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新型抗真菌药物--卡泊芬净
高磊
【期刊名称】《临床药物治疗杂志》
【年(卷),期】2005(003)005
【摘要】@@ 卡泊芬净(caspofungin,商品名科赛斯,cansidas)是迄今获准上市的第一个棘白霉素(echinocandin)类新型抗真菌药物,用于治疗念珠菌病、对标准疗法无效或不能耐受患者的侵袭性曲霉菌病.
【总页数】5页(P55-58,54)
【作者】高磊
【作者单位】北京大学临床药理研究所,北京,100083
【正文语种】中文
【中图分类】R978.5
【相关文献】
1.新型抗真菌药卡泊芬净 [J], 王曾礼;罗凤鸣
2.加拿大市场上40年来第一个新型抗真菌药卡泊芬净 [J],
3.新型抗真菌药物卡泊芬净及其在临床的应用 [J], 陈辉;刘维达
4.新型抗真菌药物卡泊芬净 [J], 纪立伟;谭玲;傅得兴
5.棘白菌素类抗真菌药物卡泊芬净的临床应用研究 [J], 李群英
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①苏州市第九人民医院 江苏 苏州 215200通信作者：荣飞普拉洛芬滴眼液联合奥洛他定滴眼液治疗过敏性结膜炎的效果陈黎珺① 石彩凤① 荣飞①【摘要】 目的：探讨普拉洛芬滴眼液联合奥洛他定滴眼液治疗过敏性结膜炎（allergic conjunctivitis，AC）的效果。
方法：选取2018年1月—2023年1月苏州市第九人民医院眼科收治的100例AC 患者。
根据抽签随机将其分为观察组和对照组，各50例。
对照组给予盐酸奥洛他定滴眼液，观察组在对照组基础上给予普拉洛芬滴眼液。
比较两组临床疗效，治疗前后泪膜稳定性及角膜上皮损伤情况、免疫功能、泪液相关指标及不良反应。
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）。
治疗后，两组泪膜破裂时间（break-up time，BUT）均增加，角膜荧光素染色实验（corneal fluorescein staining experiment，FL）均降低，观察组BUT 长于对照组，FL 低于对照组，差异有统计学意义（P <0.05）。
治疗后，两组免疫球蛋白A（immunoglobulin A，IgA）、免疫球蛋白G（immunoglobulin G，IgG）、免疫球蛋白E（immunoglobulin E，IgE）水平均降低，观察组IgA、IgG、IgE 水平均低于对照组，差异有统计学意义（P <0.05）。
治疗后，两组嗜酸性细胞阳离子蛋白（eosinophil cationic protein，ECP）、组胺（histamine，HA）、白三烯B4（leukotriene B4，LTB4）水平均降低，且观察组ECP、HA、LTB4水平均低于对照组，差异有统计学意义（P <0.05）。
两组不良反应发生率比较，差异无统计学意义（P >0.05）。
结论：普拉洛芬滴眼液联合奥洛他定滴眼液可显著改善AC 患者临床症状，降低泪液相关指标水平，且安全性良好。
消退素在炎症消退中的研究进展及其在牙髓炎症调控中的应用徐华兴;张旗【摘要】炎症消退是一个主动的程序化过程.由内源性脂质调控介质控制炎症反应,促进炎症及时消退对于防止炎症反应过度至关重要.消退素是最近发现的一类具有较强抗炎作用的内源性脂质调控介质.研究表明消退素可以限制中性粒细胞的过度活化和募集、促进凋亡和坏死细胞的清除、并且对结构细胞可起到保护作用,从而加速炎症的消退,恢复组织稳态.局部应用消退素,炎症细胞对牙髓和根尖周组织的浸润明显减少.【期刊名称】《口腔医学》【年(卷),期】2018(038)008【总页数】4页(P743-746)【关键词】炎症消退;消退素;牙髓炎【作者】徐华兴;张旗【作者单位】同济大学附属口腔医院牙体牙髓科,上海 200072;上海牙组织修复与再生工程技术研究中心,上海 200072;同济大学附属口腔医院牙体牙髓科,上海200072;上海牙组织修复与再生工程技术研究中心,上海 200072【正文语种】中文【中图分类】R781.3在牙髓炎的病理发展过程，冠髓的局部炎症可持续相当长时间而无明显的根髓循环[1-2]。
此种情况下的活髓保存，关键在于对感染的控制以及牙髓炎症的调控。
而对于炎症的调控，传统的观念主要关注于对炎症代谢产物的抑制，从而达到抗炎的效果，然而与此同样重要却一直被忽略的是炎症发生之后，如何促进炎症的消退[3]。
近年来，研究证实炎症消退是由内源性促消退介质(pro-resolving mediator)调控的程序化过程。
这些内源性促消退介质包括：脂质体、蛋白质(如:膜联蛋白A1)以及气体分子(如：硫化氢、一氧化碳)等。
其中脂质体的代谢在炎症消退过程中发挥着关键作用。
利用高通量的脂质组学(lipidomics)技术，已经成功分离这些脂质体，并将它们统一命名为特异性促消退脂质体介质(Specialized pro-resolvin lipid mediator, SPM)[4]。
HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFLUOXETINE HClC17H18F3NO•HClM.W. = 345.79CAS — 59333-67-4STABILITY INDICATINGA S S A Y V A L I D A T I O NMethod is suitable for:ýIn-process controlþProduct ReleaseþStability indicating analysis (Suitability - US/EU Product) CAUTIONFLUOXETINE HYDROCHLORIDE IS A HAZARDOUS CHEMICAL AND SHOULD BE HANDLED ONLY UNDER CONDITIONS SUITABLE FOR HAZARDOUS WORK.IT IS HIGHLY PRESSURE SENSITIVE AND ADEQUATE PRECAUTIONS SHOULD BE TAKEN TO AVOID ANY MECHANICAL FORCE (SUCH AS GRINDING, CRUSHING, ETC.) ON THE POWDER.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationTABLE OF CONTENTS INTRODUCTION........................................................................................................................ PRECISION............................................................................................................................... System Repeatability ................................................................................................................ Method Repeatability................................................................................................................. Intermediate Precision .............................................................................................................. LINEARITY................................................................................................................................ RANGE...................................................................................................................................... ACCURACY............................................................................................................................... Accuracy of Standard Injections................................................................................................ Accuracy of the Drug Product.................................................................................................... VALIDATION OF FLUOXETINE HCl AT LOW CONCENTRATION........................................... Linearity at Low Concentrations................................................................................................. Accuracy of Fluoxetine HCl at Low Concentration..................................................................... System Repeatability................................................................................................................. Quantitation Limit....................................................................................................................... Detection Limit........................................................................................................................... VALIDATION FOR META-FLUOXETINE HCl (POSSIBLE IMPURITIES).................................. Meta-Fluoxetine HCl linearity at 0.05% - 1.0%........................................................................... Detection Limit for Fluoxetine HCl.............................................................................................. Quantitation Limit for Meta Fluoxetine HCl................................................................................ Accuracy for Meta-Fluoxetine HCl ............................................................................................ Method Repeatability for Meta-Fluoxetine HCl........................................................................... Intermediate Precision for Meta-Fluoxetine HCl......................................................................... SPECIFICITY - STABILITY INDICATING EVALUATION OF THE METHOD............................. FORCED DEGRADATION OF FINISHED PRODUCT AND STANDARD..................................1. Unstressed analysis...............................................................................................................2. Acid Hydrolysis stressed analysis..........................................................................................3. Base hydrolysis stressed analysis.........................................................................................4. Oxidation stressed analysis...................................................................................................5. Sunlight stressed analysis.....................................................................................................6. Heat of solution stressed analysis.........................................................................................7. Heat of powder stressed analysis.......................................................................................... System Suitability stressed analysis.......................................................................................... Placebo...................................................................................................................................... STABILITY OF STANDARD AND SAMPLE SOLUTIONS......................................................... Standard Solution...................................................................................................................... Sample Solutions....................................................................................................................... ROBUSTNESS.......................................................................................................................... Extraction................................................................................................................................... Factorial Design......................................................................................................................... CONCLUSION...........................................................................................................................ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationBACKGROUNDTherapeutically, Fluoxetine hydrochloride is a classified as a selective serotonin-reuptake inhibitor. Effectively used for the treatment of various depressions. Fluoxetine hydrochloride has been shown to have comparable efficacy to tricyclic antidepressants but with fewer anticholinergic side effects. The patent expiry becomes effective in 2001 (US). INTRODUCTIONFluoxetine capsules were prepared in two dosage strengths: 10mg and 20mg dosage strengths with the same capsule weight. The formulas are essentially similar and geometrically equivalent with the same ingredients and proportions. Minor changes in non-active proportions account for the change in active ingredient amounts from the 10 and 20 mg strength.The following validation, for the method SI-IAG-206-02 , includes assay and determination of Meta-Fluoxetine by HPLC, is based on the analytical method validation SI-IAG-209-06. Currently the method is the in-house method performed for Stability Studies. The Validation was performed on the 20mg dosage samples, IAG-21-001 and IAG-21-002.In the forced degradation studies, the two placebo samples were also used. PRECISIONSYSTEM REPEATABILITYFive replicate injections of the standard solution at the concentration of 0.4242mg/mL as described in method SI-IAG-206-02 were made and the relative standard deviation (RSD) of the peak areas was calculated.SAMPLE PEAK AREA#15390#25406#35405#45405#55406Average5402.7SD 6.1% RSD0.1ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::PRECISION - Method RepeatabilityThe full HPLC method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method repeated six times and the relative standard deviation (RSD) was calculated.SAMPLENumber%ASSAYof labeled amountI 96.9II 97.8III 98.2IV 97.4V 97.7VI 98.5(%) Average97.7SD 0.6(%) RSD0.6PRECISION - Intermediate PrecisionThe full method as described in SI-IAG-206-02 was carried-out on the finished product IAG-21-001 for the 20mg dosage form. The method was repeated six times by a second analyst on a different day using a different HPLC instrument. The average assay and the relative standard deviation (RSD) were calculated.SAMPLENumber% ASSAYof labeled amountI 98.3II 96.3III 94.6IV 96.3V 97.8VI 93.3Average (%)96.1SD 2.0RSD (%)2.1The difference between the average results of method repeatability and the intermediate precision is 1.7%.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationLINEARITYStandard solutions were prepared at 50% to 200% of the nominal concentration required by the assay procedure. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over the concentration range required. Y-Intercept was found to be insignificant.RANGEDifferent concentrations of the sample (IAG-21-001) for the 20mg dosage form were prepared, covering between 50% - 200% of the nominal weight of the sample.Conc. (%)Conc. (mg/mL)Peak Area% Assayof labeled amount500.20116235096.7700.27935334099.21000.39734463296.61500.64480757797.52000.79448939497.9(%) Average97.6SD 1.0(%) RSD 1.0ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::RANGE (cont.)The results demonstrate linearity as well over the specified range.Correlation coefficient (RSQ)0.99981 Slope11808.3Y -Interceptresponse at 100%* 100 (%) 0.3%ACCURACYACCURACY OF STANDARD INJECTIONSFive (5) replicate injections of the working standard solution at concentration of 0.4242mg/mL, as described in method SI-IAG-206-02 were made.INJECTIONNO.PEAK AREA%ACCURACYI 539299.7II 540599.9III 540499.9IV 5406100.0V 5407100.0Average 5402.899.9%SD 6.10.1RSD, (%)0.10.1The percent deviation from the true value wasdetermined from the linear regression lineHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::ACCURACY OF THE DRUG PRODUCTAdmixtures of non-actives (placebo, batch IAG-21-001 ) with Fluoxetine HCl were prepared at the same proportion as in a capsule (70%-180% of the nominal concentration).Three preparations were made for each concentration and the recovery was calculated.Conc.(%)Placebo Wt.(mg)Fluoxetine HCl Wt.(mg)Peak Area%Accuracy Average (%)70%7079.477.843465102.27079.687.873427100.77079.618.013465100.0101.0100%10079.6211.25476397.910080.8011.42491799.610079.6011.42485498.398.6130%13079.7214.90640599.413080.3114.75632899.213081.3314.766402100.399.618079.9920.10863699.318079.3820.45879499.418080.0820.32874899.599.4Placebo, Batch Lot IAG-21-001HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION OF FLUOXETINE HClAT LOW CONCENTRATIONLINEARITY AT LOW CONCENTRATIONSStandard solution of Fluoxetine were prepared at approximately 0.02%-1.0% of the working concentration required by the method SI-IAG-206-02. Linear regression analysis demonstrated acceptability of the method for quantitative analysis over this range.ACCURACY OF FLUOXETINE HCl AT LOW CONCENTRATIONThe peak areas of the standard solution at the working concentration were measured and the percent deviation from the true value, as determined from the linear regression was calculated.SAMPLECONC.µg/100mLAREA FOUND%ACCURACYI 470.56258499.7II 470.56359098.1III 470.561585101.3IV 470.561940100.7V 470.56252599.8VI 470.56271599.5(%) AverageSlope = 132.7395299.9SD Y-Intercept = -65.872371.1(%) RSD1.1HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSystem RepeatabilitySix replicate injections of standard solution at 0.02% and 0.05% of working concentration as described in method SI-IAG-206-02 were made and the relative standard deviation was calculated.SAMPLE FLUOXETINE HCl AREA0.02%0.05%I10173623II11503731III10103475IV10623390V10393315VI10953235Average10623462RSD, (%) 5.0 5.4Quantitation Limit - QLThe quantitation limit ( QL) was established by determining the minimum level at which the analyte was quantified. The quantitation limit for Fluoxetine HCl is 0.02% of the working standard concentration with resulting RSD (for six injections) of 5.0%. Detection Limit - DLThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected. The detection limit of Fluoxetine HCl is about 0.01% of the working standard concentration.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::VALIDATION FOR META-FLUOXETINE HCl(EVALUATING POSSIBLE IMPURITIES)Meta-Fluoxetine HCl linearity at 0.05% - 1.0%Relative Response Factor (F)Relative response factor for Meta-Fluoxetine HCl was determined as slope of Fluoxetine HCl divided by the slope of Meta-Fluoxetine HCl from the linearity graphs (analysed at the same time).F =132.7395274.859534= 1.8Detection Limit (DL) for Fluoxetine HClThe detection limit (DL) was established by determining the minimum level at which the analyte was reliably detected.Detection limit for Meta Fluoxetine HCl is about 0.02%.Quantitation Limit (QL) for Meta-Fluoxetine HClThe QL is determined by the analysis of samples with known concentration of Meta-Fluoxetine HCl and by establishing the minimum level at which the Meta-Fluoxetine HCl can be quantified with acceptable accuracy and precision.Six individual preparations of standard and placebo spiked with Meta-Fluoxetine HCl solution to give solution with 0.05% of Meta Fluoxetine HCl, were injected into the HPLC and the recovery was calculated.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES].Approx.Conc.(%)Known Conc.(µg/100ml)Area in SpikedSampleFound Conc.(µg/100mL)Recovery (%)0.0521.783326125.735118.10.0521.783326825.821118.50.0521.783292021.55799.00.0521.783324125.490117.00.0521.783287220.96996.30.0521.783328526.030119.5(%) AVERAGE111.4SD The recovery result of 6 samples is between 80%-120%.10.7(%) RSDQL for Meta Fluoxetine HCl is 0.05%.9.6Accuracy for Meta Fluoxetine HClDetermination of Accuracy for Meta-Fluoxetine HCl impurity was assessed using triplicate samples (of the drug product) spiked with known quantities of Meta Fluoxetine HCl impurity at three concentrations levels (namely 80%, 100% and 120% of the specified limit - 0.05%).The results are within specifications:For 0.4% and 0.5% recovery of 85% -115%For 0.6% recovery of 90%-110%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::META-FLUOXETINE HCl[RECOVERY IN SPIKED SAMPLES]Approx.Conc.(%)Known Conc.(µg/100mL)Area in spikedSample Found Conc.