CN101693045B - Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof - Google Patents
Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof Download PDFInfo
- Publication number
- CN101693045B CN101693045B CN2009102543162A CN200910254316A CN101693045B CN 101693045 B CN101693045 B CN 101693045B CN 2009102543162 A CN2009102543162 A CN 2009102543162A CN 200910254316 A CN200910254316 A CN 200910254316A CN 101693045 B CN101693045 B CN 101693045B
- Authority
- CN
- China
- Prior art keywords
- hydrangea
- conical
- effective portion
- preparation
- 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
- 241001092080 Hydrangea Species 0.000 title claims abstract description 74
- 235000014486 Hydrangea macrophylla Nutrition 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title claims description 15
- 239000003814 drug Substances 0.000 claims abstract description 58
- 241000511974 Hydrangea paniculata Species 0.000 claims abstract description 43
- 206010020772 Hypertension Diseases 0.000 claims abstract description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- 239000007924 injection Substances 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- VPAOSFFTKWUGAD-TVKJYDDYSA-N skimmin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C(C=CC(=O)O2)C2=C1 VPAOSFFTKWUGAD-TVKJYDDYSA-N 0.000 claims description 13
- SBFTZUUHPXPXLH-UHFFFAOYSA-N skimmin Natural products OCC1OC(C(O)C(O)C1O)c2ccc3C=CC(=O)Oc3c2 SBFTZUUHPXPXLH-UHFFFAOYSA-N 0.000 claims description 13
- VPAOSFFTKWUGAD-UHFFFAOYSA-N umbelliferone beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C=CC(=O)O2)C2=C1 VPAOSFFTKWUGAD-UHFFFAOYSA-N 0.000 claims description 13
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 11
- 201000006370 kidney failure Diseases 0.000 claims description 11
- 150000001298 alcohols Chemical class 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 4
- 230000001631 hypertensive effect Effects 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 40
- 210000003734 kidney Anatomy 0.000 abstract description 32
- 208000007342 Diabetic Nephropathies Diseases 0.000 abstract description 6
- 208000033679 diabetic kidney disease Diseases 0.000 abstract description 6
- 239000002131 composite material Substances 0.000 abstract 2
- 241000700159 Rattus Species 0.000 description 54
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 51
- 241001465754 Metazoa Species 0.000 description 50
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 231100000915 pathological change Toxicity 0.000 description 34
- 230000036285 pathological change Effects 0.000 description 34
- 239000000284 extract Substances 0.000 description 33
- 102000005862 Angiotensin II Human genes 0.000 description 29
- 101800000733 Angiotensin-2 Proteins 0.000 description 29
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 29
- 229950006323 angiotensin ii Drugs 0.000 description 29
- 208000020832 chronic kidney disease Diseases 0.000 description 24
- 210000002700 urine Anatomy 0.000 description 24
- 229940109239 creatinine Drugs 0.000 description 23
- 102000004169 proteins and genes Human genes 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 23
- 210000002966 serum Anatomy 0.000 description 21
- 230000002792 vascular Effects 0.000 description 20
- 210000004369 blood Anatomy 0.000 description 18
- 239000008280 blood Substances 0.000 description 18
- 230000036772 blood pressure Effects 0.000 description 18
- 230000037396 body weight Effects 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 239000002083 C09CA01 - Losartan Substances 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 16
- 229960004773 losartan Drugs 0.000 description 15
- 238000012360 testing method Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 13
- 239000013641 positive control Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- 229960001866 silicon dioxide Drugs 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 10
- 229960004316 cisplatin Drugs 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 8
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000035487 diastolic blood pressure Effects 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 230000010354 integration Effects 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
- 230000035488 systolic blood pressure Effects 0.000 description 8
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 7
- 229960004530 benazepril Drugs 0.000 description 7
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 7
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- -1 elixir Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 108050009340 Endothelin Proteins 0.000 description 6
- 102000002045 Endothelin Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 229960000830 captopril Drugs 0.000 description 6
- 230000006378 damage Effects 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 230000002980 postoperative effect Effects 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 206010018367 Glomerulonephritis chronic Diseases 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 206010025482 malaise Diseases 0.000 description 5
- 210000002254 renal artery Anatomy 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
- 208000022461 Glomerular disease Diseases 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 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 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 208000014674 injury Diseases 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229960003753 nitric oxide Drugs 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 239000005995 Aluminium silicate Substances 0.000 description 3
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 3
- 102000004414 Calcitonin Gene-Related Peptide Human genes 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- 238000012449 Kunming mouse Methods 0.000 description 3
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 241000700157 Rattus norvegicus Species 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 210000001015 abdomen Anatomy 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- 235000012211 aluminium silicate Nutrition 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 235000010216 calcium carbonate Nutrition 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 238000006243 chemical reaction Methods 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
- 238000000502 dialysis Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 231100000682 maximum tolerated dose Toxicity 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 229960002275 pentobarbital sodium Drugs 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000011552 rat model Methods 0.000 description 3
- 206010038464 renal hypertension Diseases 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 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 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 208000002682 Hyperkalemia Diseases 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 241000220151 Saxifragaceae Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000002745 absorbent Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000009692 acute damage Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 208000028208 end stage renal disease Diseases 0.000 description 2
- 201000000523 end stage renal failure Diseases 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000013299 hypertensive rat model Methods 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000001861 immunosuppressant effect Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 238000013059 nephrectomy Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000013599 spices Nutrition 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010001580 Albuminuria Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 102000004881 Angiotensinogen Human genes 0.000 description 1
- 108090001067 Angiotensinogen Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- JKLMJPQIEWXIQC-UHFFFAOYSA-L C(CCCCCCCCCCCCCCCCC)(=O)[O-].[Mg+2].C(C)N(CC)CC.C(CCCCCCCCCCCCCCCCC)(=O)[O-] Chemical compound C(CCCCCCCCCCCCCCCCC)(=O)[O-].[Mg+2].C(C)N(CC)CC.C(CCCCCCCCCCCCCCCCC)(=O)[O-] JKLMJPQIEWXIQC-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 229920001503 Glucan 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
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 229920001543 Laminarin Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001524 infective effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- DBTMGCOVALSLOR-VPNXCSTESA-N laminarin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O[C@@H]1[C@@H](O)C(O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2O)O)O[C@H](CO)[C@H]1O DBTMGCOVALSLOR-VPNXCSTESA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960000519 losartan potassium Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- ZDTMSMWYJXKBEB-UHFFFAOYSA-N n,n-diethylethanamine;octadecanoic acid Chemical compound CC[NH+](CC)CC.CCCCCCCCCCCCCCCCCC([O-])=O ZDTMSMWYJXKBEB-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008289 pathophysiological mechanism Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000023409 throat pain Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
Landscapes
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses an effective portion extracted from a conical hydrangea (Hydrangea paniculata sieb), and the preparation method of the effective portion comprises drug composite of the effective portion and the purpose of the effective portion and other drug composite which are used as drugs, and the effective portion is particularly applied in preparing drugs for preventing and/or treating kidney incompetence, high blood pressure and diabetic kidney disease.
Description
This case is to divide an application, and female case applying date is on April 23rd, 2004, and application number is 200410034068.8, and denomination of invention is " effective portion of conical hydrangea, its preparation method and compositions thereof and a purposes ".
