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影响因子_Chem2012

Mark Rank Abbreviated Journal Title ISSN JCR Data More Information (linked to journal information)Total Cites Impact5-YearFactor ImpactFactor NATURE0028-0836********.2836.235SCIENCE0036-807548083631.20132.452P NATL ACAD SCI USA0027-84245042439.68110.4721CHEM REV0009-266510370240.19742.0542NAT MATER1476-11223924232.84136.7323CHEM SOC REV0306-00123591828.7628.0984ACCOUNTS CHEM RES0001-48423966421.6422.5075NAT CHEM1755-4330526020.52420.5336ALDRICHIM ACTA0002-5100110016.09116.8827NANO TODAY1748-0132217015.35516.0788ANNU REV PHYS CHEM0066-426X665714.1317.489ADV MATER0935-96487986013.87712.81310ANGEW CHEM INT EDIT1433-785120986213.45513.19511NANO LETT1530-69847528713.19813.84312COORDIN CHEM REV0010-85452506212.1112.74413SURF SCI REP0167-5729370211.69618.09514ACS NANO1936-0851*******.77411.17115MED RES REV0198-6325309610.710.0316J PHOTOCH PHOTOBIO C1389-5567165410.3612.45817ADV FUNCT MATER1616-301X2850310.1799.9218J AM CHEM SOC0002-78634083079.9079.76619NAT PROD REP0265-056857749.799.67120ENERG ENVIRON SCI1754-569250879.6110.81321PROG INORG CHEM0079-637914959.3338.33322ANNU REV ANAL CHEM1936-13278769.04811.80623PROG SURF SCI0079-681617288.6368.08824SMALL1613-6810151818.3498.26225ADV COLLOID INTERFAC0001-868664148.128.37226CURR OPIN COLLOID IN1359-029444788.017.83727ADV CARBOHYD CHEM BI0065-23188517.643 5.5628CHEM SCI2041-652016977.5257.54529CATAL REV0161-494027377.59.92730ANNU REV CHEM BIOMOL1947-54381587.2947.29431CHEM MATER0897-4756699267.286 6.94932ADV ORGANOMET CHEM0065-30559517 6.63633NANO RES1998-01242017 6.977.46134CHEMSUSCHEM1864-56313040 6.8277.17135GREEN CHEM1463-926212023 6.32 6.76136TRAC-TREND ANAL CHEM0165-99366620 6.273 6.87337J PHYS CHEM LETT1948-71854695 6.213 6.217 38CHEM COMMUN1359-7345105562 6.169 6.082 39ADV SYNTH CATAL1615-415014629 6.048 5.904 40J CATAL0021-951733570 6.002 6.201 41J MATER CHEM0959-942846166 5.968 5.992 42INT REV PHYS CHEM0144-235X1533 5.967 6.977 43CHEM-EUR J0947-653954127 5.925 5.866 44NANOSCALE2040-33643187 5.914 5.914 45ORG LETT1523-706068838 5.862 5.558 46ANAL CHEM0003-270095262 5.856 5.983 47J CONTROL RELEASE0168-365926071 5.7327.112 48LAB CHIP1473-019713729 5.67 6.497 49APPL CATAL B-ENVIRON0926-337320525 5.625 6.052 50BIOSENS BIOELECTRON0956-566320029 5.602 5.637 51BIOMACROMOLECULES1525-779721280 5.479 5.646 52CARBON0008-622327798 5.378 6.008 53J MED CHEM0022-262356481 5.248 5.321 54J CHEM THEORY COMPUT1549-96188327 5.215 5.673 55PROG NUCL MAG RES SP0079-65651765 5.214 6.296 56CHEMCATCHEM1867-38801502 5.207 5.207 57FARADAY DISCUSS1364-549853725 4.687 58BIOCONJUGATE CHEM1043-180213657 4.93 5.224 59CURR MED CHEM0929-867311387 4.859 4.806 60J PHYS CHEM C1932-744760782 4.805 5.049 61CRYST GROWTH DES1528-748319082 4.72 4.877 62J CHEM INF MODEL1549-959611209 4.675 4.305 63INORG CHEM0020-166982190 4.601 4.553 64J COMPUT CHEM0192-865122334 4.583 4.795 65ANAL CHIM ACTA0003-267038343 4.555 4.144 66J CHROMATOGR A0021-967360179 4.531 4.362 67CHEM-ASIAN J1861-47284472 4.5 4.461 67ELECTROANAL CHEM0070-9778451 4.56 69J ORG CHEM0022-326398614 4.45 4.204 70SOFT MATTER1744-683X10988 4.39 4.998 71CHEM REC1527-89991256 4.377 4.161 72ANALYST0003-265414243 4.23 4.119 73PROG SOLID STATE CH0079-67861516 4.188 3.551 74LANGMUIR0743-7463103776 4.186 4.514 75CURR TOP MED CHEM1568-02664646 4.174 4.417 76PHARM RES-DORDR0724-874117160 4.093 4.668 77INT J HYDROGEN ENERG0360-319926939 4.054 4.402 78J AM SOC MASS SPECTR1044-03058794 4.002 3.746 79ORGANOMETALLICS0276-733339562 3.963 3.78680CHEMBIOCHEM1439-42279059 3.944 3.719 81APPL CATAL A-GEN0926-860X26533 3.903 3.961 82CRIT REV ANAL CHEM1040-8347849 3.902 3.956 83SENSOR ACTUAT B-CHEM0925-400527323 3.898 3.751 84MAR DRUGS1660-33971161 3.854 3.704 85CRYSTENGCOMM1466-80339036 3.842 4.023 86DALTON T1477-922637605 3.838 3.887 87TALANTA0039-914024981 3.794 3.747 88CHEM RES TOXICOL0893-228X10444 3.779 3.969 89ANAL BIOANAL CHEM1618-264218911 3.778 3.733 90J PHYS CHEM B1520-6106118812 3.696 4.061 90ORG BIOMOL CHEM1477-052015667 3.696 3.652 92ACS CHEM NEUROSCI1948-7193310 3.676 3.676 93ADV CATAL0360-05641395 3.667 5.04 94FOOD CHEM0308-814636842 3.655 4.268 95CARBOHYD POLYM0144-861715055 3.628 3.987 96PHYS CHEM CHEM PHYS1463-907631819 3.573 3.931 97EXPERT OPIN THER PAT1354-37761563 3.571 2.122 98ULTRASON SONOCHEM1350-41774594 3.567 3.83 99GOLD BULL0017-15571139 3.517 3.162 100STRUCT BOND0081-59931940 3.475 6.315 101FOOD HYDROCOLLOID0268-005X5607 3.473 3.46 102COLLOID SURFACE B0927-77658715 3.456 3.354 103CURR ORG SYNTH1570-1794665 3.434 3.842 104J CHEMINFORMATICS1758-2946179 3.419 3.419 105CHEMPHYSCHEM1439-423510354 3.412 3.553 106J COMB CHEM1520-47663046 3.408 2.893 107CATAL TODAY0920-586122303 3.407 3.584 108ACS MED CHEM LETT1948-5875511 3.355 3.355 109J INORG BIOCHEM0162-01349265 3.354 3.495 110EUR J MED CHEM0223-523411332 3.346 3.509 111EUR J ORG CHEM1434-193X18591 3.329 3.289 112ELECTROPHORESIS0173-083517540 3.303 2.917 113J BIOL INORG CHEM0949-82573803 3.289 3.488 114J NANOPART RES1388-07644770 3.287 3.574 115MICROPOR MESOPOR MAT1387-181113858 3.285 3.254 116CHEM CENT J1752-153X292 3.281 3.033 117J MASS SPECTROM1076-51745549 3.268 3.301 117PHYTOMEDICINE0944-71134731 3.268 3.3 119BIOANALYSIS1757-6180829 3.223 3.223 120J ANAL ATOM SPECTROM0267-94776969 3.22 2.966 121J PHYS CHEM REF DATA0047-26894693 3.172 3.804 122MOL DIVERS1381-19911114 3.153 3.236123CHEMMEDCHEM1860-71793364 3.151 3.445 124J NAT PROD0163-386418661 3.128 3.164 125DYES PIGMENTS0143-72086586 3.126 3.28 126MAR CHEM0304-42036836 3.074 3.551 127J COLLOID INTERF SCI0021-979742700 3.07 3.263 128CURR ORG CHEM1385-27283649 3.064 3.468 129J PHARM SCI-US0022-354916617 3.055 3.324 130EUR J INORG CHEM1434-194815553 3.049 2.904 131ADV INORG CHEM0898-******** 3.048 3.049 131MICROCHEM J0026-265X3125 3.048 2.878 133MICROCHIM ACTA0026-36724182 3.033 2.508 134TETRAHEDRON0040-402053591 3.025 3.06 135J ETHNOPHARMACOL0378-874121075 3.014 3.728 136ANAL BIOCHEM0003-269740002 2.996 3.247 137PLASMONICS1557-1955654 2.989 4.026 138CATAL COMMUN1566-73677950 2.986 3.299 139J PHARMACEUT BIOMED0731-708514454 2.967 2.979 140J MOL CATAL A-CHEM1381-116917457 2.947 3.336 141J PHYS CHEM A1089-563953462 2.946 2.941 142FUEL PROCESS TECHNOL0378-******** 2.945 3.131 143BIOORGAN MED CHEM0968-089622584 2.921 3.157 144J ELECTROANAL CHEM1572-665722586 2.905 2.731 145J CHROMATOGR B1570-023221252 2.888 3.057 146DRUG DES DEV THER1177-8881203 2.877147ELECTROANAL1040-039710069 2.872 2.856 148ANTI-CANCER AGENT ME1871-52061203 2.862149J SUPERCRIT FLUID0896-84465365 2.86 3.145 150J AGR FOOD CHEM0021-856171104 2.823 3.239 151MEDCHEMCOMM2040-2503223 2.8 2.8 152RAPID COMMUN MASS SP0951-419813453 2.79 2.782 153PURE APPL CHEM0033-454512669 2.789 2.987 154J MOL CATAL B-ENZYM1381-11774576 2.735 2.701 155J SEP SCI1615-93067275 2.733 2.725 156SYNLETT0936-521417866 2.71 2.567 157TETRAHEDRON LETT0040-403976620 2.683 2.588 158TETRAHEDRON-ASYMMETR0957-416613382 2.652 2.652 159SOLID STATE IONICS0167-273822111 2.646 3.097 160RUSS CHEM REV+0036-021X3090 2.644 2.941 161PHYTOCHEM ANALYSIS0958-03441883 2.633 2.32 162TOP CATAL1022-55284801 2.624 2.973 163SEP PURIF REV1542-2119175 2.615 3.629 164NEW J CHEM1144-05469359 2.605 2.775 165INT J MOL SCI1661-65962744 2.598 2.617166PHOTOCH PHOTOBIO SCI1474-905X3988 2.584 2.688 167ENVIRON CHEM1448-25171188 2.57 2.694 168BIOORG MED CHEM LETT0960-894X31475 2.554 2.539 169MINI-REV MED CHEM1389-55752649 2.528 2.772 170FUTURE MED CHEM1756-8919616 2.522 2.522 171BEILSTEIN J ORG CHEM1860-5397812 2.517 2.078 172PLANT FOOD HUM NUTR0921-96681448 2.505 2.889 173J ANAL APPL PYROL0165-23704356 2.487 2.687 174REACT FUNCT POLYM1381-51484207 2.479 2.727 175APPL CLAY SCI0169-13175168 2.474 3.06 176SYNTHESIS-STUTTGART0039-788118726 2.466 2.448 177J CHEM THERMODYN0021-96145451 2.422 2.173 178J PHOTOCH PHOTOBIO A1010-603012665 2.421 2.925 179MINI-REV ORG CHEM1570-193X460 2.406 2.283 180ORG PROCESS RES DEV1083-61603609 2.391 2.38 181MOL INFORM1868-1743171 2.39 2.407 182MOLECULES1420-30495118 2.386 2.411 183J ORGANOMET CHEM0022-328X22966 2.384 2.085 184CHIRALITY0899-******** 2.35 2.232 185AUST J CHEM0004-94255762 2.342 2.258 186CHEM PHYS LETT0009-261455511 2.337 2.215 187CARBOHYD RES0008-621514992 2.332 2.386 188COLLOID POLYM SCI0303-402X5510 2.331 2.077 189J ALLOY COMPD0925-838836296 2.289 2.104 190CHEM BIOL DRUG DES1747-02771504 2.282 2.477 191ADV QUANTUM CHEM0065-3276754 2.275 1.356 192CATAL LETT1011-372X9443 2.242 2.314 193COLLOID SURFACE A0927-775717780 2.236 2.359 194BIOPHYS CHEM0301-46224908 2.203 2.163 195J CHEM TECHNOL BIOT0268-25756388 2.168 2.27 196THEOR CHEM ACC1432-881X4587 2.162 2.909 197MATCH-COMMUN MATH CO0340-62531420 2.161 1.826 198J SOLID STATE CHEM0022-459617779 2.159 2.412 199PLANTA MED0032-094311107 2.153 2.338 200SUPRAMOL CHEM1061-02782323 2.145 2.021 201FLUID PHASE EQUILIBR0378-******** 2.139 2.225 202J FLUORESC1053-05092486 2.107 2.197 203APPL SURF SCI0169-433228315 2.103 2.032 204PHYTOTHER RES0951-418X7721 2.086 2.469 204SAR QSAR ENVIRON RES1062-936X715 2.086 1.874 206J FOOD COMPOS ANAL0889-15753582 2.079 3.257 207APPL ORGANOMET CHEM0268-26052774 2.061 1.849 208POLYHEDRON0277-538713245 2.057 2.118209J BIOMOL SCREEN1087-05712131 2.049 2.066 210J FLUORINE CHEM0022-11394628 2.033 1.95 211SOLVENT EXTR ION EXC0736-******** 2.024 1.81 212J ANAL TOXICOL0146-47602651 2.022 1.994 213ADSORPTION0929-560713282 2.215 214SURF SCI0039-602823707 1.994 1.661 215J ENVIRON MONITOR1464-03253800 1.991 2.245 216J IND ENG CHEM1226-086X1844 1.977 1.647 216PROG ORG COAT0300-94404252 1.977 2.167 218INORG CHEM COMMUN1387-70036187 1.972 1.975 219BIOMED CHROMATOGR0269-38792728 1.966 1.88 220J PHYS ORG CHEM0894-32302668 1.963 1.648Eigenfactor® MetricsMore Information Immediacy Articles Cited Eigenfactor®Article Influence®Index Half-life Score Score9.698419.4 1.6565820.3536.0758719.4 1.4128217.5081.87436147.8 1.6033 4.8927.1581967.90.2146413.3056.246134 4.70.2208917.8915.471314 3.20.13678.0693.4612670.10127.2865.308120 1.80.032847.94472 5.70.00328 5.2462.32437 2.80.0121 5.1443.267309.70.016877.4672.15578950.26226 4.0612.8982002 5.40.513933.372.082955 4.20.34576 5.0592.1791517.70.04173.2063.2588.70.009037.8051.631114120.12069 3.5842.12524 6.80.00678 2.7330.37516 6.60.00367 3.3871.51453340.112652.9391.86531767.50.816772.7922.61172 5.70.01594 2.9722.049548 1.90.01802 2.6940>10.00.00081 2.9341.0520 3.10.0052 3.930.51290.00413 3.9451.221430 3.20.072332.5070.633797.80.01312 2.3720.829707.40.00919 2.2640.3336>10.00.00074 1.6142.8483280.90.00453 2.4890.4297>10.00.00219 2.9011.41724 1.40.000932.9691.637673 6.40.15823 1.910.52>10.00.00074 1.8340.918122 2.30.01112 2.3841.1142012.40.01339 1.8641.09442 4.20.03184 1.4971.022138 5.60.01667 1.8071.405529 1.40.024172.072 1.5033408 5.50.24077 1.547 1.003398 4.10.04809 1.4850.842389.60.04417 1.5691.0882527 4.30.12631 1.571 1.75127.10.004032.549 1.29416973.90.1688 1.527 1.187653 1.40.01164 1.561 1.48516804.90.18767 1.411 0.93313287.70.17541 1.5470.915331 6.70.04644 1.6491.143538 3.60.05012 1.7050.858471 5.40.04732 1.4211.102704 4.20.05043 1.2040.752509 4.90.06046 1.3951.081641 6.30.06074 1.595 1.0497097.40.09638 1.3 1.145413 3.10.04017 1.716 1.55207.60.004652.345 1.049224 1.60.00601 1.352 1.3771389.20.01265 1.752 0.577300 5.50.03426 1.347 0.474403 5.20.03177 1.297 0.723166 2.90.28453 1.339 0.7237333.50.053380.912 0.595289 6.30.017020.7660.82814997.40.127630.9641.0763438.40.03476 1.516 0.597626 6.80.070850.9630.622110470.09860.9211.0453772.70.02083 1.243>10.00.00011 1.506 1.09912429.90.13784 1.05 0.8981353 2.50.05461 1.584 0.3182260.0032 1.1690.75869480.0249 1.0571.25>10.00.00172 1.053 0.711936 6.50.22306 1.179 0.706201 4.70.01384 1.168 0.7392618.50.02793 1.196 0.5911753 3.30.059170.7180.711228 5.80.02249 1.0541.013827 6.90.067680.830.819337 4.30.03418 1.204 0.5245527.10.045390.929 0.235177.20.001430.864 0.355904 5.50.057310.801 0.404171 1.90.004220.839 0.8441018 2.90.021720.749 0.831492 5.50.077660.883 0.447854 5.10.05450.81 0.68921970.02114 1.039 0.702967 4.10.062970.967 0.7151689 6.70.2465 1.159 0.8941061 3.90.051860.961 0.69669 1.40.00158 1.21405>10.00.00072 1.57 0.7321483 4.70.079720.839 0.64835 4.90.028380.744 0.91231440.11162 1.241 0.70896 2.90.005410.609 0.964197 4.70.009170.739 0.28257.30.002590.91611980.00341 1.67 0.825234 5.40.011580.756 0.716524 4.20.021180.7390.43848 4.40.002050.9771.4250 1.50.000460.805 0.71410 4.50.04139 1.1870 4.50.008370.668 0.45566870.04130.919 0.793179 1.30.00205 1.044 0.635222 6.80.015560.791 0.484672 3.50.026580.705 0.766789 4.80.049630.8180.424413 6.90.029650.6261.018111 5.60.01044 1.028 0.287669 3.80.015170.929 0.796368 5.20.03430.799 0.20986 3.20.001390.839 0.58143 6.50.013621 0.441195 5.40.009240.65 0.795171 1.60.001670.422 0.6142647.70.010820.673 0.21414>10.00.004512.295 0.734943.90.002830.6860.765226 3.30.014480.8530.4644018.60.025550.6821.052213 4.90.013750.659 0.5487>10.00.01419 1.433 0.6410467.80.070860.835 0.47215 5.80.008280.868 0.6764449.50.023950.793 0.605583 5.20.036290.663 0.310>10.00.00060.798 0.686185 5.30.005860.592 0.5226 4.60.008520.479 0.588119180.085760.724 0.344756 6.80.024870.586 0.475524>10.00.034330.912 0.276105 3.30.00338 1.185 0.46378 3.80.026420.746 0.602487 5.90.028250.647 0.496280 6.20.034720.765 0.5991610 6.30.124690.81 0.402326 5.90.013060.799 0.52978550.057240.716 0.526409>10.00.020090.672 0.3015487.20.038990.75 0.64937 1.90.000820.528362 5.80.018750.583 0.495103 3.30.005940.555200 4.80.011950.645 0.36816487.70.106370.722 0.591164 1.10.000580.7 0.56342660.032820.763 0.928139>10.00.014250.916 0.574183 5.70.0090.576 0.26453 3.80.026470.7 0.59358360.04060.66 0.51817349.50.098910.574 0.33328870.023130.591 0.29421100.028010.852 0.14854>10.00.004550.917 0.533757.10.00310.519 0.237152 5.20.014030.848 0.3339 4.70.000610.947 0.684358 6.80.01790.68 0.205611 2.60.01090.6360.62216 4.70.011730.744 0.56760 5.20.00460.935 0.5051516 5.10.073520.5710.402102 4.70.008450.7241.286112 1.70.002350.689 0.491962.10.002940.478 0.311617.50.00190.52 0.2641407.50.007770.652 0.623151 5.60.009150.618 0.30427650.011510.675 0.5575198.10.032360.622 0.531271 6.80.01050.542 0.3713267.50.020820.69 0.1503.90.001480.557 0.6211774.90.008970.574 0.37777 1.40.000560.519 0.325756 2.80.015320.517 0.658584>10.00.024370.447 0.4051265.80.006880.602 0.6922089.50.008880.572 0.451010>10.00.078030.694 0.401404>10.00.017360.539 0.51319590.007720.464 0.7552050 3.80.097330.507 0.376165 3.30.006880.645 0.66712>10.00.00110.509 0.4782497.40.017690.585 0.3366606.60.036250.587 0.5871098.60.00970.678 0.3982017.80.010420.532 0.974265 5.60.011680.86 0.575120 3.70.005470.581 0.3184918.50.029120.67 0.328274>10.00.010820.469 0.26411090.003750.484 0.4863257.70.015030.544 0.237257 5.10.005680.505 0.3831811 5.30.077130.549 0.29290 6.70.012010.475 0.2563950.001450.383 0.448163 5.60.008040.74 0.4131267.20.004260.402 0.4064617.20.019290.3870.46126 5.50.006040.602 0.2781807.30.008730.496 0.15645>10.00.001770.415 0.2139480.004840.536 0.29100 5.90.003030.562 0.511319>10.00.034280.619 0.318371 5.40.010620.649 0.2145 3.70.005160.354 0.275204 6.70.007280.481 0.454476 4.80.011950.353 0.422161 4.80.006940.423 0.466146 6.60.004980.398。