(µg/100mL)Recovery (%)[0.4%]0.4174.2614283182.66104.820.4174.2614606187.11107.370.4174.2614351183.59105.36[0.5%]0.5217.8317344224.85103.220.5217.8316713216.1599.230.5217.8317341224.81103.20[0.6%]0.6261.3918367238.9591.420.6261.3920606269.81103.220.6261.3920237264.73101.28RECOVERY DATA DETERMINED IN SPIKED SAMPLESHPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::REPEATABILITYMethod Repeatability - Meta Fluoxetine HClThe full method (as described in SI-IAG-206-02) was carried out on the finished drug product representing lot number IAG-21-001-(1). The HPLC method repeated serially, six times and the relative standard deviation (RSD) was calculated.IAG-21-001 20mg CAPSULES - FLUOXETINESample% Meta Fluoxetine % Meta-Fluoxetine 1 in Spiked Solution10.0260.09520.0270.08630.0320.07740.0300.07450.0240.09060.0280.063AVERAGE (%)0.0280.081SD 0.0030.012RSD, (%)10.314.51NOTE :All results are less than QL (0.05%) therefore spiked samples with 0.05% Meta Fluoxetine HCl were injected.HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationED. N0: 04Effective Date:APPROVED::Intermediate Precision - Meta-Fluoxetine HClThe full method as described in SI-IAG-206-02 was applied on the finished product IAG-21-001-(1) .It was repeated six times, with a different analyst on a different day using a different HPLC instrument.The difference between the average results obtained by the method repeatability and the intermediate precision was less than 30.0%, (11.4% for Meta-Fluoxetine HCl as is and 28.5% for spiked solution).IAG-21-001 20mg - CAPSULES FLUOXETINESample N o:Percentage Meta-fluoxetine% Meta-fluoxetine 1 in spiked solution10.0260.06920.0270.05730.0120.06140.0210.05850.0360.05560.0270.079(%) AVERAGE0.0250.063SD 0.0080.009(%) RSD31.514.51NOTE:All results obtained were well below the QL (0.05%) thus spiked samples slightly greater than 0.05% Meta-Fluoxetine HCl were injected. The RSD at the QL of the spiked solution was 14.5%HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSPECIFICITY - STABILITY INDICATING EVALUATIONDemonstration of the Stability Indicating parameters of the HPLC assay method [SI-IAG-206-02] for Fluoxetine 10 & 20mg capsules, a suitable photo-diode array detector was incorporated utilizing a commercial chromatography software managing system2, and applied to analyze a range of stressed samples of the finished drug product.GLOSSARY of PEAK PURITY RESULT NOTATION (as reported2):Purity Angle-is a measure of spectral non-homogeneity across a peak, i.e. the weighed average of all spectral contrast angles calculated by comparing all spectra in the integrated peak against the peak apex spectrum.Purity Threshold-is the sum of noise angle3 and solvent angle4. It is the limit of detection of shape differences between two spectra.Match Angle-is a comparison of the spectrum at the peak apex against a library spectrum.Match Threshold-is the sum of the match noise angle3 and match solvent angle4.3Noise Angle-is a measure of spectral non-homogeneity caused by system noise.4Solvent Angle-is a measure of spectral non-homogeneity caused by solvent composition.OVERVIEWT he assay of the main peak in each stressed solution is calculated according to the assay method SI-IAG-206-02, against the Standard Solution, injected on the same day.I f the Purity Angle is smaller than the Purity Threshold and the Match Angle is smaller than the Match Threshold, no significant differences between spectra can be detected. As a result no spectroscopic evidence for co-elution is evident and the peak is considered to be pure.T he stressed condition study indicated that the Fluoxetine peak is free from any appreciable degradation interference under the stressed conditions tested. Observed degradation products peaks were well separated from the main peak.1® PDA-996 Waters™ ; 2[Millennium 2010]ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationFORCED DEGRADATION OF FINISHED PRODUCT & STANDARD 1.UNSTRESSED SAMPLE1.1.Sample IAG-21-001 (2) (20mg/capsule) was prepared as stated in SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 98.5%.SAMPLE - UNSTRESSEDFluoxetine:Purity Angle:0.075Match Angle:0.407Purity Threshold:0.142Match Threshold:0.4251.2.Standard solution was prepared as stated in method SI-IAG-206-02 and injected into the HPLC system. The calculated assay is 100.0%.Fluoxetine:Purity Angle:0.078Match Angle:0.379Purity Threshold:0.146Match Threshold:0.4272.ACID HYDROLYSIS2.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of conc. HCl was added to this solution The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system after filtration.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 98.8%.SAMPLE- ACID HYDROLYSISFluoxetine peak:Purity Angle:0.055Match Angle:0.143Purity Threshold:0.096Match Threshold:0.3712.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask. 20mL Diluent were added. 2mL of conc. HCl were added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with NaOH 10N, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 97.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSTANDARD - ACID HYDROLYSISFluoxetine peak:Purity Angle:0.060Match Angle:0.060Purity Threshold:0.099Match Threshold:0.3713.BASE HYDROLYSIS3.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02 : An amount equivalent to 20mg Fluoxetine was weight into a 50mL volumetric flask. 20mL Diluent was added and the solution sonicated for 10 minutes. 1mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH = 5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease. Assay result obtained - 99.3%.SAMPLE - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.063Match Angle:0.065Purity Threshold:0.099Match Threshold:0.3623.2.Standard stock solution was prepared as per method SI-IAG-206-02 : About 22mg Fluoxetine HCl was weighed into a 50mL volumetric flask. 20mL Diluent was added. 2mL of 5N NaOH was added to this solution. The solution was allowed to stand for 18 hours, then adjusted to about pH=5.5 with 5N HCl, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity did NOT decrease - 99.5%.STANDARD - BASE HYDROLYSISFluoxetine peak:Purity Angle:0.081Match Angle:0.096Purity Threshold:0.103Match Threshold:0.3634.OXIDATION4.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as per method SI-IAG-206-02. An equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent added and the solution sonicated for 10 minutes.1.0mL of 30% H2O2 was added to the solution and allowed to stand for 5 hours, then made up to volume with Diluent, filtered and injected into HPLC system.Fluoxetine peak intensity decreased to 95.2%.ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSAMPLE - OXIDATIONFluoxetine peak:Purity Angle:0.090Match Angle:0.400Purity Threshold:0.154Match Threshold:0.4294.2.Standard solution was prepared as in method SI-IAG-206-02 : about 22mg Fluoxetine HCl were weighed into a 50mL volumetric flask and 25mL Diluent were added. 2mL of 30% H2O2 were added to this solution which was standing for 5 hours, made up to volume with Diluent and injected into the HPLC system.Fluoxetine peak intensity decreased to 95.8%.STANDARD - OXIDATIONFluoxetine peak:Purity Angle:0.083Match Angle:0.416Purity Threshold:0.153Match Threshold:0.4295.SUNLIGHT5.1.Sample solution of IAG-21-001 (2) (20mg/capsule) was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1hour. The BST was set to 35°C and the ACT was 45°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak decreased to 91.2% and the dark control solution showed assay of 97.0%. The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak was observed at RRT of 1.5 (2.7%).The total percent of Fluoxetine peak with the degradation peak is about 93.9%.SAMPLE - SUNLIGHTFluoxetine peak:Purity Angle:0.093Match Angle:0.583Purity Threshold:0.148Match Threshold:0.825 ED. N0: 04Effective Date:APPROVED::HPLC ASSAY with DETERMINATION OF META-FLUOXETINE HCl.ANALYTICAL METHOD VALIDATION10 and 20mg Fluoxetine Capsules HPLC DeterminationSUNLIGHT (Cont.)5.2.Working standard solution was prepared as in method SI-IAG-206-02 . The solution was exposed to 500w/hr. cell sunlight for 1.5 hour. The BST was set to 35°C and the ACT was 42°C. The vials were placed in a horizontal position (4mm vials, National + Septum were used). A Dark control solution was tested. A 2%w/v quinine solution was used as the reference absorbance solution.Fluoxetine peak was decreased to 95.2% and the dark control solution showed assay of 99.5%.The difference in the absorbance in the quinine solution is 0.4227AU.Additional peak were observed at RRT of 1.5 (2.3).The total percent of Fluoxetine peak with the degradation peak is about 97.5%. STANDARD - SUNLIGHTFluoxetine peak:Purity Angle:0.067Match Angle:0.389Purity Threshold:0.134Match Threshold:0.8196.HEAT OF SOLUTION6.1.Sample solution of IAG-21-001-(2) (20 mg/capsule) was prepared as in method SI-IAG-206-02 . Equivalent to 20mg Fluoxetine was weighed into a 50mL volumetric flask. 