Technical field
The present invention relates to from the effective site of Hydrangea paniculata extraction, the preparation method of this effective site, the pharmaceutical composition that contains this effective site, and this effective site and its pharmaceutical composition be as the purposes of medicine, especially prevents and/or treats application in renal insufficiency, hypertension and the medicine for treating diabetic nephropathy in preparation.
Background technology
Chronic renal disease (comprising all kinds of chronic nephritiss, diabetic nephropathy and hypertensive cerebral renal damage etc.) is a kind of the most common chronic refractory disease.Natural crowd's annual morbidity of chronic renal failure (CRF) is 98～19,8/1,000,000 populations, the sickness rate of the developed country such as the U.S. and Japan is up to 800～1,000 ten thousand/1,000,000 populations, be the trend that index rises over past ten years, the definite sickness rate of China CRF still lacks statistics, is about annual 100/1000000 populations.Along with the continuous variation of China's economic situation and spectrum of disease, the sickness rate of diabetes and the relevant nephropathy of hypertension has demonstrated surprising ascendant trend year by year.Diabetes aspect, the sickness rate of China 97 years were 3.2%, and the sickness rate that WHO predicts diabetes in 2010 will increase to 14%, and what wherein develop into diabetic nephropathy at last is 40%, promptly from 97 years 1,500 ten thousand be increased to 2010 7,000 ten thousand.The hypertension aspect, China has reached 11.26% the beginning of the nineties, just increases sharply with the speed of increases in per 10 years more than 20% at present.Diabetes are since insulin is used, the acute complication of diabetes such as the mortality rate of ketoacidosis significantly descend, but along with diabetes patient's life-time dilatation, diabetic nephropathy may take place in the diabetic about 40%, and in case kidney damage takes place, albuminuria, hypertension and the renal insufficiency of progress then occur continuing, the state of an illness is often irreversible, often carries out sexual development until end stage renal failure.Predict to the year two thousand twenty that according to WHO above-mentioned non-infective disease disease will become the first place of China's population cause of death, and latter stage at end, CRF was one of most important cause of death.
No matter all can making progress gradually from early lesion, which kind of cause of disease, nephridial tissue pathological changes be the pathological changes in late period of glomerular sclerosis and/or kidney region fibrosis.If can not get effective treatment, cause chronic renal insufficiency and irreversible end stage renal failure (being uremia) at last.
The pathophysiological mechanism of the progress of chronic kidney disease renal fibrosis is very complicated, comprise that former paathogenic factor (as immune inflammation, metabolism disorder etc.) interacts to abnormal hemodynamics, the cytokine of the effect of kidney various kinds of cell and secondary thereof and extracellular matrix (ECM) synthetic unbalance or the like with degraded.
Treatment chronic kidney hypofunction method commonly used has dialysis and transplants two kinds at present, but is the treatment means of CRF in latter stage at end.Renal transplantation, internal organs sources is limited, the financial burden height, the people that can carry out kidney transfer operation seldom only has 2～5% nephrotic to have an opportunity to implement operation approximately, and postoperative also need be taken immunosuppressant for a long time.Though dialysis treatment can reach the purpose that substitutes kidney, rely on dialysis machine, medical condition require high, and exist cardiovascular intercurrent disease height, patient has risk of infection, poor compliance, financial burden is heavy, uses very limited in China.Can have ready conditions and dialyse or the patient of renal transplantation only is only a few.Therefore, a large amount of patients press for the active drug that can delay and stop the renal insufficiency progress, and it is particularly important that the development of newtype drug and exploitation seem.
Though the hormone that tradition is used, immunosuppressant, blood sugar lowering treatment etc. at the therapeutical effect that has shown aspect anti-inflammatory, adjusting immunity and the metabolism protopathy, are being difficult to prove effective aspect the control chronic kidney disease change progress.Drug therapy does not worsen most important to delaying the CRF patients " renal function entirely.At present, the active drug that is widely used in the treatment renal insufficiency in the world wide mainly contains two classes: a class is an angiotensin converting enzyme inhibitor, be ACEI, comprise Captopril, Benazapril, Ramipril etc., it is synthetic that its main mechanism of action is to block Angiotensin II (AII), thereby reduce the generation of hypertension, the interior high filtration pressure of glomerule and short hardening factor TGF-β 1 that AII caused.Another kind of is Angiotensin II 1 receptor antagonist, and promptly ATlRA comprises Losartan, Irbsartan, Versartan etc., and its main mechanism of action is to reduce by the blocking-up aii receptor the above-mentioned effect of AII.External by a large amount of studies show that, can bring really all kinds of chronic renal disease patients' early stage active drug treatment significantly to delay the effect that renal insufficiency worsens, and have remarkable social benefit and economic benefit.
If be used for the treatment of the drug main Benazepril and the Losartan of renal insufficiency at present clinically, but main dependence on import, this class drug price costliness, toxic and side effects is bigger.As cause part patient hyperkalemia, unsurmountable cough, hypotensive activity strong inadequately etc.Therefore, be difficult to be used for for a long time the chronic renal failure patients as Captopril because of easily causing hyperkalemia clinically, 5-15% patient is forced to stopped treatment because of the cough due to the Benazapril, the patient of many constitutionales or renal hypertension must add with multiple other antihypertensive drugs simultaneously in order to reach ideal bp when using said medicine.
Hydrangea paniculata (Hydrangea paniculata Sieb) is Saxifragaceae (Saxifragaceae) hydrangea (Hydrangea) plant, is distributed widely in ground such as Zhejiang, Anhui, Jiangxi, Guangxi.The throat pain that is used for the treatment of among the people, malaria, accumulation of food in the stomach and intes tine due to indigestion, distension and fullness of the chest and abdomen, fracture etc.The natural resources of Hydrangea paniculata are abundant, do not see toxic report.
Summary of the invention
In order to overcome the deficiency of the medicine of treatment renal insufficiency in the prior art, the invention provides a kind of effective portion of conical hydrangea.
Another object of the present invention provides a kind of preparation method of effective portion of conical hydrangea.
A further object of the present invention provides the pharmaceutical composition that contains effective portion of conical hydrangea.
Another purpose of the present invention provides the application of effective portion of conical hydrangea in preparation treatment renal insufficiency, blood pressure lowering and medicine for treating diabetic nephropathy.
The present invention contains 10% above skimmin (Skimmin) from the effective site that Hydrangea paniculata extracts.
Preferred, the present invention contains 50% above skimmin (Skimmin) from the effective site that Hydrangea paniculata extracts.
According to the preparation method that the invention provides effective portion of conical hydrangea.
Hydrangea paniculata crude drug drying and suitable pulverizing in order to the contact area of increase with solvent, are raised the efficiency.
The extraction solvent of crude drug makes the mixture of water, alcohols or water and alcohols.Preferred alcohols comprises methanol, ethanol, isopropyl alcohol, butanols etc.The mixture of water and alcohols, for example concentration is the alcohol of 40-99% (volume ratio).Solvent soaked medical material and was advisable during extraction, quantity of solvent be former medicine weight 2-14 doubly.Extraction can be static or down dynamic, preferably under dynamic condition.In order to improve the efficient of extraction, can use ultrasound wave etc.The temperature of extracting be from room temperature (for example 20 ℃) to the scope of solvent refluxing temperature in, preferably under the temperature of backflow.Extraction can be carried out continuously or intermittently, can repeat 1-4 time preferred 2-3 time during intermittent extraction.
