CN100337549C - 益生素和益生菌组合物及其在肠道疾病治疗中的用法 - Google Patents
益生素和益生菌组合物及其在肠道疾病治疗中的用法 Download PDFInfo
- Publication number
- CN100337549C CN100337549C CNB028100786A CN02810078A CN100337549C CN 100337549 C CN100337549 C CN 100337549C CN B028100786 A CNB028100786 A CN B028100786A CN 02810078 A CN02810078 A CN 02810078A CN 100337549 C CN100337549 C CN 100337549C
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- urea
- adsorbent
- described pharmaceutical
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 43
- 239000006041 probiotic Substances 0.000 title claims abstract description 23
- 235000018291 probiotics Nutrition 0.000 title claims abstract description 23
- 230000000529 probiotic effect Effects 0.000 title claims description 23
- 238000000034 method Methods 0.000 title abstract description 21
- 235000013406 prebiotics Nutrition 0.000 title abstract 2
- 238000002560 therapeutic procedure Methods 0.000 title description 5
- 241000894006 Bacteria Species 0.000 claims abstract description 50
- 208000037157 Azotemia Diseases 0.000 claims abstract description 25
- 208000009852 uremia Diseases 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910001868 water Inorganic materials 0.000 claims abstract description 21
- 208000024891 symptom Diseases 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 16
- 108010046334 Urease Proteins 0.000 claims abstract description 13
- 239000002250 absorbent Substances 0.000 claims abstract description 8
- 230000002745 absorbent Effects 0.000 claims abstract description 8
- 229910052816 inorganic phosphate Inorganic materials 0.000 claims abstract description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 102
- 239000004202 carbamide Substances 0.000 claims description 53
- 239000003463 adsorbent Substances 0.000 claims description 50
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 21
- 230000001580 bacterial effect Effects 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 229920000161 Locust bean gum Polymers 0.000 claims description 16
- 235000010420 locust bean gum Nutrition 0.000 claims description 16
- 239000000711 locust bean gum Substances 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 12
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 claims description 12
- 244000005700 microbiome Species 0.000 claims description 12
- 206010051640 Ammoniuria Diseases 0.000 claims description 11
- 241000186000 Bifidobacterium Species 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000002699 waste material Substances 0.000 claims description 9
- 229920002494 Zein Polymers 0.000 claims description 8
- 239000005019 zein Substances 0.000 claims description 8
- 229940093612 zein Drugs 0.000 claims description 8
- 241000726221 Gemma Species 0.000 claims description 7
- 229920000615 alginic acid Polymers 0.000 claims description 7
- 229920001542 oligosaccharide Polymers 0.000 claims description 7
- 235000010443 alginic acid Nutrition 0.000 claims description 6
- 238000009825 accumulation Methods 0.000 claims description 5
- 230000002503 metabolic effect Effects 0.000 claims description 5
- 150000002482 oligosaccharides Chemical class 0.000 claims description 5
- 208000012868 Overgrowth Diseases 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000000835 fiber Substances 0.000 claims description 4
- -1 levulan oligosaccharides Chemical class 0.000 claims description 4
- 239000003053 toxin Substances 0.000 claims description 4
- 231100000765 toxin Toxicity 0.000 claims description 4
- 206010010356 Congenital anomaly Diseases 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 235000003805 Musa ABB Group Nutrition 0.000 claims description 3
- 240000008790 Musa x paradisiaca Species 0.000 claims description 3
- 235000015266 Plantago major Nutrition 0.000 claims description 3
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000783 alginic acid Substances 0.000 claims description 3
- 229960001126 alginic acid Drugs 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229940118199 levulan Drugs 0.000 claims description 3
- 241000193395 Sporosarcina pasteurii Species 0.000 claims description 2
- 241000186652 Sporosarcina ureae Species 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 229910021536 Zeolite Inorganic materials 0.000 claims 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims 1
- 239000000920 calcium hydroxide Substances 0.000 claims 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims 1
- 235000011116 calcium hydroxide Nutrition 0.000 claims 1
- 230000007812 deficiency Effects 0.000 claims 1
- 230000000593 degrading effect Effects 0.000 claims 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims 1
- 239000010457 zeolite Substances 0.000 claims 1
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 56
- 229940109239 creatinine Drugs 0.000 abstract description 28
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 19
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 19
- 229940116269 uric acid Drugs 0.000 abstract description 19
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 6
- 150000002475 indoles Chemical class 0.000 abstract description 6
- 238000001179 sorption measurement Methods 0.000 abstract description 4
- 229960003742 phenol Drugs 0.000 abstract description 3
- 239000002594 sorbent Substances 0.000 abstract description 2
- 239000002441 uremic toxin Substances 0.000 abstract 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 46
- 210000003734 kidney Anatomy 0.000 description 44
- 210000000936 intestine Anatomy 0.000 description 32
- 229910021529 ammonia Inorganic materials 0.000 description 23
- 238000000502 dialysis Methods 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 241000700159 Rattus Species 0.000 description 18
- 238000010521 absorption reaction Methods 0.000 description 17
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 230000012010 growth Effects 0.000 description 16
- 208000020832 chronic kidney disease Diseases 0.000 description 15
- 230000000968 intestinal effect Effects 0.000 description 15
- 208000001647 Renal Insufficiency Diseases 0.000 description 11
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 11
- 201000006370 kidney failure Diseases 0.000 description 11