分子体积排阻高效液相色谱法测定低浓度重组人源化抗BCMA/CD3双特异性抗体药物的浓度

药物分析杂志Journal of Pharmaceutical Analysis药物分析杂志　线性关系考察　精密吸取混合对照品储备液、4、6、8、10 mL ，分别置10 mL 量瓶中，用70%甲醇水溶液定容至刻度，即得系列混合对照品溶液。

分别精密吸取上述系列混合对照品溶液10 μL ，按“2.1”项下色谱条件进样分析，测定峰面积。

以峰面积（Y ）葛根素（puerarin ）　2. 连翘酯苷A （forsythiaside A ）　3. 黄芩苷（baicalin 牛蒡苷（arctiin ）混合对照品（mixed reference substances ）　B. 样品（sample ）　C. 缺葛根阴性样品（negative sample of Puerariae Lobatae Radix ）　D. 缺连翘阴性样negative sample of Forsythiae Fructus ）　E. 缺黄芩阴性样品（negative sample of Scutellariae Radix ）　F. 缺炒牛蒡子阴性样品（negative sample ofArctii Fructus ）　小儿解表颗粒HPLC 色谱图　HPLC chromatograms of Xiao ’er Jiebiao granules表2　4个成分的线性回归方程、相关系数（r ）及线性范围Tab. 2　The regression equation ，correlation coefficients and linear ranges of 4 components成分（component ）回归方程（regression equation ）r线性范围（linear range ）/（μg ·mL -1）葛根素（puerarin ）Y =45.19X +7.5460.999 9 4.799~47.99连翘酯苷A forsythiaside A ）Y =16.61X +1.3590.999 93.968~39.68黄芩苷（baicalin ）Y =32.55X +13.430.999 916.76~167.6牛蒡苷（arctiin ）Y =5.843X +0.992 80.999 97.082~70.82药物分析杂志药物分析杂志药物分析杂志药物分析杂志。