Behind the last EOS, merging filtrate, the elimination medicinal residues, concentrated filtrate obtains extractum.Concentrate and preferably under dynamical state, carry out, can be under normal pressure or reduced pressure, preferably under reduced pressure.Spissated temperature 40-80 ℃, preferred temperature is 50-70 ℃, and preferred temperature is 55-65 ℃.Extractum mix sample.This extractum ethanol: oxolane: low amounts of water dissolving, lysate 100-200 order silica gel mixed sample (1: 2), oven dry.
Paste is by the adsorpting column chromatography purification, and the number of times of purification can be 1-4 time, preferably 1-2 time.
Adsorbent is selected from silica gel, aluminium oxide, macroporous resin, ion exchange resin, reverse phase silica gel (ODS), and preferably adsorbent is silica gel, macroporous resin.The consumption of adsorbent is 3-10 a times of sample size.The condition of elution system: the petroleum ether of using variable concentrations successively: acetone (mixed solvent ratios is 3: 1 to 1: 1), acetone, ethanol gradient elution.Collect partial acetone.Concentrated partial acetone gets crude product.Use ethanol: oxolane (1: 1) dissolving by the ODS post, with alcohols mobile phase eluting, obtains containing the Hydrangea paniculata extract of 50% above skimmin.Concentrated partial acetone gets the also available macroporous resin chromatography of crude product and carries out the Hydrangea paniculata extract that gradient elution obtains containing 50% above skimmin with the ethanol water system.
Also can use the method for chromatography 1 time.Use silica gel column chromatography, use CH
3Cl: MeOH: H
2O mobile phase eluting obtains containing the Hydrangea paniculata extract of 50% above skimmin.
Contain as the effective portion of conical hydrangea of active ingredient and the pharmaceutical composition of conventional medicine excipient or adjuvant according to the invention still further relates to.Usually pharmaceutical composition of the present invention contains the effective portion of conical hydrangea of 0.1-95 weight %.
The pharmaceutical composition that contains effective portion of conical hydrangea of the present invention can be according to method preparation well known in the art.When being used for this purpose, if desired, effective portion of conical hydrangea of the present invention and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make and can be used as suitable administration form or the dosage form that people's medicine or veterinary drug use.
Effective portion of conical hydrangea of the present invention or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be intestinal or non-intestinal, as in oral, muscle, nasal cavity, oral mucosa, skin, transdermal, subcutaneous, Intradermal, peritoneum, rectum, intravenous, intramuscular, the sheath, epidural, ophthalmic, intracranial, vagina administration etc.
Effective portion of conical hydrangea of the present invention or the route of administration that contains its pharmaceutical composition can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection therapy, intrathecal injection and peritoneal injection etc.
Form of administration can be liquid dosage form, solid dosage forms.SOLUTION PROPERTIES as liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.The liquid dosage form form can be syrup, elixir, injection solution, non-aqueous solution, suspension or emulsion; But solid dosage forms is tablet, lozenge, capsule, drop pill, pill, granule, powder, cream, solution, suppository dispersion powder such as lyophilized injectable powder, aerosol etc. for example.
Effective portion of conical hydrangea of the present invention can be made ordinary preparation, also can be slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier comprises that excipient is calcium carbonate, lactose, calcium phosphate, sodium phosphate for example; Diluent and absorbent be starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate, glucosan, colloidal silica, arabic gum, gelatin, magnesium trisilicate, keratin etc. for example; Wetting agent and binding agent be water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc. for example; Disintegrating agent is dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc. for example; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example Pulvis Talci, triethylamine magnesium stearate, triethylamine stearic acid, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet postponing its disintegrate and absorption in gastrointestinal tract, and provide continuous action in a long time thus.
For example, can be extensive use of various carrier well known in the art for pill is made in the administration unit.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Kaolin, Pulvis Talci etc.; Binding agent is as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.
For example for capsule is made in the administration unit, effective ingredient effective portion of conical hydrangea of the present invention is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective ingredient effective portion of conical hydrangea of the present invention can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, comprise emulsion, solution, suspension, syrup etc. for oral liquid is made in the administration unit.Suitable carriers comprises solution, suspension, syrup etc., and optional additive for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and the spice etc. of containing.
For example, effective portion of conical hydrangea of the present invention is made injection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, Polyethylene Glycol, 1 as diluent, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, vegetable oil be for example ethyl oleate, polyoxyethylene sorbitol, fatty acid ester etc. of olive oil and Semen Maydis oil, gelatin and injectable organic ester for example.Such dosage form can also contain adjuvant for example antiseptic, wetting agent, emulsifying agent and dispersant.In addition, ooze injection, can in injection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add conventional cosolvent, buffer agent, pH regulator agent etc. in order to prepare etc.These adjuvants are that this area is commonly used.
In addition, as needs, also can add coloring agent, antiseptic, spice, correctives for example Herba Menthae, Ilicis Purpureae wet goods in pharmaceutical preparation, sweeting agent is sucrose, lactose, glucide etc. or other material for example.
The used sterile media of the present invention can make by the well-known standard technique of those skilled in the art.They can be sterilized, for example by filter via biofilter, by in compositions, add biocide, by with the compositions radiation treatment or by compositions being heated Song's sterilization.Can also they be made sterile injectable medium facing with preceding.
For reaching the medication purpose, strengthen therapeutic effect, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.Certainly the route of administration that is used to implement effective portion of conical hydrangea of the present invention depends on the position that disease and needs are treated.Because the pharmacokinetics of effective portion of conical hydrangea of the present invention and pharmacodynamic profile have to a certain degree different, the most preferred method that therefore obtains treatment concentration in tissue is to increase dosage gradually and monitor clinical effectiveness.For such therapeutic dose of increase gradually, predose will depend on route of administration.
For any particular patient, the concrete treatment effective dose level of effective portion of conical hydrangea pharmaceutical composition of the present invention depends on many factors, for example to prevent or treat the character of disease, disease severity, route of administration, administration number of times, therapeutic purposes, the removing speed of effective portion of conical hydrangea, the treatment persistent period, effective portion of conical hydrangea associating or the concrete medicine that uses simultaneously, the sex of patient or animal, age, body weight, personality, diet, the well-known factors in medical science field such as individual reaction and general health situation, therefore therapeutic dose of the present invention can have large-scale variation.According to treatment patient's disease, may must make some change, and under any circumstance, all determine the suitable dose of individual patient by the doctor to dosage.
Dosage is meant and does not comprise the weight of vehicle weight at the effective portion of conical hydrangea of interior (when using carrier).In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.The actual drug quantity that can be according to the present invention be contained in the last preparation in the effective portion of conical hydrangea compositions, in addition suitable adjustment to reach the requirement of its treatment effective dose, is finished prevention of the present invention or therapeutic purposes.The suitable dose scope of the every day of effective portion of conical hydrangea of the present invention is preferably the 0.1-100mg/kg body weight, more preferably the 1-30mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations; This is subject to administration doctor's clinical experience and comprises the dosage regimen of using other treatment means.Effective portion of conical hydrangea of the present invention or compositions can be taken separately, or merge use and adjust dosage with other treatment medicine or symptomatic drugs.
