte konijnen 12 uur na intraperitoneale injecties van 200 ml oplossing die 0,2% glycogeen in steriele isotone pekel (0,85% NaCl) bevat. De cellen (PMN) worden gezuiverd van het extrudaat, verkregen uit de buikvliesholte van konijnen, en gezuiverd als beschreven 15 door Taiehman et al (Arch. Oral Biol. 21, biz. 257, 1976). Bacterieel endotoxine gezuiverd van E. coli verkregen van Associates of Cape Cod Inc. Woods Hole, Maine wordt voorbehandeld met verschillende concentraties van PDP (tetrakaliumzout) gedurende 1 uur bij 37°C. De chemotaxis-bepaling wordt daarna uitgevoerd met behandelde en niet-behandelde 20 endotoxinen onder gebruik van de Boydenkamer als eerder beschreven.New Zealand white rabbits 12 hours after intraperitoneal injections of 200 ml of solution containing 0.2% glycogen in sterile isotonic brine (0.85% NaCl). The cells (PMN) are purified from the extrudate obtained from the rabbit peritoneal cavity, and purified as described by Taiehman et al (Arch. Oral Biol. 21, biz. 257, 1976). Bacterial endotoxin purified from E. coli obtained from Associates of Cape Cod Inc. Woods Hole, Maine is pretreated with various concentrations of PDP (tetra potassium salt) for 1 hour at 37 ° C. The chemotaxis assay is then performed with treated and untreated endotoxins using the Boyden chamber as previously described.
De gegevens zijn samengevat in tabellen A en B.The data is summarized in Tables A and B.
8802140 -7-8802140 -7-
TABEL ATABLE A
Behandeling Chemotaxis-gemid- Percentage verminde- delde aantal migre- ring in chemotaxis _ rend PMN * S.D. + ____ 1. Controle ++ 139 ± 4,2 2. Serum +++ en 343,0 ± 36,7 1 nanogram/ml endotoxine 3. 0,5% PDP en 142,5 ± 12,0 serum +++ 4. Endotoxine (lng/ml) 188,0 ± 18,4 -44% vergeleken met 2 voorbehandeld met 0,5% PDP en serum ++ 5. Endotoxine 154,0 ± 2,8 -56% vergeleken met 2 (0,5 ng/ml) voorbehandeld met 0,5% PDP en serum ++ 6. Endotoxine 138,5 ± 2,8 -60% vergeleken met 2 (0,25 ng/lm) voorbehandeld met 0,5% PDP en serum ++ + S.D. = standaard deviatie ++ medium = Earl's oplossing die 10% runderserumalbumine bevat +++ serum = humaan serum (normaal)Treatment Chemotaxis Mean Percentage Decreased Number Of Migration In Chemotaxis _ PMN * S.D. + ____ 1. Control ++ 139 ± 4.2 2. Serum +++ and 343.0 ± 36.7 1 nanogram / ml endotoxin 3.5.5% PDP and 142.5 ± 12.0 serum +++ 4. Endotoxin (lng / ml) 188.0 ± 18.4 -44% compared to 2 pretreated with 0.5% PDP and serum ++ 5. Endotoxin 154.0 ± 2.8 -56% compared to 2 (0 .5 ng / ml) pretreated with 0.5% PDP and serum ++ 6. Endotoxin 138.5 ± 2.8 -60% compared to 2 (0.25 ng / lm) pretreated with 0.5% PDP and serum ++ + SD = standard deviation ++ medium = Earl's solution containing 10% bovine serum albumin +++ serum = human serum (normal)
De resultaten in tabel A tonen aan dat endotoxine als verwacht een sterke afgifte van een factor induceert die de chemotaxis van PMN (bij 2 behandelingen) verhoogde; PDP (0,5%) heeft geen effect op PMN (bij 3); en endotoxinen voorbehandeld met PDP hebben een significant 5 verlaagde chemotactische activiteit van de toxine (behandelingen 4, 5 en 6). Deze gegevens tonen aan dat een behandeling van endotoxine met PDP het biologische effect van het toxine inactiveert.The results in Table A demonstrate that endotoxin, as expected, induces a strong release of a factor that increased the chemotaxis of PMN (in 2 treatments); PDP (0.5%) has no effect on PMN (at 3); and endotoxins pretreated with PDP have a significantly reduced chemotactic activity of the toxin (treatments 4, 5 and 6). These data demonstrate that treatment of endotoxin with PDP inactivates the biological effect of the toxin.