- 238000011282 treatment Methods 0.000 description 10
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 description 9
- 101000994673 Urodacus yaschenkoi Potassium channel toxin alpha-KTx 6.21 Proteins 0.000 description 9
- 230000009286 beneficial effect Effects 0.000 description 9
- 210000001072 colon Anatomy 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 210000000056 organ Anatomy 0.000 description 9
- 210000002784 stomach Anatomy 0.000 description 9
- 235000013305 food Nutrition 0.000 description 8
- 239000001254 oxidized starch Substances 0.000 description 8
- 235000013808 oxidized starch Nutrition 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 241000588724 Escherichia coli Species 0.000 description 7
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000004060 metabolic process Effects 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 206010012735 Diarrhoea Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 150000001720 carbohydrates Chemical class 0.000 description 6
- 235000014633 carbohydrates Nutrition 0.000 description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 230000029087 digestion Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 description 6
- 229960000511 lactulose Drugs 0.000 description 6
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 210000000813 small intestine Anatomy 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000002700 urine Anatomy 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
- 229920001202 Inulin Polymers 0.000 description 5
- 240000001046 Lactobacillus acidophilus Species 0.000 description 5
- 235000013956 Lactobacillus acidophilus Nutrition 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 5
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 5
- 229940029339 inulin Drugs 0.000 description 5
- 229940039695 lactobacillus acidophilus Drugs 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 239000001856 Ethyl cellulose Substances 0.000 description 4
- 241000186660 Lactobacillus Species 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 244000052616 bacterial pathogen Species 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 201000000523 end stage renal failure Diseases 0.000 description 4
- 235000019325 ethyl cellulose Nutrition 0.000 description 4
- 229920001249 ethyl cellulose Polymers 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 208000017169 kidney disease Diseases 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 229940039696 lactobacillus Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- 238000013059 nephrectomy Methods 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000002689 soil Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 208000010643 digestive system disease Diseases 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 210000005095 gastrointestinal system Anatomy 0.000 description 3
- 208000018685 gastrointestinal system disease Diseases 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 229960004198 guanidine Drugs 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 210000000987 immune system Anatomy 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000002980 postoperative effect Effects 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 230000022558 protein metabolic process Effects 0.000 description 3
- 238000001878 scanning electron micrograph Methods 0.000 description 3
- 150000004666 short chain fatty acids Chemical class 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 2
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 241000252983 Caecum Species 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 108010001394 Disaccharidases Proteins 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 244000199885 Lactobacillus bulgaricus Species 0.000 description 2
- 235000013960 Lactobacillus bulgaricus Nutrition 0.000 description 2
- 244000199866 Lactobacillus casei Species 0.000 description 2
- 235000013958 Lactobacillus casei Nutrition 0.000 description 2
- 240000006024 Lactobacillus plantarum Species 0.000 description 2
- 235000013965 Lactobacillus plantarum Nutrition 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920000153 Povidone-iodine Polymers 0.000 description 2
- 208000033626 Renal failure acute Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000194020 Streptococcus thermophilus Species 0.000 description 2
- 208000010513 Stupor Diseases 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 230000007950 acidosis Effects 0.000 description 2
- 208000026545 acidosis disease Diseases 0.000 description 2
- 201000011040 acute kidney failure Diseases 0.000 description 2
- 208000012998 acute renal failure Diseases 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000013196 antibiotherapy Methods 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000003183 carcinogenic agent Substances 0.000 description 2
- 210000004534 cecum Anatomy 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000002016 disaccharides Chemical class 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 230000024924 glomerular filtration Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- XVARCVCWNFACQC-RKQHYHRCSA-N indican Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CNC2=CC=CC=C12 XVARCVCWNFACQC-RKQHYHRCSA-N 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229940004208 lactobacillus bulgaricus Drugs 0.000 description 2
- 229940017800 lactobacillus casei Drugs 0.000 description 2
- 229940072205 lactobacillus plantarum Drugs 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 244000005706 microflora Species 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 229960001621 povidone-iodine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 244000000000 soil microbiome Species 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 229940045136 urea Drugs 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- WURBVZBTWMNKQT-UHFFFAOYSA-N 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one Chemical compound C1=NC=NN1C(C(=O)C(C)(C)C)OC1=CC=C(Cl)C=C1 WURBVZBTWMNKQT-UHFFFAOYSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000000592 Artificial Cell Substances 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 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
