氟尿嘧啶的脂水分配系数与鼻腔吸收速率常数的相关性研究

目的:考察氟尿嘧啶(5-FU)的脂水分配系数与鼻腔吸收速率常数的关系。方法:测定不同pH值条件下(4、6、7、8、10)5-FU在正辛醇-水中的脂水分配系数;采用大鼠鼻腔在体重循环方法测定不同pH值条件下5-FU鼻腔吸收速率常数,并将2种结果数据进行回归。结果:随着pH值的升高5-FU脂水分配系数及鼻腔吸收速率常数均增大,且二者呈正相关(r=0.9838)。结论:药物鼻腔吸收速度常数与脂水分配系数之间有良好的线性关系。     

药物脂水分配系数测定的微乳液电动色谱新方法研究

目的建立一种测定药物脂水分配系数的微乳液电动色谱(MEEKC)新方法，以避免测定时必须使用微乳相标记物，以及减小和评价测量误差。方法以系列化合物在MEEKC中的迁移时间t_m值与其脂水分配系数之间的关系，进行非线性拟合得出微乳相的虚拟迁移时间t_me，再建立标准曲线以测定所选取药物的脂水分配系数；从理论上评价测定结果准确度与t_m相关性，并以此评价测定结果的准确度。结果所选取的4种药物脂水分配系数的MEEKC测定值与摇瓶法测定值基本吻合，其平均差值为0.15，其测定准确度与t_m的相关性符合理论模型的分析。结论无微乳相标记物的MEEKC新方法简单、快速、可靠、重现性好，测定脂水分配系数的准确度较高，可用作药物脂水分配系数的测定。     

三七总皂苷油包水微乳的处方筛选及体内外评价

筛选口服油包水(W/O)微乳处方以提高三七总皂苷(panax notoginsenoside，PNS)中人参皂苷Rb₁的体内肠吸收，分别采用大鼠体内肠吸收、脂质体和平行人工膜(parallel artificial membrane permeability assay，PAMPA)等模型分别研究微乳的体内药代动力学及体外对膜流动性和药物膜转运性质的影响。主要以磷脂/乙醇(SP/EtOH)为表面活性剂，与PNS水溶液(400 mg·mL^-1)和不同油相分别制备11个W/O微乳处方。多数微乳处方可提高药物的大鼠体内肠吸收，其吸收促进作用除与所含表面活性剂有关外，不同油相的选用也会产生一定影响，其吸收促进作用大小为月桂酸甘油酯≈肉蔻豆酸异丙脂>棕榈酸异丙脂>棕榈酸异辛酯。长链(>C₁₄)脂肪酸酯的吸收促进作用低于中链脂肪酸酯(C₈~C₁₄)。多数微乳处方可不同程度的提高脂质体的膜流动性。PAMPA研究中，稀释后微乳(D-ME)中药物的有效透过系数(P_e)多数高于PNS对照溶液，表明微乳中的组分可以提高药物的膜透过能力，稀释前微乳(ME)的P_e与大鼠体内肠吸收具有相对较好的直线相关性(r=0.774 0)。W/O微乳可以促进人参皂苷Rb₁的肠吸收，吸收促进作用与其提高生物膜流动性有一定关系。PAMPA可以尝试引入制剂处方研究(如吸收促进剂等)的某些领域中。     

吸收促进剂对人参皂苷Rg1鼻腔吸收的促进作用及鼻腔毒性

目的考察吸收促进剂对人参皂苷Rg1鼻腔黏膜的吸收促进作用以及对鼻腔黏膜毒性。方法采用大鼠在体鼻腔循环考察人参皂苷Rg1鼻腔吸收及吸收促进剂的促吸收作用，在体蟾蜍上腭纤毛法评价药物对纤毛运动的影响；考察吸收促进剂对家兔血红细胞的溶血作用、对鼻腔循环液中总蛋白和乳酸脱氢酶的影响及对鼻腔黏膜形态学的影响。结果人参皂苷Rg1鼻腔吸收必须加入吸收促进剂。各种吸收促进剂的促进作用为：1%去氧胆酸钠作用显著；1%甘草酸二钾和1%氮酮作用中等；1% Tween-80，2% β-环糊精、0.5%冰片、0.5%壳聚糖、5%羟丙-β-环糊精和0.1% EDTA等作用微弱。吸收促进剂对鼻腔黏膜毒性影响：1%去氧胆酸钠、1%氮酮和1%甘草酸二钾毒性大；1% Tween-80，2% β-环糊精及5%羟丙-β-环糊精等毒性中等；0.5%冰片、0.5%壳聚糖和0.1% EDTA毒性小。结论0.5%冰片与0.5%壳聚糖可安全有效地促进人参皂苷Rg1的鼻腔吸收。     