20mL Diluent was added and the solution was sonicated for 10 minutes and made up to volume with Diluent. 4mL solution was transferred into a suitable crucible, heated at 105°C in an oven for 2 hours. The sample was cooled to ambient temperature, filtered and injected into the HPLC system.Fluoxetine peak was decreased to 93.3%.SAMPLE - HEAT OF SOLUTION [105o C]Fluoxetine peak:Purity Angle:0.062Match Angle:0.460Purity Threshold:0.131Match Threshold:0.8186.2.Standard Working Solution (WS) was prepared under method SI-IAG-206-02 . 4mL of the working solution was transferred into a suitable crucible, placed in an oven at 105°C for 2 hours, cooled to ambient temperature and injected into the HPLC system.Fluoxetine peak intensity did not decrease - 100.5%.ED. N0: 04Effective Date:APPROVED::。
苯丙胺类滥用药物简述作者：许荣富， 姚付军， 张茜， Xu Rongfu， Yao Fujun， Zhang Qian作者单位：首都师范大学化学系,北京,100037刊名：北京教育学院学报(自然科学版)英文刊名：JOURNAL OF BEIJING INSTITUTE OF EDUCATION(NATURAL SCIENCE)年，卷(期)：2007,2(3)1.Forsling M L;Falion J K;hah D The effect of 3,4-Methylenedloxymethamphetamine (MDMA,"ecstasy") and its metabolites on neurohypophysial hormone release from the isolated rat hypothalamus[外文期刊] 2002(03)2.郭菘;杜万君;张大明甲基苯丙胺类混合物-摇头丸滥用方式及其对精神活动的影响[期刊论文]-中国药物依赖性杂志 2000(02)3.Cheng S;Nolte H;Otton S V Simultaneous gas chromatographic determination ofmethamphetamine,amphetamine and their phydroxylated metabolites in plasma and urine[外文期刊] 19974.李金苯丙胺类物质及其检测[期刊论文]-中国药物依赖性杂志 2003(01)5.Gianpiero Boatto;Maria Virginia Faedda;Amedeo Pau Determination of amphetamines in human whole blood by capillary electrophoresis with photodiode array detection[外文期刊] 2002(6)6.An-Shu liau;Ju-Tsungg Liu;Li-Chan Lin Optimization of a simple method for the chiral separation of methamphetamine and related compounds in clandestine tablets and urine samples by β-cyclodextrine modified capillary electrophoresis:a complementary method to GCMS[外文期刊] 2003(1)7.Véronique Piette;Frans Parmentier Analysis of illicit amphetamine seizures by capillary zone electrophoresis 20028.Emmanuel Varesio;Jean-Luc Veuthey Chiral separation of amphetamines by high-performance capillary electrophoresis 19959.Pizarro N;Ortuno J;Farre M Determination of MDMA and its metabolites in blood and urine by gas chromatography-mass spectrometry and analysis of enantiomers by capillary electrophoresis[外文期刊] 2002(03)10.刘伟;沈敏SPME-GC/NPD法快速分析尿液中苯丙胺类化合物[期刊论文]-法医学杂志 1999(02)11.Knut Einar Rasmussen;Stig Pedersen-Bjergaard;Mette Krogh Development of a simple in-vial liquidphase microextraction device for drug analysis compatible with capillary gas chromatography,capillary electrophoresis and high-performance liquid chromatography[外文期刊] 2000 12.Yoo Jeong Heo;Yoon Sung Whang;Moon Kyo In Determination of enantiomeric amphetamines as metabolites of illicit amphetamines and selegiline in urine by capillary electrophoresis using modified β-cyclodextrin[外文期刊] 200013.Satoshi Chinaka;Scishi Tanaka;Nariaki Takayama Simultaneous chiral analysis of methamphetamine and related compounds by capillary electrophoresis[外文期刊] 2000(1)14.沈敏体内滥用药物分析 200315.王玫GDX-403固相萃取分析尿、血中安非他明类毒品 1999(02)17.Peter R Stout;Carl K Horn;Kevin L Klette Rapid simultaneous determination ofamphetamine,methamphetamine,3,4-methylenedioxyamphetemine,3,4-methylenedioxymethamphetarnine in urine by solid-phase extraction and GC-MS:a method optimized for high-volume laboratories 2002(01)18.沈敏;沈保华;向平血、尿中甲基苯丙胺以及代谢物产物苯丙胺的分析研究[期刊论文]-法医学杂志 1997(03)19.Nobuyuki Nagasawa;Mikio Yashiki;Yasumasa Iwasaki Rapid analysis of amphetamines in blood using head space-solid phase microextraction and selected ion monitoring[外文期刊] 199620.Kathryn S;Kalasinsky;Barry Levine Fourier transform infrared spectroscopy techniques for the analysis of drugs of abuse 199321.杨小红;田开珍;王峰高效液相色谱-二极管阵列检测法同时测定临床中毒患者血浆中的甲基苯丙胺及苯丙胺[期刊论文]-色谱 2003(09)22.C Cháfer-Pericás;P Campíns-Faleó;R Herráez-Hemández Application of solid-phase microextraction combined with derivatizafion to the determination of amphetaminesby liquid chromatography 200423.H P Hendrickson;A Milesi-Hallé;E M Laurenzana Development of a liquid chromatography-tandem mass spectrometric method for the determination of methamphetamine and amphetamine using small volumes of rat serum[外文期刊] 2004(2)24.F Sadeghipour;J L Veuthey Sensitive and selective determination of methylenedioxylated amphetamines by high-performance liquid chromatography with fluorimetrie detection[外文期刊]1997(1/2)25.Ming-Ren Fuha;Chiuan-Hung Haunga;Shiang-Ling Lin b Determination of free-form amphetamine in rat brain by ion-pair liquid chromatography-electrospray mass spectrometry with in vivo microdialysis[外文期刊] 200426.Rosa Herraez-Hernandez;Pilar Camp?ns-Falco Derivatization of ephedrine with o-phthaldialdehydefor liquid chromatography after treatment with sodium hypochlorite[外文期刊] 200027.Dinesh Talwar;Ian D Watson;Mike J Stewart Routine analysis of amphetamine class drugs as their naphthaquinone derivative in human urine by high-performance liquid chromtography[外文期刊] 1999 28.Y McAvoy;M D Cole;O Gueniat Analysis of amphetamines by supercritical fluid chromatography,high-Performance liquid chromatography,gas chromatography and capillary zone electrophoresis,apreliminary comparison[外文期刊] 199929.Palar Campims-Falco;Adela Sevillano-Cabeza;Carmen Molins -Legua Amphetamine and methamaphetamine determination in urine by reversed-phase high-performance liquid chromatography with simultaneous sample clean-up and derivatization with 1,2-naphthoquinone 4-sulphonate on solid-phase catridges[外文期刊] 199630.Katja Pihlainen a b;Risto Kostiainen b Effect of the eluent on enantiomer separation ofcontrolled drugs by liquid chromatography-ultraviolet absorbance detection-electrospray ionisation tandem mass spectrometry using vancomycin and native -cyclodextrin chiral stationary phases[外文期刊] 200431.Myung Ho Hyun;Sang Cheol Han;Bruce H Lipshutz Liquid chromatographic resolution of racemic32.Myung Ho Hyun;Jong Sung Jin;Hye Jin Koo Liquid chromatographic resolution of racemic amines and amino alcohols on a chiral stationary phase derived from crown ether[外文期刊] 199933.M Katagi;H Nishioka;K Nakajima Direct high-performance liquid chromatographic and high-performance liquid chromatographic -thermospray -mass spectrometric determination of enantiomers of methamphetamine and its main metabolites amphetamine and p-hydroxymethamphetamine in human urine[外文期刊] 199634.Chandrani Gunaratna;Peter T Kissinger Investigation of stereoselective metabolism of amphetamine in rat liver microsomes by microdialysis and liquid chromatography with precolumn chiral derivatization[外文期刊] 199835.Gianpiero Boatto;Maria Virginia Faedda;Amedeo Pau Determination of amphetamines in human whole blood by capillary electrophoresis with photodiode array detection[外文期刊] 2002(6)36.F P Smith;S Turrina;V Equisetto Complementary use of capillary zone electrophoresis and micellar electrokinetic capillary chromatography for mutual confirmation of results in forensic drug analysis [外文期刊] 1996(1/2)37.Tuulia Hy?tyl?inen;Heli Sirén;Marja -Liisa Riekkola Determination of morphine analogues,caffeine and amphetamine in biological fluids by capillary electrophoresis with the marker technique[外文期刊] 1996(1/2)38.Ulli Backofen;Frand-Michael Matysik;Werner Hoffmann Analysis of illicit drugs by nonaqueous capillary electrophoresis and electrochemical detection 200039.V Craige Trenerry;James Robertson;Robert J Wells Analysis of illicit amphetamine seizures by capillary electrophoresis[外文期刊] 1995(1)urent Geiser;Samir Cherkaoui;Jean -Luc Veuthey Simultaneous analysis of some amphetamine derivatives in urine by uonaqueous capillary electrophoresis coupled to electrospray ionization mass spectrometry[外文期刊] 200041.Ulli Backofen;Frand-Michael Matysik;Werner Hoffmann Analysis of illicit drugs by nonaqueous capillary electrophoresis and electrochemical detection 200042.Jeongeun Choi;Choonmi Kim;Myung Ja Choi Immunological analysis of methamphetamine antibody andits use for the detection of mehtamphetamine by capillary electrophoresis with laser-induced fluorescence[外文期刊] 199843.An-Shu Liau;Ju-Tsungg Liu;Li-Chan Lin Optimization of a simple method for the chiral separationof methamphetamine and related compounds in clandestine tablets and urine samples by β-cyclodextrine modified capillary electrophoresis:a complementary method to GCMS[外文期刊] 2003(1) 44.Iio R;Chinaka S;Takayama N Simultaneous chiral analysis of methamphetamine and related compounds by capillary electrophoresis/mass spectrometry using anionic cyclodextrin[外文期刊] 2005(01)45.Juraj Sevcík;Zdenek Stránsky;Benno A Ingelse Capillary electrophoretic enantioseparation of selegiline,methamphetamine and ephedrine using a neutral β-cyclodextrin epichlorhydrin polymer 1996 46.Yoo Jeong Heo;Yoon Sung Whang;Moon Kyo In Determination of enantiomeric amphetamines as。