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 208000001019 Inborn Errors Metabolism Diseases 0.000 description 1
- 208000008081 Intestinal Fistula Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000010538 Lactose Intolerance Diseases 0.000 description 1
- 241000736262 Microbiota Species 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 101000869659 Mus musculus Relaxin receptor 2 Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000588912 Pantoea agglomerans Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 241000588767 Proteus vulgaris Species 0.000 description 1
- 229920000297 Rayon Polymers 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 229920000294 Resistant starch Polymers 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000009470 Theobroma cacao Nutrition 0.000 description 1
- 241000294142 Vascellum Species 0.000 description 1
- 239000011358 absorbing material Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000009840 acute diarrhea Diseases 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000019169 all-trans-retinol Nutrition 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003409 anti-rejection Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000009028 cell transition Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000019902 chronic diarrheal disease Diseases 0.000 description 1
- 210000004913 chyme Anatomy 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000000028 corpus adiposum pararenale Anatomy 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 235000013325 dietary fiber Nutrition 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007160 gastrointestinal dysfunction Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- BXFFHSIDQOFMLE-UHFFFAOYSA-N indoxyl sulfate Natural products C1=CC=C2C(OS(=O)(=O)O)=CNC2=C1 BXFFHSIDQOFMLE-UHFFFAOYSA-N 0.000 description 1
- XVARCVCWNFACQC-UHFFFAOYSA-N indoxyl-beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CNC2=CC=CC=C12 XVARCVCWNFACQC-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229940066544 lactobacillus sporogenes Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000002366 lipolytic effect Effects 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000020905 low-protein-diet Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 235000020166 milkshake Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 108700011006 mouse mighty Proteins 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 230000002632 myometrial effect Effects 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 210000001819 pancreatic juice Anatomy 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000003415 peat Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000002694 phosphate binding agent Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 229940007042 proteus vulgaris Drugs 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 235000021254 resistant starch Nutrition 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000021262 sour milk Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
- LEHFSLREWWMLPU-UHFFFAOYSA-B zirconium(4+);tetraphosphate Chemical compound [Zr+4].[Zr+4].[Zr+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O LEHFSLREWWMLPU-UHFFFAOYSA-B 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
- A61K33/08—Oxides; Hydroxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/742—Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/745—Bifidobacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/483—Gleditsia (locust)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/68—Plantaginaceae (Plantain Family)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5052—Proteins, e.g. albumin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/51—Bifidobacterium
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Microbiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种微囊化和/或肠衣包被的组合物,其包括益生菌、益生素和具有高尿素酶活性的亲氨细菌的混合物,所述混合物含有或不含有对诸如肌酸酐、尿酸、酚、吲哚、中等分子量的分子以及无机磷酸盐的尿毒性毒素有特异亲和力的吸附剂,以及包括水吸附剂。本发明还提供了缓解病人体内***症状的方法,所述方法包括给患有***的病人口服施用微胶囊化和/或肠衣包被的组合物。
Description
发明领域
本发明涉及药物组合物以及使用所述组合物通过排除毒素和其它代谢废物以及减少或抑制不需要的细菌过度生长来治疗肾、肝及肠胃疾病的方法。在一个实施方案中,所述药物组合物包括一种益生素,一种益生菌,一种亲氨细菌,以及吸附剂,上述所有物质均被微囊化和/或肠衣包被起来。或者,所述益生素,益生菌和亲氨细菌聚集在一个微胶囊中给药,而如果需要的话,所述吸附剂单独以一个微囊化的和/或肠衣包被的制剂给药。这些药物组合物对于治疗肾病和肝病以及胃肠道***细菌的过度生长是有用的。
发明背景
在美国,肾脏疾病在主要疾病中位居第四,超过20,000,000的美国人为此痛苦。每年,超过90,000的病人死于肾脏疾病。近几年来,慢性肾衰竭的人数已经以每年11%的速率增长。每年大约80,000透析的美国人死于不同的并发症并且每年名单上有超过27,000人正在等待肾移植而他们当中只有约11,000病人接受肾移植。此外,将近250,000的美国人患有慢性肾衰竭的最后阶段—末期肾病(ESRD)。
通常,健康人的氮代谢废物主要通过肾脏以尿素形成从尿液中排出。然而,对于患有肾病以及许多其它疾病如尿循环酶先天缺乏的个体来说,废氮在体内积累从而出现中毒症状。铵过多会导致智力迟钝,严重的话,会导致昏迷。
目前,血液或腹膜透析和肾移植是唯一的治疗方式。然而,这些治疗方式的费用非常高。比如,1996年单单在美国,ESRD的年治疗费用超过140亿美元。在卫生保健预算较低的发展中国家和欠发达国家,由于高额的治疗费用,ESRD病人无法利用上述方式治病。因此,还需要治疗***的替代方式。
许多治疗试验一直建立在用肠代替肾起作用的基础上。在正常的消化过程中肠胃***传递营养物和水到血液中并且通过肠道排除废物和未消化物。肠壁调节营养物、电解质、水和某些助消化物质如胆汁酸的吸收。肠壁也起到半透膜的作用,允许小分子从肠道进入血液并阻止大分子进入循环。
氮废物如尿素、肌酸酐和尿酸以及某些其它小的和中等分子量化合物流入到小肠中并且跨越小肠上皮平衡。肠道透析研究已经显示进入肠液的日流量为尿素71克,肌酸酐2.9克,尿酸2.5克和2.0克的磷酸盐(Sparks,R.E.Kidney Int.Suppl.1975 Suppl 3,7:373-376)。从而,人们已经做了各种介入性和非介入性的尝试从胃肠道中提取***废物,这些尝试包括外部肠瘘,肠道透析,导泄,口服吸附剂和/或胶囊尿素酶给药(Twiss,E.E.和Kolff,W.J.JAMA 1951 146:1019-1022;Clark等,Trans.Am.Soc.Artif.Intrn.Organs 19628:246-251;Pateras等,Trans.Am.Soc.Artif.Intrn.Organs 196511:292-295;Shimizu等,Chemical Abstracts 1955103:129004;Kjellstrand等,Trans.Am.Soc.Artif.Intern.Organs 198127:24-29;以及Kolff,W.J.Kidney Int.1976 10:S211-S214)。
活性炭是第一个用来治疗***的口服吸附剂。活性炭是一种具有大的表面积的高度多孔材料,它是有机材料如木头、石油、煤、泥炭和椰子壳炭化后再经过蒸汽、二氧化碳或化学药品如氯化锌活化后获得的。活性炭的溶质吸附取决于许多因素,包括体相中溶质的浓度,溶质的化学性质,温度和pH值。而总体上说,相对于极性溶质,活性炭更易于吸收非极性溶质。在体内实验中,190克活性炭需要除去450毫克肌酸酐(Goldenhersh等,Kidney Int.197610:8251-8253)。这一减少的效力被认为是由于它还吸收了其它亲脂性的化合物如胆固醇和相关的胆汁酸(Kolff,W.J.Kidney Int.1976 10:8211-8214;Goldenhersh等,Kidney Int.1976 10:8251-8253)。微囊化的活性炭表明所需炭的数量可以减少到50克(Goldenhersh等,Kidney Int.1976 10:8251-8253)。
AST-120是一种专有的经特制的0.2-0.4毫米多孔炭的包被材料,已经证实它是一种更为有效的炭基吸附剂。已经公开,施用3.2至7.2克剂量到***病人身上可以延缓血液肌酸酐水平的上升,并且延迟了肾切除大鼠和27个***病人肾功能异常的发作(Owadu,A.和Shiigai,T.Am.J.Nephrol.1996 16(2):124-7;及Okada,K.Takahashi,S.Nephrol.Dial.Transplant.1995 10(5):671-6)。AST-120作为口服吸附剂也延迟了肾衰竭的发展(Miyazaki,T等,Nephrol Dial Transplant 2000Nov;15(11):1773-81)。
