双波长紫外分光光度法测定复方恩诺沙星可溶性粉中恩诺沙星和盐酸多西环素的含量

建立了复方恩诺沙星可溶性粉中恩诺沙星和盐酸多西环素含量的检测方法.采用双波长紫外分光光度法,直接测定两组分的含量.结果显示可同时测出复方恩诺沙星可溶性粉中恩诺沙星和盐酸多西环素的各自含量,且吸收度与各自的浓度成良好线性关系.恩诺沙星平均回收率为100.1%,RSD为0.04%(n=5).盐酸多西环素平均回收率为100.2%,RSD为0.14%(n=5).本方法简便、快速、可靠,可用于复方恩诺沙星可溶性粉的含量测定.     

Comparison of the pharmacokinetics of tilmicosin in plasma and lung tissue in healthy chickens and chickens experimentally infected with Mycoplasma gallisepticum

The objectives of this study were to compare the plasma and lung tissue pharmacokinetics of tilmicosin in healthy and Mycoplasma gallisepticum-infected chickens. Tilmicosin was orally administered at 4, 7.5 and 10 mg/kg body weight (b.w) for the infected and 7.5 mg/kg b.w for the uninfected control group. We found no significant differences in plasma tilmicosin pharmacokinetics between diseased and healthy control chickens. In contrast, the lung tissues in M. gallisepticum-infected chickens displayed a t_1/2 (elimination half-life) 1.76 times longer than for healthy chickens. The C_max (the maximum concentration of drug in samples) of tilmicosin in M. gallisepticum-infected chickens was lower than for controls at 7.5 mg/kg b.w (p < .05), and the AUC_inf (the area under the concentration–time curve from time 0 extrapolated to infinity) in infected chickens was higher than for the healthy chickens (p < .05). The mean residence time of tilmicosin in infected chickens was also higher than the healthy chickens. These results indicated that the lungs of healthy chickens had greater absorption of tilmicosin than the infected chickens, and the rate of elimination of tilmicosin from infected lungs was slower.     

恩诺沙星与其他抗菌药对鸡毒支原体的体外联合抑菌试验

采用2倍稀释法测定了恩诺沙星及其他8种抗菌药对鸡毒支原体BG44T株的最小抑菌浓度（MIC）,再以棋盘法测定恩诺沙星分别与其他8种抗菌药不同联合对鸡毒支原体BG44T株的敏感性。结果显示：恩诺沙星、替米考星、泰乐菌素、吉他霉素、林可霉素、沃尼妙林、泰妙菌素、氯霉素及氟苯尼考对鸡毒支原体BG44T株的MIC分别为0．063、0．004、0．016、0．063、16、〈0．004、0．008、8、8μg／mL。在8种不同联合用药对鸡毒支原体BG44T株的药敏试验中,恩诺沙星＋替米考星、恩诺沙星＋泰乐菌素、恩诺沙星＋吉他霉素、恩诺沙星＋林可霉素、恩诺沙星＋沃尼妙林、恩诺沙星＋泰妙菌素联合表现出相加作用,恩诺沙星＋氯霉素、恩诺沙星＋氟苯尼考表现出拮抗作用。     

乳酸恩诺沙星可溶性粉在鸡体内的药动学研究

24只苏禽黄羽肉鸡随机分成2组,分别按10 mg/kg体重剂量静注和内服乳酸恩诺沙星。测定乳酸恩诺沙星在鸡体内的药动学参数和生物利用度。恩诺沙星血药浓度数据用3p87计算机软件处理。静注乳酸恩诺沙星后的血药浓度-时间数据符合二室开放模型,主要动力学参数:t1/2α(0.45±0.16)h,t1/2β(7.02±1.42)h,CL(s)(0.38±0.10)L/kg/h,AUC(23.69±5.56)(mg/L)×h。内服乳酸恩诺沙星的血药浓度时间数据,符合有吸收因素二室模型,主要动力学参数:t1/2ka(0.60±0.01)h,t1/2ke(8.25±1.73)h,tpeak(2.44±0.17)h,Cmax(1.44±0.30)mg/L,AUC(20.74±3.80)(mg/L)×h,F 87.54%。结果表明,乳酸恩诺沙星可溶性粉在鸡体内具有吸收快、分布广、消除较慢以及内服生物利用度高的药动学特征。     