WHO_TRS_937__annex8_eng

© World Health OrganizationWHO Technical Report Series, No. 937, 2006Annex 8Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms Introduction1. Background2. WHO revisions to the criteria for Biopharmaceutics Classiﬁ cation Systemclassiﬁ cation3. WHO extensions to the scope of application of the biowaiver4. WHO additional criteria for application of the biowaiver procedure5. Explanation of the tables6. Biowaiver testing procedure according to WHOIntroductionThis proposal is closely linked to the Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchange-ability (WHO Technical Report Series, No. 937, Annex 7). It aims to give national authorities sufﬁ cient background information on the various orally administered active pharmaceutical ingredients (APIs) on the WHO Model List of Essential Medicines (EML), also taking into account local usage of the API, to enable them to make an informed decision as to whether generic formulations should be subjected to in vivo bioequivalence (B E) studies or whether a biowaiver can be granted. In light of scientiﬁ c work and dis-cussion in the last decade, some of the criteria used to evaluate the API in terms of potential for a biowaiver have been revised to allow a broadened scope of application. The result is that many APIs on the EML can now be considered for the biowaiver procedure, subject to the usage and risks in the national setting.1. Background1.1Initiatives to allow biowaivers based on the BiopharmaceuticsClassiﬁ cation SystemIn 1995 the American Department of Health and Human Services, US Food and Drug Administration (HHS-FDA) instigated the B iopharmaceutics391Classiﬁ cation System (BCS), with the aim of granting so-called biowaiv-ers for scale-up and post-approval changes (SUPAC) (/cder/ guidance/cmc5.pdf). A biowaiver means that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). Instead of conducting expensive and time-consuming in vivo studies, a dissolution test could be adopted as the surrogate basis for the decision as to whether two pharmaceutical products are equivalent. At that time the biowaiver was only considered for SUPAC to pharmaceutical products.More recently, the application of the biowaiver concept has been extended to approval of certain orally administered generic products (/ cder/guidance/3618fnl.htm).Within the context of the documents cited above, only APIs with high solu-bility and high permeability and which are formulated in solid, immediate-release (IR) oral formulations can be approved on the basis of the biowaiver procedure. A major advantage of the biowaiver procedure is the simpliﬁ ca-tion of the product approval process and the reduction of the time required, thus reducing the cost of bringing new products to market.1.2What is the Biopharmaceutics Classiﬁ cation System?The Biopharmaceutics Classiﬁ cation System (BCS) was proposed in 1995 by Amidon et al.1 It is a scientiﬁ c framework which divides APIs into four groups, according to their solubility and permeability properties.1.3 Classiﬁ cation of active pharmaceutical ingredients accordingto the Biopharmaceutics Classiﬁ cation SystemAccording to the HHS-FDA deﬁ nitions in the documents cited above, the four possible categories for an API according to the BCS are:•BCS class I: “high” solubility – “high” permeability•BCS class II: “low” solubility – “high” permeability•BCS class III: “high” solubility – “low” permeability•BCS class IV: “low” solubility – “low” permeability.Depending on the classiﬁ cation, the oral availability of the API may be expected to range from being heavily dependent on the formulation and manufacturing method (e.g. Class II APIs: poorly soluble yet highly perme-able) to being mostly dependent on the API permeability properties (e.g.Class III APIs: highly soluble yet poorly permeable).1Amidon GL, Lennemas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classiﬁ cation: the correlation of in vitro drug product dissolution and in vivo bioavailability. Phar-maceutics Research, 1995, 12:413–420.3921.4How is high or low solubility currently deﬁ ned by the Departmentof Health and Human Services, US Food and Drug Administration?The aqueous solubility of a drug substance is considered as high according to the HHS-FDA BCS criteria when:• the ratio of the highest orally administered dose (in mg) to the solubility (mg/ml) is 250 ml or lower.—This criterion is met over the pH range 1–7.5 at 37 °C.According to HHS-FDA guidances, the determination of the equilibrium solubility should be carried out with the shake-ﬂ ask method (other methods such as acid or base titration are permitted when their ability to predict the equilibrium solubility is justiﬁ ed). The experiments should be carried out at a temperature of 37 ± 1°C. Further, a sufﬁ cient number of pH conditions should be chosen to cover the pH range of 1–7.5 and each determination should be carried out at least in triplicate. The buffer solutions given in the United States Pharmacopeia (USP) are appropriate for the tests, but other buffers are also allowed for these experiments. The pH value of each buffer solution should be checked before and after each experiment. Degradation of the API due to pH or buffer composition should be reported together with other stability data.The reason for the 250-ml cut-off criterion for the dose:solubility ratio is that in pharmacokinetic bioequivalence studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1–7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine.The other important parameter for the BCS is the intestinal permeability of the API.1.5How is high or low permeability currently deﬁ ned by the Departmentof Health and Human Services, US Food and Drug Administration?According to HHS-FDA a drug is considered highly permeable, when 90 % or more of the orally administered dose is absorbed in the small intestine.Permeability can be assessed by pharmacokinetic studies (for example, mass balance studies), or intestinal permeability methods, e.g. intestinal perfusion in humans, animal models, Caco 2 cell lines or other suitable, validated cell lines. In vivo or in situ animal models or in vitro models (cell lines) are only considered appropriate by HHS-FDA for passively trans-ported drugs. It should be noted that all of these measurements assess the fraction absorbed (as opposed to the bioavailability, which can be reduced substantially by ﬁ rst-pass metabolism).393HHS-FDA suggests use of two different methods for determining the per-meability classiﬁ cation if results with one method are inconclusive.1.6Which pharmaceutical formulations can currently be consideredfor a biowaiver according to the Department of Health andHuman Services, US Food and Drug Administration?To be considered bioequivalent according to the HHS-FDA biowaiver pro-cedure, a pharmaceutical product:• should contain a Class I API;• should be rapidly dissolving, meaning it should release at least 85% of its content in 30 minutes in three different media (pH 1.2, pH 4.5 and pH6.8, composition see “Multisource document”)1 in a paddle (50 rpm) orbasket (100 rpm) apparatus at 37 °C and a volume of 900 ml;• should not contain excipients which could inﬂ uence the absorption of the API;• should not contain an API with a narrow therapeutic index; and• should not be designed to be absorbed from the oral cavity.The reasoning for the above-mentioned dissolution restrictions is that whena highly soluble, highly permeable API dissolves rapidly, it behaves like asolution in the gastrointestinal tract. If this is the case, the pharmaceutical composition of the product is insigniﬁ cant, provided that excipients which inﬂ uence the uptake across the gut wall are excluded from the formulation.The API is not prone to precipitation after its dissolution due to its good solu-bility under all pH conditions likely to be found in the upper gastrointestinal tract. The high permeability ensures the complete uptake (> 90%) of the API during its passage through the small intestine. The rapid dissolution of the product guarantees that the API is available long enough for the uptake in the small intestine (the passage time in the small intestine is approximately four hours) and negates any slight differences between the formulations.Pharmaceutical products containing an API with a narrow therapeutic index should always be tested with in vivo methods, because the risk to the patient resulting from a possible incorrect bioequivalence decision using the bio-waiver procedure is considered too high with these kinds of APIs.As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver.It is clear that the HHS-FDA requirements for the classiﬁ cation of APIs and eligibility criteria for the biowaiver are very strict. During the last decade,1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).394several publications and continuing scientiﬁ c discussions have suggested that the original HHS-FDA criteria for application of the biowaiver pro-cedure could be relaxed without substantially increasing the risk to public health or to the individual patient. On the basis of these publications and dialogue, WHO has proposed revised BCS criteria and additional consid-erations for the eligibility of a pharmaceutical product for the biowaiver procedure in the “Multisource document”.12.WHO revisions to the criteria for BCS classiﬁ cationWHO revisions to the BCS criteria are as follows:•WHO high-solubility deﬁ nitionWhen an API shows a dose:solubility ratio of 250 ml or lower at 37 °C over a pH range of 1.2–6.8, it can be classiﬁ ed as “highly soluble”. The decrease in pH from 7.5 in the FDA guidances to 6.8 reﬂ ects the need to dissolve the drug before it reaches the mid-jejunum to ensure absorption from the gastrointestinal tract.• Furthermore, the dose that is to be used for the calculation is the highestdose indicated in the Model List of Essential Medicines (EML). In some countries, products may be available at doses exceeding the highest dose on the EML. In such cases, the classiﬁ cation given in the tables at the end of this Annex may no longer be appropriate and the dose:solubil-ity ratio and the permeability will have to be reassessed at the product dose.•WHO permeability deﬁ nitionWhen an API is absorbed to an extent of 85% or more, it is considered to be “highly permeable”. The permeability criterion was relaxed from 90% in the FDA guidance to 85% in the WHO “Multisource document”.Some examples of APIs now included in BCS Class I that were previ-ously considered to be in Class III are paracetamol, acetylsalicylic acid, allopurinol, lamivudine and promethazine.Application of these revised criteria has changed the classiﬁ cation of some APIs in the list. Thus, the classiﬁ cations in the tables attached to this docu-ment supersede those in previous publications. As new APIs appear on the EML, it will be necessary to classify them according to the revised BCS;so it is therefore anticipated that the tables will be revised regularly. In addition, some APIs have not yet been sufﬁ ciently characterized to assign them a BCS classiﬁ cation. As the tables evolve, it is anticipated that more concrete information will be generated for these APIs as well.1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).395the basket apparatus (applies to pharmaceutical products containingClass III APIs);—rapidly dissolving (release of > 85% of the labelled amount of drug in 30 minutes) in standard media at pH 1.2, 4.5 and 6.8, at a rota-tional speed of 75 rpm in the paddle apparatus or 100 rpm in the bas-ket apparatus (applies to pharmaceutical products containing Class IAPIs and/or Class II APIs which are weak acids and meet the 250 mldose:solubility requirement at pH 6.8).(4)Considerations relating to excipientsThe national authority should be aware that some excipients can inﬂ uencemotility and/or permeability in the gastrointestinal tract. Therefore, the ex-cipients used in the multisource product formulation should be scrutinized.In this regard, the national authority can draw on the experience relat-ing to formulations which have been approved on the basis of humanbioequivalence studies in their own or in other jurisdictions.If the multisource product under consideration contains excipients thathave been used before in similar amounts in other formulations of thesame API, it can be reasonably concluded that these excipients will haveno unexpected consequences for the bioavailability of the product. If,however, the formulation contains different excipients, or amounts ofthe same excipients that are very different from usual, the national au-thority may choose to declare the biowaiver procedure inapplicable.A list of usual and acceptable excipients can be found at the following website: /cder/iig/iigfaqWEB.htm; formulations of some productscan be found on the web sites of some national drug regulatory authorities.5.Explanation of the tablesThe decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability char-acteristics as well as the therapeutic use and therapeutic index of the API, its pharmacokinetic properties, the similarity of the dissolution proﬁ les of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37 °C. Data related to the excipients compo-sition in the multisource product are also required. A systematic approach to the biowaiver decision has been established by the International Pharma-ceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences (/cgi-bin/jhome/68503813).The relevant documents can also be downloaded from the FIP web site at: http://www.ﬁ/. These monographs provide detailed information which should be taken into account whenever available in the biowaiver consideration.3985.1Which active pharmaceutical ingredients are included in thetables?The substances listed in the 14th WHO Model List of Essential Medicines (EML) of March 2005 have been evaluated and classiﬁ ed according to the revised criteria given above.5.2Where do the data come from?The solubility and permeability values were found in the publicly available literature, such as Martindale’s, the Merck Index and scientiﬁ c journals.Please note that the doses used for the calculation of the dose:solubility ratio are those stated in the EML.The indications given in the tables are reproduced directly from the EML. If the EML speciﬁ es the dosage form (e.g. sublingual tablet) this is indicated under “comments”.5.3“Worst case” approach to the Biopharmaceutics Classiﬁ cationSystemThe drugs listed in the EML were classiﬁ ed according to the criteria explained above. Where no clear classiﬁ cation could be made, the “worst case” was as-sumed. For example if a substance is highly soluble, but absolute bioavailability data were not available, the test conditions for BCS Class III substances have been proposed. The same procedure was adopted for ﬁ xed combinations, for example amoxicillin and clavulanic acid, the testing procedure was always ﬁ xed according to the “worst” BCS classiﬁ cation, in this example clavulanic acid (BCS Class III/1), because amoxicillin is a BCS Class I drug. This com-bination would therefore be tested according to BCS Class III requirements.The results of the revised classiﬁ cation can be found in Tables 1–3.5.4Why are there three Tables?Table 1 lists all APIs on the EML that are administered orally, with the excep-tion of the APIs listed as complementary. Table 2 summarizes the APIs listed as complementary in the EML and Table 3 lists the APIs for which no classiﬁ cation had previously been assigned, or that had been introduced with the 14th EML (March 2005), together with a more detailed explanation of their classiﬁ cation.5.5 Risk assessmentTo minimize the risks of an incorrect biowaiver decision in terms of public health and risks to individual patients, the therapeutic indications of the API, known pharmacokinetic variations, food effects, etc. should be evalu-ated based on local clinical experience, taking into account the indications399for which the API is prescribed in that country as well as speciﬁ c pharmaco-kinetic population variations (for example CYP polymorphisms). Known potential risks are listed under “potential risks” in the tables. The absence of an entry under “potential risks” should not, however, be misconstrued as meaning that there are no risks associated with the use of the medicine. 6.Biowaiver testing procedure according to WHODepending on the BCS classiﬁ cation of the API, based on solubility and permeability characteristics listed in the accompanying tables, the testing procedure is deﬁ ned in section 9.2.1 of the “Multisource document”1:6.1For pharmaceutical products containing BiopharmaceuticsClassiﬁ cation System Class I (highly soluble, highlypermeable) APIsFor rapidly dissolving (as deﬁ ned above) pharmaceutical products contain-ing BCS Class I APIs, more than 85% dissolution of the labelled amount is required within 30 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm. The dis-solution proﬁ les of the comparator and the multisource products should be compared by an f> 50 or an equivalent statistical criterion.2If within 15 minutes more than 85% of the API are released from the compar-ator and the multisource formulation under the above-mentioned conditions the products will be considered very rapidly dissolving. In this case the prod-ucts are deemed to be equivalent and a proﬁ le comparison is not required.6.2For pharmaceutical products containing BiopharmaceuticsClassiﬁ cation System Class III (highly soluble, lowpermeability) APIsA biowaiver can be considered only if both the multisource and the com-parator product are very rapidly dissolving. Eighty-ﬁ ve per cent or more dissolution of the labelled amount of the API should be achieved within15 minutes in standard media at pH 1.2, 4.5 and 6.8 using the paddle ap-paratus at 75 rpm or the basket apparatus at 100 rpm.Generally, the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g. site-speciﬁ c absorption, induction/competition at the absorption site, excipient composition and therapeutic risks) for prod-ucts containing BCS Class III APIs than for BCS Class I drugs.1Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).4006.3For pharmaceutical products containing APIs with highsolubility at pH 6.8 but not at pH 1.2 or 4.5 and with highpermeability (by deﬁ nition, BCS Class II compoundswith weak acidic properties)These are eligible for a biowaiver provided that the multisource product:• is rapidly dissolving, i.e. 85% or more dissolution of the labelled amount of the API should be achieved within 30 minutes in standard media at pH 6.8 using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and• the multisource product exhibits similar dissolution proﬁles, as deter-mined with the f2 value or equivalent statistical evaluation, to those ofthe comparator product in buffers at all three pH values (pH 1.2, 4.5 and6.8).For multisource products containing BCS Class II APIs with dose:solubility ratios of 250 ml or less, at pH 6.8, the excipients should also be critically evaluated in terms of type and amounts of surfactants in the formulation.Further details of eligibility for the biowaiver and appropriate test proce-dures can be found in sections 5 and 9 of the “Multisource document”.11Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (WHO Technical Report Series, No. 937, Annex 7).401405c h l o r p h e n a -m i n e h yd r o ge n m a l e a t e 4 m g h i g hB A 25-59%, ﬁ r s t p a s s 3/19.2.1.2C Y P 2D 6 p o l y -m o r p h i s m a n t i a l l e r g i ce x t e n t of ﬁ r s t -p a s s m e t a b o l i s m u n c e r t a i nc h l o r p r o m a z i n e h yd r o c h l o r i de 100 m gh i g hl o w39.2.1.2 p s y c h o t h e r a p e u -t i c m e d i c i n e c i p r o ﬂ o x a c i nh y d r o c h l o r i d e 250 m g h i g hB A 70–82%, p o s s i b l e ﬁ r s t p a s s , h i g h i nC a c o -2 c e l l s3/19.2.1.2 a n t i b a c t e r i a le x t e n t of ﬁ r s t - p a s s m e t a b o l i s m u n c e r t a i nc l o f a z i m i n e100 m gi n s u f ﬁ c i e n t l i t e r a t u r e l o w 4/3N o t e l i g i b l e f o r b i o w a i v e r a t p r e s e n t a n t i l e p r o s y m e d i c i n ec l o m i f e n e c i t r a t e50 m g h i g h i n s u f ﬁ c i e n t l i t e r a t u r e 3/19.2.1.2o v u l a t i o n i n d u c e rc l o m i p r a m i n e h yd r o c h l o r i de 25 m g h i g h66% e x c r e t e d i n t h e u r i n e , t h e r e m a i n d e r b e i n g e l i m i -n a t e d i n t h e f a e c e s 3/19.2.1.2p s y c h o t h e r a p e u -t i c m e d i c i n el a c k o f a b s o l u t e b i o a v a i l a b i l i t y d a t ac l o x a c i l l i n (a s s od i u m s a l t )1000 m g h i g hl o w 39.2.1.2a n t i b a c t e r i a lc ode i n e p h o s p h a t e 30 m g h i g h l o w39.2.1.2r i s k o f a b u s eo p i o i d a n a l g e s i c ,d i a r r h oe a i n a d u l t sd a p s o n e100 m gl o w (w e a k b a s e ) h i g h 2N o t e l i g i b l e f o r b i o w a i v e rG 6P D d e ﬁ -c i e n c ya n t i l e p r o s y m e d i c i n ed i a ze p a m 5 m g h i g hh i g h19.2.1.1p s y c h o t h e r a p e u -t i c m e d i c i n e s c o r e d t a b l e tB A , B i o a v a i l a b i l i t y ; G 6P D , g l u c o s e -6-p h o s p h a t e d e h y d r o g e n a s e .409g l y c e r y l t r i n i t r a t e 500 μgh i g hs u b l i n g u a l a p p l i c a t i o n ,p e r m e a b i l -i t y i n t h e o r a l c a v i t y m o r e i m p o r t a n t t h a n G I p e r m e a b i l i t y3/1N A hl o c a l a b s o r p t i o n a n t i a n g i n a l m e d i c i n e s u b l i n g u a l a p p l i c a t i o ng r i s e o f u l v i n 250 m gl o w (n e u t r a l ) h i g h2N o t e l i g i b l e f o r b i o w a i v e r a n t i f u n g a lh a l o p e r i d o l2 m gb o r d e r l i n e < 0.01 m g /m l 2l o w 4/3N o t e l i g i b l e f o r b i o w a i v e rp s y c h o t h e r a p e u -t i c m e d i c i n eh y d r a l a z i n e h y d r o c h l o r i d e50 m g h i g hl o w 39.2.1.2a n t i h y p e r t e n s i v e m e d i c i n eh y d r o c h l o r o -t h i a z i d e 25 m g h i g h l o w 39.2.1.2a n t i h y p e r t e n s i v e m e d i c i n e , d i u r e t i c a n d u s e d i n h e a r t f a i l u r es c o r e d t a b l e ti b u p r o f e n 400 m gl o w , w e a k a c i d (p K a 4.4,5.2)h i g h 29.2.1.3N S A I D , a n t i m i -g r a i n e m e d i c i n ei n d i n a v i r s u l f a t e 400 m g l o w l o w (?)4/2N o t e l i g i b l e f o r b i o w a i v e r C Y P 450 3A 4, f o o d e f f e c t (–)a n t i r e t r o v i r a lu n k n o w n w h e t h e r p o o r B A i s d u e t o p o o r s o l u b i l i t y o r p o o r s o l u b i l i t y a n d p o o r p e r m e a b i l i t yD :S , D o s e :s o l u b i l i t y r a t i o ; B A , b i o a v a i l a b i l i t y .426T a b l e 3C o m p o u n d s i n t r o d u c e d t o t h e W H O M o d e l L i s t o f E s s e n t i a l M e d i c i n e s s i n c e M a r c h 2005 f o r w h i c h n o c e r t a i n c l a s s i ﬁ c a t i o n h a d b e e n p r e v i o u s l y r e p o r t e d (t h e s e c o m p o u n d s a l s o a p p e a r i n T a b l e 1 a n d T a b l e 2)M e d i c i n e aH i g h e s t o r a l s t r e n g t h a c c o r d i n g t o W H O E s s e n t i a l M e d i c i n e s L i s t a S o l u b i l i t y bP e r m e a b i l i t y c B C S c l a s s dD i s s o l u t i o n t e s t (f o r b i o w a i v e r )e P o t e n t i a l r i s k s fI n d i c a t i o n (s )a c c o r d i n g t o W H O E s s e n t i a l M e d i c i n e s L i s t (E M L )aC o m m e n t s a n d s p e c i a l d o s a g e f o r m i n d i c a t i o n s aa m l o d i p i n e 5 m gs l i g h t l y s o l u b l e (1),D :S 5 m lB A a b s60–65%,e x c r e t i o n o f d r u g m e t a b o -l i t e s i n u r i n e 90–95% (2)19.2.1.1a n t i h y p e r t e n s i v e m e d i c i n eB A a b s < 85% a s c r i b e d t o ﬁ r s t -p a s s m e t a b o l i s ma m o d i a q u i n e(b a s e )200 m g45 m g /m l 2,D :S 4.4 m lB A > 75% (3)3/19.2.1.2C Y P 2C 8p o l y m o r p h i s m ,i n c r e a s e d r i s k f o r a g r a n u l o c y -t o s i s a n d h e p a -t o t o x i c i t y (4)a n t i m a l a r i a la m o x i c i l l i n + c l a v u l a n i c a c i d 500 m g + 125 m gf r e e l y s o l u b l e i n w a t e r (1),D :S 1.25 m la b s o r p t i o n > 73% (5)1 + 3/19.2.1.2a n t ib ac t e r i a lt e s t s b a s e d o n c l a v u l a n i c a c i d c l a s s i ﬁ c a t i o na r t e s u n a t e 50 m gv e r ys l i g h t l y s o l u b l e (6),D :S 500 m l ;(w e a k a c i d ,p K a ~ 6.4)B A a b s 82% (1),B A a b s 88% (7),B A a b s 61% (8)4/2N o t e l i g i b l e f o r b i o w a i v e ra n t i m a l a r i a lp e r m e a b i l i t y d e p e n d s o n s e v e r i t y o f d i s e a s eD :S , D o s e : s o l u b i l i t y ; B A , B i o a v a i l a b i l i t y .427a z i t h r o m y c i n 500 m gp r a c t i c a l l y i n s o l u b l e i n w a t e r (1)< 0.01m g /m l , D :S 50 000 m lB A a b s 16% (9);B A 37%(10, 11); 4/2N o t e l i g i b l e f o r b i o w a i v e ra n t ib ac t e r i a l u n k n o w n w h e t h e r p o o r B A i sd ue t o p o o r s o l u b i l i t y o r p o o r s o l u b i l i t y a n d p o o r p e r m e a b i l i t yc a l c i u m f o l i n a t e 15 m gs p a r i n g l y s o l u b l e i n w a t e r (P h . E u r . 5.2); v e r y s o l u b l e (U S P 28); D :S 15 m l a n d 0.015 m l , r e s p e c -t i v e l yB A a b s 92% 25 m g (12, 13);B A a b s 73.4%(15 m g ) (14);f u l l y a b s o r b e d ;A UC a n d t 1/2s i m i l a r a f t e r i.v . & p .o (15)19.2.1.1 a n t i c y t o t o x i c m e d i c i n el e v o d o p a (l ) + c a r b i d o p a (c )(l ) 250 m g + (c ) 25 m g(l ) h i g h +(c ) s o l u b l e 1 i n 500 o f w a t e r , f r e e l y s o l u b l e i n 3 M H C l (1)(l ) h i g h +(c ) B A 58% (16); B A a b s88% (d o g s ) (17)(l ) 1 +(c ) 3/19.2.1.2n a r r o w t h e r a p e u t i c i n d e xa n t i p a r k i n s o n m e d i c i n et e s t s b a s e d o n c a r b i d o p a c l a s s i ﬁ c a t i o nc e ﬁ x i m e 400 m gs l i g h t l ys o l u b l e (2),D :S 400 m l22–54% (2)4N o t e l i g i b l e f o r b i o w a i v e ra n t ib ac t e r i a lD :S , D o s e : s o l u b i l i t y ; B A : B i o a v a i l a b i l i t y ; P h .E u r ., E u r o p e a n P h a r m a c o p o e i a ; U S P , U n i t e d S t a t e s P h a r m a c o p o e i a ; A U C , a r e a u n d e r t h e c u r v e ; i.v ., i n t r a v e n o u s .。