Voorbeeld IIExample II
Tabel B geeft gegevens verkregen met verdere Boydenkamerproeven 10 als in voorbeeld I. PDP wordt als het tetrakaliumzout gebruikt.Table B gives data obtained by further Boyden chamber tests 10 as in Example 1. PDP is used as the tetrapotassium salt.
8602140 -8-8602140 -8-
TABEL BTABLE B
Behandeling Chemotaxis-gemid- Percentage vermindering delde aantal migre- in chemotaxis ____________ rend PMN + S.D._ _ 1. Controle medium 136,5 ±6,3 (zoals in voorbeeld I) 2. Endotoxine 1 ng/ml 329,0 ±39,5 en serum + 3. PDP 0,5% en serum + 139,5 ± 4,9 4. Endotoxine (1 ng/ml) 188,0 ±9,8 -43.0% voorbehandeld met 0,5% PDP en serum + 5. Endotoxine (1 ng/ml) 206,5 ± 17,6 -37% voorbehandeld met 0,25% PDP en serum + 6. Endotoxine (1 ng/ml) 231,0 ± 17,6 -30% voorbehandeld met 0,1% PDP en serum +Treatment Chemotaxis Average- Percent Reduction in Number of Migrin in Chemotaxis ______________ PMN + SD_ _ 1. Control Medium 136.5 ± 6.3 (as in Example I) 2. Endotoxin 1 ng / ml 329.0 ± 39, 5 and serum + 3. PDP 0.5% and serum + 139.5 ± 4.9 4. Endotoxin (1 ng / ml) 188.0 ± 9.8 -43.0% pretreated with 0.5% PDP and serum + 5. Endotoxin (1 ng / ml) 206.5 ± 17.6 -37% pretreated with 0.25% PDP and serum + 6. Endotoxin (1 ng / ml) 231.0 ± 17.6 -30% pretreated 0.1% PDP and serum +
+ serum zoals in voorbeeld I+ serum as in example I.
De gegevens in de bovenstaande tabel tonen dat een concentratie van'PDP van ten minste slechts 0,1% effectief de biologische activiteit van endotoxine inactiveert.The data in the table above show that a concentration of PDP of at least only 0.1% effectively inactivates the biological activity of endotoxin.
Voorbeeld IIIExample III
5 Effect van PDP op endotoxine-activlteit in botbreuksysteem5 Effect of PDP on endotoxin activity in bone fracture system
De proef waarin endotoxine geïsoleerd uit Acintobacillus actinomycetemcomitans Y4 (AAY4) de resorptie van bot in een botkweek-systeem induceert (Kiley en Holt, Infect. Immun. 30: 362-373, 1980) wordt toegepast om te bepalen of PDP al of niet de botresorptieve acti-10 viteit van endotoxine uit Y4 inactiveert. Foetaal rattebotkweek als beschreven door Raisz, J. Clin. Invest. 44: 103-116, 1965 wordt verkregen 45 door ratten met CaCl^ op de 18e dag van de zoogtijd te injecteren.The test in which endotoxin isolated from Acintobacillus actinomycetemcomitans Y4 (AAY4) induces bone resorption in a bone culture system (Kiley and Holt, Infect. Immun. 30: 362-373, 1980) is used to determine whether or not PDP inactivates bone resorptive activity of endotoxin from Y4. Fetal rat bone culture as described by Raisz, J. Clin. Invest. 44: 103-116, 1965 is obtained by injecting rats with CaCl 2 on the 18th day of the lactation period.
De ratten worden daarna op de 19e dag geofferd en de spaakbenen en ellepijpen van de embryo's met hun kraakbeenuiteinden, worden verwijderd 15 en voor kweek in een BGJ medium gebracht (Gibco, Buffalo, NY) bij 37°C met 5% CO , Het medium wordt gesuppleerd met 5% verhit (57°C gedurende 8802140 -9- 3 uur) foetaal kalfsserum. De botten worden in vieren in een putje in schalen met 24 putjes geplaatst (Nunc, Gibco) die per putje 0,5 ml 45 medium bevatte. De afgifte van Ca in de kweekmedia uit bot geincubeerd in aanwezigheid van een proefagens wordt vergeleken met de afgifte uit 5 botten geincubeerd in controlemedia, waarbij de resultaten van de bot-resorptie worden uitgedrukt als een verhouding.The rats are then sacrificed on the 19th day and the spoke legs and ulna of the embryos with their cartilage ends are removed and placed in a BGJ medium for culture (Gibco, Buffalo, NY) at 5 ° C with the medium. is supplemented with 5% heated (57 ° C for 8802140-9 hours) fetal calf serum. The bones are placed in quarters in a well in 24-well dishes (Nunc, Gibco) containing 0.5 ml of medium per well. The release of Ca into the culture media from bone incubated in the presence of a test agent is compared to the release from 5 bones incubated in control media, the results of bone resorption being expressed as a ratio.