一些研究已经表明,摄入二醛基淀粉,也指氧化淀粉,会导致非蛋白氮的***量增长(Giordano等,Bull.Soc.Ital.Biol.Sper.1968 44:2232-2234;Giordano等,Kidney Int.1976 10:S266-8268;Friedman等,Proc.Clin.Dia.Trans.Forum 1977 7:183-184).不象活性炭吸附尿毒性溶质是一种容易可逆的物理过程,二醛基淀粉是通过包括共价结合二醛基的化学吸附来结合尿素和氨的。然而,象活性炭一样,摄入大量的大约30-50克的含氧淀粉仅能除去1.5克的尿素。二醛基淀粉和活性炭都摄入的其他研究证实了一些***废物去除的改进(Friedman等,Proc.Clin.Dia.Trans.Forum 19777:183-184)。而且,与未包被的二醛基淀粉相比,用明胶和白蛋白包被的二醛基淀粉的吸附结果要好6倍(Shimizu等,Chemical Abstracts 198297:222903)。最近,慢性肾衰竭在给药包被有氧化纤维素(oxycel)或纤维素二醛的壳聚糖之后显示发展延迟(Nagano等,Medline Abstract UI 96058336 1995)。
刺槐豆胶是一种可天然获得的以碳水化合物为基础的聚合口服吸附剂,将其以25克/天的剂量于棉籽油中给药于***病人,也可证明去除了大量的尿素、肌酸酐和磷酸盐。而且,刺槐豆胶吸附了大约10倍自身重量的水(Yatzidis等,Clinical Nephrology 197911:105-106)。通过饮食补充***纤维胶也被证明可使低蛋白饮食的慢性肾衰竭病人粪便中的氮***量增加以及血清氮浓度减少(Bliss等,Am.J.Clin.Nutr.1996 63:392-98)。
胶囊化的尿素酶也已被试验作为一种不可吸收的口服吸附剂来结合氨。在早期大量研究中,磷酸锆和胶囊化的尿素酶被用作一种不可吸收的口服吸附剂来结合氨(Kjellstrand等,Trans.Am.Soc.Artif.Intern.Organs 1981 27:24-29)。还研究了使用一种具有胶囊化尿素酶的液体膜胶囊装置将尿素水解为氨和柠檬酸以中和氨的方法(Asher等,KidneyInt.1976 10:8254-8258)。土壤细菌也被用来将尿素再生成为代谢有用的氨基酸(Setala,K.Kidney Intl Suppl.1978 8:8194-202)。
此外,遗传工程细胞E.herbicola也已被胶囊化并证明它可在氨经肠道排出之前将其转变成为对细胞有用的氨基酸。微囊化的遗传工程细胞大肠杆菌(E.coli)DH5在体外***和***大鼠动物模型中也已显示出去除尿素和氨的有效性(Prakash,S.和Chang,T.M.S.Biotechnology and Bioengineering 1995 46:621-26;及Prakash,S.和Chang,T.M.S.Nature Med.19962:883-887)。然而,基因工程菌株的给药带来控制和安全担心以及增加的伦理问题可能导致病人不服从用药。
为了有效治疗肾衰竭,而且,已经估计出至少10至25.0克的尿素,1.0至2.5克的肌酸酐,0.7至1.5克的尿酸必须去除。因此,需要更为有效的治疗方法去除高浓度的多种尿毒素以缓解***病人的症状。
小肠细菌生长过度(SBO)也是肾衰竭发展的另外一个临床症状,其肾小球滤过率降到低于20ml/分钟。含氮废物流入小肠。结果,细菌更加过度生长,同时有益菌和致病菌的比例发生改变,这些致病菌可以产生次级毒素物质,这些次级毒素物质有致癌和诱变化合物如胺类,亚硝基胺类,酚类和吲哚衍生物。
人的胃肠道***隐藏着复杂的微生物生态***,包括大量的各种各样的细菌。这些在人的胃肠道中定居的细菌群主要影响着胃肠的功能,从而影响着人的健康和幸福。在此当中,一些细菌是条件性的或者被认为是有害的并能导致不利状况,如腹泻、感染、胃肠炎和内毒素血症,而一些菌种被认为是“益生菌”,它们对人类有机体起有益作用(Holzapfel WH等,Int J Food Microbiol 1998 May 26;41(2):85-101)。
在这些益生菌中,双歧杆菌是最突出的。当双歧杆菌活着并有存活能力时,它可以刺激免疫***并发挥竞争性作用排除致病和腐败细菌,减少血液中氨和胆固醇的数量,并可促进矿物质的吸收。此外,双歧杆菌已经被证明对结肠癌有预防作用,它能使一些酶的活性减少,这些酶将前致癌物转化为致癌物(von Wright等,Eur J GastroenterolHepatol 1999 Nov;11(11):1195-1198)。
乳酸菌如保加利亚乳杆菌(Lactobacillus bulgaricus),嗜酸乳杆菌(Lactobacillus acidophilus),干酪乳杆菌(Lactobacillus casei),植物乳杆菌(lactobacillus plantarum)和粪链球菌(streptococcus faecium),嗜热链球菌(Streptococcus thermophilus)也是益生菌。这些细菌对于病原微生物产生拮抗作用,刺激免疫***,改善乳糖消化,具有使脂肪更多消化的脂解活性,减少血浆的胆固醇值,保护肠粘膜以确保营养物质有均匀的消化吸收,产生在一些肿瘤中有活性的多糖,以及使一些产酶的微生物成活力降低,所述酶可催化前致癌物转变成为致癌物。
益生菌被认为能以协同的方式发挥作用从而减少并延迟肠道的致病菌/有害细菌的生长(Marteau,PR等,Am J Clin Nutr Feb;73(2Suppl):430S-436S;Cummings JH等,Am J Clin Nutr 2001 Feb;73(2Suppl):415S-420S)。
在接受抗生素治疗或其它疗法的病人体内,以及在患有肠炎,肾病和肝病的个体内,肠道细菌群能够减少,变得不平衡或者被除去。此外,已经表明,在正常衰老过程中,双歧杆菌种群在减少而致病菌和腐败细菌的浓度随之在增加(Orrhage K等,Drugs Exp Clin Res 2000;26(3):95-111)。
已知象双歧杆菌这样的微生物的有益作用部分是由于它们具有发酵结肠中存在的不易消化的糖的能力,这种糖就是通常所说的益生素。益生素是一种不易消化的食品成分,它通过选择性地刺激结肠中一个或有限数量细菌的生长和/或活性来有益地影响着宿主。益生素通常被认为是具有相对短链的碳水化合物。与其它碳水化合物如非淀粉多糖,糖醇和抗性淀粉一样,益生素可以到达盲肠成为发酵的基质。然而,它们在选择性影响微生物区系上是有区别的。为了有效,它们必须到达盲肠(Bezkorovainy,A.Am J Clin Nutr 2001 Feb;73(2Suppl):399S-405S)。
能够发挥最佳益生素效果的不易消化的寡糖是菊粉型果聚糖,它能抵抗被体内的胃酸和胰酶消化。在纯培养基中,大多数双歧杆菌适合利用这些不易消化的寡糖。然而,许多其它细菌也能代谢它们。当菊粉和寡果糖或乳果糖(Lactulose)被加入到受控饮食中时,结肠中的双歧杆菌群出现显著增长,而这些变化通过调整肠道微生物区系促进了结肠和全身健康。菊粉和寡果糖由结肠的微生物区系迅速而完全地发酵,其发酵产物为醋酸盐和其它短链脂肪酸。菊粉、乳果糖和其它不可吸收的碳水化合物的有效性起源于它们都是二糖或寡糖并且人的胃肠道缺乏二糖酶来水解它们这一事实。这些可发酵的碳水化合物于是没有被消化就进入结肠。在结肠中,具有二糖酶的定居菌群能够水解这些寡糖或二糖并且把它们当作能量并用于生长。在这一过程中,它们产生了大量的酸化肠道的短链脂肪酸,并通过渗透机理,将水汲取到肠腔内,提供通便作用,阻止生长过度,并使得氨和其它废物氮易于清除。象乳果糖一样,它们也可以导致粪便生物量的增长,并在这种情况下,捕获氨用于合成细菌蛋白或者将其转变成铵离子。通过刺激细菌生长和发酵,益生素也影响了肠习惯并会发生轻度腹泻(Jenkins,DJ等,J Nutr 1999 Jul;129(7Suppl):1431S-1433S)。
美国专利5,733,568教导使用微囊化的乳杆菌治疗与抗生素相关的或其它急性或慢性腹泻以及皮肤和***真菌感染的方法。所述微囊化据说能抑制杆菌的失活并且将其传送至肠道中也避免了腹泻中见到的乳糖不耐性。
美国专利5,032,399教导使用嗜酸乳杆菌附着在肠粘膜上,从而减少了抗生素疗法对于胃肠道的副作用,抗生素疗法能削弱有益菌群。
美国专利5,531,988除了有益细菌外还教导在组合物中使用免疫球蛋白作为补充饮食。
美国专利5,840,318也教导一种能够调节动物免疫***的有益细菌组合物。
使用诸如嗜酸乳杆菌的益生菌已提示能够减少细菌的过度生长和尿毒素与致癌物的积累。***病人饮食中不可吸收的碳水化合物也表明益生菌可以增加氮***量。使用乳果糖和食用纤维也显示可减少血浆尿素11-27%并使粪便中氮的***量增至39-62%(Wrong,O.,Nature Medicine 2-3,1997)。
然而,上述这些现有技术方法的主要问题之一是,它们倾向于针对个别的尿毒性溶质或毒素。然而临床上,肾、肝和胃肠疾病或紊乱事实上需要减轻多种症状。
发明概述
本发明的目的是为肾机能不全、肝机能不全、尿素代谢先天性障碍以及胃肠紊乱和疾病提供一种完整的、以肠为基础的、低成本的替代治疗方法。本发明不同于现有技术的是,可以同时减缓一个以上的症状。而且,肠内菌群在恢复正常健康状况的有益效果可以加以控制。
因此,本发明提供了一种包含益生菌的药物组合物,可使有益菌和有害菌恢复正常的平衡,除去正常蛋白代谢的过量尿素废物,从而减轻病态肾的负担,还可除去氨以避免智力迟钝和相关症状。本发明的药物组合物还包含一种益生素,可刺激有益菌群,也可确保益生菌的活力,以便使尿素和氨等氮源可以被有效利用。此外,该药物组合物可以包含一种具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物。在一些实施方式中,益生菌可以恢复有益菌和有害菌之间正常平衡,除去正常蛋白代谢的过量尿素废物从而减轻病态肾的负担,还可除去氨以避免智力迟钝和相关症状,以及可用作亲氨尿素降解微生物。
在一个实施方式中,本发明的药物组合物可以进一步包含一种水吸附剂,以在腹泻和肾机能不全时除去水,还包含吸附剂混合物,它能除去其它氮代谢废物和细胞过度生长产物如尿酸、肌酸酐和胍,以及酚和吲哚,和/或无机磷酸盐吸附剂以保持磷酸盐平衡。在优选的实施方式中,活性炭和无机磷酸盐吸附剂在组合物中组合在一起以产生协同效应并可减少这两种成分相对于益生菌和益生素的相对比例。而且,由于益生菌和益生素除去了大部分的尿素并削弱了细菌的过度生长,所以其它正常氮废物和细菌终产物的量被降到最小,因而比起现有技术的组合物,本申请的组合物需要较少的活性炭和无机吸附剂。
此外,药物组合物包含一种益生菌和益生素,和亲氨微生物,它可以预防性地用于由于疾病发展而患有***的急性或慢性症状的病人,仅当必须控制腹泻或其它胃肠紊乱时,水吸附剂、吸附剂混合物和/或无机磷酸盐吸附剂可以单独给药。
本发明的药物组合物最好用肠衣包被或微囊化,用于传送至需要它的病人肠内的回肠或结肠区域。
该药物组合物尤其用于阻止或延迟肾病患者的透析需要,使透析的频率和持续时间减少。
发明详述
肾衰竭时,肾小球滤过率减少且肾脏不能维持血液的体内平衡。水、钠、钾、钙和其它盐的稳态平衡不再是可能的,且氮废物不能被排出。水滞留导致浮肿,且随着氢离子浓度的增加,产生酸中毒。氮废物积累,一种被称为***的病状产生于血液和组织中。尿毒素可以被定义为具有下列性质的溶质:(i)它们通常由健康的肾排出,(ii)在肾衰竭发展过程中日益积累以致浓度增加,以及(iii)抑制各种生理和生化机能,总之,尿毒素导致了一系列复杂的包含***综合症的临床症状。尿毒素的实例包括但不限于氨、尿素、肌酸酐、酚类、吲哚和中等分子量分子。更具体而言,在***中,血清肌酸酐浓度,血液尿素氮(BUN),尿酸和胍基化合物如N-甲胍(NMG)和胍基琥珀酸(GSA)都随着酸基平衡、电解质和水分保持的异常而产生了显著的改变。另外,还有一些已知的或未知的小的和中等分子量的物质被鉴定为尿毒素,它们也可积累。如果不经治疗,酸中毒和***将导致昏迷并最终导致死亡。
进一步,由于缺乏对代谢废物的清除,出现了一些补偿性和适应性的过程,这使得病状变得更加复杂。例如,当肾功能减少至小于20%并且血清内肌酸酐水平增至8mg/dl时,肠内正常菌群的细菌就会出现过度生长。正常基质代谢基本上增长和大量各种毒性胺如甲胺、二甲胺、三甲胺、酚类和吲哚代谢也在该菌的过度生长物中出现。当小肠细菌生长增长时,氨释放也增加,然而其进入到肠肝循环并转化为尿素。
肾透析的引入为肾衰竭的临床治疗和***解释的快速进步作出了贡献。一个具有轻度肾衰竭病人的血清肌酸酐水平少于400μmol/L,该病人不需要肾脏置换治疗如透析或肾移植。然而,通常当血清肌酸酐水平上升到900μmol/L时,病人需要常规透析或肾移植以维持生命。
对于ESRD病人,透析可以作为一种终身疗法。磷酸盐粘合剂,如乙酸钙、碳酸钙或氢氧化铝,通常也要给接受透析的***病人使用,以减少升高的磷酸水平。而一般来说,透析非常昂贵、不方便、耗费时间并且偶尔产生一种或多种副作用。如果肾移植成功,病人可以过上更正常的生活而不用支出长期的费用。然而,移植手术、恢复期以及需要连续的抗排斥药物治疗仍需高额费用。况且,经常缺少合适的捐赠体。因此需要可替代的方法。
本发明涉及的药物组合物包括益生菌和益生素的混合物,和具有高尿素酶活性的亲氨细菌,和/或对尿毒素具有特定吸附亲和力的吸附剂,所述尿毒素如肌酸酐、尿酸、酚类、吲哚、中等分子量分子和无机磷酸盐,以及水吸附剂,用来减轻***。在一个优选实施方案中,该组合物包括益生菌细菌,益生素如菊粉、果聚糖寡糖、乳果糖以及其它植物纤维,还包括具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物,吸附剂如刺槐豆胶,其对肌酸酐和尿素具有特定的吸附亲和力,对肌酸酐、胍、酚、尿蓝母和中等分子量的不确定成分具有特定亲和力的活性炭,以及水吸附剂如车前子纤维(Psilliumfiber)、瓜尔胶和刺槐豆胶。
优选益生菌的细菌源能够将尿素和氨代谢成尤其可被细菌或病人利用的氨基酸。具有上述特性的典型菌是双歧杆菌和乳杆菌。