SCI_Chem 影响因子

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246Tetrahedron-Asymmetr0957-416611707 2.115 2.1430.384 247Appl Surf Sci0169-433231193 2.112 2.0990.33 248Synthetic Met0379-677913916 2.109 2.1020.334 249Colloid Surface A0927-775718414 2.108 2.3330.333 249Mat Sci Eng A-Struct0921-509340513 2.108 2.3490.307 251J Anal Toxicol0146-47602660 2.107 1.7580.429 252Solid State Nucl Mag0926-20401202 2.1 2.0570.711 253J Food Compos Anal0889-15753737 2.088 2.7430.19 254J Environ Monitor1464-03254378 2.085 2.1370.322 255Mater Chem Phys0254-058417174 2.072 2.3950.286 256J Pept Sci1075-26171942 2.071 1.8280.434 257Phytother Res0951-418X8059 2.068 2.4380.444 258Nano-Micro Lett2150-5551205 2.057 1.910.35 259Solid State Ionics0167-273820728 2.046 2.5640.26260Carbohyd Res0008-621514176 2.044 2.1780.357 261J Solid State Chem0022-459618166 2.04 2.2950.392 262Curr Org Synth1570-1794673 2.038 2.9140.76 263Ultrasonics0041-624X3651 2.028 2.0540.456 264Smart Mater Struct0964-17267120 2.024 2.3770.289 265Inorg Chem Commun1387-70036416 2.016 1.8810.434 266Appl Organomet Chem0268-26052866 2.011 1.9220.272 267Electrochem Solid St1099-00628883 2.01 2.0260.596 268J Chem Eng Data0021-956815169 2.004 2.1150.295 269Comb Chem High T Scr1386-207314532 1.9750.268 269J Organomet Chem0022-328X217932 1.9920.527 271Thermochim Acta0040-603111408 1.989 2.0460.327 272J Mol Model1610-29403157 1.984 2.3010.378 273J Therm Anal Calorim1388-61509934 1.982 1.7420.243 274Int J Fatigue0142-11235248 1.976 1.9740.352 275J Vib Control1077-54631649 1.966 1.7360.672 276Chem Phys0301-010412935 1.957 2.0590.592 277J Mater Process Tech0924-013618426 1.953 2.1760.332 277Sensors-Basel1424-82207082 1.953 2.3950.321 279Biomed Chromatogr0269-38792861 1.945 1.8150.385 280J Fluorine Chem0022-11394998 1.939 1.9490.465ArticlesCited Half-life Eigenfactor ®Metrics ScoreArticleInfluenc e® Score8699.6 1.5750820.8448329.7 1.3598717.71238018 1.55663 4.8921768.20.2266114.294141 5.20.2278819.481121 3.70.1543615.607390 3.50.178418.8542370.015018.643126 2.40.054018.927207 6.50.108177.90837 3.20.01489 5.62318>10.00.013647.55389.40.008828.821867 5.10.27819 4.24368.40.00872 6.542227 5.50.53637 3.497299.90.01888.1211078 4.40.37491 5.1891191 2.40.20333 4.012473 1.80.05534 3.461368.20.03818 3.07130997.70.83183 2.99465 5.90.01757 3.141169 1.40.00944 3.344569 4.20.12336 3.006377.20.00647 2.73229 1.90.00155 3.27323 3.90.00716 4.441557.70.01045 2.068458 1.40.02121 2.833576 6.70.15215 2.032167.90.00342 3.148457 3.60.07856 2.503112 4.60.01202 1.97501 6.90.05008 1.9062220.00197 2.73916>10.00.003282.792Eigenfactor®Metrics286 2.60.0208 2.0046>10.00.00142 1.13896 2.80.01517 2.301119.20.00397 3.974>10.00.00086 1.894 44940.03848 1.5233>10.00.00076 2.537437.60.01013 2.301 63220.04884 2.393 2150.003483173 4.80.28954 1.5629>10.00.00211 3.009 138 5.80.01695 1.794 1015 1.70.02966 1.597 508.20.01226 2.37 160850.18182 1.40244 5.40.01448 3.213188.30.00431 2.295 107.10.00156 2.34 674 6.40.06437 1.6 1916 4.10.1766 1.469 480 5.40.05059 1.419 284>10.00.04014 1.60356 1.20.00194 1.703 617 3.70.05475 1.603 14797.80.17236 1.533 8907.80.09182 1.35 404 4.40.04405 1.352 239.20.00403 2.705 448 4.10.05929 1.252 507 3.50.04948 1.865 480 5.30.05919 1.416 315 1.30.00585 1.6362>10.00.00057 1.543 255 2.10.01222 1.495 116 6.20.01779 2.376 953 2.30.03563 1.2844>10.00.00016 2.2160 5.10.006940.708137.90.00319 2.303 3283 3.40.34957 1.353 2798.70.02859 1.299 773 3.90.057280.943 493 5.30.04212 1.304 11447.10.090460.92115617.50.124780.98 259 5.70.03346 1.295 372 2.80.02555 1.219 1289>10.00.12482 1.03 7277.10.06585 1.03830 5.80.00343 1.39794 6.80.01439 1.685 303 6.60.019140.892 2119 6.70.21487 1.164 9987.10.059110.76263 3.40.002370.436140.000190.962 475 5.50.03101 1.1898.60.00225 1.225 194 2.50.00680.908 817 6.60.031350.985 68170.09849 1.714 1358 2.50.073 1.334 1194 2.60.032550.749 10720.00309 1.26 1021 4.40.12987 1.194 459 3.20.02416 1.192 2618.90.03446 1.396 1804 3.70.15067 1.296 1418.60.01298 1.609 1709 4.50.08330.842 327 1.30.00320.94181 4.90.00904 1.23 327 4.70.03579 1.258 17750.0131 1.044 2597.10.02119 1.078 877 4.30.068460.99799 1.40.001410.915 449 6.30.028910.786 16157.50.18356 1.081 22860.020170.96535 1.90.00176 1.224 1160 3.80.055440.914 201 6.30.017610.949 426 4.10.025740.772 2120 3.70.074070.708 1016 5.80.054290.757 321 5.50.013530.63690 3.30.006210.726 184 4.80.010070.73123>10.00.00228 1.513 610 3.80.032170.72 842 5.40.057730.829 213 5.40.01270.77439 2.40.001731002 4.80.033670.729 208 4.30.00930.537 5247.60.043570.93 116>10.00.02104 1.812 173>10.00.013330.936 589 5.30.032210.807 108 6.10.009190.931 487 4.70.03951 1.142 76450.047770.779 1666 5.20.091160.854 193 1.80.004620.921 120 2.20.004670.894 3338.70.027140.756 4327.10.027040.625 19520.003610.533 194 6.90.011710.909 2597.30.013360.716 266 6.80.026850.752 87080.070140.869 2187.70.01310.75610 5.60.00062 1.012 4189.20.026590.815 622 5.20.034970.666 1709.90.01712 1.222 178 5.80.009120.836 907.70.00320.65258>10.00.01221 1.371 4877.30.041850.896 187 5.60.009820.662 338 6.50.019280.711 443 6.30.026840.651 20850.01330.806 409 4.50.027060.735 774 3.20.034350.762 15287.90.107180.745 739 5.40.053960.715 227.60.001180.774 105 5.10.007480.647 129 4.90.00780.74475 3.50.002990.639212 3.70.013920.784 201 5.60.009290.599 500 6.30.06138 1.238 >10.00.00042 1.049 290 6.10.019640.625 251 5.60.017330.895 12498.40.075460.68 241 2.20.005560.628 1341 6.70.120620.829 651 6.90.026690.572 224 5.10.010210.672 290 5.30.013220.702 194 1.60.002660.7278>10.00.000620.792 314>10.00.019270.649 32830.001390.381 520 6.30.034550.62153 5.20.004350.904 200 1.30.002460.856 109 3.70.00563143 5.80.013670.825 439 4.20.025470.66 441>10.00.03210.853 17290.80.002020.494 1527.40.009010.741 624 2.40.016810.714 337 6.40.02850.71 173 1.90.002010.614 124 6.30.008010.593 2207.60.010810.602 4708.20.028730.596 221 5.20.00853 1.29 4957.50.036490.714 967.20.003150.52311>10.00.000450.543 184 3.50.006730.588 1064 2.80.017560.666 2437.60.014140.744 257.10.002380.868 105130.022770.574 10130.003550.834 2518.20.017620.63 16669.90.081330.508 1478 4.10.10840.548 14830.008560.8753427.80.015630.587 559.80.002470.6496 1.50.001250.668648.10.002270.561 178 6.20.010850.6 247>10.00.011750.526 202 5.20.013550.701 1484 5.40.069550.546 116 6.40.005740.60572 2.10.00140.58954>10.00.004010.856 351 6.60.011110.57 960 3.90.021660.681 1549.50.006150.597 5790.008180.646 6720.0008353 2.30.00061176 2.60.005320.633 1947.80.016490.569 223 5.60.014960.968 25280.006360.457 1626 5.50.049760.537 1977.10.008730.585 128 5.40.00580.57919>10.00.001080.734 650 3.70.017210.673 9419.10.050830.59113>10.00.00130.598 21090.007690.475 906>10.00.066080.687 350 3.90.005590.396 2247.80.01640.479 1789 5.50.074220.539 419>10.00.014550.491 579 6.80.034280.585 11717.30.084950.73 918.60.003920.471 458.60.00220.655 100 6.20.007370.666 335 5.10.012850.644 964 5.50.038290.59199 5.20.004810.478 302 6.60.012460.48640 2.10.000610.345 392>10.00.021350.719339>10.00.01560.489 5138.90.025150.615 50 4.50.001620.659 1368.50.005580.639 353 5.90.018730.713 495 4.80.011170.321 1147.60.003960.391 156 6.70.022520.706 508 6.50.027410.476 82 5.10.003380.472 410>10.00.020760.421 400>10.00.012770.531 463 4.70.008250.53 728 5.70.012880.253 2367.10.012090.669 180 3.80.004490.45 360>10.00.018270.679 2957.80.035210.653 950 3.40.026580.586 218 5.20.006840.446 2547.50.007820.487。