Enmein的平衡溶解度、油水分配系数及环糊精包合作用的研究

目的 测定Enmein的平衡溶解度、油水分配系数,考察环糊精对其包合作用,为制剂研究奠定基础。方法 采用HPLC测定Enmein在不同溶剂中的平衡溶解度;采用摇瓶法测定Enmein在不同条件下的油水分配系数;以羟丙基-β-环糊精（HP-β-CD）、羟丙基-γ-环糊精（HP-γ-CD）2种材料制备Enmein包合物,经溶解度试验,比较溶解性能的变化。结果 （25±0.5）℃振摇24 h,Enmein在纯水中溶解度为（239.32±4.99）μg·mL^-1,在多种常见的有机溶剂中微溶,在常用的药用油溶剂中不溶;正辛醇-水体系中,测得Enmein油水分配系数P为4.64,不同生理pH环境及环糊精材料,对其lgP影响不大;经过2种材料包合后,Enmein的溶解度有所提高,其中以HP-γ-CD的增溶效果最好。结论 Enmein在水、常见的药用油溶剂中溶解性均不好;消化道生理pH变化及包合材料对Enmein的吸收影响不大;用Enmein的HP-γ-CD包合物为原料制备制剂,有利于提高其生物利用度。     

艾司氯胺酮鼻腔喷雾剂辅助治疗难治性抑郁症安全性meta分析

目的 采用meta分析全面了解艾司氯胺酮鼻腔喷雾剂辅助治疗难治性抑郁症的安全性。方法 搜索艾司氯胺酮鼻腔喷雾剂+口服抗抑郁药的随机对照试验，并进行meta分析。结果 最终5个随机对照试验，1 019例患者纳入研究。与对照组比较，试验组出现了更多的解离症状（RR=6.35，95% CI，2.84~14.23，P<0.000 01）、镇静（RR=5.47，95% CI，2.05~14.57，P=0.000 7）、嗜睡（RR=2.66，95% CI，1.30~5.44，P=0.007）、头痛（RR=1.38，95% CI，1.05~1.83，P=0.02）、眩晕（RR=5.87，95% CI，3.30~69.79，P<0.000 01）、头晕（RR=2.98，95% CI，1.33~6.68，P=0.008）、感觉迟钝（RR=10.25，95% CI，3.65~28.83，P<0.000 1）、焦虑（RR=2.01，95% CI，1.20~3.37，P=0.008）、感觉异常（RR=6.62，95% CI，2.75~15.98，P<0.000 1）、恶心（RR=4.05，95% CI，2.71~6.05，P<0.000 01）、味觉异常（RR=1.81，95% CI，1.35~2.42，P<0.000 1）。亚组分析显示，与对照组比较，艾司氯胺酮鼻腔喷雾剂28 mg组不良反应没有统计学意义；除了嗜睡、头痛、味觉异常以外，56，84 mg 2个亚组的不良反应有统计学意义。结论 艾司氯胺酮鼻腔喷雾剂辅助治疗会增加患者不良反应，但是不良反应轻微。     

前列腺素E1经不同途径给药后的大鼠体内药效学比较

本文研究了前列腺素E₁(PGE₁)分别经不同途径给药后的大鼠体内药效学，旨在寻找目前PGE₁注射给药的替代途径。以PGE₁降压效应作为药效学指标，以静脉注射为对照，分别测定PGE₁经鼻腔、舌下、肌肉(im)、腹腔(ip)给药后的药效学参数，包括峰效应时间(Tmax)，血压下降最大百分数(Emax，%)，效应持续时间(T_d)以及血压下降百分数-时间曲线下面积(AUC，%·min)。研究结果表明，PGE₁经上述途径给药后，药效学参数Emax，T_d，AUC等均随给药剂量的增加而增大，提示存在明显的剂量-效应关系。根据所测Tmax值，推断上述给药途径其吸收速率的大小顺序为：鼻腔≈im>ip>舌下；依据所测药理生物利用度(PF)值，预测药物绝对生物利用度的顺序为：鼻腔>im≈ip>舌下。上述研究结果提示，PGE₁经鼻腔与舌下黏膜给药，有望替代目前的注射给药。     