巴氏芽孢杆菌(Bacillus pasteurii)和脲芽孢八叠球菌(Sporosarcinaureae)与土壤细菌密切相关,二者均对尿素具有高度的亲和力。这些细菌是非致病且无害的。而且,它们在高浓度的铵离子和碱性pH下生长得很好,这种条件存在于肠内,尤其是***情形中。在巴氏芽孢杆菌和脲芽孢八叠球菌中,不会发生铵积累并且这些有机物依赖于氨跨越细胞膜的被动扩散。巴氏芽孢杆菌和脲芽孢八叠球菌都显示出对铵的低亲和力,Km值分别为55.2mM和36.7mM。相比于只能在中性pH和2mM的低铵浓度下生长的病原体普通变形杆菌(P.vulgaris),巴氏芽孢杆菌和脲芽孢八叠球需要高氨浓度(40mM)和高碱性pH(Kaltwasser,Morsdorf G. H.Arch Microbiol 1989;152(2):125-31)。此外,已知在pH7.5下,脲芽孢八叠球菌的尿素酶比活性为每分钟降解高于9300μmol尿素。
因此,本发明用作亲氨细菌的细菌源的实例包括,但不限于,脲芽孢八叠球菌,巴氏芽孢杆菌,驯化的乳杆菌和芽孢杆菌菌种,以及乳酸菌新种KB-I或其它适合的芽孢杆菌菌种。
在一些实施方式中,益生菌可以用作恢复有益菌和有害菌之间的正常平衡,除去正常蛋白代谢的过剩尿素废物从而减轻病态肾的负担,除去氨来避免智力迟钝和相关症状,还可以作为亲氨尿素降解微生物。因此,在本实施方式中,不需要单独的亲氨尿素降解有机体。取而代之,在本实施方式中,益生菌和亲氨尿素降解有机体包含同菌种的细菌。
含有这些混合物的组合物被肠衣包被和/或被微囊化。组合物的肠衣特定地设计为传送吸附剂和细菌源至肠的回肠和结肠区域,尿素溶质和其他分子可以在此处以最大的吸收出现。这更适宜通过在pH为7.5或更高时崩解和溶解的肠衣物质实现。具有这些特征的肠衣的实例包括,但不限于,玉米蛋白,聚glycolactic acid,聚乳酸,聚丙交酯-乙交酯共聚物和类似的包被物质。肠衣也能将吸附剂在到达靶区域之前以相对天然的形式传送至其作用区域,而不会将消化物质结合到吸附剂上。
此外,本发明的组合物被微囊化,因此如Chang,T.M.S.所述,允许组合物象显微的透析单元一样起作用(人工单元(ArtificialCells),第5章,在“Biomedical Applications of Microencapsulation”,Lim,F.主编CRC Press Florida,第86-100页)。在本实施方式中,组合物包被有一层不宜吸收的聚合物,该聚合物仅能使小的和中等尺寸的分子进入到溶剂混合物和细菌源所在的核心部位。用于微囊化的不易吸收的聚合物包被的实例包括,但不限于,藻酸盐/藻酸,壳聚糖,醋酸邻苯二甲酸盐纤维素,羟乙基纤维素,以及类似的包被物质。微囊化阻止了大分子和其它消化物质的结合,这些物质基本上削弱吸附剂特异性地将尿毒性溶质吸附到混合物的吸附剂中的效力。随着吸附剂混合物吸附多种尿毒性溶质、细菌源代谢尿素、氨和尿素,微囊化囊通过了肠,然后从肠内完整地排出。因而,在本实施方式中,由于细菌源保持在微胶囊中,病人避免了由细菌源引起的微生物感染的可能性。
在本发明的优选方案中,药物组合物既被微囊化,又被肠衣包被。
本发明的药物组合物可进一步包含一种磷酸盐结合剂如氢氧化铝凝胶、碳酸钙或醋酸钙、氢氧化镁凝胶和/或水结合剂如车前子纤维,天然胶,如刺槐豆胶,瓜尔豆胶或改性淀粉。
本申请的药物组合物是口服给药至需要的受试者,从而减缓毒素和代谢废物的集聚和/或抑制或降低受试者中非需要细菌的过度生长。在一个实施方式中,将该药物组合物施于患有***的受试者以减轻***症状。***的“症状减轻”意味着组合物除去了足够水平的尿毒素,以至于患有***的病人不需要透析,或透析频率减少,或透析的持续时间缩短,或不需要马上透析。本发明的组合物也可以施于需要其的受试者,从而不仅治疗肾机能不全和先天性肾代谢障碍,还可治疗肝机能不全和胃肠功能紊乱和疾病。
在优选实施方案中,用2-4盎司的乳液或糊状物混合易于食用的食品如奶昔或酸奶等来口服组合物。微囊化的细菌益生菌和益生素可以与乳状或糊状吸附剂混合物一起给药或单独以可吞咽的明胶胶囊给药。
口服吸附剂溶质传输的数学模型基于溶质受控扩散流入肠腔然后物理结合或化学诱捕已经发展起来(Gotch等,Journal of Dialysis 1976-19771(2):105-144)。这一模型为从肠中除去溶质提供了理论依据。
例如,在正常的肾功能中,尿素的肠清除率是10-12ml/分钟,而对肾功能严重削弱的病人,该值减少到3-4ml/分钟。这种清除率的减少与血液尿素浓度无关,并直接关系到受损的肾功能。正常的肌酸酐清除率是2-5ml/分钟。
进一步,在稳定状态时,由于质量产生率与质量消除率是相同的,第一级吸附剂促进任何溶质的肠内清除,由质量平衡方程式给出:
Gs=(Kr+Kg)Cs
其中Gs=溶质产生率,Kr=肾清除率,Kg=肠清除率,以及Cs=溶质浓度
对于给定数量的吸附剂,吸附结合过程是可饱和的。当低于饱和水平时,由于溶质的肠清除率是第一级的,因而上述平衡可以描述如下:
Cs=Gs/(Kr+Kg)。
当高于饱和水平时,由于肠清除率为零,该等式可写为:
Cs=(Gs-吸附能力)/Kr。
这些等式根据体外研究预测从肠中除去溶质的有效性是有用的。
事实上,通过对***病人的肠道使用氧化淀粉口服吸附剂,该模型被应用到Friedman氏去除尿素数据(Friedman等,Trans.Am.Soc.Artif.Intern.Organs 1974 20:161-167)。通过这些数据,该模型显示天然氧化淀粉口服吸附剂的最大吸附能力是1.5克/天,这不足以取代透析或减少透析频率。这一模型也预测,对于蛋白质分解代谢率为0.95克/千克/24小时和尿素产率为5毫克/分钟的同样的病人资料,氧化淀粉的最大吸附能力应为7.2尿素氮/天以及肠清除率应为5.6毫升/分钟。吸附力低于该值,如5.4克尿素/天,最多会延迟每月透析,只要蛋白分解代谢率保持在0.6克/千克/24小时。这样,该模型对于本发明组合物的不同组成确定最优结是有用的,以减缓病人***症状。
以下不受限制的实施例将对本发明提供进一步的说明。
实施例
实施例1:吸附剂来源
氧化淀粉(二醛基淀粉)购自MPD Labs,Feasterville,PA。这是一种药物级物质(纯度98%),含水量为13%,根据供应商分析证明,具有最小90%的氧化物质。
刺槐豆胶(最小纯度99%)购自Sigma-Aldrich,St.Louis,MO。
活性炭,超A,药物级(纯度99.9%),购自Norit Corporation ofAmerica,GA。每种吸附剂都由玉米蛋白肠衣包被,乙基纤维素(ethocel)微囊化,以及先用乙基纤维素微囊化然后用玉米蛋白肠衣包被作为外壳材料。胶囊化利用圆盘工艺进行运转。三种壳溶液分别加以制备:仅乙基纤维素,仅玉米蛋白,玉米蛋白结合乙基纤维素。壳物质制备完后,各种吸附剂加入到壳溶液中(为了提供60%的理论有效负荷)并混合形成分散液。然后分散液经声波处理并以接近50克/分钟的速度泵送到以接近20,000rpm旋转的圆盘中从而形成微球。这些微球在内部温度将近50℃的热锥体内形成以蒸发掉乙醇和水。胶囊通过旋风分离器收集。天然的粒度和经过各种吸附剂胶囊化后的粒度在表1中描述。
表1
氧化淀粉 | ||
氧化淀粉% | 尿素/肌酸酐/尿酸 | 细菌% |
0.1 | 150/30/30 | 10 |
0.2 | 150/30/30 | 10 |
0.3 | 150/30/30 | 10 |
0.4 | 150/30/30 | 10 |
0.5 | 150/30/30 | 10 |
刺槐豆胶 | ||
刺槐豆胶% | 尿素/肌酸酐/尿酸 | 细菌% |
0.1 | 150/30/30 | 10 |
0.2 | 150/30/30 | 10 |
0.3 | 150/30/30 | 10 |
0.4 | 150/30/30 | 10 |
0.5 | 150/30/30 | 10 |
WATERLOCKTM(A-220) | ||
WL% | 尿素/肌酸酐/尿酸 | 细菌% |
0.1 | 150/30/30 | 10 |
0.2 | 150/30/30 | 10 |
0.3 | 150/30/30 | -10 |
0.4 | 150/30/30 | 10 |
0.5 | 150/30/30 | 10 |
活性炭 | ||
炭% | 尿素/肌酸酐/尿酸 | 细菌% |
0.1 | 150/30/30 | 10 |
0.2 | 150/30/30 | 10 |
0.3 | 150/30/30 | 10 |
0.4 | 150/30/30 | 10 |
0.5 | 150/30/30 | 10 |
单个微生物 | |
尿素/肌酸酐/尿酸 | 接种% |
100/15/15 | 3 |
100/15/15 | 5 |
100/15/15 | 10 |
150/30/30 | 5 |
150/30/30 | 10 |
原材料的扫描电子显微照片(SEM)包括二醛基淀粉,刺槐豆胶,活性炭和氢氧化铝,并且预备了十二种微胶囊配方。第11批产生了棒状胶囊,因其没有直接加料到盘的中间或因其固体含量太高。第13批重复了第11批只是玉米蛋白含量从15%降到12%,结果成功了。
除了每一批的扫描电子显微照片之外,还拍摄了数字光显微照片。
实施例2:大肠杆菌(E.coli)DHS和其它细菌源
依照Chang和Prakash(Biotechnology and Bioengineering 1995 46:621-26)所述的程序,基因工程大肠杆菌DH5经接种后培养,生长,收集并进行微囊化。本发明的益生菌和亲氨细菌也以同样的方式处理。
实施例3:制剂
各种益生菌,益生素和吸附剂与不同的食品添加剂混合形成本发明的不同制剂。它们的一般组分描述于下表2中。
表2:60克剂量中的成分和数量(以B.I.D.摄入量为基础)
成分 | 范围(克) | 最优选量(克) |
益生菌 | 5-20 | 12.5 |
刺槐豆胶 | 10-20 | 15 |
WATERLOCKTM | 1-5 | 3 |
活性炭 | 0.5-2 | 1 |
菊粉 | 1-10 | 5 |
食品添加剂 | ~3-~42 | ~23 |
总计 | 60克 | 60克 |
实施例4:体外效力评价
制备模拟胃液,其含有NaCl,HCl和胃蛋白酶的蒸馏水,pH调节至1.2。根据美国药典规程在酸性pH和胃环境下对制剂的稳定性进行试验。每种改性吸附材料和二元的和三元的制剂都在37℃通过将近5克量的材料搅拌进入模仿胃液的测试溶液中测试1-2小时,以确保改性吸附剂的完整性。
模拟合成的小肠液含有磷酸二氢钾,氢氧化钠,胰酶制剂混合物及蒸馏水,它也是根据美国药典的试液制剂来制备并调节pH至7.5。小肠液用尿毒性溶质强化以得到每100毫升的合成小肠液中含有150毫克尿素,30毫克肌酸酐和30毫克尿酸的溶液。
为改变浓度,原液用非强化的肠原液稀释得到75%和50%浓度的可变的尿毒性肠液。首先,100%、75%和50%浓度的尿毒性肠液由15克吸附制剂来评价,所述吸附制剂分别含有5克的氧化淀粉,刺槐豆胶和活性炭。从这些数据可知,各种实验参数可以被优化,它们包括但不限于,体积、尿毒性肠液浓度和预处理和后处理的时间。优化参数于是用于所有其他吸附剂的评价,配制和实验确定。所有实验的观测重复三次。
然而,最初,含有5,10或15克吸附剂或制剂的吸附剂/制剂试验批次是在量筒中用500毫升不同浓度的强化肠液处理并轻晃8小时进行的。样品以一小时的间隔从上清液中吸出,必要时离心,通过商业上可获得的试剂盒(Sigma Diagnostics Company,St.Louis,MO)分析尿素,肌酸酐和尿酸。一旦吸收能力和平衡时间得以确定,至少估算2小时,这一周期就可使用。
用生孢乳杆菌(Lactobacillus sporogenes),嗜酸乳杆菌,巴氏芽孢杆菌(B.p.)和大肠杆菌(Escherichia coli)DH5(E.c.)通过尿素酶活性来评价它们从强化的人工肠液(FAIF:100/150mg/dL尿素,15/30mg/dL肌酸酐和15/30mg/dL尿酸的水性胰酶制剂,KH2PO4和NaOH)中去除尿素的能力。
在无菌条件下,不同的混合物中,各天然细菌,活性炭和刺槐豆胶分别加入到50毫升FAIF中并在37℃和100rpm下培养。在单独研究中,含有B.p.或E.c.、直径接近1毫米的藻酸盐-聚-L-赖氨酸-藻酸盐的微胶囊以一定量加入,以使得对于50毫升FAIF的细胞蛋白含量正常化。在1,2,3,4,6和24小时取等分试样并评价尿素氮、氨组成及尿酸和肌酸酐稳定性的减少。所有的试验都重复三次,结果取平均值。
细菌浓度被优化之后,将不同浓度的Water Lock(WL)A-220加入到50mg/dL氨的溶液中并评价氨的摄入值。氨浓度的分析测定由过滤悬浮液的上清液确定。然后向***中加入不同浓度的刺槐豆胶(LBG)至高浓缩的FAIF,而不需要加入细菌。在37℃和100rpm下培养2小时后,该***通过剩余肌酸酐和尿酸来分析。一旦确定了合适浓度的LBG,以变量加入活性炭至高浓缩FAIF,而不需加入细菌。该***在37℃和100rpm下培养,并且经过2小时培养后确定剩余肌酸酐和尿酸。
尿素,氨,肌酸酐和尿酸的定量分析方法可利用市售的诊断试剂盒(分别为Sigma,St.Louis,MO.目录号535和171,以及分别为Advanced Diagnostics,Inc.Division of Inamco Group,South Plainfield,NJ.目录号131500和CASO-50)。
实施例6:TNO胃肠模型(TIM)
TNO胃肠模型(TIM)非常近似地模仿了胃肠道腔内成功的动力学条件(van der Werf等,J.Agric.Food Chem.49,378-383,2001)。模仿的动力学参数包括:食品和饮料摄入量,pH曲线,包括唾液的胃和包括胰液的小肠中的酶和酶原浓度;肠不同部位的胆汁浓度;经过胃和小肠的食糜的动力学通道;以及水溶性消化产物和水的吸收。大肠模型中,在天然的结肠环境(模拟pH值、水分吸收和微生物代谢物如短链脂肪酸和气体的吸收),人源复杂的高密度微生物区系发酵未消化的食品化合物。因此,这一模型用来评价大小肠中本发明组合物不同配方的结果。
实施例7:体内研究
重约150±15克的大鼠,其慢性肾衰竭(CRF)程度类似于人的末期肾病,接近10次透析初期(10 initiation of dialysis),用该大鼠测试口服微囊化的吸附剂和大肠杆菌DH5细胞对于去除积累在CRF中的尿毒素和缓解***症状的效果。总体上,包括对照组在内共有4组,1组患有慢性肾衰竭(n=15)而2组患有急性肾衰竭。具体而言,雄大鼠重250-300克,将近8周龄大,它们购自Charles River或Harlan,并饲养在笼子中,所述笼子禁止与其粪便接近。对于所有的动物,标准临床化学的基线测定和20种被认为是尿毒素的化合物的测定加以确定。然后,使用外科方法使大鼠患有急性或慢性***。