·87·522105October抗骨质疏松胶囊治疗老年骨质疏松性髋部骨折近期疗效观察张上上，刘志刚，张鹏，毕梦娜，李钟，陈经勇（四川省骨科医院，四川成都610041）摘要：目的观察抗骨质疏松胶囊治疗老年骨质疏松性髋部骨折的近期临床疗效。
方法将我院接受治疗的130例老年骨质疏松性髋部骨折患者随机分为中医组与西医组各65例，在骨专科治疗基础上，西医组应用西药进行抗骨质疏松治疗，中医组应用抗骨质疏松胶囊治疗，对比两组患者骨折治疗效果、髋关节功能以及各项临床指标。
结果治疗前，两组患者髋关节功能评分（Harris ）、治疗优良率差异不明显（>0.05）；治疗结束后两组血清骨钙素（BGP ）、Ⅰ型胶原交联羧基末端肽（CTX ）、脱氧吡啶啉（DPD ）指标水平相比，中医组优于西医组（<0.05）；两组不良反应发生率相比，中医组低于西医组（<0.05）。
结论抗骨质疏松胶囊治疗老年骨质疏松性髋部骨折能够获得满意的近期临床疗效，有标本兼顾的作用，能帮助患者促进骨折愈合，改善相关指标，调节机体整体状况，且有较高的用药安全性。
关键词：老年骨质疏松；髋关节骨折；抗骨质疏松胶囊；不良反应；髋关节功能中图分类号：R274.1文献标识码：Bdoi ：10.3969/j.issn.1008987x.2020.05.24The Short-term Efficacy of Anti-osteoporosis Capsule in Treatment of SenileOsteoporotic Hip FractureZHANG Shangshang ，LIU Zhigang ，ZHANG Peng ，BI Mengna ，LI Zhong ，CHEN Jingyong（Sichuan Provincial Orthopaedic Hospital ，Chengdu 610041）Abstracts ：Objective To observe the short-term clinical efficacy of Anti-osteoporosis Capsule in treatment of senile os-teoporotic hip fracture.Methods A total of 130elderly patients with osteoporotic hip fractures were randomly divided intoTCM group and western medicine group ，65cases in each.On the basis of bone specialist treatment ，western medicine group received western medicine for anti-osteoporosis treatment ；TCM group received Anti-osteoporosis Capsule.The fracture treatment effects ，hip functions and various clinical indicators were compared between the two groups.Results There was no significantdifference in Harris score and total effective rate between the two groups （>0.05）；BGP ，CTX ，DPD and other indicators were better in TCM group than those in control group ；the incident rate of adverse reactions of TCM group was lower than that of western medicine group ，and the difference was significant （<0.05）.Conclusion Anti-osteoporosis Capsule can achieve sat-isfactory of short-term clinical effect in treatment of senile osteoporotic hip fracture.It can help patients to promote fracture healing ，improve related indicators ，and adjust the overall condition of the body ，with higher medication safety.Keywords ：senile osteoporosis ；hip fracture ；Anti-osteoporosis Capsule ；adverse reactions ；hip function骨质疏松症多发老年人群，是指骨量减少，同时骨质成份中，骨矿物质与基质的比例发生改变，相对减少，通过显微镜可以发现骨组织显微结构已经有退化的趋势。
血管性痴呆（vascular dementia,VD）是一种由脑血管病变导致的疾病，其临床症状包括引起记忆和执行功能障碍等。
它被认为是继阿尔茨海默病之后的第二大常见痴呆类型[1]。
目前，在亚洲和发展中国家的痴呆病例中，VD 约占30%，高于北美和欧洲（15%～20%）[2-3]。
据研究资料显示，我国60岁及以上人群的血管性痴呆发病率为每年每千人中有2.42例[4-5]。
研究表明，我国约有1507万人60岁以上的痴呆患者，其中约有392万人为VD 患者[6]。
VD 会造成日常生活质量不断下降，而且不能扭转，给家庭和社会带来极大的冲击和负担。
复方苁蓉益智胶囊是由王永炎院士多年临床实践研制的具有益智养肝,化浊活血和增智健脑等功效的中成药[7]，主料何首乌、肉苁蓉、荷叶、地龙、漏芦等。
Progress of compound ciYizhi capsule in the treatment of vascular dementia Di Shuai, Zhang Jiapeng, Liu Yixuan, LiYanan, Zhang Jiang, Zhou Fuling. The Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China【Abstract 】Compound ciYizhi capsule has the effect of nourishing liver,promoting turbidity and activating blood, and increasing wisdom and brain. It is suitable for mild to moderate vascular dementia with liver and kidney deficiency and phlegm stasis blocking collateral syndrome. Recently, it has been widely used in the long-term and synergistic treatment of vascular dementia with remarkable efficacy.To summarizes the clinical and experimental studies of compound ciYizhi capsule. It is found that compound ciYizhi capsule can treat vascular dementia by reducing the expression of MARKS mRNA in hippocampus, inhibiting oxidative stress in brain tissue, protecting mitochondria, reducing the range of cerebral infarction, protecting cerebral ischemic injury and pound ciYizhi capsule combined with other anti-dementia drugs can significantly improve the clinical symptoms of patients with vascular dementia and improve the self-care ability and quality of life.In order to provide some reference for the subsequent study of compound cistanche qianyi capsule.【Key words 】Vascular dementia; Compound ciYizhi capsule; Dementia; Clinical application 复方苁蓉益智胶囊治疗血管性痴呆的研究进展邸帅 张佳朋 刘乙璇 李亚楠 张江* 周福玲作者单位：063000 河北省唐山市，华北理工大学附属医院神内二、四病区*通讯作者【摘要】 复方苁蓉益智胶囊具有益智养肝,化浊活血和增智健脑的功效，适用于肝肾亏虚兼痰瘀阻络证的轻中度血管性痴呆。
Acta zoologica cracoviensia,48A(1-2):93-117,Kraków,30June,2005 New data on Late Miocene–Pleistocene ochotonids(Ochotonidae,Lagomorpha)from North ChinaMargarita A.E RBAJEVA and Shaohua Z HENGReceived:12Jan.,2005Accepted for publication:13May,2005E RBAJEVA M.A.,Z HENG Sh.2005.New data on Late Miocene–Pleistocene ochotonids(Ochotonidae,Lagomorpha)from North China.Acta zoologica cracoviensia,48A(1-2):93-117.Abstract.Detailed study of ochotonids from the Late Miocene-Pleistocene of North Chinarevealed more than fifteen ochotonid taxa.They include Ochotona plicodenta sp.nov.,O.gracilis sp.nov.,O.lingtaica sp.nov.,O.youngi sp.nov.,O.magna sp.nov.,O.zhangisp.nov.,greli,O.cf.O.minor,O.cf.O.cansus,O.aff.O.tibetana,O.aff.O.bazarovi,O.aff.O.dodogolica,O.aff.O.intermedia,Ochotona sp.(small),plici-dens and plicidens near to Ochotonoma.Of these species,the former ten are the en-demics to China and the other forms are widely-distributed in Asia.Evolutionary historyof ochotonids is shortly discussed.Key words:Late Miocene,Pliocene,Pleistocene,North China,Lagomorpha,Ochotona,systematics,evolution,history.Margarita A.E RBAJEVA,Geological Institute of Siberian Branch,Russian Academy ofSciences,Ulan-Ude,670047,Russia.E-mail:erbajeva@gin.bsc.buryatia.ruShaohua Z HENG,Institute of Vertebrate Paleontology and Paleoanthropology,ChineseAcademy of Sciences,Beijing,100044,China.I.INTRODUCTIONThe Late Miocene-Pleistocene ochotonids from North China,including the genera Ochotonoides and Ochotona,have been extensively studied and are relatively well known(S CHLOSSER1924;B OULE &T EILHARD DE C HARDIN1928;T EILHARD DE C HARDIN&P IVETEAU1930;T EILHARD DE C HARDIN& Y OUNG1931;J I et al.1980;Z HENG1982;Z HENG&L I1982;C AI1989;Q IU1987;Q IU&S TORCH2000).While we were reviewing all ochotonids from the Late Miocene-Pleistocene of North China we discovered many taxa which are either new species of the genus Ochotona,or new forms of ocho-tonid faunas of the region.The specimens described in this paper were collected from Leijiahe sections,Wenwanggou, Lingtai County,Gansu Province(Z HANG&Z HENG2000,2001;Z HENG&Z HANG2000,2001), from Danangou sections,Yuxian County(Z HENG&C AI1991;C AI et al.in press)and from the Ma-juangou Locality,Yangyuan County,Hebei Province(C AI&L I2003),from the fissure-fillings of Sunjiashan,south of city Zibo,and Xiaoxishan Locality,both of Pingyi County,Shandong Province (Z HENG et al.1997,1998).All the materials are now stored at the Institute of Vertebrate Palaeontol-ogy and Palaeoanthropology,Chinese Academy of Sciences,Beijing.From Leijiahe sections,10taxa,Ochotona plicodenta sp.nov.,O.lingtaica sp.nov.,O.gracilis sp.nov.,O .minor B OHLIN ,1942,O greli S CHLOSSER ,1924,O .aff.intermedia E RBAJEVA ,1976,O .aff.bazarovi E RBAJEVA ,1983,Ochotona sp.(small),Ochotonoides complicidens T EILHARD DE C HARDIN &Y OUNG ,1931and plicidens near to Ochotonoma are recognized.Their distribu-tion in Biozone I-VI (Late Miocene or Mammal units or zones 12-13(MN12-13)to early Early Pleistocene,or MN17)are given in Table I.In Danangou section,Ochotona sp.