2010—2019年柳州市中医医院肺炎克雷伯菌耐药率与抗菌药物使用量的相关性分析

目的 分析柳州市中医医院2010—2019年肺炎克雷伯菌耐药情况,并探讨肺炎克雷伯菌耐药率与抗菌药物使用量的相关性。方法 回顾性分析柳州市中医医院2010年1月—2019年12月收治的住院患者送检标本资料,统计肺炎克雷伯菌对不同抗菌药物的耐药率,采用Pearson分析法分析肺炎克雷伯菌耐药率与抗菌药物的使用量的相关性。结果 广西壮族自治区柳州市中医医院2010—2019年共分离出肺炎克雷伯菌8 082株,检出的肺炎克雷伯菌对各类抗菌药物的耐药率呈波动变化,未见明显的持续增长。抗菌药物使用中,β-内酰胺类占主导,每年使用量均占总使用量的50%以上,排名第2位的为喹诺酮类。相关性分析显示肺炎克雷伯菌对阿米卡星的耐药率与氨基糖苷类、阿米卡星使用量具有相关性（R=0.890,P=0.010;R=0.175,P=0.011）;对环丙沙星的耐药率与环丙沙星的使用量具有相关性（R=0.949,P=0.000）;对美罗培南的耐药率与美罗培南的使用量具有相关性（R=0.729,P=0.0.017）。结论 某些抗菌药物的使用与肺炎克雷伯菌的耐药率具有相关性,为减少细菌耐药,应继续加强抗菌药物监管,提高临床合理使用抗菌药物水平。     

关于电穿孔对咖啡因透皮过程影响的一种数学建模方法

目的建立描述电穿孔促渗药物经皮渗透的数学模型,分析电脉冲对经皮渗透过程的影响。方法以咖啡因为模型药物,测定不同电脉冲强度(电压、脉冲数等)下的渗透速率,建立快-慢响应双通道假设的近似数学模型。 结果对1组咖啡因实验资料,在仅视慢响应通道扩散系数的最大增加量D₁和快响应扩散通道的最大有效面积分数a₂为条件相关参数的假定下,模型偏差远小于重复实验误差,而且这两个参数与脉冲总能量E的线性相关系数各为0.955(P=0.00)和0.924(P=0.00)。结论模型很好地拟合数据,关于Fick扩散律及快-慢响应双通道假设均可接受;而且可视D₁和a₂为条件相关参数,余为条件无关参数。     

药物透过血脑屏障的3D-QSPR:H2受体拮抗剂的CoMFA和EVA分析

目的：药物透过血脑屏障是药代动力学的重要过程,H₂受体拮抗剂是作用于神经外周的抗溃疡药物,为避免该类药物透过血脑屏障损伤中枢神经,产生毒副作用,指导该类药物的设计与合成。方法和结果：选择了不依赖于实验参数的比较分子力场分析(CoMFA)方法和最近发展的本征值(EVA)方法,建立了有关的三维药代动力学性质(3D-QSPR)模型。CoMFA模型的统计参数为：交叉验证系数r²_cv=0.625,相关系数r2=0.893,F_3,17=47.270,标准偏差SE=0.254;EVA模型的统计参数为：交叉验证系数r²_cv=0.697,相关系数r²=0.922,F_3,17=67.766,标准偏差SE=0.203。结论：两种方法都能建立三维定量构效模型,EVA模型有更高的预测能力。     

Mechanism of nasal absorption of drugs I: Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats

The effect of rate of perfusion, volume, pH of the perfusate, and partition coefficient of the drug on the rate of in situ nasal absorption in rats was examined. The studies showed that the rate constant for the nasal absorption of phenobarbital was independent of the rate of perfusion above a value of 2 mL/min. The nasal absorption of benzoic acid was found to depend on the pH of the perfusate with the benzoate anion being absorbed at a rate one-fourth of that of benzoic acid. The effect of lipid solubility on the extent of nasal absorption was studied using a series of barbiturates. The rate and extent of absorption was found to be dependent on the chloroform-water partition coefficient of the barbiturate. The effect of the volume of the perfusate on the absorption rate constant of phenobarbital, phenol red, tyrosine, and propranolol was studied. The data obtained showed that a linear relationship existed between the rate constants of absorption and the reciprocal of the volume of the perfusate. Using this in situ relationship it was possible to predict in vivo absorption rate constants for propranolol and L-tyrosine when volumes of 0.1 mL were administered. The calculated values for these compounds were found to be close to those determined in in vivo experiments. This indicates that the in situ technique can be used to predict in vivo absorption rate constants.     

Absorption of drugs from the nasal mucosa of rat

Absorption of drugs through the nasal mucosa was studied to find out the suitability of the nasal mucosa as a new site of administration. The in situ recirculation test with the nasal cavity of rat showed that absorption of weak electrolytes such as salicylic acid and aminopyrine was highly dependent on the amount of undissociated molecules following the pH partition theory. The in vivo studies on absorption through the nasal mucosa showed that an orally well-absorbed drug such as salicylic acid and bucolome was absorbed comparably to that by injection, while poorly absorbed drugs such as phenol red, sulbenicillin, cefazolin, cephacetrile and insulin, were also absorbed well through the nasal mucosa. These results suggest that the nasal route of administration would be useful as a new route of administration of drugs, to enhance the drug bioavailability.     

鼻腔作为全身给药途径的研究

目的：以安乃近、对乙酰氨基酚、双氯灭痛、吲哚美辛、吡罗昔康和普罗帕酮为模型药，进行药物的鼻腔吸收研究，完善和发展鼻腔吸收的系统研究方法。方法：采用Ｖ－Ｃ扩散池进行离体透膜试验；采用大鼠鼻腔循环装置进行在体内吸收试验；鼻腔全身吸收实验在志愿者体内进行，同时还采用示踪元素标记化合物法进行了药物的鼻腔吸收研究。此外，对药物的鼻粘膜纤毛毒性也进行了研究。结果：安乃近、对乙酰氨基酚鼻腔吸收良好，有望开发为鼻腔给药制剂；普罗帕酮鼻纤毛毒性较大，不适合鼻腔给药；另三种药物初步结果表明鼻腔吸收良好，值得进一步研究。结论：本文提出并采用的一系列研究方法适合作药物鼻腔吸收研究     

石杉碱甲的大鼠鼻黏膜吸收研究

目的研究治疗早老性痴呆症药物石杉碱甲的鼻黏膜吸收特性。方法采用石杉碱甲进行大鼠鼻腔灌流实验,测定循环液中药物浓度。结果随着石杉碱甲的浓度增加(0.125~0.75mg/mL),其吸收速度呈线性增加(r=0.995)。在pH值5.5~7.5内,随pH值的升高,其吸收速度增加。结论石杉碱甲的鼻黏膜吸收良好,其吸收程度与药液的浓度和pH值有较好的相关性。     

Nasal absorption of tyrosine-linked model compounds

The objective of this research is to explore the amino acid carrier-mediated pathway for nasal uptake of tyrosine-linked model compounds. These molecules were synthesized by ether linkage between the aromatic hydroxyl group of L-tyrosine and the terminal hydroxyl group of model compounds. An enzymatically stable linkage was utilized to link the model compounds to L-tyrosine so that the loss of the compound from perfusate signals absorption only without complication from metabolism. The rat in situ nasal perfusion technique was utilized in this investigation. The analyte concentrations remaining in the nasal perfusates were quantitated by a reversed-phase high-performance liquid chromatography. All L-tyrosine-linked model compounds were absorbed across the nasal mucosa (15-50% absorbed), and the extent of nasal absorption was concentration dependent. The apparent first-order rate constants of intact conjugate loss from the nasal perfusate were calculated. The Michaelis-Menten kinetic model was applied to fit the perfusion data. The Michaelis constant, K(m), and maximum or saturation rate of compound loss from the perfusate, V(max), were calculated from Lineweaver-Burk plots [e.g., K(m) and V(max) are 0.57 mM and 0.00515 micromol/min, respectively, for one of the model compounds, O-(4-carboxyphenylmethyl)-L-tyrosine]. The absorption characteristics of all these model compounds exhibited saturable kinetics, whereas their parent compounds, possessing different octanol-water partition coefficients, showed either no absorption or transport by passive diffusion. Nasal uptake of L-tyrosine conjugates was inhibited by L-tyrosine. The results from this study indicate that nasal absorption of L-tyrosine-linked compounds is probably through an amino acid transport system. Exploitation of the amino acid transport pathway may be utilized to improve nasal absorption of poorly permeable drugs.     