恩诺沙星及其代谢产物在奶山羊的药动学及乳中药物浓度

本试验研究单剂量静脉注射、肌肉注射和乳房灌注恩诺沙星（2.5mg/kg)在健康奶山羊的药动学及乳中药物浓度。采用HPLC法测定血浆和乳中恩诺沙星及其代谢产物环丙沙星的浓度，用统计矩原理处理血浆中药物浓度－时间数据，计算非房室模型的药动学参数。静脉注射、肌肉注射和乳房灌注恩诺沙星的t1/2β分别为1.32、1．55、0．99h;AUC为1．06、3．04、2．66mghL^-1；恩诺沙星的代谢分数为35．01％、44．06％、45．73％；环丙沙星的t1/2β为1．81、2．94、2．32h。乳中的药物浓度高于同期血中药物浓度，且乳中环丙沙星浓度高于恩诺沙星浓度并维持更长的时间。     

复方硫氰酸红霉素可溶性粉对人工感染鸡慢性呼吸道病的疗效试验

用复方硫氰酸红霉素可溶性粉以每升水中加0.5、0.6、0.7、0.8、0.9 g 5个剂量对人工感染鸡慢性呼吸道病的鸡群混饮治疗,同时设立硫氰酸红霉素可溶性粉对照组.试验结果表明,用药5d后,复方硫氰酸红霉素可溶性粉每升水加0.6、0.7、0.8、0.9g剂量组的有效率和治愈率皆高于硫氰酸红霉素可溶性粉组.     

Some pharmacokinetic parameters of doxycycline in East African goats after intramuscular administration of a long-acting formulation

A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employingBacillus cereus varmycoides (ATCC 11778) as the test organism. The mean serum concentration (C _max) and the time of maximum concentration (T _max) were 1.87 µg/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h.The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.41 h. The mean values for the volume of distribution at steady state (V _dss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared.It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.Abbreviations ATCC American Type Culture Collection - AVC total area under the plasma concentration-time curve - AUMC area under the curve of the product from time zero to infinity - C1 total body clearance - i.m. intramuscular - i.v. intravenous - MRT mean residence time - MIC minimum inhibitory concentration - PVP polyvinyl pyrolidone - V_d volume of distribution - V _dss volume of distribution at steady state     

Pharmacokinetics of enrofloxacin and danofloxacin in premature calves

The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramuscular (IM) administrations in premature calves. The study was performed on twenty‐four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six premature calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncompartmental methods. Mean PK parameters of ENR and DNX following IV administration were as follows: elimination half‐life (t_1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC_0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr^?1 kg^?1, respectively. The PK parameters of ENR and DNX following IM injection were t_1/2λz 21.10 and 28.41 hr, AUC_0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was determined to be 118% and 124%, respectively. The mean AUC_0‐48CPR/AUC_0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC_0‐24/minimum inhibitory concentration (MIC) and maximum concentration (C_max)/MIC ratios for susceptible bacteria, with the MIC₉₀ of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.     

盐酸多西环素在猪体内的药物动力学及其残留

试验建立了反相高效液相色谱(RT-HPLC)法测定盐酸多西环素的浓度,探讨了盐酸多西环素在猪体内的药物动力学和残留特征。结果表明,盐酸多西环素以2.5mg/kg单剂量肌内注射给猪(n=6),药物动力学模型符合有吸收一室模型,药物动力学参数:吸收半衰期(t1/2ka)、消除半衰期(t1/2ke)为(0.400±0.312)h、(9.530±0.956)h,药时曲线下面积(AUC)为(44.414±4.123)mg·h·L-1,最大血药浓度(Cmax)为(2.811±0.136)mg/L,达峰时间(Tp)为(1.910±0.213)h。另外,以相同剂量肌内注射给猪(n=6),每天1次,连续给药4d后,在不同时间测定盐酸多西环素在猪的肌肉、肝脏、肾脏、皮肤和脂肪中的残留量。在给药后16d,盐酸多西环素在各组织均能检测到,且残留均低于残留限量。盐酸多西环素注射液在猪体内消除缓慢,残留期较长,建议休药期不低于16d。     

Tissue distribution and disposition kinetics of enrofloxacin in healthy and E. coli infected broilers