(small)is distributed in layers 1-26(from Late Pliocene,or MN16to Middle Pleistocene);O.youngi sp.nov.–in layers 4-23(from early Early Pleistocene,or MN17to Middle Pleistocene);O .cf.youngi sp.nov.in layers 13-15(late Early Pleistocene);both O.magna sp.nov.and O .aff.dodogolica E RBAJEVA ,1966in layer 15(late Early Pleistocene);O .aff.tibetana M ILNE -E DWARDS ,1871in layer 18(late Early Pleistocene)(Table II).At Loc.Majuangou,there exist O.youngi sp.nov.,O .aff.intermedia and plicidens .They can be estimated to place into the layer 5of the Danangou section (early Early Pleistocene,or MN 17)(see Table II).At Locs.1and 4of Xiaoxishan (Middle Pleistocene),only Ochotona zhangi sp.nov.is recog-nized,but at Locs.1and 2of Sunjiashan (MN17),both O .aff.intermedia and O .cf.c ansus ,respec-tively are present.They can also be correlated with the Danangou section (see Table II).Six new species,O .plicodenta sp.nov.,O.magna sp.nov.,O.lingtaica sp.nov.,O.gracilis sp.nov.,O .youngi sp.nov.,O .zhangi sp.nov.,and two another species,one tentatively reffered to O.cansus and plicidens are described in this paper in detail.The other taxa need futher study and await the discovery of additional material.To correlate the stratigraphic range of Chinese ochotonids with European continental stages we use the Neogene mammal units or zones (MN)initially proposed by M EIN (1975,1989).Tooth terminology used here primarily follows L OPEZ M ARTINEZ (1989)but also E RBAJEVA (1988).Capital and lower-case letters,P/p (premolar)and M/m (molars)used in the tables indicate the upper and lower cheek teeth,respectively.Tooth-measurements were made on occlusal surface and are given millimeters as the length (L)and width (W)of the tooth.In the tables,the anteroconid and posteroconid are abbreviated as “ac”and “pc,”respectively.A c k n o w l e d g m e n t s.We are grateful for assistance from our colleagues Profes-sors Z HANG Z HAOQUN ,L I C HUANKUI ,Q IU Z HUDING and W U W ENYU in the field investigation and in the course of research work.We thank Alisa W INKLER ,Southern Methodist University,Dallas for correction of our English.This study was supported by the project of National Natural Science Foundation of China (No.40472012)and partially by grant N 05-05-97212,Baikal-RFFI.II.SYSTEMATIC PALEONTOLOGY Order Lagomorpha B RANDT ,1855Family Ochotonidae T HOMAS ,1897Subfamily Ochotoninae T HOMAS ,1897T y p e g e n u s:Ochotona L INK ,1795.I n c l u d e d g e n e r a:Marcuinomys G ROIZET ,1839,Lagopsis S CHLOSSER ,1884,Proochotona C HOMENKO ,1914,Ochotonoides T EILHARD DE C HARDIN and Y OUNG ,1931,Paludo-tona D AWSON ,1959,Alloptox D AWSON ,1961,Pliolagomys E RBAJEVA ,1983,Albertona L OPEZ M ARTINEZ ,1986,Ochotonoma S EN ,1998.S t r a t i g r a p h i c r a n g e:Early Miocene to Recent.G e o g r a p h i c d i s t r i b u t i o n:Eurasia,North America.M.A.E RBAJEVA ,S.Z HENG94Late Miocene–Pleistocene ochotonids from North China95Table I Stratigraphic distribution of the Ochotonids in Leijiahe sections,Lingtai Array C Loc.93001section,+Loc.72074(3~4)section,ÅLoc.93002section;Î=WL1~2,Ï=WL4,Ð=WL8,Ñ=WL9;WL1+~WL27:stratigraphic sequence from top to bottom(after Z HENG&Z HANG2001).Table IIStratigraphic distribution of the Ochotonids in Nihewan sectionsC Loc.Danangou section,+Loc.Majuangou,ÅLocs.1and 4of Xiaoxishan, Loc.1and Loc.2of Sunjiashan;Î=7=L17,Ï=12,Ð=14,Ñ=17,Ò=20=L5,Ó=21,Ô=23=L3;L1+~L27:stratigraphic sequence from bottom to top (after C AI et al.2004).M.A.E RBAJEVA ,S.Z HENG96Genus Ochotona L INK ,1795Ochotona plicodenta sp.nov.(Fig.1a-g,Tables III,IV)H o l o t y p e:Fragment of right mandibular ramus with p3-m2,lacking incisor,angular process and condyle,IVPP,V14182.T y p e l o c a l i t y:Loc.93001,Wenwanggou,Lingtai county,Gansu Province,level =WL8.A g e:Late Pliocene (MN 16).E t y m o l o g y:“plicodenta”–plication,denta -tooth.H y p o d i g m:Loc.93001:WL8:1left and 2right P2,1left p3;WL10:1left P2,2left p3;WL12:1damaged right p3.Loc.72074(4):L5:1damaged right p3.M e a s u r e m e n t s:Holotype:crown length of p3-m27.0mm;length and width of p31.8x 1.7mm.Fig.1.Ochotona plicodenta sp.nov.a –p3-m2dex.,holotype;b,c –p3sin.;d,e –p3dex.;f –P2dex.;g –P2sin.Late Miocene –Pleistocene ochotonids from North China97D i a g n o s i s:Medium-sized pika (Tables III,IV).Lower third premolar with antero-internal and posteroexternal flexids deeper than anteroexternal ones;anteroconid rhomboid type with rather sharp anterior end covered by enamel and plicated posterointernal border.D i f f e r e n t i a l d i a g n o s i s:Ochotona plicodenta sp.nov.differs from all known extinct and extant species of the genus Ochotona by having a plicated anterointernal flexid on p3.Moreover it differs from O.gracilis sp.nov.,O.lingtaica sp.nov.,O.youngi sp.nov.,O.in-termed ia,O.bazarovi ,O.dodogolica ,O.gureevi (E RBAJEVA ,1966),O.sibirica (E RBAJEVA ,1983)by its larger size.Ochotona plicodenta sp.nov.differs from O.zhangi sp.nov.,O.nihewanica Q IU ,1985,O.tologoica H ABAEVA ,1958,O.gromovi E RBAJEVA ,1976and O.zazhigini E RBAJEVA ,1983by having a deep anterointernal flexid of p3.It is slightly smaller in size than O.magna sp.nov.D e s c r i p t i o n:The occlusal outline of P2is oval with one deep cement-filled anterior flexus in the midline of the tooth (Fig.1,6-7).The tooth is longer internally than externally.The mandibular ramus is rather robust,with its external surface is rough and unequal,because of dam-aged by post-depositional diagenetic processes.The lower incisor extends posteriorly along the ventral border of a mandible in a line below p4.The lower third premolar is longer than wide with a large and long anteroconid.The anteroconid has a narrow confluence with posteroconid in the holo-type and in some paratypes,however in some specimens of paratypes conids are completely sepa-rated from posteroconid (Fig.1a-e).The internal and external borders of the posteroconid are comparable in length.The anterointernal flexid is deeper than anteroexternal one and directed pos-teriorly,whereas the anteroexternal flexid directed posterointernally.Table IIIMeasurements (in mm)of Ochotona plicodenta sp.nov.(upper teeth);L –length;W –widthnMeanMinMaxSDP2L 20.70.70.75W 2 1.6 1.5 1.6P3L 7 1.10.95 1.350.138W 6 2.1 1.9 2.30.126M2L 5 1.2 1.1 1.30.084W51.91.820.084Table IVMeasurements (in mm)of Ochotona plicodenta sp.nov.(lower teeth);L –length;W –widthnMeanMin Max SDAlveolar L of p3-m217.8Crown L of p3-m217Crown L of p4-m21 5.4p3L 5 1.5 1.35 1.80.175ac L510.9 1.250.152pc L internally 50.960.85 1.150.124pc L externally 50.840.7 1.050.177ac W 50.80.70.90.076pc W4 1.4 1.25 1.70.210Mandible ramus depth at p413.25M.A.E RBAJEVA ,S.Z HENG98Ochotona magna sp.nov.(Fig.2a-d,Table V)H o l o t y p e:Right p3,IVPP,V14183.T y p e l o c a l i t y:Loc.Danangou,Yuxian County,Hebei Province,layer =L15.A g e:Late Early Pleistocene (late Nihewanian,or MN17).E t y m o l o g y:“magna”-large.H y p o d i g m:Two right p3from Loc.Danangou:layer =L15.Fig.2.Ochotona magna sp.nov.a –p3dex.,holotype;b –p3dex.;c,d –p3dex.:c –occlusal view,d -bottomview.Table VMeasurements (in mm)of Ochotona magna sp.nov.(lower teeth);L –length;W –widthnMeanMinMaxSDp3L 3 1.8 1.75 1.850.05ac L3 1.25 1.2 1.30.05pc L internally 3 1.00.95 1.050.076pc L externally 3 1.1 1.05 1.150.05ac W 30.820.70.950.126pc W31.631.51.80.153Late Miocene –Pleistocene ochotonids from North China99M e a s u r e m e n t s.Holotype:length and width of p31.85x 1.8mm.D i a g n o s i s:Large-sized (Table V).Lower third premolar with robust rhomboid antero-conid,deep anterointernal flexid extending posterointernally,the posteroconid wider than long,and posteroexternal loop relatively short.D i f f e r e n t i a l d i a g n o s i s:Ochotona magna sp.nov.is close to O.plico-denta sp.nov.,O.zasuchiniE RBAJEVA ,1983,O.zazhigini and O.gromovi in size,but differs from the latter three species by having a deeper anterointernal flexid.It differs especially from O.plico-denta sp.nov.by absence of a plication in the anterointernal flexid.O.magna sp.nov.is larger than O.gracilis sp.nov .,O.youngi sp.nov.,O.lingtaica sp.nov.,O.zhangi sp.nov.and O.nihewanica.Moreover,O.magna sp.nov.differs from all of them by its p3having a deeper anterointernal flexid,and a relatively short and wide posteroconid.It is larger than all extant species and has a more robust rhomboid anteroconid.D e s c r i p t i o n:The anteroconid of p3is very large and has a narrower confluence with posteroconid,which is shorter than wide.The enamel is rather thick on the labial border and absent on the posterior border of the tooth.All flexids on p3are of similar depth and filled with thin ce-ment.The anterointernal flexid in the holotype extends first transversely and then turns suddenly posteriorly;it is directed posteroexternally in the other specimens (Fig.2a-d).Ochotona youngi sp.nov.