JCR2015影响因子(所有期刊从高到低排序)+中科院分区

Rank ISSN Abbreviated JournalTitleFull Title Category2940007-9235CA-CANCER J CLIN CA-A CANCER JOURNAL FOR CLINICIAN医学10200028-4793NEW ENGL J MED NEW ENGLAND JOURNAL OF MEDICINE医学3410009-2665CHEM REV CHEMICAL REVIEWS化学17260140-6736LANCET LANCET医学63341474-1776NAT REV DRUG DISCOV NATURE REVIEWS DRUG DISCOVERY医学51741087-0156NAT BIOTECHNOL NATURE BIOTECHNOLOGY工程技术10020028-0836NATURE NATURE综合性期刊32570732-0582ANNU REV IMMUNOL ANNUAL REVIEW OF IMMUNOLOGY医学62471471-0072NAT REV MOL CELL BIO NATURE REVIEWS MOLECULAR CELL B生物63331474-175X NAT REV CANCER NATURE REVIEWS CANCER医学62461471-0056NAT REV GENET NATURE REVIEWS GENETICS生物63621476-1122NAT MATER NATURE MATERIALS工程技术16260098-7484JAMA-J AM MED ASSOC JAMA-JOURNAL OF THE AMERICAN ME医学63321474-1733NAT REV IMMUNOL NATURE REVIEWS IMMUNOLOGY医学75191748-3387NAT NANOTECHNOL Nature Nanotechnology工程技术12390036-8075SCIENCE SCIENCE综合性期刊27400306-0012CHEM SOC REV CHEMICAL SOCIETY REVIEWS化学14560066-4146ANNU REV ASTRON ASTR ANNUAL REVIEW OF ASTRONOMY AND地学天文75331749-4885NAT PHOTONICS Nature Photonics物理15680092-8674CELL CELL生物67681548-7091NAT METHODS NATURE METHODS生物62451471-003X NAT REV NEUROSCI Nature Reviews Neuroscience NEUROSCIENCES 14570066-4154ANNU REV BIOCHEM ANNUAL REVIEW OF BIOCHEMISTRY生物11940034-6861REV MOD PHYS REVIEWS OF MODERN PHYSICS物理48751061-4036NAT GENET NATURE GENETICS生物15060079-6425PROG MATER SCI PROGRESS IN MATERIALS SCIENCE工程技术51051078-8956NAT MED NATURE MEDICINE医学11140031-9333PHYSIOL REV PHYSIOLOGICAL REVIEWS医学15100079-6700PROG POLYM SCI PROGRESS IN POLYMER SCIENCE化学76261755-4330NAT CHEM Nature Chemistry化学62371470-2045LANCET ONCOL LANCET ONCOLOGY医学74001740-1526NAT REV MICROBIOL NATURE REVIEWS MICROBIOLOGY生物66151535-6108CANCER CELL CANCER CELL医学67091543-5008ANNU REV PLANT BIOL ANNUAL REVIEW OF PLANT BIOLOGY生物63191473-3099LANCET INFECT DIS LANCET INFECTIOUS DISEASES医学150001-4842ACCOUNTS CHEM RES ACCOUNTS OF CHEMICAL RESEARCH化学80331934-5909CELL STEM CELL Cell Stem Cell生物57941364-6613TRENDS COGN SCI TRENDS IN COGNITIVE SCIENCES医学63351474-4422LANCET NEUROL LANCET NEUROLOGY医学14660066-4308ANNU REV PSYCHOL ANNUAL REVIEW OF PSYCHOLOGY医学50621074-7613IMMUNITY IMMUNITY医学19000163-769X ENDOCR REV ENDOCRINE REVIEWS医学580001-8732ADV PHYS ADVANCES IN PHYSICS物理17250140-525X BEHAV BRAIN SCI BEHAVIORAL AND BRAIN SCIENCES医学76141754-5692ENERG ENVIRON SCI Energy & Environmental Science化学74791745-2473NAT PHYS Nature Physics物理29820370-1573PHYS REP PHYSICS REPORTS-REVIEW SECTION 物理65501529-2908NAT IMMUNOL NATURE IMMUNOLOGY医学61991465-7392NAT CELL BIOL NATURE CELL BIOLOGY生物84372159-8274CANCER DISCOV Cancer discovery ONCOLOGY 18180147-006X ANNU REV NEUROSCI ANNUAL REVIEW OF NEUROSCIENCE医学60511433-8351LIVING REV RELATIV Living Reviews in Relativity物理28850360-1285PROG ENERG COMBUST PROGRESS IN ENERGY AND COMBUST工程技术医学68241553-4006ANNU REV PATHOL-MECH Annual Review of Pathology-Mechanisms o14640066-4278ANNU REV PHYSIOL ANNUAL REVIEW OF PHYSIOLOGY医学32580732-183X J CLIN ONCOL JOURNAL OF CLINICAL ONCOLOGY医学29200362-1642ANNU REV PHARMACOL ANNUAL REVIEW OF PHARMACOLOGY 医学1520003-4819ANN INTERN MED ANNALS OF INTERNAL MEDICINE医学地学天文39930935-4956ASTRON ASTROPHYS REV ASTRONOMY AND ASTROPHYSICS REV71031614-4961LIVING REV SOL PHYS LIVING REVIEWS IN SOLAR PHYSICS ASTRONOMY & AS 67881550-4131CELL METAB Cell Metabolism生物39970935-9648ADV MATER ADVANCED MATERIALS工程技术76391756-1833BMJ-BRIT MED J BMJ-British Medical Journal MEDICINE, GENER 36650893-8512CLIN MICROBIOL REV CLINICAL MICROBIOLOGY REVIEWS医学1830003-9926ARCH INTERN MED ARCHIVES OF INTERNAL MEDICINE医学10940031-6997PHARMACOL REV PHARMACOLOGICAL REVIEWS医学680002-5100ALDRICHIM ACTA ALDRICHIMICA ACTA化学11890034-4885REP PROG PHYS REPORTS ON PROGRESS IN PHYSICS物理生物26600301-5556ADV ANAT EMBRYOL CEL ADVANCES IN ANATOMY EMBRYOLOGY化学14630066-426X ANNU REV PHYS CHEM ANNUAL REVIEW OF PHYSICAL CHEMIS5210016-5085GASTROENTEROLOGY GASTROENTEROLOGY医学51251081-0706ANNU REV CELL DEV BI ANNUAL REVIEW OF CELL AND DEVELO生物医学32960735-1097J AM COLL CARDIOL JOURNAL OF THE AMERICAN COLLEGE20440169-5347TRENDS ECOL EVOL TRENDS IN ECOLOGY & EVOLUTION生物71041614-6832ADV ENERGY MATER Advanced Energy Materials CHEMISTRY, PHYS 52791097-6256NAT NEUROSCI NATURE NEUROSCIENCE医学化学59481389-5567J PHOTOCH PHOTOBIO C JOURNAL OF PHOTOCHEMISTRY AND P81491946-6234SCI TRANSL MED Science Translational Medicine CELL BIOLOGY医学64501520-765X EUR HEART J SUPPL EUROPEAN HEART JOURNAL SUPPLEM14600066-4197ANNU REV GENET ANNUAL REVIEW OF GENETICS生物39160927-796X MAT SCI ENG R MATERIALS SCIENCE & ENGINEERING 工程技术80491936-122X ANNU REV BIOPHYS Annual Review of Biophysics生物76891759-4758NAT REV NEUROL Nature Reviews Neurology医学21640195-668X EUR HEART J EUROPEAN HEART JOURNAL医学37130896-6273NEURON NEURON医学20380169-409X ADV DRUG DELIVER REV ADVANCED DRUG DELIVERY REVIEWS医学75131748-0132NANO TODAY Nano Today工程技术86088755-1209REV GEOPHYS REVIEWS OF GEOPHYSICS地学81551947-5454ANNU REV CONDEN MA P Annual Review of Condensed Matter Physi PHYSICS, CONDEN 19620167-5729SURF SCI REP SURFACE SCIENCE REPORTS化学11550033-2909PSYCHOL BULL PSYCHOLOGICAL BULLETIN医学5530017-5749GUT GUT医学51931088-9051GENOME RES GENOME RESEARCH生物生物52311092-2172MICROBIOL MOL BIOL R MICROBIOLOGY AND MOLECULAR BIOL83072047-7538LIGHT-SCI APPL Light-Science & Applications OPTICS 76811758-678X NAT CLIM CHANGE Nature climate change ENVIRONMENTAL 57581359-4184MOL PSYCHIATR MOLECULAR PSYCHIATRY医学1820003-990X ARCH GEN PSYCHIAT ARCHIVES OF GENERAL PSYCHIATRY医学3590009-7322CIRCULATION CIRCULATION医学67721549-1676PLOS MED PLOS MEDICINE MEDICINE, GENER 49041063-5157SYST BIOL SYSTEMATIC BIOLOGY生物81041941-1405ANNU REV MAR SCI Annual Review of Marine Science地学73441723-8617WORLD PSYCHIATRY World Psychiatry医学64881523-9829ANNU REV BIOMED ENG ANNUAL REVIEW OF BIOMEDICAL ENG工程技术76901759-4774NAT REV CLIN ONCOL Nature Reviews Clinical Oncology医学58401369-7021MATER TODAY Materials Today工程技术52771097-2765MOL CELL MOLECULAR CELL生物26720302-2838EUR UROL EUROPEAN UROLOGY医学14580066-4170ANNU REV ENTOMOL ANNUAL REVIEW OF 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ENVIRONMENT AN81081941-3289CIRC-HEART FAIL Circulation-Heart Failure医学35880889-1591BRAIN BEHAV IMMUN BRAIN BEHAVIOR AND IMMUNITY医学1350003-3022ANESTHESIOLOGY ANESTHESIOLOGY医学47501049-250X ADV ATOM MOL OPT PHY ADVANCES IN ATOMIC MOLECULAR AN物理医学53951180-4882J PSYCHIATR NEUROSCI JOURNAL OF PSYCHIATRY & NEUROSC47961053-5888IEEE SIGNAL PROC MAG IEEE SIGNAL PROCESSING MAGAZINE工程技术57551359-0294CURR OPIN COLLOID IN CURRENT OPINION IN COLLOID & INTE化学31020390-6078HAEMATOLOGICA HAEMATOLOGICA HEMATOLOGY地学天文63551475-7516J COSMOL ASTROPART P JOURNAL OF COSMOLOGY AND ASTRO生物60021420-682X CELL MOL LIFE SCI CMLS-Cellular and Molecular Life Sciences9170024-9297MACROMOLECULES MACROMOLECULES工程技术84962192-2640ADV HEALTHC MATER Advanced healthcare materials工程技术82952046-2441OPEN BIOL Open biology BIOCHEMISTRY &工程技术18870162-8828IEEE T PATTERN ANAL IEEE TRANSACTIONS ON PATTERN ANA54041198-743X CLIN MICROBIOL INFEC CLINICAL MICROBIOLOGY AND INFECT医学84402161-1653ACS MACRO LETT ACS Macro Letters化学62151467-7644PLANT BIOTECHNOL J PLANT BIOTECHNOLOGY JOURNAL生物62121467-3037CURR ISSUES MOL BIOL CURRENT ISSUES IN MOLECULAR BIOL生物65071525-7797BIOMACROMOLECULES BIOMACROMOLECULES化学36340891-5849FREE RADICAL BIO MED FREE RADICAL BIOLOGY AND MEDICIN医学40690947-6539CHEM-EUR J CHEMISTRY-A EUROPEAN JOURNAL化学50391072-4710ARCH PEDIAT ADOL MED ARCHIVES OF PEDIATRICS & ADOLESC医学医学24640269-2813ALIMENT PHARM THER ALIMENTARY PHARMACOLOGY & THER9590025-7974MEDICINE MEDICINE医学12840039-2499STROKE STROKE医学69011560-7917EUROSURVEILLANCE EUROSURVEILLANCE INFECTIOUS DISEASES 66541538-7933J THROMB HAEMOST JOURNAL OF THROMBOSIS AND HAEM医学84262157-6564STEM CELL TRANSL MED Stem cells translational medicine CELL & TISSUE ENGINEERING 15130079-6816PROG SURF SCI PROGRESS IN SURFACE SCIENCE工程技术84982192-8606NANOPHOTONICS-BERLIN N anophotonics NANOSCIENCE &66161535-7163MOL CANCER THER MOLECULAR CANCER THERAPEUTICS医学医学70591600-6135AM J TRANSPLANT AMERICAN JOURNAL OF TRANSPLANTA35210885-3185MOVEMENT DISORD MOVEMENT DISORDERS医学35010883-7694MRS BULL MRS BULLETIN工程技术26690301-9268PRECAMBRIAN RES PRECAMBRIAN RESEARCH地学71071615-4150ADV SYNTH CATAL ADVANCED SYNTHESIS & CATALYSIS化学42180957-9672CURR OPIN LIPIDOL CURRENT OPINION IN LIPIDOLOGY医学81131941-7705CIRC-CARDIOVASC QUAL Circulation: Cardiovascular Quality and Ou CARDIAC & CARDI1320003-2700ANAL CHEM ANALYTICAL CHEMISTRY化学26970304-3835CANCER LETT CANCER LETTERS医学84312158-3188TRANSL PSYCHIAT Translational Psychiatry PSYCHIATRY43740969-2126STRUCTURE STRUCTURE生物78331863-2653BRAIN STRUCT FUNCT Brain Structure & Function医学27410306-2619APPL ENERG APPLIED ENERGY工程技术450001-690X ACTA PSYCHIAT SCAND ACTA PSYCHIATRICA SCANDINAVICA医学17750143-5221CLIN SCI CLINICAL SCIENCE医学57371355-6037HEART HEART医学82852045-2322SCI REP-UK Scientific reports Natural Science Disciplines 47861052-9276REV MED VIROL REVIEWS IN MEDICAL VIROLOGY医学34040749-6419INT J PLASTICITY INTERNATIONAL JOURNAL OF PLASTIC工程技术24600268-960X BLOOD REV BLOOD REVIEWS医学64761522-8517NEURO-ONCOLOGY NEURO-ONCOLOGY医学18600160-4120ENVIRON INT ENVIRONMENT INTERNATIONAL环境科学24800269-9370AIDS AIDS医学2780007-1323BRIT J SURG BRITISH JOURNAL OF SURGERY医学13480043-1354WATER RES WATER RESEARCH环境科学57241354-3784EXPERT OPIN INV DRUG EXPERT OPINION ON INVESTIGATIONA医学7550022-0957J EXP BOT JOURNAL OF EXPERIMENTAL BOTANY生物7450022-0477J ECOL JOURNAL OF ECOLOGY环境科学77031759-9954POLYM CHEM-UK POLYMER CHEMISTRY POLYMER SCIENCE 82141994-0416CRYOSPHERE Cryosphere GEOGRAPHY, PHY 18630160-6689J CLIN PSYCHIAT JOURNAL OF CLINICAL PSYCHIATRY医学67821549-9618J CHEM THEORY COMPUT J ournal of Chemical Theory and Computat化学65401527-8999CHEM REC CHEMICAL RECORD化学61951465-542X BREAST CANCER RES BREAST CANCER RESEARCH ONCOLOGY。