Concentrations of enrofloxacin equivalent activity were determined by microbiological assay in the plasma of healthy and E. coli-infected broilers following single intravenous and oral administrations at 10 mg/kg. Tissue distribution and residue-depletion following multiple oral doses (10 mg/kg for 3 successive days) were investigated. Pharmacokinetic variables were determined using compartmental and non-compartmental analytical methods. Plasma enrofloxacin concentrations after intravenous dosing to healthy and infected birds were best described by a two-compartments model. Enrofloxacin concentrations in plasma of infected birds were lower than those of healthy ones. The disposition kinetics of intravenously administered drug in healthy and infected birds were somewhat different. The elimination half-life (t1/2 beta) was 4.75 vs. 3.63 h; mean residence time (MRT) was 6.72 vs 4.90 h; apparent volume of the central compartment (Vc) was 1.11 vs 1.57 l/kg; rate constant for transfer from peripheral to central compartment (k21) was 1.15 vs 1.41 h-1 and total body clearance (ClB) was 0.35 vs 0.53 l/h/kg in healthy and infected birds, respectively. After oral administration, the absorption half-life (t1/2abs) in the infected birds was significantly longer than in healthy birds, while elimination half-life (t1/2el) and MRT were significantly shorter. Bioavailability was higher in infected birds (72.50%) as compared to healthy ones (69.78%). Enrofloxacin was detected in the tissues of healthy and infected birds after daily oral dosing of 10 mg/kg for 3 days. It was more concentrated in liver, kidney, and breast muscle. The minimal inhibitory concentration (MIC) of enrofloxacin against E. coli was 0.064 microgram/ml. On the basis of maintaining enrofloxacin plasma concentrations over the MIC, a dose of 10 mg/kg given intravenously every 20.14 hrs or orally every 20.86 hrs should provide tissue concentrations effective against E. coli infection in chickens.     

盐酸多西环素微囊制备及其在家兔体内的药动学研究

以可生物降解材料壳聚糖为囊材,采用乳化交联法制备盐酸多西环素壳聚糖微囊,考查其形态学特征、载药量、及体外释药情况等;将12只小鼠随机分为2组,每组6只,分别按药物剂量20 mg·kg-1灌胃,采用HPLC法,以C18为固定相,流动相为乙腈∶甲醇∶0.01 mol· L-1草酸溶液(2∶1∶7),在346 nm处对不同时间点的血药浓度进行检测,研究其在家兔体内药动学特征.结果成功制得外观较均一、光滑,平均粒径约10 μm,药物含量为20.60％,平均包封率为85.54％且具有明显缓释作用的盐酸多西环素微囊;家兔口服给药盐酸多西环素原药和微囊后主要药动学参数Cmax分别为(1.74士0.00)和(1.10士0.00)mg·L-1,Tmax分别为3和12 h,AUC(0-t)分别为(11.71±0.17)和(32.51士0.20) mg· L-1 ·h,T1/2.分别为(1.16士0.53)和(7.51士2.87)h,T1/2β分别为(2.19士0.38)和(9.00±1.60)h,相对生物利用度为289.4％,药时数据符合一级吸收二室模型.说明微囊化后的盐酸多西环素吸收、分布缓慢,生物利用度有了很大提高.     

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in freshwater crocodiles (Crocodylus siamensis) after intravenous and intramuscular administration

To the best of the authors’ knowledge, pharmacokinetic information to establish suitable therapeutic plans for freshwater crocodiles is limited. Therefore, the purpose of this study was to clarify the pharmacokinetic characteristics of enrofloxacin (ENR) in freshwater crocodiles, Crocodylus siamensis, following single intravenous and intramuscular administration at a dosage of 5 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 168 hr. The plasma concentrations of ENR and its metabolite ciprofloxacin (CIP) were measured by liquid chromatography tandem–mass spectrometry. The concentrations of ENR and CIP in the plasma were quantified up to 144 hr after both the administrations. The half-life was long (43–44 hr) and similar after both administrations. The absolute i.m. bioavailability was 82.65% and the binding percentage of ENR to plasma protein ranged from 9% to 18% with an average of 10.6%. Percentage of CIP (plasma concentrations) was 15.9% and 19.9% after i.v. and i.m. administration, respectively. Based on the pharmacokinetic data, susceptibility break point and PK-PD indexes, i.m. single administration of ENR at a dosage of 5 mg/kg b.w. might be appropriate for treatment of susceptible bacteria (MIC > 1 μg/mL) in freshwater crocodiles, C. siamensis.     

Pharmacokinetics and tissue residues of enrofloxacin in the largemouth bass (Micropterus salmoides) after oral administration

The study was carried out to evaluate the pharmacokinetic disposition of enrofloxacin (ENF) with a single dose of 20 mg/kg after oral administration in largemouth bass (Micropterus salmoides) at 28°C. The concentrations of ENF and of its metabolite ciprofloxacin (CIP) in plasma, liver, and muscle plus skin in natural proportions were determined using HPLC. The concentration–time data for ENF in plasma were best described by a two-compartment open model. After oral administration, the maximum ENF concentration (C_max) of 10.99 μg/ml was obtained at 0.60 hr. The absorption half-life (T_1/2Ka) of ENF was calculated to be 0.07 hr whereas the elimination half-life (T_1/2β) of the drug was 90.79 hr. The estimates of area under the plasma concentration–time curve (AUC) and apparent volume of distribution (Vd/F) were 1,185.73 μg hr/ml and 2.21 L/kg, respectively. ENF residues were slowly depleted from the liver and muscle plus skin of largemouth bass with the T_1/2β of 124.73 and 115.14 hr, respectively. Very low levels of ciprofloxacin were detected in the plasma and tissues. A withdrawal time of 24 days was necessary to ensure that the residues of ENF + CIP in muscle plus skin were less than the maximal residue limit (MRL) of 100 μg/kg established by the European Union.     