The present invention has observed the acute toxicity of Hydrangea paniculata extract at a gastric infusion of mice, finds to give mice once to irritate stomach 5g/kg, and the no abnormal reaction of animal after the administration does not have dead in two weeks.Female mice weight increase 52.8% after two weeks, male mice weight increase 84.8%, each main organs of postmortem perusal is not found obvious pathological change.The toxicity that the Hydrangea paniculata extract is described is lower.
The present invention also find the Hydrangea paniculata extract to cisplatin induced mice acute injury of kidney with having the better protect effect, act on suitable with positive control drug Benzaepril.
What the present invention had also observed the Hydrangea paniculata extract causes the influence of chronic renal insufficiency to 5/6 kidney of rats excision.Excision 5/6 kidney, postoperative 4 months, the residual nephropathy change of rat characteristics meet the chronic nephritis model.Before being administration in 2 weeks of modelling, 2 weeks after the administration, 4 weeks, 6 weeks, 8 weeks and 12 weeks are distinguished serum urea nitrogen (BUN) and serum creatinine (Cre), urine protein content, plasma angiotensinogen II (AII) level and the weight of animals in the test experience Mus serum biochemistry indexs, illustrate that effective portion of conical hydrangea has to treat by the caused chronic renal insufficiency of most of nephrectomy preferably and have no side effect.
Administration finishes the back nephridial tissue of experimental mouse has been carried out pathological examination, by each treated animal glomerulopathy variation level is found, sham operated rats 96% above glomerule is not seen pathological changes, model group (operation group) II-IV level glomerule pathological changes is more than 94%, and wherein IV level pathological changes glomerule can reach 27.6%.Positive control drug group and effective portion of conical hydrangea group have the certain protection effect to the glomerule pathological changes, and particularly IV level glomerule percent is starkly lower than model group.
To each treated animal glomerule pathological changes total mark, normal control group glomerule pathological changes integration is minimum, respectively organize the comparing difference highly significant with other, model group bead pathological changes integration is the highest, and the heavy dose of group of positive drug group and effective portion of conical hydrangea glomerule pathological changes integration is starkly lower than model group.Except that the glomerule pathological changes, tangible pathological change also took place in matter between renal tubules reached, these variations mainly show as a matter inflammatory cell infiltration, proliferation of fibrous tissue in various degree, renal tubular epithelial is flat, tube chamber expansion and protein cast etc., the above-mentioned pathological changes of model group is the most serious, and the big or middle dosage group of positive drug group and Hydrangea paniculata extract obviously alleviates.Pathological examination also illustrates and is subjected to the big or middle dosage group of reagent, chronic nephritis rat kidney pathological changes is had the certain protection effect.
The present invention observes the influence of effective portion of conical hydrangea to animal blood pressure also by two kidneys, one folder type renal vascular hypertension rat model.Under study for action, after the animal via two kidneys one folder type operation, arteriotony raises gradually, compares with sham operated rats during to the 7th week to have tangible significant difference (P＜0.01).Give positive control drug angiotensin-convertion enzyme inhibitor (ACEI)---captopril and AT
1Receptor antagonist---losartan is after two weeks, and animal blood pressure obviously descends, and illustrates that this experiment hypertensive rat model is successful.By observing the influence of Hydrangea paniculata, find Hydrangea paniculata low dose group (7.5mg/kg) two weeks of oral administration the renal vascular hypertension rat to be shunk the tangible reduction effect that is pressed with to renal vascular hypertension rat systolic pressure, diastolic pressure and heart rate.Heart rate to animal does not then have obvious influence; Its mechanism may be relevant with the balance of the positive negative regulatory factor of endogenous blood pressure in the control agent.After two weeks of effective portion of conical hydrangea treated animal drug withdrawal, the equal rebound significantly of systolic pressure and diastolic pressure is not so see and be subjected to the test product effective portion of conical hydrangea to have after effect.
The specific embodiment
The preparation of extract
Embodiment 1
Hydrangea paniculata root or stem 1kg, 95% alcohol reflux 3 times, each 2 hours, 60 ℃ of concentrating under reduced pressure obtained extractum.This extractum ethanol: oxolane: low amounts of water (8: 8: 1) dissolving, get supernatant and 100-200 order 250g silica gel mixed sample, 60 ℃ of oven dry of water-bath, by 1 100-200 order 100g silicagel column, use the 3500ml petroleum ether respectively: acetone (1: 1), 2000ml acetone, ethanol elution, collect the acetone eluent, 60 ℃ of concentrating under reduced pressure obtain various piece respectively.Partial acetone (crude product part) is used ethanol: oxolane: water (7: 8: 3) dissolving by the ODS post, with 10-15% ethanol mobile phase eluting, obtains containing the Hydrangea paniculata extract of 50% above skimmin.
Embodiment 2
Hydrangea paniculata root or stem 1kg, 95% alcohol reflux 3 times, each 2 hours, 60 ℃ of concentrating under reduced pressure obtained extractum.This extractum ethanol: oxolane: low amounts of water (8: 8: 1) dissolving, get supernatant and 100-200 order 250g silica gel mixed sample, 60 ℃ of oven dry of water-bath, by 1 100-200 order 100g silicagel column, use the 3500ml petroleum ether of variable concentrations respectively: acetone (1: 1), 2000ml acetone, ethanol elution, collect the acetone eluent,, obtain partial acetone (crude product part) at 60 ℃ of concentrating under reduced pressure acetone eluents.Partial acetone is used the 10-40% ethanol elution through macroporous resin column chromatography, obtains containing the Hydrangea paniculata extract of 50% above skimmin.
Embodiment 3
Hydrangea paniculata root or stem 1kg, 95% alcohol reflux 3 times, each 2 hours, 60 ℃ of concentrating under reduced pressure obtained extractum.This extractum ethanol: oxolane: low amounts of water (8: 8: 1) dissolving, get supernatant and 100-200 order 250g silica gel mixed sample, silica gel column chromatography (ratio of applied sample amount and silica gel) is carried out in 60 ℃ of oven dry of water-bath, uses CH
3Cl: MeOH: H
2O (8: 2: 0.1) mobile phase eluting obtains containing the Hydrangea paniculata extract of 50% above skimmin.
Pharmacological evaluation
The chmice acute toxicity test of experimental example 1 Hydrangea paniculata extract
Experiment purpose:
Observe the acute toxicity of Hydrangea paniculata extract, obtain maximum tolerated dose (MTD) at a gastric infusion of mice.
Be subjected to the reagent thing:
Title: Hydrangea paniculata extract (by method 1 preparation)
The unit of providing: institute of Materia Medica,Chinese Academy of Medical Sciences plant chamber
Compound method: 0.5% Sodium Tvlose is mixed with suspension and irritates stomach.
Animal:
Kunming mouse, male and female half and half are provided by laboratory animal institute of Chinese Academy of Medical Sciences breeding field.The quality certification number: scxk11-00-0006
Experimental technique:
Choose and state 20 of Kunming mouses, male and female half and half, fasting is 12 hours before the administration.Once irritate stomach and give Hydrangea paniculata extract 5g/kg.Mice toxic reaction and death condition after the observation administration were observed 14 days continuously.Weigh, dissect.