血管外膜细胞钙化及其钙化机制研究

血管外膜细胞钙化及其钙化机制研究谭小青,张旭升,樊小容,黄战军摘要目的:研究经体外诱导钙化建立大鼠血管外膜细胞钙化模型,检测钙化过程中成骨相关指标及凋亡㊁自噬相关蛋白的表达变化,旨在为心血管疾病模型提供更精确的细胞模型,并初步探讨其钙化机制㊂方法:原代提取大鼠胸主动脉外膜纤维细胞,取3~6代细胞使用诱导培养基(高糖DMEM +10%胎牛血清+10mmol/L β-甘油磷酸+0.05mmol/L 抗坏血酸+100mmol/L 地塞米松)诱导钙化,诱导时间为3d ㊁6d ㊁9d ㊁12d ㊁15d ,筛选出诱导细胞钙化的最佳时间㊂对细胞采用茜素红S 染色㊁细胞内钙含量测定和碱性磷酸酶(ALP )活性检测,鉴定是否成功构建钙化模型㊂采用实时定量聚合酶链式反应(PT -PCR )检测成骨相关因子骨形态生成蛋白2(BMP2)和核心结合因子α1(Runx2)的mRNA 含量,蛋白免疫印迹法(Western Blot )检测凋亡蛋白Bax ㊁Bcl -2和自噬相关蛋白微血管相关蛋白(LC3)㊁Beclin -1的表达水平,找出血管外膜细胞钙化的潜在机制㊂结果:当诱导钙化时间为15d 时,血管外膜细胞中主要钙化指标胞内钙含量及ALP 活性上调(P <0.05),茜素红S 染色显示钙化组有明显钙盐沉积㊂血管外膜细胞经钙化诱导后,BMP2和Runx2的mRNA 水平上调,Bax 蛋白水平上调,Bcl -2和Beclin -1蛋白水平下调,LC3-Ⅱ/LC3-Ⅰ比值上调(P <0.05)㊂结论:钙化诱导培养基培养血管外膜细胞15d 可成功构建钙化细胞模型,血管外膜细胞钙化可能与细胞向成骨样表型转化有关,血管外膜细胞钙化过程涉及细胞自噬及凋亡调控㊂关键词血管外膜细胞;钙化;成骨样表型转化;自噬与凋亡;实验研究d o i :10.12102/j.i s s n .1672-1349.2023.18.010 Calcification of Vascular Adventitial Cells and Its MechanismTAN Xiaoqing,ZHANG Xusheng,FAN Xiaorong,HUANG Zhanjun Longgang District People 's Hospital of Shenzhen,Shenzhen 518172,Guangdong,China Corresponding Author ZHANG Xusheng,E -mail:*****************Abstract Objective:To investigate the mananism of calcification of rat vascular adventitial cells,establish the calcification model of rat vascular adventitial cells,and detect the expression changes of osteogenesis -related indicators,apoptosis,and autophagy -related proteins during the calcification process.It aimed to provide more accurate cell models for cardiovascular disease and initially explore the mechanism of calcification.Methods:Rat thoracic aortic adventitial fibroblasts were extracted from the primary generation,and the 3rd to 6th generation cells were used for induction medium(high glucose DMEM +10%fetal bovine serum +10mmol/L β-glycerophosphate +0.05mmol/L ascorbic acid +100mmol/L dexamethasone)to induce calcification,the induction time was 3,6,9,12,and 15d,and the optimal time for inducing cell calcification was selected.The cells were stained with alizarin red S,detected by intracellular calcium content and alkaline phosphatase(ALP)to identify whether the calcification model was successfully constructed.Real -time quantitative reverse transcription polymerase chain reaction(RT -PCR)was used to detect the mRNA levels of osteogenesis -related factors bone morphogenetic protein(BMP2)and runt -related transcription factor 2(Runx2);Western Blot was used to detect the apoptosis proteins Bax,Bcl -2,the autophagy -related proteins LC -3,and Beclin -1expression level;then the potential mechanism of vascular adventitial cell calcification would be revealed.Results:When calcification was induced for 15days,the intracellular calcium content in the adventitial cells of the main calcification indicators and ALP activity were up -regulated(P <0.05).Alizarin red S staining showed obvious calcium deposits in the calcification group.After calcification was induced in adventitial cells,the mRNA levels of BMP2and Runx2up -regulated,the protein levels of Bax up -regulated,the protein levels of Bcl -2and Beclin -1down -regulated,and the ratio of LC3-Ⅱ/LC3-Ⅰdown -regulated(P <0.05).Conclusion:Adventitial cells cultured in the calcification -inducing medium for 15days could successfully construct a calcified cell model.calcification of adventitial cells might be related to the transformation of cells to an osteoblast -like phenotype.The Calcification process of adventitial cells involved autophagy and apoptosis regulation.Keywords adventitial cells;calcification;osteogenic phenotype transformation;autophagy and apoptosis;experimental study血管钙化常见于动脉粥样硬化㊁血脂异常㊁高血压㊁糖尿病㊁慢性肾病及衰老等人群[1],血管钙化引起血管硬度增加㊁顺应性降低,导致心肌缺血㊁心力衰竭㊁血栓形成等,增加脑卒中㊁心脏病㊁动脉粥样硬化斑块破裂等的风险,被认为是影响心血管疾病的重要因素之一[2-4]㊂目前关于血管内膜㊁中膜和心脏瓣膜钙化的关注和研究相对较多㊂临床工作中发现,血管外膜也可发生钙化,然而调查发现,现阶段对血管外膜钙化的作者单位深圳市龙岗区人民医院(广东深圳518172)通讯作者张旭升,E -mail :*****************引用信息谭小青,张旭升,樊小容,等.血管外膜细胞钙化及其钙化机制研究[J ].中西医结合心脑血管病杂志,2023,21(18):3347-3350.关注较少,因此,需要更多的研究来阐明血管钙化的致病机制㊂最初血管钙化被认为是被动和退行性病变,标志着血管老化,但是越来越多研究表明血管钙化是类似于胚胎骨形成的病理生物学过程[5-6]㊂Bostr öm 等[7-8]研究发现,钙化过程中大鼠血管中膜细胞由原有收缩表型转变成为成骨样细胞表型,原有的收缩标志物如平滑肌肌动蛋白α(α-SMA )等表达减少,并表达核心结合因子α1(Runx2)㊁骨形态生成蛋白2(BMP2)等多种成骨样标志物,从而介导骨基质在血管中沉积㊂细胞凋亡与自噬为2种细胞死亡的方式,与血管钙化息息相关,研究表明,血管中膜细胞在细胞凋亡过程中释放凋亡小体,促进细胞钙化,而细胞自噬通过多种机制调控细胞钙化[9-10]㊂本研究对大鼠血管外膜细胞进行体外诱导钙化,建立大鼠血管外膜细胞钙化模型,并检测钙化过程中成骨相关指标及凋亡㊁自噬相关蛋白的表达变化,旨在为心血管疾病模型提供更精确的细胞模型,并初步探讨其钙化机制㊂1材料与方法1.1试剂胎牛血清(FBS,Gibco),青霉素,链霉素(Gibco,美国),茜素红S溶液,β-甘油磷酸,抗坏血酸,地塞米松(Sigma,美国),抗GAPDH抗体(Bioworld),抗Bcl-2, Bax,Bcelin1和微血管相关蛋白(LC3)抗体(CST),碱性磷酸酶检测试剂盒㊁钙(Ca)检测试剂盒(南京建城生物工程研究所)㊂1.2大鼠血管外膜细胞分离与培养取10只4~6周龄雄性Wistar-Kyoto大鼠(体质量120~180g)胸主动脉分离血管外膜,采用组织黏附法培养㊂使用添加10%胎牛血清的高糖DMEM培养基(Gibco dmem)在37ħ㊁5%二氧化碳条件下培养细胞㊂当细胞增殖至80%~90%融合时,用0.25%胰酶消化传代㊂使用第3代至第6代的细胞进行后续实验㊂1.3体外钙化模型的建立钙化诱导培养基为含10%胎牛血清,10mmol/L β-甘油磷酸钠,0.05mmol/L抗坏血酸和100mmol/L 地塞米松的高糖DMEM培养液㊂将第3代至第6代细胞分为对照组和钙化组,待细胞长至50%融合时,使用钙化诱导培养基培养,每3d更换1次培养基,连续培养15d㊂1.4碱性磷酸酶(ALP)酶活测定细胞钙化诱导后,弃去培养基,1ˑ磷酸缓冲盐溶液(PBS)洗细胞3次,加入裂解液500μL(1%T ritonX-100),冰上裂解40min后,离心,取上清液㊂使用上清液根据试剂盒说明书检测ALP活性及总蛋白含量㊂1.5细胞内钙含量检测细胞钙化诱导后,弃去培养基,1ˑPBS洗细胞3次,每孔加入500μL0.6mol/L的盐酸4ħ脱钙过夜,取上清,根据钙测试试剂盒说明书检测钙含量㊂将脱钙后的细胞用4ħPBS洗3次,每孔加入500μL NaOH/0.1%SDS裂解细胞,取上清,用二喹啉甲酸法(BCA)测定细胞蛋白含量㊂1.6茜素红S染色细胞钙化诱导15d,弃去培养基,1ˑPBS洗细胞3次,加入0.5mL4%多聚甲醛室温固定15min,用双蒸水洗3次,加入1mL0.1%茜素红室温孵育15min,吸去染液,双蒸水洗3次,在倒置显微镜下观察㊂1.7实时定量聚合酶链式反应(RT-PCR)检测细胞钙化诱导后,弃去培养基,1ˑPBS洗细胞3次,使用TaKaRa MiniBEST Universal RNA Extraction Kit提取总RNA,使用PrimeScrip TM RT reagent Kit将所提取的RNA逆转录合成cDNA,以cDNA为模板,通过SYBR Green I嵌合荧光定量RT-PCR检测BMP-2㊁Runx2和GAPDH的表达量㊂引物序列见表1㊂表1引物序列基因方向序列Runx2正向5'-TGGCTTTGGTTTCAGGTTAGG-3'反向5'-TGGAGATGTTGCTCTGTTCG-3' BMP-2正向5'-TGAGGATTAGCAGGTCTTTGC-3'反向5'-TCTCGTTTGTGGAGTGGATG-3' GAPDH正向5'-GGCTGCCCAGAACATCAT-3'反向5'-CGGACACATTGGGGGTAG-3'1.8蛋白免疫印迹法(Western Blot)检测细胞钙化诱导15d,弃去培养基,1ˑPBS洗细胞3次,提取细胞总蛋白㊂使用12%SDS-PAGE胶电泳分离,并转移到聚偏二氟乙烯膜(PVDF)上,封闭后,加入一抗(Bax1ʒ1000,Bcl-21ʒ1000,Beclin11ʒ1000, LC31ʒ1000,GAPDH1:1000)稀释液,4ħ孵育过夜;加入二抗稀释液(1ʒ10000)室温孵育1h后,使用ECL发光试剂盒显影并计算灰度值㊂1.9统计学处理应用SPSS19.0软件进行统计处理,符合正态分布的定量资料以均数ʃ标准差(xʃs)表示,比较采用t检验,以P<0.05为差异有统计学意义㊂2结果2.1大鼠血管外膜细胞可在体外被诱导钙化为验证高磷是否能诱导大鼠血管外膜细胞钙化,使用钙化诱导培养基培养细胞,在不同时间点检测ALP活性和胞内钙含量㊂随着培养时间延长,ALP活性逐渐上升,在培养第12天达到峰值,与对照组比较差异有统计学意义(P<0.05);诱导第3天开始所测得的胞内钙含量与对照组比较升高(P<0.05),ALP 活性和钙含量升高具有时间依赖性㊂详见图1㊁图2㊂诱导15d所测得钙含量最高,因此,后续实验选择的诱导时间为15d㊂对钙化诱导15d的细胞进行茜素红S染色,结果显示,对照组细胞呈长梭形,而钙化组细胞变成菱形㊂茜素红S染色后,钙化组可观察到大量的橘红色钙结节(见图3),而对照组完全没有㊂这也证明大鼠血管外膜细胞可在体外被钙化培养基诱导钙化㊂图1钙化诱导培养基诱导外膜细胞后ALP含量(与0d时比较,*P<0.05)图2钙化诱导培养基诱导外膜细胞后胞内钙含量(与0d时比较,*P<0.05)图3培养15d时细胞经茜素S红染色切片图(ˑ100)2.2血管外膜细胞钙化与细胞向成骨样表型转化有关血管钙化的增加与成骨细胞特异性标志物如BMP2㊁和Runx2的增加有关[11]㊂RT-PCR结果显示,与对照组比较,钙化组的成骨细胞特异性标志物BMP2和Runx2mRNA表达量增加,与对照组比较差异有统计学意义(P<0.05)㊂详见图4㊂图4外膜细胞钙化过程中BMP2和Runx2mRNA表达量(与对照组比较,*P<0.05)2.3血管外膜细胞钙化过程涉及细胞自噬及凋亡调控通过Western Blot检测凋亡和自噬相关蛋白的表达量变化㊂与对照组比较,钙化组促凋亡蛋白Bax表达上调,抑凋亡蛋白Bcl-2表达下调(P<0.05)㊂详见图5㊂钙化组自噬相关蛋白Beclin1表达上调,LC3-Ⅱ/ LC3-Ⅰ比例上调(P<0.05),说明钙化诱导培养后细胞内凋亡水平上调㊁自噬水平升高㊂详见图6㊂图5诱导钙化后促凋亡蛋白及抑凋亡蛋白表达变化图6诱导钙化后凋亡及自噬蛋白Beclin1等表达变化3讨论血管钙化作为心血管疾病病人的并发症之一,其发病率与严重程度逐年增高及加重,是导致心血管疾病病人高死亡率的重要因素㊂血管钙化缺乏有效的治疗药物㊂因此,探究血管钙化发病机制,在分子水平寻找有效的诊断和防治靶点是急需开展的基础研究工作㊂本研究证明,使用10mmol/Lβ-甘油磷酸+0.05 mmol/L抗坏血酸+100mmol/L地塞米松培养外膜细胞即可诱导大鼠血管外膜细胞在体外发生钙化,这是通过茜素红S染色㊁ALP活性检测及胞内钙含量检测结果得以确定的㊂血管钙化过程中,血管中膜细胞向成骨样细胞表型转变并表达相关成骨标志物,从而引起骨基质的沉积,是血管钙化的重要特点及机制[5]㊂本实验所用的血管外膜细胞钙化条件与血管中膜细胞钙化条件一致,说明血管外膜细胞钙化的机制可能与中膜细胞钙化的机制部分一致㊂血管中膜细胞钙化过程中,细胞表达成骨相关的转录因子如Runx2等,进而促进下游表达骨相关蛋白如骨形态发生蛋白BMP2等的表达,从而促使细胞向成骨样细胞主动分化[12-13],本研究也观察到类似的机制㊂通过PT-PCR检测,发现钙化培养基培养大鼠血管外膜细胞15d后,BMP2和Runx2的mRNA表达水平升高㊂本研究通过对钙盐沉积与成骨样细胞表型转变2个维度的探讨,证明血管外膜细胞可在体外被诱导钙化,丰富了血管钙化的分型㊂血管钙化的发生机制复杂,涉及多种信号通路,如细胞自噬和凋亡㊁Wnt/β-catenin信号通路激活㊁内质网应激等均参与调控血管钙化的过程㊂自噬作为一种细胞应激的适应性反应,在维持血管结构与功能中十分关键㊂研究表明,血管钙化过程中自噬水平增高[14-15]㊂在体外实验中,高磷可提高大鼠血管中膜细胞的自噬水平,增加细胞内自噬体数量,从而抑制凋亡与钙化[16]㊂还有研究表明,自噬可通过抑制大鼠血管中膜细胞氧化应激,抑制血管内皮细胞的炎症反应,对三酰甘油等脂代谢进行调控,从而减轻血管钙化[17-18]㊂LC3和Beclin1是2种典型的自噬标志物,Western Blot实验结果表明,用钙化培养基诱导大鼠血管外膜细胞15d,LC3-Ⅱ/LC3-Ⅰ比率升高,Beclin1蛋白水平表达升高,说明细胞内自噬水平升高㊂多项研究表明,细胞凋亡参与促进血管钙化的发生,抑制细胞凋亡和抑制钙化[16-17]㊂在对大鼠的体内研究发现,成纤维细胞生长因子21通过内质网应激调控Caspase-12信号通路来减少血管内中膜细胞凋亡,从而抑制血管钙化[18]㊂另外,提高培养基中的Pi 或Ca2+浓度,可诱导细胞质膜形成并释放基质囊泡(如凋亡小体),从而导致细胞外基质钙化,这种基质钙化可能成为血管钙化的成核位点[19]㊂Bax和Bcl-2是2种典型的凋亡和抑制凋亡蛋白,本实验结果证明,利用钙化培养基对血管外膜细胞诱导钙化过程中,细胞内凋亡水平升高㊂同时细胞内自噬水平也升高,这可能是细胞自我调控以对抗钙化的结果㊂本研究证实血管外膜细胞可在体外被诱导钙化,且外膜钙化过程与骨组织钙化过程类似,为主动可调控的过程㊂血管钙化是一个复杂的过程,涉及细胞凋亡和自噬等调控通路,仍需进一步研究㊂参考文献:[1]梁英权,段亚君,韩际宏.血管钙化分子机制研究进展[J].中国动脉硬化杂志,2020,28(11):921-929.[2]NICOLL R,HENEIN M Y.The predictive value of arterial andvalvular calcification for mortality and cardiovascular events[J].Int J Cardiol Heart Vessel,2014,3:1-5.[3]JOHNSON R C,LEOPOLD J A,LOSCALZO J.Vascularcalcification:pathobiological mechanisms and clinical implications[J].Circulation Research,2006,99(10):1044-1059.[4]YAMADA S,GIACHELLI C M.Vascular calcification in CKD-MBD:roles for phosphate,FGF23,and Klotho[J].Bone,2017,100:87-93.[5]LIN M E,CHEN T M,WALLINGFORD M C,et al.Runx2deletion insmooth muscle cells inhibits vascular osteochondrogenesis andcalcification but not atherosclerotic lesion formation[J].Cardiovascular Research,2016,112(2):606-616.[6]DURHAM A L,SPEER M Y,SCATENA M,et al.Role of smoothmuscle cells in vascular calcification:implications in atherosclerosis andarterial stiffness[J].Cardiovascular Research,2018,114(4):590-600.[7]BOSTRÖM K I,RAJAMANNAN N M,TOWLER D A.The regulationof valvular and vascular sclerosis by osteogenic morphogens[J].Circulation Research,2011,109(5):564-577.[8]SPEER M Y,YANG H Y,BRABB T,et al.Smooth muscle cells giverise to osteochondrogenic precursors and chondrocytes incalcifying arteries[J].Circulation Research,2009,104(6):733-741.[9]PROUDFOOT D,SKEPPER J N,HEGYI L,et al.Apoptosisregulates human vascular calcification in vitro:evidence forinitiation of vascular calcification by apoptotic bodies[J].Circulation Research,2000,87(11):1055-1062.[10]AN S J,BOYD R,ZHU M,et al.NADPH oxidase mediatesangiotensin II-induced endothelin-1expression in vascularadventitial fibroblasts[J].Cardiovascular Research,2007,75(4):702-709.[11]ZEADIN M,BUTCHER M,WERSTUCK G,et al.Effect of leptin onvascular calcification in apolipoprotein E-deficient mice[J].Arterioscler Thromb Vasc Biol,2009,29(12):2069-2075. [12]LEOPOLD J A.Vascular calcification:mechanisms of vascularsmooth muscle cell calcification[J].Trends in CardiovascularMedicine,2015,25(4):267-274.[13]刘聿秀.高尿酸诱导血管钙化的机制研究[D].青岛:青岛大学,2015.[14]LIU Q,LUO Y,ZHAO Y,et al.Nano-hydroxyapatite acceleratesvascular calcification via lysosome impairment and autophagydysfunction in smooth muscle cells[J].Bioact Mater,2022,8:478-493.[15]LIANG J,HUANG J,HE W,et al.β-Hydroxybutyric Inhibits vascularcalcification via autophagy enhancement in models induced byhigh phosphate[J].Front Cardiovasc Med,2021,8:685748. [16]CICERI P,ELLI F,CAPPELLETTI L,et al.A new in vitro model todelay high phosphate-induced vascular calcification progression[J].Mol Cell Biochem,2015,410(1/2):197-206.[17]BYON C H,JAVED A,DAI Q,et al.Oxidative stress inducesvascular calcification through modulation of the osteogenictranscription factor Runx2by AKT signaling[J].The Journal ofBiological Chemistry,2008,283(22):15319-15327.[18]OUIMET M,FRANKLIN V,MAK E,et al.Autophagy regulatescholesterol efflux from macrophage foam cells via lysosomal acidlipase[J].Cell Metabolism,2011,13(6):655-667.[19]REYNOLDS J L,JOANNIDES A J,SKEPPER J N,et al.Humanvascular smooth muscle cells undergo vesicle-mediatedcalcification in response to changes in extracellular calcium andphosphate concentrations:a potential mechanism for acceleratedvascular calcification in ESRD[J].Journal of the AmericanSociety of Nephrology,2004,15(11):2857-2867.(收稿日期:2022-03-30)(本文编辑王雅洁)。