肉鸽新城疫和霉形体病混合感染的诊治

1999年 1 1月 2 5日 ,长春某肉鸽养殖专业户饲养的白羽王肉鸽发生以咳嗽、结膜炎、排黄绿色稀便和死亡为主要特征的疾病 ,发病率 70 %,死亡率 7%。经临床症状、病理剖检和实验室检查 ,确诊为新城疫和霉形体混合感染。采用泰乐菌素和新城疫高免卵黄液治疗 ,收到良好效果。     

Pharmacokinetics of enrofloxacin HCl‐2H2O (ENRO‐C), PK/PD,and Monte Carlo modeling vs. Leptospira spp. in cows

The pharmacokinetics, PK/PD ratios, and Monte Carlo modeling of enrofloxacin HCl‐2H₂O (Enro‐C) and its reference preparation (Enro‐R) were determined in cows. Fifty‐four Jersey cows were randomly assigned to six groups receiving a single IM dose of 10, 15, or 20 mg/kg of Enro‐C (Enro‐C₁₀, Enro‐C₁₅, Enro‐C₂₀) or Enro‐R. Serial serum samples were collected and enrofloxacin concentrations quantified. A composite set of minimum inhibitory concentrations (MIC) of Leptospira spp. was utilized to calculate PK/PD ratios: maximum serum concentration/MIC (C_max/MIC₉₀) and area under the serum vs. time concentration of enrofloxacin/MIC (AUC_0‐24/MIC₉₀). Monte Carlo simulations targeted C_max/MIC = 10 and AUC_0‐24/MIC = 125. Mean C_max obtained were 6.17 and 2.46 μg/ml; 8.75 and 3.54 μg/ml; and 13.89 and 4.25 μg/ml, respectively for Enro‐C and Enro‐R. C_max/MIC₉₀ ratios were 6.17 and 2.46, 8.75 and 3.54, and 13.89 and 4.25 for Enro‐C and Enro‐R, respectively. Monte Carlo simulations based on C_max/MIC₉₀ = 10 indicate that only Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cows, predicting a success rate ≥95% when MIC₅₀ = 0.5 μg/ml, and ≥80% when MIC₉₀ = 1.0 μg/ml. Although Enro‐C₁₅ and Enro‐C₂₀ may be useful to treat leptospirosis in cattle, clinical trials are necessary to confirm this proposal.     

林可-大观可溶性粉治疗雏鸡大肠杆菌和支原体人工混合感染试验

目的:观察国产盐酸林可霉素-硫酸大观霉素(Lincomycin Hydrochloride and Spectinomycin Sulfate)可溶性粉对鸡支原体和大肠杆菌混合感染所致雏鸡气囊病的治疗效果.方法:雏鸡气囊人工混合感染鸡毒支原体和大肠杆菌.结果:林可-大观可溶性粉按0.75～1.88g/l饮水治疗5 d,能有效地控制雏鸡大肠杆菌及支原体感染,降低感染鸡发病率、气囊病变指数、支原体抗体阳性率和死亡率;其效果与对照药物利高霉素100相近.     

Pharmacokinetics and bioavailability of doxycycline in ostriches (Struthio camelus) at two different dose rates