Experimental result:
The Hydrangea paniculata extract of once irritating stomach 5g/kg for mice, the no abnormal reaction of animal after the administration does not have dead in two weeks.Female mice weight increase 52.8% after two weeks, male mice weight increase 84.8%, each main organs of postmortem perusal is not found obvious pathological change.
Conclusion:
The Hydrangea paniculata extract is 5g/kg at the MTD of a gastric infusion of mice.
The influence to cisplatin induced mice acute injury of kidney of experimental example 2 Hydrangea paniculata extracts.
Get male Kunming KM mice, 16g～18g is divided into solvent control group, cisplatin model group and administration group at random by body weight, 8 every group.Matched group intraperitoneal injection of saline, cisplatin are with physiological saline solution, and lumbar injection is pressed 7mg/kg.More than each administration volume be 0.4ml/20g, began to contrast medicine and extract in preceding 2 days in the injection cisplatin, behind the injection cisplatin the 3rd day, 5 days, 7 days respectively eyeball get blood, detect serum BUN, Cre with test kit.
Result of study
Table 1. extract is to the protective effect of cisplatin induced mice injury of kidney (after the modeling 3 days)
Annotate: the positive contrast medicine of B Benazepril in the table, HP represents the Hydrangea paniculata extract, *: P＜0.05, compare with model group; ↑: for raising.
Table 2. extract is to the protective effect of cisplatin induced mice injury of kidney (after the modeling 5 days)
Annotate: the positive contrast medicine of B Benazepril in the table, HP represents the Hydrangea paniculata extract, *: P＜0.05, compare with model group; ↑: for raising.
Table 3. extract is to the protective effect of cisplatin induced mice injury of kidney (after the modeling 7 days)
Annotate: the positive contrast medicine of B Benazepril in the table, HP represents the Hydrangea paniculata extract, *: P＜0.05, compare with model group; ↑: for raising.
Above-mentioned experimental result shows, behind the modeling type 3 days, model group serum creatinine (Cre), blood urea nitrogen (Bun) significantly raise, the Hydrangea paniculata extract can obviously reduce serum creatinine and urea nitrogen levels under 12.5mg/kg dosage, reduce by 53.4%, 66.3% respectively, effect is better than Benazepril10mg/kg dosage group.
Behind the modeling type 5 days, model group serum creatinine, blood urea nitrogen still keep higher level, the Hydrangea paniculata extract can obviously reduce serum creatinine and urea nitrogen levels under 12.5mg/kg dosage, be respectively 53.9%, 38.1%, acts on suitable with Benazepril 5mg/kg dosage group.
Behind the modeling type 7 days, model group and each administration group serum creatinine level are recovered normal (Benazepril 10mg/kg dosage group serum creatinine level is lower than normal level), model group blood urea nitrogen level still is significantly higher than negative control group, Hydrangea paniculata extract 12.5mg/kg and 25mg/kg dosage group reduce the blood urea nitrogen level and reach 65.6% and 58.1%, and be suitable with positive drug Benazepril effect.
Experimental result shows that the Hydrangea paniculata extract has the certain protection effect to the mice injury of kidney that cisplatin causes, and acts on suitable with positive control drug Benzaepril.
Experimental example 3 Hydrangea paniculata extracts excise the influence that causes chronic renal insufficiency to 5/6 kidney of rats
Method:
Get the male Wistar rat about body weight 200g, lumbar injection pentobarbital sodium 35mg/kg, after waiting to anaesthetize, the right kidney of surgical removal excises left kidney utmost point excess of the kidney matter up and down, stops blooding, closes the abdominal cavity, sews up.
Perform the operation after 2 weeks,, and begin administration the survival rats random packet.Effective portion of conical hydrangea is a gastric infusion, 6 times weekly, continued medication for 10 weeks, and Losartan (10mg/kg/day) gastric infusion 6 times weekly continued medication for 16 weeks.
Experiment is established 6 groups altogether, and every group of 6 Mus are established sham operated rats (negative control group), operation group (model group), Losartan positive drug control group, effective portion of conical hydrangea 7.5mg/kg, 15mg/kg, three dosed administration groups of 30mg/kg.
Operation back 2 all serum urea nitrogen, creatinine, Angiotensin II and urine protein indexs measured, later per 2 weeks survey once, finish to testing.Weigh weekly, observe the rat upgrowth situation, after the last administration 24 hours, get serum and survey above-mentioned biochemical indicator; Put to death animal, get kidney and make detailed pathologic finding.
Experimental result:
Serum biochemistry index, urine protein content, plasma A II level, the weight of animals and pathological change.Concrete outcome sees table 4-9 for details
Table 4. operation back 2 all effective portion of conical hydrangea are to the therapeutical effect of rat chronic renal insufficiency
4-A. blood Cre, blood BUN level
4-B. the level of Angiotensin II, urine protein and body weight
Attention: each processed group does not all have administration, comprises matched group and model group.
Table 5. operation back 4 weeks (2 weeks after the administration) effective portion of conical hydrangea is to the therapeutical effect of rat chronic renal insufficiency
5-A. the level of blood Cre, blood BUN
5-B. the level of Angiotensin II, urine protein and body weight
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
Table 6. operation back 6 weeks (4 weeks after the administration) effective portion of conical hydrangea is to the therapeutical effect of rat chronic renal insufficiency
6-A. the level of blood Cre, blood BUN
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
6-B. the level of Angiotensin II, urine protein and body weight
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
Table 7. operation back 8 weeks (6 weeks after the administration) effective portion of conical hydrangea is to the therapeutical effect of rat chronic renal insufficiency
7-A. the level of blood Cre, blood BUN
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
7-B. the level of Angiotensin II, urine protein and body weight
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
Table 8. operation back 12 weeks (8 weeks after the administration) effective portion of conical hydrangea is to the therapeutical effect of rat chronic renal insufficiency
8-A. the level of blood Cre, blood BUN
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group
8-B. the level of Angiotensin II, urine protein and body weight
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group
8 back 2 weeks of drug withdrawal in week of operation, continue administration after 2 weeks, dosage is adjusted into 3.75mg/.kg, 7.5mg/kg, 15.0mg/kg.
Table 9. operation back 16 weeks (12 weeks after the administration) effective portion of conical hydrangea is to the therapeutical effect of Mus chronic renal insufficiency
9-A. the level of blood Cre, blood BUN
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group
9-B. the level of Angiotensin II, urine protein and body weight
*P＜0.05,
*P＜0.01: compare with matched group,
#: P＜0.05,
##: P＜0.01: compare with model group.
(1) 2 weeks of modelling
Model group serum BUN 223.2% (P＜0.01) that raises, serum creatinine 14.8% (the seeing table 4 for details) that raise.Operation treated animal body weight all descends to some extent.
(2) 4 weeks of modelling (2 weeks of administration)
Biochemical indicator:
Model group serum BUN 164.7% (P＜0.01) that raises, creatinine (Cre) raises 38.1%, and urine protein raises 67.3%, and the model group the weight of animals descends 18.1%.