(Fig.3a-h,4a-u,8r-u,Tables VI,VII)H o l o t y p e:Right p3,IVPP,V14184.T y p e l o c a l i t y:Loc.Danangou,Yuxian County,Hebei Province,layer =L15.A g e:Early Early Pleistocene (MN17)–Middle Pleistocene.E t y m o l o g y:For the Prof.C.C.Y OUNG -a well-known paleontologist.H y p o d i g m:Locality Danangou:L23:1left p3;L18:2P3,2M2,8p3;L16:1M2,1p3;L15:5fragments of skull with different numbers of tooth,15fragments of lower jaw with different numbers of teeth,14P2,22P3,21M2,25p3;L9:2P2,8P3,3P4,8M1,3M2,2p3;L6:2M2,1p3;L4:1p3;Loc.Majuangou:1P2,5P3,3P4,5M1,6M2,2p3.M e a s u r e m e n t s:Holotype:length and width p31.3x 1.55mm.D i a g n o s i s:Small-sized pika (Tables VI,VII).Lower third premolar with a rectangular anteroconid consisting of short anteroexternal and posterointernal borders,and longer anterointer-nal and posteroexternal borders;an asymmetric posteroconind which is wider than long and longer external compared to internal borders;all flexids of equal depth.D i f f e r e n t i a l d i a g n o s i s:By its smaller size Ochotona youngi sp.nov.differs from O.magna sp.nov.,O.zhangi sp.nov.and O.plicodenta sp.nov.Other than size,the main difference with O.plicodenta sp.nov.is the absence of plication on the anterointernal flexid of p3.Differs from O.magna sp.nov.,O.lingtaica sp.nov.,O.zhangi sp.nov.and O.gracilis sp.nov.in its asymmetric posteroconid;from O.youngi sp.nov.in its rhomboid posteroconid.O.youngi sp.nov.differs from the other extinct and extant larger species of Ochotona ,-greli,O.gromovi,O.tologoica,O.nihewanica,O.zazhigini,O.zasuchini,O.guizhongensis J I ,X U &H UANG ,1980,O whartoni G UTHRIE &M ATTHEWS ,1971,O.koslovi B UECHNER ,1894,O.rutila S EVERTZOV ,1873,dacensis G UENTHER ,1875,and O.alpina P ALLAS ,1773by its smaller pared to the smaller species,O.minor,O.bazarovi,O.gureevi,O.sibirica,O.hyperborea P ALLAS ,1811,O.thomasi A RGYROPULO ,1948,O.pusilla P ALLAS ,1769,and pikas of the “ti-betana ”group it is larger in size,has a more rectangular anteroconid,and a wider posteroconid,which is completely separated from or has a narrow confluence with the anteroconid on p3.D e s c r i t p i o n:P2is wider than long and the lingual border is longer than the external one.The anterior flexus is filled with thin cement and extends posteroexternally close to the poste-rior border of the tooth.The posterior border is almost straight in contrast to the convex anterior bor-M.A.E RBAJEVA ,S.Z HENG100Fig.3.Ochotona youngi sp.nov.a –P3-M2sin.;b –P2sin.;c –P2dex;d –P3-M1sin.;e,f –P3dex.;g –M2sin.;h –M2dex.Late Miocene –Pleistocene ochotonids from North China101Fig.4.Ochotona youngi sp.nov.a –p3dex.,holotype;b-h –p3dex.,j,k,n,o,r,s –p3sin.;i,m –p3sin.:i –occlusal view,m –bottom view;l,p –p3dex.:l –occlusal view,p –bottom view;t,u –p3dex.:t –occlusal view,u –bottomview.M.A.E RBAJEVA ,S.Z HENG102der (Fig.3b-c).P3is trapezoidal in shape and has a short anterior and a long posterior border.Its short hypostria filled with thin cement (Fig.4,1-20;Fig.9,17-20).P4-M2have deep hypostria filled with cement (Fig.3a,d-h).The mandibular ramus is slender (Table VII)and the diastema is relatively short.The lower inci-sor extends posteriorly along the ventral border to the root end under p4,where it forms a visible tu-bercle on lingual side of the ramus.The anterior mental foramen is situated below p3and the posterior one is below m3.Ochotona lingtaica sp.nov.(Fig.5a-l,Tables VIII,IX)H o l o t y p e:Right p3,IVPP,V14185.T y p e l o c a l i t y:Loc.93001,Wenwanggou,Lingtai County,Gansu Province,layer =WL8.Table VIMeasurements (in mm)of Ochotona youngi sp.nov.(upper cheek teeth);L –length;W –widthnMeanMinMaxSDAlveolar L of P2-M227.3 6.87.8Alveolar L of P3-M22 5.7556.5Crown L of P3-M21 6.1Crown L of P3-M11 4.5Crown L of P3-P42 2.7 2.43Crown L of P4-M123P2L20.5W 2 1.12 1.1 1.15P3L30 1.040.9 1.20.090W 30 2.11 1.7 2.50.214M2L21 1.39 1.15 1.70.122W212.011.62.60.254Table VIIMeasurements (in mm)of Ochotona youngi sp.nov.(lower cheek teeth);L –length;W –widthnMeanMinMaxSDAlveolar L of p3-m387.48 6.880.417Alveolar L of p3-m212 6.47670.345Crown L of p3-m21 5.7Crown L of p3-p41 2.7Crown L of p4-m34 5.25 5.30.126Crown L of p4-m212 4.68 4.2 5.20.319p3L 34 1.150.95 1.350.101ac L340.650.50.850.092pc L internally 340.700.60.80.057pc L extenally 340.830.710.075ac W 340.550.40.70.069pc W341.301 1.550.133Late Miocene –Pleistocene ochotonids from North China103A g e:Late Pliocene (MN 16).E t y m o l o g y:The name is from Lingtai County where it is found.H y p o d i g m:Loc.93001:WL7:2p3;WL8:1P2,6P3,5P4,4M1,5M2;3p3;WL10:2P2,2P3,1P4,5M1,2M2,1p3;WL11:4P2,8P3,5P4,2M1,4M2,13p3.M e a s u r e m e n t s:Holotype:length and width of p31.55x 1.45mm.D i a g n o s i s:Medium-sized pika (Tables VIII,IX).Lower third premolar with rhom-boid anteroconid relatively large,posteroconid wider than long,posteroexternal “loop”signifi-cantly long,anterointernal flexid deeper than anteroexternal one and directed posteroexternally.D i f f e r e n t i a l d i a g n o s i s:Ochotona lingtaica sp.nov.is close in size to O.nihewanica ,but is smaller than all known extinct and extant “large-sized”species,O.plicodenta sp.nov.,O.zhangi sp.nov.,O.magna sp.nov.,O.guizhongensis,greli,O.gromovi,O.tologoica,O.zasuchini,O.koslovi,O.rutila,dacensis,and O.alpina .O.lingtaica sp.nov.is larger than extinct and extant “small-sized”species,O.gracilis sp.nov.,O.minor,O.sibirica,O.pusilla,O.thomasi and pikas of the “tibetana ”group.Unlike O.youngi sp.nov.the p3of O.lingtaica sp.nov.has a rhomboid anteroconid and asymmetric posteroconid.Fig.5.Ochotona lingtaica sp.nov.a –p3dex.,holotype;b-d –p3dex.,e-l –p3sin.M.A.E RBAJEVA ,S.Z HENG104D e s c r i p t i o n:P2has an almost straight internal border which is slightly longer than the external one,and a deep anterior flexus filled with cement.P3is trapezoidal in shape,its poste-rior border is wider than the anterior one.The short hypostria of P3is filled with thin cement The anteroconid may have a sharp or rounded top and be covered with thick to thin enamel.It is com-pletely separated from the posteroconid with the internal wall slightly curved to straight or with shallow depression.Ochotona gracilis sp.nov.(Fig.6a-c,Table X)H o l o t y p e:Right p3,IVPP,V14186.T y p e l o c a l i t y:Loc.93001,Wenwanggou,Lingtai county,Gansu Province,layer =WL10.A g e:Late Pliocene (MN 16).E t y m o l o g y:”gracilis”means delicate.H y p o d i g m:Loc.72074(3):1right p3(MN13?);Loc.72074(4),L4:1left left p3(MN15).M e a s u r e m e n t s:Holotype:length and width of p31.2x 1.1mm.D i a g n o s i s:Small-sized pika (Table X).Lower third premolar with a square-shaped posteroconid,internal and external borders of the tooth of equal length,and with comparable depth of both anterointernal and anteroexternal flexids.These flexids are directed toward the midline of the tooth and are inclined slightly posteriorly.Table VIIIMeasurements (in mm)of Ochotona lingtaica sp.nov.(upper teeth);L –length;W –widthnMeanMinMaxSDP2L 30.730.70.8W 3 1.3 1.2 1.35P3L 13 1.00.95 1.20.068W 12 2.1 1.9 2.40.148P4L 9 1.1 1.05 1.350.087W 9 2.1 1.85 2.40.186M1L 10 1.20.95 1.40.130W 10 2.1 1.9 2.250.123M2L 10 1.21 1.40.125W101.81.52.050.144Table IXMeasurements (in mm)of Ochotona lingtaica sp.nov.