A bioavailability and pharmacokinetics study of doxycycline was carried out on 30 healthy ostriches after a single intravenous (IV), intramuscular (IM) and oral dose of 15 mg/kg body weight. The plasma doxycycline concentration was determined by HPLC/UV at 0 (pretreatment), 0.08, 0.25, 0.5 1, 2, 4, 6, 8, 12, 24 and 48 h after administration. The plasma concentration-time curves were examined using non-compartmental methods based on the statistical moment theory for only the higher dose. After IV administration, the elimination half-life (t_1/2β), mean residence time (MRT), volume of distribution at the steady-state (V_ss), volume of distribution (Vd_area) and total body clearance (Cl_B) were 7.67 ± 0.62 h, 6.68 ± 0.86 h, 0.86 ± 0.16 l/kg, 1.67 ± 0.52 l/kg and 2.51 ± 0.63 ml/min/kg, respectively. After IM and oral dosing, the mean peak plasma concentrations (C_max) were 1.34 ± 0.33 and 0.30 ± 0.04 µg/ml, respectively, which were achieved at a post-administration time (t_max) of 0.75 ± 0.18, 3.03 ± 0.48 h, respectively. The t_1/2β, Vd_area and Cl_B after IM administration were 25.02 ± 3.98 h, 23.99 ± 3.4 l/kg and 12.14 ± 1.71 ml/min/kg, respectively and 19.25 ± 2.53 h, 61.49 ± 7 l/kg and 40.19 ± 3.79 ml/min/kg after oral administration, respectively. The absolute bioavailability (F) of doxycycline was 5.03 and 17.52% after oral and IM administration, respectively. These results show that the dose data from other animals particularly mammals cannot be extrapolated to ostriches. Therefore, based on these results along with those reported in the literature, further studies on the pharmacokinetic/pharmacodynamic, in vitro minimum inhibitory concentration values and clinical applications of doxycycline in ostriches are required.     

单诺沙星对鸡败血支原体与大肠杆菌合并感染的药效学研究

采用试管二倍稀释法测得单诺沙星及其对照药物恩诺沙星、泰乐菌素对鸡败血支原体（MG）的最低抑菌浓度分别为0．0625、0.125、0.5mg/L。试验鸡每只左右气囊分别接种MG S6株菌液0.75ml、滴鼻约0.3ml，同时腹腔注射大肠杆菌菌液0.3ml,人工诱发鸡败血支原体与大肠杆菌合并感染的疾病模型。25、50、100mg/L的单诺沙星、500mg／L的恩诺沙星和500mg/L的泰乐菌素连续饮水5d给药，对人工合并感染鸡败血支原体与大肠杆菌病的治愈率分别为93.3%、96.6%、96.6%、93.3%、86.6%，而感染对照组的死亡率为23.3％。单诺沙星及其对照药物组的增重率显著高于感染对照组，并能极显著的降低感染鸡的死亡率、抗体反应阳性率、气囊损伤率及病原再分离率。     

1株鸡毒支原体的分离鉴定及体外敏感中药的筛选

本研究旨在对山东泰安地区鸡毒支原体的流行菌株进行分离培养及鉴定和纯化,并针对该分离株筛选体外敏感的中药,为后续进一步研究提供材料。采用液体培养法与固体培养法从病鸡组织样品中分离、培养和纯化鸡毒支原体,并通过瑞士染色和姬姆萨染色、血清学方法及分子生物学方法对分离株进行初步鉴定,在此基础上,采用微量稀释法测定8种中药对分离菌株的最小抑菌浓度（MIC）,从而筛选到对分离菌株敏感的中药。结果显示,分离菌株在鸡毒支原体液体培养基中增殖后,培养基颜色由红变黄且呈半透明状态,在固体培养基中培养后呈典型的"煎蛋"样儿菌落,均符合鸡毒支原体培养特性;瑞士染色和姬姆萨染色结果显示,菌体形态符合鸡毒支原体的特征;血清学鉴定结果显示,分离株与鸡毒支原体阳性血清发生凝集;分子生物学鉴定结果显示,所扩增的核酸序列与鸡毒支原体匹配度高达99%;MIC测定结果显示,中药黄连和黄柏对分离的鸡毒支原体的抑菌活性较强,属敏感范畴,其MIC分别为≤0.98和0.39 mg/mL,而中药金荞麦和鱼腥草对鸡毒支原体中度敏感,MIC均≥125 mg/mL,板蓝根、白鲜皮、当归、艾叶对鸡毒支原体均不敏感。综上所述,本研究成功分离到1株鸡毒支原体,并且筛选出4种对该菌株敏感的中药,分别为黄连、黄柏、金荞麦和鱼腥草,为后期进一步研究防治鸡毒支原体病的中药组方时提供参考依据。     

三种抗菌药体外对鸡败血支原体的敏感性

本研究测定了蒽诺沙星、泰乐菌素及土霉素对鸡败血支原体（BG44T株）的体外最小抑菌浓度（MIC）及泰乐菌素与土霉素的联合药敏作用。MIC测定采用试管两倍稀释法，联合药敏采用棋盘法，重复三次试验，以平均值作为结果。蒽诺沙星、泰乐菌素及土霉素对鸡败血支原体的MIC分别为0.025μg/ml、0.00625μg/ml和0.5μg/ml。泰乐菌素与土霉素的联合药敏试验的抑菌浓度指数为0.5，合用有协同作用。