Compare with model group, the BUN of effective portion of conical hydrangea 7.5mg/kg, 15mg/kg, 30mg/kg 5.3%, 1.9% and 8.37% (P＞0.05 that descends respectively, P＞0.05, P＞0.05), creatinine level is at 30mg/kg, descend 4.88%, the BUN of positive control drug Losartan rises 9.3%, creatinine level 28.0% (P＞0.05) that descended.The AII level of effective portion of conical hydrangea 7.5mg/kg, 15mg/kg and 30mg/kg reduces by 12.4%, 21.1% and 28.96% respectively, and positive control drug Losartan has raise 78.8%.The urine protein content of effective portion of conical hydrangea 30mg/kg reduces by 11.24%, and positive drug Losartan reduces renal failure rat urine protein 2.71% (the results are shown in Table 5).
(3) 6 weeks of modelling (4 weeks of administration)
Biochemical indicator
Model group serum BUN 117.1% (P＜0.01) that raises, creatinine (Cre) 58.6% (P＜0.05) that raises, urine protein 122.54% (P＜0.01) that raises.AII level, animal body weight average do not have significant difference.
Compare with model group, the BUN of effective portion of conical hydrangea 7.5mg/kg, 15mg/kg and 30mg/kg descends 0.3%, 19.7% and 11.09% respectively; Creatinine level 8.9%, 21.2% and 64.48% (P＜0.01) that descends respectively, urine protein descend 56.4%, 21.4% and risen 16.3% respectively; Angiotensin II (AII) reduces by 31.36%, 24.31% and 10.82% respectively; The BUN of positive control drug Losartan descends 11.90%, and creatinine level descends 37.0%.Urine protein decline 56.4% (result sees table 6 for details).
(4) 8 weeks of modelling (6 weeks of administration)
Biochemical indicator
Model group serum BUN 73.61% (P＜0.01) that raises, creatinine (Cre) 134.12% (P＜0.05) that raises, urine protein 154.15% (P＜0.01) that raises.AII level, animal body weight average do not have significant difference.
Compare with model group, the BUN of HP preparation 7.5mg/kg, 15mg/kg and 30mg/kg descends 8.49%, 10.58% and 0.64% respectively; Creatinine level descends 25.04%, 2.51% and 24.20% respectively, urine protein middle dosage and heavy dose descend respectively 19.76% and and 26.69%; The BUN of positive control drug Losartan descends 0.90%, urine protein decline 53.19% (result sees table 7 for details).
(5) 2 week of 12 weeks of modelling (8 weeks of administration) drug withdrawal midway back decrement continuation administration
Biochemical indicator
Model group serum BUN 128.16% (P＜0.01) that raises, creatinine (Cre) 37.68% (P＜0.05) that raises, urine protein 187.68% (P＜0.01) that raises.AII level, animal body weight average do not have significant difference.
Compare with model group, the BUN of HP preparation 3.75mg/kg, 7.5mg/kg and 15mg/kg descends 8.75%, 23.53% and raise 1.83% respectively; Creatinine level descends 17.89%, 0% and 7.16% respectively, and urine protein descends 23.84% and 5.34% respectively at 7.5mg/kg and 15mg/kg; Angiotensin II (AII) reduces by 15.48%, 28.44% and 5.53% respectively; The BUN of positive control drug Losartan descends 10.65%, and creatinine level rises 4.21%.Urine protein decline 23.50% (result sees table 8 for details).
(6) 16 weeks of modelling (12 weeks of administration)
Biochemical indicator
Model group serum BUN 160.00% (P＜0.01) that raises, creatinine (Cre) 55.78% (P＜0.05) that raises, urine protein 275.22% (P＜0.01) that raises.AII level, animal body weight average do not have significant difference.
Compare with model group, the BUN of HP preparation 3.75mg/kg, 7.5mg/kg and 15mg/kg rises 5.64% respectively, has descended 22.04% and 2.08%; Creatinine level 45.93%, 42.58% (P.0.05) and 54.07% (P＜0.01) that descend respectively, urine protein has descended 16.74% at 3.75mg/kg; Angiotensin II (AII) reduces by 38.45%, 25.56% and 18.89% respectively; The BUN of positive control drug Losartan descends 39.76%, and creatinine level descends 46.97%.Urine protein decline 58.13% (result sees table 9 for details).
The nephridial tissue pathological examination
Experimental technique:
With kidney of rats excision 5/6, the postoperative administration, drug withdrawal was put to death animal in 24 hours, got residual kidney, and specimen is through 10% formaldehyde fixed, paraffin embedding, HE dyeing, light microscopy checking.30 glomerule of every routine animal counting, according to reported in literature with glomerulopathy variation Pyatyi (0-IV), the big more pathological changes of progression is serious more, on fractionated basis, multiply by different flexible strategy (from 0-IV difference x0.05-0.4) again, (X ± S), integration is high more, and pathological changes is heavy more to obtain the percent (%) of every animal pathological changes glomerule at different levels and every group of glomerule pathological changes total mark.
Experimental result:
Table 10 is each treated animal glomerulopathy variation level result, matched group 96% above glomerule is not seen pathological changes, model group II-IV level glomerule pathological changes is more than 94%, and wherein IV level pathological changes glomerule can reach 27.6%, has only individual animal can see 0 grade and I level glomerule.The big or middle dosage group of positive controls and effective portion of conical hydrangea administration has the certain protection effect to the glomerule pathological changes, and particularly IV level glomerule percent is starkly lower than model group (because of individual variation is bigger, routine number is added up less and do not seen notable difference).
Table 10 glomerulopathy variation level
Table 11 is each treated animal glomerule pathological changes total mark, normal control group glomerule pathological changes integration minimum (1.55 ± 0.06), respectively organize comparing difference highly significant (P＜0.01) with other, model group bead pathological changes integration the highest (8.77 ± 1.55), the heavy dose of group of positive drug group and effective portion of conical hydrangea administration bead pathological changes integration is starkly lower than model group, and wherein positive group and model group comparing difference be (P＜0.05) significantly.Postoperative is except that the glomerule pathological changes, tangible pathological change also took place in matter between renal tubules reached, these variations mainly show as a matter inflammatory cell infiltration, proliferation of fibrous tissue in various degree, renal tubular epithelial is flat, tube chamber expansion and protein cast etc., the above-mentioned pathological changes of model group is the most serious, and the big or middle dosage group of positive drug group and effective portion of conical hydrangea administration obviously alleviates.
Table 11 glomerule pathological changes integration (X ± S)
Annotate: compare with model group * P＜0.05; Compare with the normal control group Δ P＜0.01
Conclusion:
1. excision 5/6 kidney, postoperative 4 months, the residual nephropathy change of rat characteristics meet the chronic nephritis model;
2. positive drug and be subjected to the big or middle dosage group of reagent has certain protective role to chronic nephritis kidney of rats pathological changes.Be that effective portion of conical hydrangea has therapeutical effect preferably to the caused chronic renal insufficiency of most of nephrectomy.
Embodiment 4 effective portion of conical hydrangea are to the influence of renal vascular hypertension rat blood pressure
Purpose:, observe the influence of Hydrangea paniculata to animal blood pressure by two kidneys, one folder type renal vascular hypertension rat model.
1 material:
1.1 animal: the Wistar rat, body weight 160-180g is provided by Institute of Experimental Animals, Chinese Academy of Medical Sciences, the quality certification number: SCXK11-00-0006.
1.2 instrument: BESN-II multichannel animal noinvasive pressure measuring system, Nanjing Bioisystech Co., Ltd of DESAY provides.