急性肾衰竭按照Waynforth,H.B.和Flecknell,P.A.Nephrectomy.在“大鼠的实验和外科技术”(1992年第2版,学术出版社(Harcourt,Brace,Jovanovich),伦敦,第29,274-275页)中所描述的程序通过双侧肾切除术的方法制备。术后,将大鼠随机配对成年龄或大小匹配的组,并成对饲养。大鼠利用一个弯曲的服药针通过胃内给药饲养。一组用口服吸附剂连同Kayexylate处理以控制钾(处理组)。另外一组仅接受Kayexylate用于控制钾(对照组)。对这两组进行密切监测至少7至10天。相对于非处理组,有效的吸附剂可使生命延长。
慢性肾衰竭(CRF)通过一个两阶段外科步骤产生,类似于Niwa等(Miner.Electr.Metab.199723:179-184)及Einbacher和Carter(J.Exp.Med.1966 123:239-250)所公开的5/6肾切除术模型,但是有一些修改发现可以引起深度肾衰竭,类似于人接近需要血液透析的程度。在这一修改过程中,在残肾周围缝合一个软的塑料盒子以防止对侧肾切除术后肾的过度增大。这也有助于控制器官出血。
具体而言,使用一种两步途径。在建议的外科手术当天,禁食一个小时。然后让动物吸入异氟烷(FORANE)麻醉。被麻醉的大鼠腹面向上对着外科医生从左向右放置。两个侧面用剃刀最小限度的清除毛皮,并用聚维酮碘预处理。在大鼠的左侧准备一块无菌区域。在大鼠左侧胸廓接近肋骨边缘的下方,做一个背腹侧的切口进入到腹腔。把左肾与其相连的组织游离开来并小心取出,优选地,同时抓取肾周脂肪。肾上腺被***和脂肪松弛地连接到肾的前极,撕开附着物,小心的取下肾上腺。肾脏被安置到两个极都紧紧的连接到肾动脉进入器官的位点上。把一个4.0单丝的套索环绕到上面的极上,系紧,小心不破坏结节。打一个双结。检查器官是否过多的失血。有必要的话,使用热透疗法阻止出血并在皮层上使用氧化纤维素(oxycel)。对下方的极重复同样的操作。剩下的肾装入事先准备好的塑料盒,优选是SARAN包中,并保护好。然后把器官放回进腹腔,将切口缝合两层。用聚维酮碘擦拭这个区域,让动物痊愈。施用一种止痛药叔丁啡(buprenor phine)(0.25mg/kg)来止痛。大约3-4周后,移去右肾。在这个手术中,使用了一种腹部的途径,从而能对残余的肾进行检查。用同样的方法麻醉,但沿着脑白质做一个中线的切口,以减少流血。轻轻的移开肠,观察残余的左肾,确保其功能。如果有必要,对盒子做一些调整。假定左肾完全正常,暴露出右肾,使其从包膜上游离出来(留下肾上腺),然后给肾血管四周绑上绷带,取下右肾。在输尿管上的尽量远离肾的位置绑上另一个绷带,朝着中线,但是不要破坏或阻塞周围可能碰到的任何一条侧血管。绷带安全地打上双结,把靠近肾脏的血管阻断,之后把肾移出。缝合切口,给动物施用止痛剂,让其在温暖的环境中痊愈。
通过这一修改步骤,在大鼠身上取得了一致的结果:血清肌酸酐值为2.6±0.2(范围是2.3-2.5)和血液尿素值98±5,发病率低,(术后4星期,少于20%)。
在第二次手术后大约5天,抽出对侧的血液,尽可能接近地匹配大鼠的体重、血清肌酸酐和血液尿素的数值。把它们随机分为4组。A组和B组成对饲养。A组由没有接受任何吸附剂的CRF大鼠组成,B组的大鼠接受了吸附剂。第三组C组,施用吸附剂,让其自由摄取食物和水。比较B组和C组,发现了***对食欲和营养的影响。第四组为假性操作组D组,用作对照。对大鼠进行4-7个月的观察,在这期间,每两周收集血和尿,用Dunn等在《分析化学》197648:41-44中所描述的方法,对二甲基和/或三甲基胺进行气相色谱分析。同时,每周测量一次体重,每月测量一次血压和尿渗透性(osmalities)。每天通过食物和水的摄取量来衡量他们的食欲。每月还定时收集尿样一次,每两周收集斑点尿样一次。同时测量皮肤褶厚度作为评价营养状况的辅助性指标。大鼠在7个月时被杀死,最后的血液被抽出来用作临床化学和其他特殊的检验。血、尿和脑组织也进行了二甲胺的化验。在上述研究中,无菌盐水中以悬浮形式存在的吸附剂是用12-号的洗胃管给大鼠口服给药的。
Claims (13)
1.一种药物组合物,包括一种益生菌,一种益生素,以及一种具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物,所述组合物被选自藻酸盐/藻酸,壳聚糖,醋酸邻苯二甲酸盐纤维素或羟乙基纤维素的材料微囊化或被选自玉米蛋白,聚glycolactic acid,聚乳酸,聚丙交酯-乙交酯共聚物的材料肠衣包被,所述材料使得组合物以完整形式传递到其靶部位并且防止释放亲氨尿素降解微生物。
2.权利要求1所述的药物组合物,进一步包括一种水吸附剂。
3.权利要求2所述的药物组合物,其中所述水吸附剂选自刺槐豆胶,车前子纤维,瓜尔豆胶和沸石。
4.权利要求1所述的药物组合物,进一步包括一种无机磷酸盐吸附剂和一种除尿素以外的特异尿毒性溶质吸附剂。
5.权利要求4所述的药物组合物,其中所述无机磷酸盐吸附剂选自氢氧化铝凝胶,氢氧化钙凝胶和氢氧化镁凝胶,且特异尿毒性溶质吸附剂是活性炭。
6.权利要求1所述的药物组合物,其中所述益生菌选自双歧杆菌或乳酸杆菌。
7.权利要求1所述的药物组合物,其中所述益生素选自果聚糖寡糖和***聚糖寡糖。
8.权利要求1所述的药物组合物,其中所述亲氨细菌选自巴氏芽孢杆菌(Bacillus pasteurii)、脲芽孢八叠球菌(Sporosarcina ureae)、芽孢杆菌和乳酸杆菌KB-I。
9.权利要求1所述的药物组合物,其中所述益生菌和具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物包含同种细菌。
10.一种药物组合物,包括一种益生菌,一种益生素,一种具有高碱性pH稳定性和高尿素酶活性的亲氨尿素降解微生物,一种水吸附剂,一种无机磷酸盐吸附剂和一种除尿素以外特异尿毒性溶质吸附剂,所述组合物被选自藻酸盐/藻酸,壳聚糖,醋酸邻苯二甲酸盐纤维素或羟乙基纤维素的材料微囊化或被选自玉米蛋白,聚glycolactic acid,聚乳酸,聚丙交酯-乙交酯共聚物的材料肠衣包被,所述材料使得组合物以完整形式传递到其靶部位并且防止释放亲氨尿素降解微生物。
11.权利要求1-10任一项所述的药物组合物在制备用于抑制毒素和代谢废物积累以及不需要的细菌过度生长的药物中的应用。
12.权利要求1-10任一项所述的药物组合物在制备用于减轻***症状的药物中的应用。
13.权利要求12所述的应用,其中所述***症状是由肾病或一种先天性尿素代谢缺陷引起的。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/855,346 | 2001-05-15 | ||
US09/855,346 US6706287B2 (en) | 2001-05-15 | 2001-05-15 | Prebiotic and probiotic compositions and methods for their use in gut-based therapies |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1509144A CN1509144A (zh) | 2004-06-30 |
CN100337549C true CN100337549C (zh) | 2007-09-19 |
Family
ID=25321010
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB028100786A Expired - Lifetime CN100337549C (zh) | 2001-05-15 | 2002-05-10 | 益生素和益生菌组合物及其在肠道疾病治疗中的用法 |
Country Status (8)
Country | Link |
---|---|
US (1) | US6706287B2 (zh) |
EP (1) | EP1397044A4 (zh) |
JP (1) | JP4693085B2 (zh) |
KR (1) | KR100896669B1 (zh) |
CN (1) | CN100337549C (zh) |
AU (1) | AU2002342641B2 (zh) |
CA (1) | CA2447376C (zh) |
WO (1) | WO2002091833A1 (zh) |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7029702B2 (en) * | 1998-07-07 | 2006-04-18 | Ritter Natural Sciences Llc | Method for increasing lactose tolerance in mammals exhibiting lactose intolerance |
US6933104B1 (en) * | 1999-04-23 | 2005-08-23 | Shiva Biomedical, Llc | Diagnosis and treatment of human kidney diseases |
US20040161422A1 (en) * | 1999-04-30 | 2004-08-19 | Natarajan Ranganathan | Nutritional compositions comprising probiotics |
US20040105848A1 (en) * | 1999-04-30 | 2004-06-03 | Natarajan Ranganathan | Enteric dialysis compositions and methods |
NO320671B1 (no) * | 2001-11-30 | 2006-01-16 | Fmc Biopolymer As | Fremgangsmate for a stimulere vektokning i fisk. |
KR20050004805A (ko) * | 2002-03-13 | 2005-01-12 | 키보우 바이오테크 인코포레이티드 | 신장 기능을 강화시키는 화합물 및 방법 |
WO2005000034A2 (en) * | 2003-06-23 | 2005-01-06 | Agtech Products, Inc. | Lactic bacteria and its use in direct-fed microbials |
AU2004249060A1 (en) * | 2003-06-24 | 2004-12-29 | Otsuka Pharmaceutical Co., Ltd. | Composition for lowering serum uric acid level |
RU2006108554A (ru) * | 2003-08-18 | 2007-09-27 | Дзе Байо Бэлэнс Корпорейшн (Us) | Устойчивая жидкая пробиотическая композиция, ее получение и применения |
EP1675617B1 (en) * | 2003-09-30 | 2017-07-26 | Kibow Biotech, Inc. | Compositions for augmenting kidney function |
US6936598B2 (en) * | 2003-11-21 | 2005-08-30 | Hill's Pet Nutrition, Inc. | Composition and method |
US7754677B2 (en) * | 2003-12-05 | 2010-07-13 | Hill's Pet Nutrition, Inc. | Composition and method for reducing diarrhea in a mammal |
JP2005247784A (ja) * | 2004-03-05 | 2005-09-15 | Ueda Shikimono Kojo:Kk | 排便消臭剤 |
WO2005105068A1 (en) * | 2004-04-15 | 2005-11-10 | Dow Global Technologies Inc. | In vivo stimulation of intestinal transporters for excretion of nitrogenous wastes |
EP1600060A1 (en) * | 2004-05-25 | 2005-11-30 | Cognis IP Management GmbH | Oral and/or topical compositions comprising prebiotics and fatty acid |
EP1600062A1 (en) * | 2004-05-25 | 2005-11-30 | Cognis IP Management GmbH | Oral and/or topical compositions comprising prebiotics and sterols |
ITMI20041232A1 (it) * | 2004-06-18 | 2004-09-18 | Dietetics Pharma S R L | Composizione nutraceutica contenente un numero elevato di fermenti lattici utile come sinbiotico |
EP1614357A1 (en) * | 2004-07-10 | 2006-01-11 | Cognis IP Management GmbH | Dietary supplements comprising prebiotics and fatty acid |
WO2006012536A2 (en) * | 2004-07-22 | 2006-02-02 | Ritter Andrew J | Methods and compositions for treating lactose intolerance |
DE102004037505A1 (de) * | 2004-08-03 | 2006-02-23 | Henkel Kgaa | Präbiotische Intimpflege |