益生菌对阿尔茨海默病作用的研究进展

益生菌对阿尔茨海默病作用的研究进展发布时间：2021-12-14T06:08:15.523Z 来源：《中国结合医学杂志》2021年12期作者：宋鑫萍1,2，李盛钰2，金清1[导读] 阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。

近年来研究显示，益生菌在适量使用时作为有益于宿主健康的微生物，在防治阿尔茨海默病方面具有积极影响，其作用机制可能通过调节肠道菌群，影响神经免疫系统，调控神经活性物质以及代谢产物，通过肠-脑轴影响该病发生和发展。

宋鑫萍1,2，李盛钰2，金清11.延边大学农学院，吉林延吉 1330022.吉林省农业科学院农产品加工研究所，吉林长春 130033摘要：阿尔茨海默病已成为威胁全球老年人生命健康的主要疾病之一，患者数量逐年攀升，其护理的经济成本高，给全球经济造成重大挑战。

本文综述了近几年来国内外益生菌对阿尔茨海默病的作用进展，以及其预防和治疗阿尔茨海默病的潜在作用机制。

关键词：益生菌；阿尔茨海默病；肠道菌群；机制Recent Progress in Research on Probiotics Effect on Alzheimer’s DiseaseSONG Xinping1,2，LI Shengyu2，JI Qing1*(1.College of Agricultural, Yanbian University, Yanji 133002，China)(2.Institute of Agro-food Technology, Jilin Academy of Agricultural Sciences, Chanchun 130033, China)Abstract：Alzheimer’s disease has become one of the major diseases threatening the life and health of the global elderly. The number of patients is increasing year by year, and the economic cost of nursing is high, which poses a major challenge to the global economy. In recent years, studies have shown that probiotics, as microorganisms beneficial to the health of the host, have a positive impact on the prevention and treatment of Alzheimer’s disease. Its mechanism may be through regulating intestinal flora, affecting the nervous immune system, regulating the neuroactive substances and metabolites, and affecting the occurrence and development of the disease through thegut- brain axis. This paper reviews the progress of probiotics on Alzheimer’s disease at home and abroad in recent years, as well as its potential mechanism of prevention and treatment.Key words：probiotics; Alzheimer’s disease; gut microbiota; mechanism阿尔茨海默病（Alzheimer’s disease, AD），系中枢神经系统退行性疾病，属于老年期痴呆常见类型，临床特征主要包括：记忆力减退、认知功能障碍、行为改变、焦虑和抑郁等。