1.3 medicine: be subjected to test product: effective portion of conical hydrangea, white powder, lot number 030703.The Losartan Potassium sheet, Hangzhou Mo Shadong pharmaceutical Co. Ltd product, lot number 02103.The captopril sheet, Beijing Taiyang Pharmaceutical Co., Ltd., lot number 030301.Pentobarbital sodium, the packing of Beijing chemical reagents corporation, lot number 020919.The injection benzylpenicillin potassium, animal health product Co., Ltd of North China pharmacy group, lot number 030553.The renal artery folder: interior through 0.2mm ~ 0.3mm, provide by professor Fu Jihua of physiology teaching and research room of China Medicine University.
2 methods
2.1 the vascular hypertension rat model is set up: totally 140 of healthy Wistar rats, male, adaptability was fed 4 days.Measure the animal basic blood pressure with the BESN-II pressure measuring system, weekly, METHOD FOR CONTINUOUS DETERMINATION three times.Then randomly draw 10 animals volumes and be sham operated rats.Rat is with pentobarbital sodium (30mg/kg) intraperitoneal injection of anesthesia, shave a hair sterilization abdominal part, open the abdominal cavity, expose left kidney and passivity separation renal artery in the abdomen median line 0.5mm place that takes back, with interior renal artery folder constriction left renal artery through 0.2mm～0.3mm, then successively abdomen is closed in sterilization.Do not touch the right side kidney in the operation process.Sham operated rats is only separated left renal artery, but constriction not.Operation finishes back intramuscular injection penicillin 50,000 U/ only with prevention infection, places cage to raise.
2.2 experimental program:
The treatment administration: postoperative continues to monitor the operation rat blood pressure, and systolic pressure 〉=160mmHg person is defined as hypertension model and forms.The rat of modeling success is divided into 9 groups by the blood pressure stratified random, be respectively: model group, losartan (4.5mg/kg), Captopril group (6mg/kg), Hydrangea paniculata high dose group (30mg/kg), middle dosage group (15mg/kg), low dose group (7.5mg/kg), each treated animal gastric infusion, once a day, model group and sham operated rats wait the capacity distilled water.Administration volume 0.5ml/100g.Successive administration is observed the variation of each treated animal blood pressure and heart rate after two weeks.
Recover experiment: each stops administration after five weeks of treated animal administration.The 3rd week was measured animal blood pressure and heart rate after drug withdrawal, observed the pharmacodynamics aftereffect that is subjected to test product.
3 results
3.1 effective portion of conical hydrangea is to the influence of renal vascular hypertension rat systolic pressure, diastolic pressure and heart rate
The renal vascular hypertension rat is one of animal model of estimating of at present the most frequently used research hypertension drug, and it has model stability, characteristics such as simple to operate and similar to human renal hypertension pathogeny.In this research, after the animal via two kidneys one folder type operation, arteriotony raises gradually, compares with sham operated rats during to the 7th week to have tangible significant difference (P＜0.01).Give positive control drug angiotensin-convertion enzyme inhibitor (ACEI)---captopril and AT
1Receptor antagonist---losartan is after two weeks, and animal blood pressure obviously descends, and the success of this experiment hypertensive rat model is described.
By table 12-14 as seen, compare, be subjected to test product Hydrangea paniculata live part low dose group (7.5mg/kg) two weeks of oral administration that the renal vascular hypertension rat is shunk the tangible reduction effect that is pressed with model group; Diastolic pressure and model group relatively there are no significant difference after other each treated animal two weeks.
All renal vascular hypertension rats are compared heart rate with the sham-operation animal after six weeks of modeling does not have significant difference.Positive control drug captopril and losartan are not seen obvious influence to the animal heart rate after the two weeks.Compare with model group, the effective portion of conical hydrangea high dose group can slightly reduce outside the animal heart rate, and other each administration treated animal heart rate does not have significant change.
After being subjected to two weeks of test product treated animal drug withdrawal, the equal rebound significantly of systolic pressure and diastolic pressure, statistical result show that each dosage group of effective portion of conical hydrangea is compared there was no significant difference (P＞0.05) with model group.Renal vascular hypertension rat heart rate also there is not obvious influence.Each organize before the administration and administration after animal systolic pressure, diastolic pressure and heart rate see Table 12-14.
Table 12. effective portion of conical hydrangea is to the influence (mmHg) of renal vascular hypertension rat systolic pressure
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 13. effective portion of conical hydrangea is to the influence (mmHg) of renal vascular hypertension rat diastolic pressure
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 14. effective portion of conical hydrangea is to the influence of renal vascular hypertension rat heart rate (inferior/minute)
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
3.2 effective portion of conical hydrangea is to the influence of nitric oxide, Angiotensin II, Endothelin, nitricoxide synthase and calcitonin-gene-related peptide content in the renal vascular hypertension rat serum
The stable balance that depends on the positive negative regulatory factor of blood pressure in the body of animal blood pressure.Nitric oxide is an endogenous blood pressure negative regulatory factor, brings high blood pressure down, effect such as vasodilator and inhibition vascular smooth muscle cell proliferation.Model group rat body intracellular nitric oxide level obviously reduces in this experiment, and this is consistent with other bibliographical information.Be subjected to each dosage group of test product effective portion of conical hydrangea to nitric oxide and synthase thereof all active do not have obviously influence (see Table 15 and table 19).
Angiotensin II and Endothelin (ET) are the positive regulatory factor of blood pressure stronger in the body.Experiment in vitro proves that the two has the effect of mutually promoting and transforming.Interior AII of model group rat body and ET level obviously raise in this experiment, illustrate that the rising of animal blood pressure and interior this type of regulatory factor level of body are proportionate, and be consistent with other bibliographical information.After the two weeks, be subjected to test product effective portion of conical hydrangea low dose group can reduce AII and ET level in the Hypertensive Rats blood plasma, but not statistically significant (P＞0.05), we think that this result is more relevant with standard deviation.Do not seen obviously by the internal source depressor material of each dosage group of test product calcitonin-gene-related peptide influences (see Table 16, table 17 and table 18).
Table 15. effective portion of conical hydrangea is to the influence (μ mol/L) of kidney blood vessel spare Hypertensive Rats blood plasma NO
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 16. effective portion of conical hydrangea is to the influence (pg/ml) of renal vascular hypertension rat plasma Angiotensin II
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 17. effective portion of conical hydrangea is to the influence (pg/ml) of renal vascular hypertension rat plasma Endothelin
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 18. effective portion of conical hydrangea is to the influence (pg/ml) of renal vascular hypertension rat plasma calcitonin-gene-related peptide
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
Table 19. effective portion of conical hydrangea is to the influence (U/mgprot) of renal vascular hypertension rat plasma NOS
Annotate: * P＜0.05, compare with model group * * P＜0.01; + P＜0.05, ++ P＜0.01, compare with sham operated rats.
4. conclusion
1, is subjected to test product effective portion of conical hydrangea low dose group can obviously reduce renal vascular hypertension rat artery blood pressure, the heart rate of animal is not had obvious influence; Its mechanism may be relevant with the balance of the positive negative regulatory factor of endogenous blood pressure in the control agent.
2, be subjected to two weeks of test product treated animal drug withdrawal after, the equal rebound significantly of systolic pressure and diastolic pressure is not so see and be subjected to the test product effective portion of conical hydrangea to have after effect.