(lower teeth);L –length;W –widthnMeanMinMaxSDp3L 14 1.38 1.25 1.50.070ac L140.910.7510.174pc L internally 140.800.650.950.072pc L externally 140.870.80.950.043ac W 140.700.55 1.050.126pc W141.321.21.50.097Late Miocene –Pleistocene ochotonids from North China105D i f f e r e n t i a l d i a g n o s i s:Ochotona gracilis sp.nov.is close in size to small extant ochotonids,O.thomasi ,O.pusilla and pikas of the “tibetana ”group,as well as to the extinct species,O.minor ,O.sibirica and extinct pikas of the “pusilla ”group.However,in p3mor-phology,it differs from all extant and extinct taxa of the “pusilla ”group in having a larger anteroco-nid and a narrow or completely separated antero-and posteroconid,nd by the straight inner border of the posteroconid.O.thomasi and ochotonids of the “tibetana ”group are different from O.gra-cilis sp.nov.by their slightly larger size and deeper internal flexids on p3.Ochotona gracilis sp.nov.differs from O.plicodenta sp.nov.,O.lingtaica sp.nov.,O.magna sp.nov.,O.youngi sp.nov.,O.intermedia ,O.bazarovi ,O.dodogolica ,O.gureevi ,O.zhangi sp.nov.,O.nihewanica ,O.tologoica ,O.gromovi and O.zazhigini by its smaller size and almost square-shaped posteroconid on p3.D e s c r i p t i o n:All four sides of the rhomboid anteroconid of p3are almost equal in length.The anteroconid has a narrow confluence or is completely separated from the posteroconid,which has a straight internal border,and the posteroconid internal and external borders of equal length.Ochotona zhangi sp.nov.(Fig.7a-j,8i-j,n,Tables XI,XII)Synonymy:1998Ochotona daurica ,Z HENG et al.,p.37,textfig.3,A and BH o l o t y p e:Fragment of left mandibular ramus with incisor and p3-m2,angular process and condyle lacking,IVPP,V14187.T y p e l o c a l i t y:Loc.1of Xiaoxishan,Pingyi County,Shandong Province.A g e:Middle Pleistocene.E t y m o l o g y:Named after Prof.Z HANG Z HAOQUN who excavated this locality in 1996.H y p o d i g m:Loc.1of Xiaoxishan:fragments of four skulls of different condition,all with P2-M2,fragments of 12lower jaws with different numbers of teeth;Loc.4of Xiaoxishan:6p3.Table XMeasurements (in mm)of Ochotona gracilis sp.nov.(lower teeth);L –length;W –widthnM eanMin Maxp3L 3 1.2ac L 30.5pc L 30.770.70.8ac W 30.520.50.55pc W31.081.05 1.1M.A.E RBAJEVA ,S.Z HENG106Fig.6.Ochotona gracilis sp.nov.a –p3dex.,holotype;b –p3dex.,c –p3sin.M e a s u r e m e n t s:Holotype:length and width of p31.6x 2.0mm.D i a g n o s i s:Large-sized pika (Tables XI,XII).Lower third premolar proportionally large,with rectangular anteroconid separated completely from posteroconid which is wider than long,with internal and external borders of comparable length.D i f f e r e n t i a l d i a g n o s i s:Ochotona zhangi sp.nov.is larger than O.gra-cilis sp.nov.,O.lingtaica sp.nov.,O.youngi sp.nov.,O.sibirica,O.minor and the extant “small-sized”pikas O .hyperborea,O.thomasi and O.pusilla.Moreover,the p3of O.zhangi sp.nov.has aFig.7.Ochotona zhangi sp.nov.a –P2-M2dex.;b –p3sin.,holotype;c –p3sin.;d-f –p3dex.;h-j –p3sin.Late Miocene –Pleistocene ochotonids from North China107Fig.8.Ochotona cf cansus L YON ,1907.a-c,13–p3sin.,d,h –p3sin.:d –occlusal view,h –bottom view;e –p3sin.,recent;f –p3sin.,g –p3dex.;Ochotona zhangi sp.nov.i –p3sin.,j,n –p3dex.:j –occlusal view,n –bottom view;Ochotona aff.intermedia .k,l,o,p –p3dex.:k,l –occlusal view,o,p –bottom view.Ochotona youngi sp.nov.r,s –p3dex.,t,u –p3sin.:t –occlusal view,u –bottomview.M.A.E RBAJEVA ,S.Z HENG108shorter and wider posteroconid than that of O.gracilis sp.nov.and a more inclined posterointernal border of the posteroconid than that of O.lingtaica sp.nov.The p3of O.zhangi sp.nov.has a trape-ziodal posteroconid compared to that of O.youngi sp.nov.O.zhangi sp.nov.can be distinguished by its slightly smaller size and absence of the plication on the anterointernal flexid of p3from O.magna sp.nov.,O.plicodenta sp.nov.,and with other Asian extinct and extant species,such as O.guizhongensis,greli,O.tologoica,O.gromovi,dacensis,O.koslovi,O.alpina.D e s c r i p t i o n:Skull is relatively flat,except a weak convex near the parietofrontal boundary.Interorbital region is narrow and has a shallow groove in the midline.Orbits are oval in shape.Jugal bones first extends posteriorly and slightly dorsally,and has a robust anterior process.The diastema on the maxilla is relatively long.The incisive foramina are confluent with the pear-shaped palatal foramen.The palate is rather wide.The mandibular ramus is relatively low,but ro-bust.Diastema on the mandible is long (Table XI).On the outer surface of the lower jaw there is a well-developed depression just below p3and p4.The lower incisor extends posteriorly along the ventral border of mandibular ramus approximately in a line.It ends below p4and m1and produces well-developed tubercles on both the lingual and labial sides of the ramus.The mental foramen is just below m2.On the labial side of the mandible there are many small foramina below p3.P2is oval in outline,wider than long,and has a slightly sharp internal border,and a deep anterior flexus filled with cement and directed posteroexternally.P3is trapezoidal,has a narrower anterior border than posterior one,and a shallow hypostria lacking cement.The hypostriae of P4-M2are deep and filled with thin cement.The upper teeth have thick enamel on their anterior and internal borders but the enamel is rare or absent on their posterior and external borders.The lower third premolar is shaped like as an asymmetrical triangle,and is wider than long.The flexids are of comparable depth.The apex of anteroconid is gently convex and is covered with thin cement.The shape of the anteroconid is variable,especially in young individuals when it is near square.Structure of the p4-m2is that of a typical ochotonid.The talonid of p4is wider than the trigonid;the talonid is proportionally narrower on m2while it is contrary on m2(Table XII).R e m a r k s:Among ochotonids from Sunjiashan Localities 1and 4,Shandong,a smaller-sized pikas reffered to Ochotona aff.intermedia (Fig.8k-l,and o-p)can be distinguished from O.Table XIMeasurements (in mm)of Ochotona zhangi sp.nov.(upper teeth);L –length;W –widthnMeanMinMaxAlveol L of P2-M2498.59.3Alveol L of P2-M14 6.75 6.57Alveol L of P3-M14 5.3 4.8 5.8Crown L of P2-M247.957.38.5Crown L of P3-M24 5.5 4.8 6.7Crown L of P3-M14 6.58 4.77.7Crown L of P3-P44 3.13 3.3P2L30.750.70.8W 3 1.63 1.6 1.7P3L4 1.28 1.2 1.4W 4 2.63 2.253M2L4 1.85 1.65 2.1W4 2.44 2.2 2.7Diastema210.38.811.8Interorbital width 2 4.2 4.1 4.3Skull width at bullae223.222.6823.71Late Miocene –Pleistocene ochotonids from North China109zhangi sp.nov.by the structure of its teeth.The taxonomic status of Ochotona aff.intermedia will be established when more abundant materials is recovered.Ochotona cf.cansus L YON ,1907(Fig.8a-h,Table XIII)M a t e r i a l.Six isolated p3,Loc.2of Sunjiashan,Zibo,Shandong Province.A g e:Late Early Pleistocene (MN17).D e s c r i p t i o n:Both shape and size of third premolar are close to that of the recent smaller-sized species,Ochotona cansus (Fig.8a-h,Table XIII).The lower p3has a relatively large rhomboid anteroconid separated almost completly from the posteroconid by anteroexternal and an-terointernal flexids.These flexids have almost the same depth.The enamel bands on the anterior and external and partially on the posterointernal borders of the tooth are well developed.The inter-nal border of the posteroconid is variable in shape,most of them are straight or slightly convex,but on one specimen it is concave and filled with thin cement.Table XIIMeasurements (in mm)of Ochotona zhangi sp.nov.(lower teeth);L –length;W –widthnMeanMinMaxSDAlveolar L of p3-m329.38.510Alveolar L of p4-m327.477.7Crown L of p3-m328.17.58.7Crown L of p3-m237.3 6.77.7Crown L of p3-m14 5.55 5.7Crown L of p3-p44 3.5 3.2 3.7Crown L of p4-m23 5.7 5.2 6.1Crown L of p4-m32 6.567p3L 15 1.58 1.4 1.750.105ac L 150.790.70.950.069pc L 15 1.080.9 1.20.084ac W 150.900.7 1.050.107pc W 14 1.70 1.4520.188p4L4 1.86 1.62Trigonid L 410.9 1.05Talonid L 40.850.750.95Trigonid W 4 1.69 1.5 1.9Talonid W 4 1.85 1.75 2.1m2L3 1.92 1.752Trigonid L 310.9 1.1Talonid L 30.830.80.85Trigonid W 3 1.9 1.72Talonid W 3 1.75 1.7 1.85Diastema17.4Mandible height at p44 6.7567Mandible height at m32 6.5 5.87.2Mandible depth at p44 4.25 3.9 4.3Mandible depth at m323.2533.5M.A.E RBAJEVA ,S.Z HENG110。