雌二醇甲基化-β-环糊精包合物鼻黏膜吸收动力学研究

目的研究雌二醇甲基化 β环糊精包合物鼻黏膜吸收动力学,考察循环液的体积和流速对雌二醇甲基化 β环糊精包合物鼻黏膜吸收的影响。方法采用大鼠在体灌流模型,并固定循环液体积和流速。结果吸收速度常数(k)随着循环液体积的增加呈下降趋势;当流速较小时,随着流速的增加,k增大,但超过2 5mL·min-1后,k反而随着流速的增加而减小;循环液为5mL、流速2 5mL·min-1时,不同浓度的雌二醇甲基化 β环糊精包合物鼻黏膜吸收速度常数不同,且随药液浓度的增加而增大,经t检验(P <0 0 5 ) ,不同浓度间存在显著差异。结论雌二醇环糊精包合物鼻黏膜吸收具有浓度依赖性,在固定浓度条件下其动力学过程符合零级动力学模型,吸收速度常数与包合物的药物动力学解离 缔合平衡有关     

Mechanism of nasal absorption of drugs. II: Absorption of L-tyrosine and the effect of structural modification on its absorption

The nasal absorption of L-tyrosine and the effect of structural modification on that absorption have been studied using an in-situ experimental technique. The extent of nasal absorption of the amino acid was found to be the same at pH values of 4.0 and 7.4 but dependent on concentration in the range of 2.8 X 10(-4)-2.2 X 10(-3) M. O-Acyl-L-tyrosine esters, although possessing higher octanol-water (pH 7.4) partition coefficients, have the same rate of nasal absorption as the parent amino acid. N-Acetyl-L-tyrosine, on the other hand, was found to have both partition coefficient and nasal absorption rate similar to those of L-tyrosine. Esterification of the carboxyl moiety of L-tyrosine results in derivatives that hydrolyze in the in-situ perfusion medium generating the original amino acid. The rate of nasal absorption of these derivatives was, therefore, determined from an overall disappearance rate which accounted for the rate of hydrolysis to L-tyrosine. These carboxylic esters were absorbed 4 to 10 times faster than L-tyrosine. Although the carboxylic esters of L-tyrosine possess higher octanol-water partition coefficients than the parent amino acid, the differences in the rates of nasal absorption could not be attributed solely to partition coefficient. The enhancement in the rate of absorption observed for these esters was attributed instead to the absence of the negative charge on the carboxylate moiety. It is a result of this negative charge that the rates of nasal absorption of L-tyrosine, O-acyl-L-tyrosine esters and N-acetyl-L-tyrosine are similar, despite significant differences in their partition coefficients.     

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure-pharmacokinetic relationships

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.     

GI absorption of beta-lactam antibiotics I: kinetic assessment of competing absorption and degradation in GI tract

An equation was derived for the simultaneous assessment of rate constatns for absorption and nonenzymatic degradation of unstable drugs in in situ absorption experiments. The equation was substantiated by using a variety of beta-lactam antibiotics in the recirculation technique through the rat small intestine. Plots of the apparent first-order rate constant for the disappearance of the drug from the gut lumen versus the reciprocal of the volume of recirculating solution yielded a straight line with a slope equal to the intrinsic absorption rate constant and with an intercept equal to the nonenzymatic degradation rate constant in the GI lumen. The kinetic method for evaluation of the absorption rate constant also was developed for a more complex situation in the GI lumen involving absorption, nonenzymatic degradation, and enzymatic metabolism. The proposed method was confirmed with carbenicillin indanyl, which was metabolized rapidly to carbenicillin by the action of nonspecific esterase in the intestine. In the absence of information of Michaelis--Menten kinetic parameters, the present method is advantageous for evaluation of the intrinsic absorption rate of all unstable drugs.