Claims (11)
1. a preparation method that contains the effective portion of conical hydrangea of 10% above skimmin is characterized in that, comprises the steps:
(a) Hydrangea paniculata root or stem solvent extraction concentrate, and obtain extractum; Described solvent is the mixture of water, alcohols or water and alcohols;
(b) use silica gel column chromatography, use CH
3Cl: MeOH: H
2O mobile phase eluting, chromatography obtains effective portion of conical hydrangea 1 time.
2. preparation method according to claim 1 is characterized in that described alcohols is selected from one of methanol, ethanol, isopropyl alcohol or butanols.
3. preparation method according to claim 1 is characterized in that, concentrated described in the step (a) is under reduced pressure.
4. the effective portion of conical hydrangea of each preparation among the claim 1-3 is characterized in that, contains the skimmin more than 10%.
5. according to the effective portion of conical hydrangea of claim 4, it is characterized in that, contain the skimmin more than 50%.
6. a pharmaceutical composition that prevents and/or treats renal insufficiency is characterized in that, each effective site and pharmaceutical carrier among the claim 4-5 that contains.
7. according to the pharmaceutical composition of claim 6, it is characterized in that described pharmaceutical composition is selected from tablet, capsule, pill, injection.
8. according to the pharmaceutical composition of claim 6, it is characterized in that described pharmaceutical composition is selected from slow releasing preparation or controlled release preparation.
9. according to the pharmaceutical composition of claim 6, it is characterized in that described pharmaceutical composition is selected from particulate delivery system.
10. each effective site prevents and/or treats application in the medicine of renal insufficiency in preparation among the claim 4-5.
11. each effective site prevents and/or treats application in the hypertensive medicine in preparation among the claim 4-5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102543162A CN101693045B (en) | 2004-04-23 | 2004-04-23 | Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102543162A CN101693045B (en) | 2004-04-23 | 2004-04-23 | Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200410034068A Division CN100584854C (en) | 2004-04-23 | 2004-04-23 | Efficient parts of hydrangea paniculata, their preparing method and compositions and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101693045A CN101693045A (en) | 2010-04-14 |
| CN101693045B true CN101693045B (en) | 2011-06-29 |
Family
ID=42092071
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102543162A Expired - Lifetime CN101693045B (en) | 2004-04-23 | 2004-04-23 | Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101693045B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911224A (en) * | 2011-08-02 | 2013-02-06 | 苏州宝泽堂医药科技有限公司 | Preparation method of skimmin |
| CN111727884B (en) * | 2020-07-21 | 2022-03-11 | 江苏农林职业技术学院 | In-vitro bud culture method of hydrangea paniculata |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001206819A (en) * | 2000-01-24 | 2001-07-31 | Sansho Seiyaku Co Ltd | Bleaching cosmetic |
-
2004
- 2004-04-23 CN CN2009102543162A patent/CN101693045B/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001206819A (en) * | 2000-01-24 | 2001-07-31 | Sansho Seiyaku Co Ltd | Bleaching cosmetic |
Non-Patent Citations (2)
| Title |
|---|
| Hirozi Suzuki,et al.Isolation and identification of phyllodulcin and skimmin from the cultured cells of amacha(Hydrangea macrophylla seringe var. Thunbergii Makino).《Agricultural Biology and Chemistry》.1977,第41卷(第4期),719-720. * |
| 刘自民等.长毛风毛菊化学成分的研究.《高等学校化学学报》.1989,第10卷(第11期),1090-1094. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101693045A (en) | 2010-04-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107714949A (en) | Dendrobium candidum is preparing the application process in treating hypertension drug | |
| CN104940479A (en) | TCM composition for treating AD diseases | |
| CN103446525A (en) | Traditional Chinese medicine composition for treating skin diseases as well as preparation method and application of traditional Chinese medicine composition | |
| CN101693045B (en) | Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof | |
| CN1989990B (en) | Medicine for treating erection dysfunction and preparation method thereof | |
| CN107281386B (en) | Method for preparing medicine for treating hypertension by using dendrobium officinale and radish seeds and application | |
| CN100584854C (en) | Efficient parts of hydrangea paniculata, their preparing method and compositions and use thereof | |
| CN101991757B (en) | Chinese medicinal composition for reinforcing kidney and supporting yang and preparation method thereof | |
| CN101804083A (en) | Application of pollen pini and extract thereof in treating inflammatory bowel disease and method for preparing extract | |
| CN100486621C (en) | Chinese medicinal composition for treating hemilateral headache and its preparation method | |
| CN102058764B (en) | Medicinal composition for treating acquired immune deficiency syndrome (AIDS) and application thereof | |
| CN100589800C (en) | Chinese medicine preparation of total coumarins extract from peu cedanum praeruptorum dunn, and its preparing method and use | |
| CN100512827C (en) | Chinese medicine tablet of total coumarins extract from peucedanum praeruptorm and its preparing method and use | |
| CN100387245C (en) | Medicine for treating erection dysfunction and preparation method thereof | |
| CN100574754C (en) | A kind of preparation method of total coumarins extract from peucedanum praeruptorm | |
| CN102068670B (en) | Chinese medicinal composition for treating hyperlipidemia | |
| CN101461872B (en) | Medicament composition for treating erectile dysfunction and preparation method thereof | |
| CN102349956A (en) | Compound extract for moisturizeing pathogenic dryness and relieving itching and preparation thereof | |
| CN101590109B (en) | Compound preparation for treating back pain caused by senile osteoporosis and preparation method thereof | |
| CN1256093C (en) | Application of skimming in the preparing process of medicine for preparing and treating kidney function failure | |
| CN102309561A (en) | Pharmaceutical composition used for preventing and treating urarthritis and hyperuricemia | |
| CN102018849A (en) | Traditional Chinese medicine composition for preventing irregular menstruation and preparation method thereof | |
| CN1709298A (en) | Chinese medicine formulation for treating chronic prostatitis and its preparing method | |
| CN103705775B (en) | One protects the liver analgesia Chinese medicine composition and preparation method thereof | |
| CN104434920B (en) | A kind of pharmaceutical composition treating heart failure and application thereof |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: BEIJING XIEHE NO. 2 PHARMACEUTICAL FACTORY Free format text: FORMER OWNER: BEIJING UNION PHARMACEUTICAL FACTORY Effective date: 20130130 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20130130 Address after: 102600, Beijing, Daxing District Huang Town, Xingye North Road, Beijing Concord pharmaceutical factory two Patentee after: BEIJING XIEHE PHARMACEUTICAL SECOND FACTORY Patentee after: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES Address before: 102600, Xingye Road, Huangcun Town, Daxing District, Beijing Patentee before: Beijing Union Pharmaceutical Factory Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 102600 Beijing Daxing District Yongwang Road 37 Courtyard 2 Building 1-3 Floor 101 Patentee after: Beijing Xiehe Pharmaceutical Second Factory Co.,Ltd. Patentee after: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES Address before: Beijing Xiehe Pharmaceutical No. 2 Factory, Xingye North Road, Huangcun Town, Daxing District, Beijing 102600 Patentee before: BEIJING XIEHE PHARMACEUTICAL SECOND FACTORY Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| CX01 | Expiry of patent term |
Granted publication date: 20110629 |
|
| CX01 | Expiry of patent term |