JP2008540602A (ja) * | 2005-05-18 | 2008-11-20 | ダ・ボルテラ | 吸着剤の結腸送達 |
US7572474B2 (en) * | 2005-06-01 | 2009-08-11 | Mead Johnson Nutrition Company | Method for simulating the functional attributes of human milk oligosaccharides in formula-fed infants |
US8287931B2 (en) | 2005-06-30 | 2012-10-16 | Mead Johnson Nutrition Company | Nutritional composition to promote healthy development and growth |
US8075934B2 (en) * | 2008-10-24 | 2011-12-13 | Mead Johnson Nutrition Company | Nutritional composition with improved digestibility |
CN100357444C (zh) * | 2005-10-10 | 2007-12-26 | 东南大学 | 利用微生物沉积制备碳酸钙的方法 |
EP1993384A2 (en) * | 2006-01-11 | 2008-11-26 | Attune Foods | Probiotic food, process for its preparation and dietary regimen |
ES2580127T3 (es) * | 2006-01-30 | 2016-08-19 | Panion & Bf Biotech Inc. | Procedimiento de tratamiento de la nefropatía crónica |
US8012118B2 (en) * | 2006-03-08 | 2011-09-06 | Fresenius Medical Care Holdings, Inc. | Artificial kidney dialysis system |
US8715221B2 (en) * | 2006-03-08 | 2014-05-06 | Fresenius Medical Care Holdings, Inc. | Wearable kidney |
US8048413B2 (en) | 2006-05-17 | 2011-11-01 | Helene Huguet | Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules |
CA2654457A1 (en) * | 2006-06-06 | 2007-12-13 | Mcgill University | Fermented milk product and use thereof |
US8871283B2 (en) * | 2006-07-11 | 2014-10-28 | Gosudarstvennoe Nauchnoe Uchrezhdenie “Institut Phyziki Im. B.I.: Stepanova” Nacionalnojj Acadzhemii Nauk Belarusi | Method of making sorbent, the sorbent obtained by this method and the uses of the sorbent as feed additive and medicine |
US20100047320A1 (en) * | 2006-09-07 | 2010-02-25 | Satya Prakash | Oral polymeric membrane feruloyl esterase producing bacteria formulation |
US9084434B2 (en) * | 2006-09-27 | 2015-07-21 | Little Calumet Holdings Llc | Probiotic oral dosage forms |
CN100535119C (zh) * | 2006-11-07 | 2009-09-02 | 上海交通大学医学院附属第九人民医院 | 一种制备唾液链球菌尿素酶基因的方法 |
KR100878339B1 (ko) * | 2007-07-20 | 2009-01-14 | 고려대학교 산학협력단 | 프리바이오틱 기질을 이용한 유산균의 이중 미세피복 방법 |
US20090061008A1 (en) | 2007-08-30 | 2009-03-05 | Levy Mark M | Fiber/granule complex for treatment of the gi tract |
US20090110663A1 (en) * | 2007-10-24 | 2009-04-30 | Halow George M | Method for treatment of bowel disorders |
WO2009069219A1 (ja) * | 2007-11-29 | 2009-06-04 | Meiji Dairies Corporation | 血中尿酸値低減作用を有する乳酸菌 |
US20110223248A1 (en) * | 2007-12-12 | 2011-09-15 | Ritter Pharmaceuticals, Inc. | Methods and compositions for treating lactose intolerance |
EP2293802A4 (en) * | 2008-06-25 | 2011-11-09 | Ritter Pharmaceuticals Inc | LACTOSE COMPOSITIONS HAVING REDUCED LACTOSE CONTENT |
US8986769B2 (en) * | 2008-10-24 | 2015-03-24 | Mead Johnson Nutrition Company | Methods for preserving endogenous TGF-β |
CA2741572C (en) * | 2008-11-03 | 2017-10-31 | Fresenius Medical Care Holdings, Inc. | Portable peritoneal dialysis system |
US8425955B2 (en) * | 2009-02-12 | 2013-04-23 | Mead Johnson Nutrition Company | Nutritional composition with prebiotic component |
KR20110124780A (ko) * | 2009-02-24 | 2011-11-17 | 리터 파마슈티컬즈 인코오포레이티드 | 프리바이오틱 제제 및 사용 방법 |
CN102438639A (zh) * | 2009-03-06 | 2012-05-02 | 魁北克枫业制造商公会 | 共生元枫树产品组合物和方法 |
US8293264B2 (en) * | 2009-05-11 | 2012-10-23 | Mead Johnson Nutrition Company | Nutritional composition to promote healthy development and growth |
US9848760B2 (en) * | 2009-06-29 | 2017-12-26 | Gearbox, Llc | Devices for continual monitoring and introduction of gastrointestinal microbes |
SI23130A (sl) * | 2009-09-24 | 2011-03-31 | Prof.dr. CENCIČ AVRELIJA | Kompozitni dietetiäśni mleäśni napitek in postopek za proizvodnjo kompozitnega dietetiäśnega mleäśnega napitka z reduciranim nivojem seäśne kisline in purina |
US20110117629A1 (en) * | 2009-11-19 | 2011-05-19 | Family Medicine Interantional Co., Ltd. | Lactobacillus plantarum bb9 capable of adhering to gastrointestinal tract and cholesterol removal |
CN103037877A (zh) | 2010-03-12 | 2013-04-10 | 可尔必思株式会社 | 用于在大肠中增加双歧杆菌和抑制双歧杆菌减少的试剂 |
EP2563372A4 (en) | 2010-04-28 | 2013-10-02 | Ritter Pharmaceuticals Inc | PREBIOTIC FORMULATIONS AND METHODS OF USE |
ES2350436B1 (es) * | 2010-07-21 | 2011-11-28 | Fundacion Leia, C.D.T. | Material simbiotico microencapsulado |
US9011909B2 (en) | 2010-09-03 | 2015-04-21 | Wisconsin Pharmacal Company, Llc | Prebiotic suppositories |
US9125935B1 (en) | 2011-05-31 | 2015-09-08 | Nutech Ventures | Probiotics and methods of obtaining same |
CN102864088B (zh) * | 2011-07-05 | 2014-08-27 | 中南大学湘雅二医院 | 一种基因工程乳酸杆菌及其应用 |
CN103536909A (zh) * | 2013-10-18 | 2014-01-29 | 天津太平洋制药有限公司 | 一种新型的尿素氮固体吸附制剂及其制备方法 |
US20170326186A1 (en) * | 2014-11-26 | 2017-11-16 | Probiotical S.P.A. | Strains of lactobacillus and bifidobacteria for the maintenance of a long-lasting homeostasis condition in a human body |
DK3240426T3 (da) | 2014-12-29 | 2019-07-22 | Mofin S R L | Fremstilling af en gærfri, meget fordøjelig pizza ved anvendelse af en dej indeholdende mælkesyrebakterier |
KR101589465B1 (ko) | 2015-05-21 | 2016-02-01 | 주식회사 쎌바이오텍 | 성장 촉진을 위한 비피도박테리움 브레베 cbt br3 균주 및 이를 포함하는 성장촉진용 기능성 식품 조성물 |
CN105454234A (zh) * | 2015-12-08 | 2016-04-06 | 唐山金土生物有机肥有限公司 | 单方或复方壳寡糖制剂及其在防治番茄病毒病中的应用 |
MX2018007376A (es) * | 2015-12-15 | 2018-12-06 | Kuragobiotek Holdings S A P I De C V | Una mezcla de probioticos y prebioticos mas nutrimentos en interaccion biologica y su uso para el tratamiento de la disbiosis intestinal en aves de corral, incrementar su respuesta inmunologica y factor de conversion. |
CN106173751A (zh) * | 2016-08-05 | 2016-12-07 | 北京致成生物医学科技有限公司 | 一种治疗***的保健饮品及其制备方法 |
CN106234896A (zh) * | 2016-08-05 | 2016-12-21 | 北京致成生物医学科技有限公司 | 一种治疗肾病的保健饮品及其制备方法 |
CA3067991A1 (en) | 2017-06-26 | 2019-01-03 | Kibow Biotech, Inc. | Methods for maintaining and improving kidney function in patients with kidney disease and on standard of care therapy |
EP3741376A4 (en) | 2017-12-15 | 2021-09-22 | Green Cross WellBeing Corporation | PROBIOTICS TO INHIBIT AND PREVENT THE DEVELOPMENT OF KIDNEY DISEASES AND COMPOSITIONS TO INHIBIT AND PREVENT THE EVOLUTION OF KIDNEY DISEASES INCLUDING THEM |
JP6999175B2 (ja) * | 2018-07-31 | 2022-02-04 | 株式会社東洋新薬 | 経口組成物 |