Expression, Purification and Crystallization of

Expression, Purification and Crystallization of the Mycobacterium Tuberculosis HSP16.3 Molecular Chaperone Background of Mycobacterium Tuberculosis HSP16.3HSP16.3, a 16.3 kDa protein from Mycobacterium Tuberculosis, was originally identified as a prominent antigen (Kingston et al., 1987). During the stationary phase, HSP16.3 is maximally expressed and becomes a main protein of the latent phase (Yuan et al., 1996). Previous studies showed that HSP16.3 can make the cell structure stable and prevent stationary Mycobacterium Tuberculosis from autolysing (Cunningham et al., 1998). In previous studies, HSP16.3 was found as one of theα-crystallin-related small heat shock proteins (sHSP) with molecular chaperone activity. Experiments in vitro revealed that HSP16.3 can suppress the thermal aggregation of citrate synthase at 39.5˚C, without consumption of A TP (Chang et al., 1996).Now the Mycobacterium Tuberculosis HSP16.3 gene was cloned to the plasmid pSTE-HSP16.3, and transformed to E.Coli. BL21(DE3) strain.Material and MethodExpressionThings to have ready before Starting.-Plate or glycerol culture-Sterile LB 25ml in a 50mL shaker flasker, 250ml in a 500mL shaker flasker, all together autoclaved, antibiotic added afterword.- antibiotic and sterile water- TipsPrepare the LB and autoclave:Fomula of the LB medium for 1 Liter:Bacto Tryptone (BT) 10 gBacto Y east Extract (BYE) 10 gNaCl 10gThe LB medium, dd H2O and the tips all together autoclaved at 121 ˚C for 20 minutes.Method:1 Innoculate 25 ml LB Medium ( containing 100 ug) and grow culture overnight(37˚C, 200rpm).2 Next morning inoculate 250 ml prewarmed LB Medium ( containing 100 ug) with the 25 ml overnight culture and grow at 37 ˚C, 200rpm, HSP16.3 was overexpressed in soluble form intracellularly without IPTG induction.3 Incubate the Culture for 10 hours before havesting the cell at 4000 g for 20 minutes.4 Resuspend the cell pellet in 30 ml Butter A and freeze the Sample in -80˚C refigerator.PurificationDE52 Ion-Exchange columnThings to have ready before Starting.-Butter A: 50 mM Imidazole pH 6.5 (1 liter)-Butter B: 50 mM Imidazole pH 6.5 , 300mM NaClall together Fitrate with 0.2 um membrane.- DE52 medium , column ,Gradient maker, UV-monitor and Fractioner- TipsMethod:1 Thaw the cell pellet and vortex .2 Add 0.4ml 100 mM PMSF and sonicate (400kw, 4s-6s 50 cycle* 5 )3 Centrifuge 15000 rpm, 30 minutes to pellet debris4 Transfer supernatant to a 50 ml conicale tube and discard the pellet.5 The supernatant dilute to 50 ml with Buffer A and then load to DE52 ion-exchange columns (20ml), which was pre-equibrated with 100ml Buffer A. And then wash the unbound proteins with 100 ml Buffer A.6 Elute the protein with a linear gradient : 200ml buffer A plus 200ml buffer B, 2ml/min, 6ml each fraction.7 Run 15% SDS-PAGE to determine the HSP16.3 peak.Desalting by dialysis1 Preparation of the dialysis tubeCut the tube in a suitable length (20-30 cm)Boil the tube in solution containing 10 mM NaHCO3 for a few minutes.Boil the tube in solution containing 10 mM EDTA for a few minutes.Rasin the tube with de-ion water2 Pool the HSP16.3 peak and dialysis the Sample against 1000ml Buffer A for more than 6hours.Q-Separose (HP) Ion-Exchange Column1 load the sample to Q-Separose (HP) Ion-Exchange column (20ml), which was pre-equibrated with 100ml Buffer A. And then wash the unbound proteins with 100 ml Buffer A.2 Elute the protein with a linear gradient : 200ml buffer A plus 200ml buffer B, 2ml/min, 6ml each fraction.3 Run 15% SDS-PAGE to determine the purity of the HSP16.3 peak.Gel filtration ColumnThe HSP peak was a final volumn 0.3ml and then run though a Superdex75 (HR, 10/30mm) gel filtration column in 150mM NaCl and 5mM Imdazole, pH6.5. Crystallization1 The purified HSP16.3 was solvent-exchanged to water and concentrated to 20mg/ml before crystallization trails (Bradford). All the crystallization trials were carried out using the hanging-drop vapor-diffusion method at 291K: drops consisted of2 microlitres of HSP16.3 protein solution plus 2 microlitres of the precipitant. The drops were equilibrated against 0.2 ml precipitant at room temperature. The crystallization conditions were investigated with a PEG4000 Kit.Result and discussionThe purity of the final HSP16.3 was over 95% by SDS-PAGE. The crystallization trials of HSP16.3 yielded Cubic crystals with a size of 0.8*0.8*0.6mm in a few days.20040060080010001200mAUBuffer Tris-HCL pH 8.5 Precipitant PEG 4000 MethodV apor Diffusion Temperature 293 K Size0.8*0.8*0.6mmReferencesChang Z., Primm, T.P., Jakana J., Lee H. I., Serysheva I., Chiu W., Gilber H. F., Quiocho F. A., (1996) J Biol Chem 271:7218-7223Cunningham A. F., Spreadbury C. L., (1998) J. Bacteriol. 184:801-808Kingston A. E., Salgame P. R., Mitchison N.A., Colston M. J. (1987) Infect. Immun 55,3149-3154Yuan Y., Crane D. D., Barry C. E. III (1996) J Bacteriol178: 4484-4492。

1,4,5-三磷酸肌醇受体与神经变性疾病

1，4，5-三磷酸肌醇受体与神经变性疾病赵吉利1，岳雅蓉1，张鑫1，杜文倩1，王云霞1综述，薛慧2，项文平2，孟天予2审校摘要：1，4，5-三磷酸肌醇受体（inositol 1，4，5-trisphosphate receptors，IP3Rs）是细胞内质网上的钙离子（cal‑cium ion，Ca2+）通道，通过调控Ca2+参与细胞生物学功能，是维持中枢神经系统正常功能的关键分子。

近年来，越来越多的研究发现，IP3Rs结构和功能异常与神经变性疾病如阿尔茨海默病、帕金森病、亨廷顿病、脊髓小脑共济失调等的发病机制密切相关，这些结构和功能异常如何影响IP3Rs功能，及相关钙信号，并且如何在这些疾病的发病和严重程度中发挥作用，仍尚不清楚。

IP3Rs如何在神经变性疾病中发挥作用将于本文中进行综述。

关键词：1，4，5-三磷酸肌醇受体；钙离子；神经变性疾病；认知障碍中图分类号：R741 文献标识码：AInositol 1，4，5-trisphosphate receptors and neurodegenerative diseases ZHAO Jili，YUE Yarong，ZHANG Xin，et al.（Central School of Clinical Medicine，Baotou Medical College，Inner Mongolia University of Science and Technology，Baotou 014040，China）Abstract：Inositol 1，4，5-trisphosphate receptor （IP3R），which is a calcium ion （Ca2+） channel in the endoplasmic re‑ticulum，participates in cellular biological functions through regulating the Ca2+ signal，and it is a key molecule in maintaining the normal function of the central nervous system. In recent years，more and more studies have found that the structural and functional abnormalities of IP3Rs are closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease，Parkinson disease，Huntington disease，and spinocerebellar ataxia. However，it remains unclear how these structural and functional abnormalities affect the function of IP3Rs and the related calcium signal as well as the pathogenesis and sever‑ity of neurodegenerative diseases. This paper reviews the role of IP3Rs in neurodegenerative diseases.Key words：Inositol 1，4，5-trisphosphate receptor；Calcium ion；Neurodegenerative disease；Cognitive disorder1，4，5-三磷酸肌醇受体（inositol 1，4，5-trisphos‑phate receptors，IP3Rs）是一种位于内质网上的配体门控的Ca2+通道，1998年Supattapone等人［1］首次在大鼠小脑中发现IP3Rs，其广泛表达于单细胞原生动物在内的动物细胞中，通过调节内质网中Ca2+的释放，产生钙信号。

德谷门冬双胰岛素注射液治疗2_型糖尿病临床效果及安全性探讨

DOI：10.16658/ki.1672-4062.2023.17.098德谷门冬双胰岛素注射液治疗2型糖尿病临床效果及安全性探讨林生，谢平，陈予福州市长乐区人民医院内分泌科，福建福州350200[摘要]目的研究德谷门冬双胰岛素注射液治疗2型糖尿病的临床效果及安全性。

方法选取于2022年7月—2023年4月福州市长乐区人民医院收治的2型糖尿病患者98例为研究对象，采用随机抓阄法分为两组，每组49例。

两组均联用常规降糖药物治疗，对照组采用甘精胰岛素注射液治疗，观察组采用德谷门冬双胰岛素注射液治疗。

对比两组临床治疗效果、临床症状好转时间和胰岛素用量情况、糖代谢指标、胰岛素功能指标、不良反应发生情况、心血管不良事件发生情况。

结果观察组总有效率高于对照组，差异有统计学意义（P<0.05）。

观察组尿酮体转阴时间、血糖达标时间、胰岛素用量均优于对照组，差异有统计学意义（P< 0.05）。

观察组空腹血糖、餐后2 h血糖、糖化血红蛋白均低于对照组，差异有统计学意义（P<0.05）。

观察组胰岛β细胞功能指数高于对照组，胰岛素抵抗指数、空腹胰岛素低于对照组，差异有统计学意义（P<0.05）。

两组恶心呕吐、倦怠乏力、低血糖总发生率比较，差异无统计学意义（P>0.05）。

两组心绞痛、心力衰竭总发生率比较，差异无统计学意义（P>0.05）。

结论德谷门冬双胰岛素注射液治疗2型糖尿病临床效果显著优于甘精胰岛素注射液，但是治疗安全性无显著变化。

[关键词] 2型糖尿病；德谷门冬双胰岛素注射液；不良反应；心血管不良事件[中图分类号] R59 [文献标识码] A [文章编号] 1672-4062（2023）09（a）-0098-04Discussion on the Clinical Effect and Safety of Insulin Degludec and Insu⁃lin Aspart Injection in the Treatment of Type 2 Diabetes MellitusLIN Sheng, XIE Ping, CHEN YuDepartment of Endocrinology, Changle District People's Hospital, Fuzhou, Fujian Province, 350200 China[Abstract] Objective To study the clinical effect and safety of insulin degludec and insulin aspart injection in the treatment of type 2 diabetes mellitus. Methods A total of 98 patients with type 2 diabetes admitted to Fuzhou Changle District People's Hospital from July 2022 to April 2023 were selected as the study objects and divided into two groups with 49 cases in each group by random lottery method. Both groups were treated with conventional hypoglycemic drugs, the control group was treated with insulin glargine injection, and the observation group was treated with Degu asparton double insulin injection. The clinical therapeutic effect, time of improvement of clinical symptoms, insulin dosage, glucose metabolism index, insulin function index, occurrence of adverse reactions and cardiovascular adverse events were compared between the two groups. Results The total effective rate of the observation group was higher than that of the control group, and the difference was statistically significant (P<0.05). The time of urine ketone body turning negative, blood glucose reaching standard and insulin dosage in observation group were better than those in control group, and the differences were statistically significant (P<0.05). Fasting plasma glucose, 2-hour postprandial blood glucose and glycated hemoglobin in the observation group were lower than those in the control group, and the differences were statistically significant (P<0.05). The function index of islet β cells in observation group was higher than that in control group, the insulin resistance index and fasting insulin was lower than that in control group, the dif⁃ference was statistically significant (P<0.05). There was no statistically significant difference in the total incidence of [作者简介]林生（1981-），男，本科，副主任医师，研究方向为糖尿病及其并发症的相关临床研究。

BIBR 1532_端粒酶新型的选择性抑制剂_321674-73-1_Apexbio

产品说明书
化学性质
产品名: Cas No.: 分子量: 分子式:
BIBR 1532 321674-73-1 331.36 C21H17NO3
产品名: BIBR 1532 修订日期: 6/30/2016
化学名: SMILES: 溶解性: 储存条件: 一般建议:
运输条件:
2-[[(E)-3-naphthalen-2-ylbut-2-enoyl]amino]benzoic acid
ApexBio Technology
和三氧化二砷抑制细胞增殖能力和端粒酶活性[3]。
参考文献: [1]. Damm, K.; Hemmann, U.; Garin-Chesa, P.; Hauel, N.; Kauffman, I.; Priepke, H.; Niestroj, C.; Daiber, C.; Enenkel, B.; Guilliard, B.; Lauritsch, I.; Muller, E.; Pascolo, E.; Sauter, G.; Pantic, M.; Martens, U. M.; Wenz, C.; Linger, J.; Kraut, N.; Rettig, W. J.;Schnapp, A. A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J. 2001, 20, 69586968. [2]. Bashash D1, Ghaffari SH, Mirzaee R, Alimoghaddam K, Ghavamzadeh A. Telomerase inhibition by non-nucleosidic compound BIBR1532 causes rapid cell death in pre-B acute lymphoblastic leukemia cells. Leuk Lymphoma. 2013 Mar;54[4]:561-8. doi: 10.3109/10428194.2012.704034. Epub 2012 Sep 28. [3]. Bashash D1, Ghaffari SH, Zaker F, Kazerani M, Hezave K, Hassani S, Rostami M, Alimoghaddam K, Ghavamzadeh A. Anticancer Agents Med Chem. 2013 Sep;13(7):1115-25. BIBR 1532 increases arsenic trioxide-mediated apoptosis in acute promyelocytic leukemia cells: therapeutic potential fo应用

小分子抑制剂、激动剂、拮抗剂--DNA损伤DNA修复信号通路

DNA损伤/DNA修复人类细胞中的DNA每天会受到数以万计的外源性损伤（化学污染、紫外线、电离辐射、烷基化/甲基化等引起）和内源性损伤（碱的氧化、烷基化、水解等引起）。

损伤后DNA会发生单链和双链断裂，未修复的DNA损伤会导致细胞衰老、凋亡和恶性肿瘤等等。

为了避免此类情况，激发了细胞的DNA损伤反应（DDR）。

DNA损伤反应（DDR）能够检测DNA的损伤并介导其修复，包含DNA损伤、细胞周期停滞、DNA复制调控、DNA损伤修复旁路等一系列通路的调控，以维持基因组的稳定性和细胞活力。

异常的DNA损伤反应与衰老、癌症和免疫疾病有关。

DNA损伤/DNA修复通路转导过程当DNA受到外源性或内源性损伤后，会发生单链和双链断裂，DNA损伤反应会被激活。

DNA双链断裂激活DNA-PK与ATM/ATR激酶。

DNA-PK诱导DNA修复，涉及错配、碱基切除、核苷酸切除修复等多种机制。

RPA、Rad51和fanconi贫血蛋白等也可直接用于DNA修复。

ATM/ATR激酶经过两个并行级联最终将CyclinB-cdc2复合体失活：1）ATM/ATR激酶激活Chk2激酶，Chk2激酶磷酸化并使失活Cdc25，同时也通过Chk1抑制Cdc25，从而阻止cdc2的激活，快速抑制细胞有丝分裂从G2期进入M期。

此外，ATR通过刺激Cdk1抑制激酶Wee1来抑制Cyclinb/Cdk1的激活，防止DNA损伤的细胞进入有丝分裂。

2）另一级联反应稍慢，Chk2激酶磷酸化p53，使其从MDM2和MDM4(MdmX)上分离，激活p53下游调节基因，从而抑制CyclinB-cdc2复合体活性或将其从细胞核中排出。

p300/PCAF对p53乙酰化可进一步增强其转录能力。

同时，p53也可诱导细胞凋亡。

DNA单链断裂后，激活ATR激酶，ATR通过Chk1进一步激活Cdc25A。

Cdc25A是一种CDK2激活所需的磷酸酶。

CDK2抑制周期素E/A，使有丝分裂无法从G1期进入S期。

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