Endotoxine uit AAY4 is verkregen van de üniversiteit van Pennsylvania, tandheelkundige afdeling. ΑΔΥ4 endotoxine wordt behandeld met verschillende concentraties van PDP tetrakaliumzout bij 37°C. De 10 overmaat PDP wordt door een dialysemembraan . (3500 molecuulgewicht maximaal) verwijderd. Hierbij kan inreactief PDP wegdiffunderen, terwijl het endotoxine met een molecuulgewicht groter dan 3500 binnen de zak wordt gehandhaafd. Tabel C geeft een samenvatting van de gegevens.Endotoxin from AAY4 is obtained from the University of Pennsylvania dental department. ΑΔΥ4 endotoxin is treated with different concentrations of PDP tetrapotassium salt at 37 ° C. The excess PDP is passed through a dialysis membrane. (3500 molecular weight maximum) removed. In this, inreactive PDP can diffuse away, while the endotoxin with a molecular weight greater than 3500 is retained within the bag. Table C summarizes the data.
TABEL C 45TABLE C 45
Behandeling Aantal Ca vrijgegeven Test/ Significant ratten + S.D. Controle _ % _ _ _ 1. Controle 6 30,11 ±1,98 2. 10 ug/ml 6 85,46+4,71 2,87±0,16 97% vergeleken endotoxine met 1Treatment Number of Ca released Test / Significant rats + S.D. Control _% _ _ _ 1. Control 6 30.11 ± 1.98 2.10 µg / ml 6 85.46 + 4.71 2.87 ± 0.16 97% compared endotoxin with 1
Y4 AAY4 AA
3. 10 ug/ml 6 78,47 + 2,9 2,61+0,1 niet endotoxine significant voorbehandeld met3.10 µg / ml 6 78.47 + 2.9 2.61 + 0.1 non-endotoxin significantly pretreated with
100 mcg PDP100 mcg PDP
4. 10 ug/ml 6 31,98+4,27 1,06±0,14 97% vergeleken endotoxine met 2 voorbehandeld met4.10 µg / ml 6 31.98 + 4.27 1.06 ± 0.14 97% compared endotoxin with 2 pretreated with
1000 mcg PDP1000 mcg PDP
De gegevens tonen aan dat endotoxine uit Y4 AA significant bot-15 resorptie induceerde (vergelijk 1 met 2) terwijl door een voorbehandeling van het endotoxine met 1000 mcg/ml PDP (0,1%) op effectieve wijze de bot-resorptie-activiteit van het endotoxine wordt belemmerd.The data show that endotoxin from Y4 AA significantly induced bone resorption (compare 1 to 2) while by pretreatment of the endotoxin with 1000 mcg / ml PDP (0.1%) effectively the bone resorption activity of the endotoxin is inhibited.
De voomoemde resultaten in voorbeelden I-III zijn representatief voor het effect van PDP tetrakaliumzout en andere niet-giftige 20 wateroplosbare farmaceutisch aanvaardbare PDP-zouten, zoals andere alka- SS δ 214 0 -10- ν' ν' limetaalzouten, zinkzout en tinzout alsmede alkirl PDP-zouten en andere organische PDP-verbindingen, in het bijzonder met inbegrip van de adenylyl-, guanylyl-, citosylyl- en thylmylylesters en kwaternaire ammonium PDP-zouten voor het remmen van chemotaxis geïnduceerd door 5 endotoxine-gegenereerde factor in serum en voor het remmen van de endo-toxine giftigheid ten opzichte van bot in ratten, konijnen en zoogdieren in het algemeen- 8602140The aforementioned results in Examples I-III are representative of the effect of PDP tetrapotassium salt and other non-toxic water-soluble pharmaceutically acceptable PDP salts, such as other alkali δ 214 0 -10-ν 'ν' limetal salts, zinc salt and tin salt as well as alkirl PDP salts and other organic PDP compounds, in particular including the adenylyl, guanylyl, citosylyl and thylmylyl esters and quaternary ammonium PDP salts for inhibiting chemotaxis induced by serum endotoxin-generated factor and inhibiting endotoxin toxicity to bone in rats, rabbits and mammals in general- 8602140
Claims (10)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US76839685A | 1985-08-22 | 1985-08-22 | |