SG11202103556VA (en) * | 2018-10-12 | 2021-05-28 | Univ Washington | System and method for removing uremic toxins from a patient's body |
FR3097742B1 (fr) * | 2019-06-25 | 2021-06-25 | Lnc Therapeutics | Bactérie de la famille desChristensenellacéeset composition en contenant pour la prévention et/ou le traitement de l’insuffisance rénale. |
KR20220072855A (ko) * | 2019-09-23 | 2022-06-02 | 더 리젠츠 오브 더 유니버시티 오브 미시건 | 면역치료제 및 백신의 효율을 증가시키는 조성물 및 방법 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5733568A (en) * | 1993-12-03 | 1998-03-31 | Lafor Laboratories Limited | Micro-encapsulated lactobacilli for medical applications |
US5968569A (en) * | 1997-01-09 | 1999-10-19 | Nestec S.A. | Pet food product containing probiotics |
US6180099B1 (en) * | 1994-10-28 | 2001-01-30 | Metagenics, Inc. | Method of using immunoglobulin and fiber-containing compositions for human health |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1466702A (en) * | 1973-02-09 | 1977-03-09 | Sandoz Ltd | Polymer encapsulated-activated carbon |
DE2414156A1 (de) * | 1974-03-23 | 1975-09-25 | Kleist Johann Georg Dr | Arzneimittel zur beseitigung uraemischer symptome und verfahren zu seiner herstellung |
US4581141A (en) * | 1978-02-27 | 1986-04-08 | Purdue Research Foundation | Dialysis material and method for removing uremic substances |
JPS5731864A (en) * | 1980-08-04 | 1982-02-20 | Teijin Ltd | Oral activated carbon microcapsule |
JPS59110621A (ja) * | 1982-12-17 | 1984-06-26 | Meiji Seika Kaisha Ltd | 利尿剤 |
DE3406772A1 (de) * | 1984-02-24 | 1986-03-13 | Angelo 8137 Berg Schuler | Diaetetisches mittel zur herabsetzung der harnstoffkonzentration in koerperfluessigkeiten und seine herstellung |
US4839281A (en) | 1985-04-17 | 1989-06-13 | New England Medical Center Hospitals, Inc. | Lactobacillus strains and methods of selection |
DE3936319C3 (de) * | 1989-11-01 | 1997-05-07 | Bartz Volker | Phosphatbinder zur oralen Verabreichung |
GB2276170B (en) * | 1993-02-17 | 1997-04-16 | British Tech Group | Polymers containing guanidine groups for use in therapy |
US5840318A (en) | 1993-05-11 | 1998-11-24 | Immunom Technologies, Inc. | Methods and compositions for modulating immune systems of animals |
US5531988A (en) | 1994-10-28 | 1996-07-02 | Metagenics, Inc. | Bacteria and immunoglobulin-containing composition for human gastrointestinal health |
JPH09110707A (ja) * | 1995-10-12 | 1997-04-28 | Wakamoto Pharmaceut Co Ltd | 慢性腎不全改善剤および透析患者のクオリティー オブ ライフ改善剤 |
GB9601333D0 (en) * | 1996-01-23 | 1996-03-27 | Univ Mcgill | Microencapsulated genetically engineered microorganisms for clinical application |
JPH11199495A (ja) * | 1998-01-10 | 1999-07-27 | Nichinichi Seiyaku Kk | 腸溶性カプセルを用いた抗アレルギー剤 |
JPH11302158A (ja) * | 1998-04-16 | 1999-11-02 | Oruto Corporation:Kk | 腸溶性シームカプセルを用いた整腸作用を有する健康食品 |
IT1304170B1 (it) * | 1998-12-15 | 2001-03-08 | Novartis Nutrition Ag | Composti organici |
-
2001
- 2001-05-15 US US09/855,346 patent/US6706287B2/en not_active Expired - Lifetime
-
2002
- 2002-05-10 CN CNB028100786A patent/CN100337549C/zh not_active Expired - Lifetime
- 2002-05-10 WO PCT/US2002/015073 patent/WO2002091833A1/en active IP Right Grant
- 2002-05-10 EP EP02769723A patent/EP1397044A4/en not_active Withdrawn
- 2002-05-10 KR KR1020037014919A patent/KR100896669B1/ko active IP Right Grant
- 2002-05-10 AU AU2002342641A patent/AU2002342641B2/en not_active Expired
- 2002-05-10 CA CA2447376A patent/CA2447376C/en not_active Expired - Lifetime
- 2002-05-10 JP JP2002588760A patent/JP4693085B2/ja not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5733568A (en) * | 1993-12-03 | 1998-03-31 | Lafor Laboratories Limited | Micro-encapsulated lactobacilli for medical applications |
US6180099B1 (en) * | 1994-10-28 | 2001-01-30 | Metagenics, Inc. | Method of using immunoglobulin and fiber-containing compositions for human health |
US5968569A (en) * | 1997-01-09 | 1999-10-19 | Nestec S.A. | Pet food product containing probiotics |
Also Published As
Publication number | Publication date |
---|---|
US20020187134A1 (en) | 2002-12-12 |
JP4693085B2 (ja) | 2011-06-01 |
AU2002342641B2 (en) | 2007-04-26 |
CA2447376A1 (en) | 2002-11-21 |
WO2002091833A1 (en) | 2002-11-21 |
EP1397044A4 (en) | 2008-10-29 |
KR20040029995A (ko) | 2004-04-08 |
CA2447376C (en) | 2012-04-24 |
CN1509144A (zh) | 2004-06-30 |
US6706287B2 (en) | 2004-03-16 |
KR100896669B1 (ko) | 2009-05-14 |
EP1397044A1 (en) | 2004-03-17 |
JP2004533442A (ja) | 2004-11-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100337549C (zh) | 益生素和益生菌组合物及其在肠道疾病治疗中的用法 | |
AU2002342641A1 (en) | Prebiotic and probiotic compositions and methods for their use in gut-based therapies | |
CN1221182C (zh) | 具有改进营养特性的菊糖产品 | |
EP1675617B1 (en) | Compositions for augmenting kidney function | |
US6706263B2 (en) | Composition for alleviating symptoms of uremia in patients | |
FR2771009A1 (fr) | Biostimulant | |
JP6148218B2 (ja) | 腎不全進行抑制剤、腎不全予防剤、***治療剤、インドキシル硫酸産生阻害剤、心血管系疾患予防剤、及び食品組成物 | |
CN1300187A (zh) | 用于预防骨质疏松的来源于发酵乳汁的食品强化剂 | |
US7998470B2 (en) | Compositions and methods improving renal function | |
US20040197352A1 (en) | Methods of improving or augmenting kidney function | |
CN103919815A (zh) | 一种使用益生菌制备用于清除尿毒素的组合物的用途 | |
US7026160B2 (en) | Oral bacteriotherapy compositions and methods | |
CN107073032B (zh) | 肾衰竭发展抑制剂、肾衰竭预防剂及硫酸吲哚酚产生抑制剂 | |
US20040105848A1 (en) | Enteric dialysis compositions and methods | |
CN1871031A (zh) | 用于增强肾功能的组合物和方法 | |
RU2325187C1 (ru) | Фармацевтическая композиция антибиотиков и пребиотиков (варианты) для профилактики и лечения дисбиозов в процессе антибактериальной терапии | |
CN115177642B (zh) | 一种调节溃疡性结肠炎肠道菌群的组合物及其制备方法和应用 | |
RU2122868C1 (ru) | Способ энтеросорбции | |
Di Cerbo et al. | The use of probiotics in the end-stage renal disease management | |
US20220000938A1 (en) | System and method for removing uremic toxins from a patient's body | |
CN110812391B (zh) | 用于宠物犬猫肠道透析组合物及其制备方法 | |
RU2201755C2 (ru) | Способ лечения уремического синдрома | |
CN118320052A (zh) | 一种用于痛风调理的组合物、制备方法及用途 | |
CN115089596A (zh) | 新琼寡糖用于制备治疗抑郁症产品的新用途 | |
Lim | Microcapsules immobilizing activated charcoal and metabolically induced Lactobacillus acidophilus cells as potential oral renal failure therapy formulation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20070919 |