| US76839685 | 1985-08-22 | ||
| US85191586A | 1986-04-14 | 1986-04-14 | |
| US85191586 | 1986-04-14 |
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| Publication Number | Publication Date |
|---|---|
| NL8602140A true NL8602140A (en) | 1987-03-16 |
Family
ID=27118049
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8602140A NL8602140A (en) | 1985-08-22 | 1986-08-22 | METHOD FOR PREVENTING A HYPOTENSIVE SHOCK AND LOCALIZED BONE RESORPTION CAUSED BY BACTERIAL ENDOTOXINS. |
Country Status (12)
| Country | Link |
|---|---|
| BE (1) | BE905319A (en) |
| CA (1) | CA1282004C (en) |
| CH (1) | CH670046A5 (en) |
| DE (1) | DE3627759A1 (en) |
| DK (1) | DK168513B1 (en) |
| FR (1) | FR2586351B1 (en) |
| GB (1) | GB2180451B (en) |
| HK (1) | HK593A (en) |
| IT (1) | IT1196587B (en) |
| NL (1) | NL8602140A (en) |
| SE (1) | SE468626B (en) |
| SG (1) | SG108892G (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2586350B1 (en) * | 1985-08-22 | 1992-05-15 | Colgate Palmolive Co | PHARMACEUTICAL COMPOSITION BASED ON PEROXODIPHOSPHATE FOR INHIBITION OF SECRETION OF PARATHYROIDIAN HORMONE |
| DE4201858A1 (en) * | 1992-01-24 | 1993-07-29 | Renschler Aloys Dr Med | AGENT FOR TREATING MALIGNER CELLS |
| NO20024880L (en) * | 2002-03-19 | 2003-09-22 | Per Hamre | Composition containing phosphate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4041149A (en) * | 1976-01-12 | 1977-08-09 | Colgate-Palmolive Company | Composition and method of controlling and preventing mouth odor |
| US4430325A (en) * | 1981-12-23 | 1984-02-07 | Colgate-Palmolive Company | Topical treatment of skin lesions |
| DK168191B1 (en) * | 1984-06-27 | 1994-02-28 | Colgate Palmolive Co | Use of peroxydiphosphates for the preparation of pharmaceutical tablets or pharmaceutical aqueous solutions |
| US4975423A (en) * | 1984-06-27 | 1990-12-04 | Colgate-Palmolive Company | Inhibition of tumor development |
-
1986
- 1986-08-16 DE DE19863627759 patent/DE3627759A1/en not_active Ceased
- 1986-08-18 FR FR868611812A patent/FR2586351B1/en not_active Expired - Lifetime
- 1986-08-19 SE SE8603486A patent/SE468626B/en not_active IP Right Cessation
- 1986-08-19 IT IT48389/86A patent/IT1196587B/en active
- 1986-08-21 CA CA000516466A patent/CA1282004C/en not_active Expired - Lifetime
- 1986-08-22 BE BE0/217073A patent/BE905319A/en not_active IP Right Cessation
- 1986-08-22 GB GB8620482A patent/GB2180451B/en not_active Expired
- 1986-08-22 CH CH3377/86A patent/CH670046A5/de not_active IP Right Cessation
- 1986-08-22 DK DK402086A patent/DK168513B1/en not_active IP Right Cessation
- 1986-08-22 NL NL8602140A patent/NL8602140A/en not_active Application Discontinuation
-
1992
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1993
- 1993-01-07 HK HK5/93A patent/HK593A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE468626B (en) | 1993-02-22 |
| FR2586351B1 (en) | 1991-10-18 |
| GB8620482D0 (en) | 1986-10-01 |
| DE3627759A1 (en) | 1987-03-19 |
| HK593A (en) | 1993-01-15 |
| DK168513B1 (en) | 1994-04-11 |
| IT8648389A0 (en) | 1986-08-19 |
| FR2586351A1 (en) | 1987-02-27 |
| GB2180451B (en) | 1989-10-18 |
| DK402086D0 (en) | 1986-08-22 |
| DK402086A (en) | 1987-02-23 |
| SE8603486L (en) | 1987-02-23 |
| CA1282004C (en) | 1991-03-26 |
| SE8603486D0 (en) | 1986-08-19 |
| SG108892G (en) | 1992-12-24 |
| CH670046A5 (en) | 1989-05-12 |
| GB2180451A (en) | 1987-04-01 |
| IT1196587B (en) | 1988-11-16 |
| BE905319A (en) | 1987-02-23 |
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