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1.
Solute-solvent interactions have been studied by observing the influences of carbon tetrachloride, carbon disulphide, ethyl oleate, isopropyl myristate and octanol on the solubilities of testosterone and testosterone propionate in an inert solvent (cyclohexane). Complexation with testosterone was detected, but there was no evidence of complexation between testosterone propionate and these solvents. The solvent-induced infrared shifts were due to non-specific solvent effects. The existence of solute-solvent complexes between the two solutes and chloroform, previously detected by infrared absorption, was confirmed. The solubility technique, which has previously only been used with solid complexing agents, is adaptable to liquid complexing agents, but has limitations.  相似文献   

2.
The effects of 1-O-ethyl-3-butylcyclohexanol (OEBC) on the in vitro skin permeation of ten model drugs with different physicochemical properties across excised rat skin were evaluated. The results showed that the addition of OEBC significantly improved the in vitro skin permeation of the model drugs compared with the control (without OEBC). To clarify the promoting mechanism of OEBC, a multiple regression analysis was employed. When the permeation study was performed without OEBC, the permeability coefficient was quantitatively predicted as a linear function of molecular weight (log MW) and their lipophilicity (partition coefficient of drugs between octanol and water (log K(o/w)) with a sufficiently high correlation coefficient (r=0.842). It was suggested that skin permeation of drugs without OEBC was explained as a function of diffusion of drugs through the skin and partitioning of drugs to the skin. Although OEBC was administered, the permeability coefficient of drugs cannot be predicted as a linear function of log MW and log K(o/w) (r=0.572).  相似文献   

3.
Tissue:plasma (P(t:p)) partition coefficients (PCs) are important parameters describing tissue distribution of drugs. The ultimate goal in early drug discovery is to develop and validate in silico methods for predicting a priori the P(t:p) for each new drug candidate. In this context, tissue composition-based equations have recently been developed and validated for predicting a priori the non-adipose and adipose P(t:p) for neutral organic solvents and pollutants. For ionizable drugs that bind to different degrees to common plasma proteins, only their non-adipose P(t:p) values have been predicted with these equations. The only compound-dependent input parameters for these equations are the lipophilicity parameter, such as olive oil-water PC (K(vo:w)) or n-octanol-water PC (P(o:w)), and/or unbound fraction in plasma (fu(p)) determined under in vitro conditions. Tissue composition-based equations could potentially also be used to predict adipose tissue-plasma PCs (P(at:p)) for ionized drugs. The main objective of the present study was to modify these equations for predicting in vivo P(at:p) (white fat) for 14 structurally unrelated ionized drugs that bind substantially to plasma macromolecules in rats, rabbits, or humans. The second objective was to verify whether K(vo:w) or P(o:w) provides more accurate predictions of in vivo P(at:p) (i.e., to verify whether olive oil or n-octanol is the better surrogate for lipids in adipose tissue). The second objective was supported by comparing in vitro data on P(at:p) with those on olive oil-plasma PC (K(vo:p)) for five drugs. Furthermore, in vivo P(at:p) was not only predicted from K(vo:w) and P(o:w) of the non-ionized species, but also from K*(vo:w) and P*(o:w), taking into account the ionized species in addition. The P(at:p) predicted from K*(vo:w), P*(o:w), and P(o:w) differ from the in vivo P(at:p) by an average factor of 1.17 (SD = 0.44, r = 0.95), 15.0 (SD = 15.7, r = 0.59), and 40.7 (SD = 57.2, r = 0.33), respectively. The in vitro values of K(vo:p) differ from those of P(at:p) by an average factor of 0.86 (SD = 0.16, r = 0.99, n = 5). The results demonstrate that (i) the equation using only data on fu(p) as input and olive oil as lipophilicity surrogate is able to provide accurate predictions of in vivo P(at:p), and (ii) olive oil is a better surrogate of the adipose tissue lipids than n-octanol. The present study is an innovative method for predicting in vivo fat partitioning of drugs in mammals.  相似文献   

4.
The barrier properties of skin originate from its lipid bilayers whose ordered structure retards solute transport. The objective of this study is to develop a mathematical model that can predict skin permeability to small (MW < 500 Da), hydrophobic solutes based on the fundamental transport properties of skin lipid bilayers. We developed a mathematical model to predict two major transport properties (i.e., partition and diffusion coefficients) using important structural properties of lipid bilayers and molecular properties of the solute. The predictions are based on Scaled Particle Theory that calculates these properties using statistical mechanics of lipid chains. The calculations predict that solute partition coefficients in lipid bilayers are of the same order as those measured in isotropic solvents, such as octanol (K(o/w)). On the other hand, solute diffusion coefficients decrease exponentially with solute cross-sectional area. The resulting equation to predict skin permeability is given by P = 5.6 x 10(-6)K(0.7)(o/w)exp(-0.46r(2)(A1)--where r is solute molecular radius in Angstroms (A) and P is in cm/s. The predicted skin permeabilities compare well with the experimental data.  相似文献   

5.
The preparation and characteristics of insulin enteric microspheres (EMS) were studied and the gastrointestinal absorption enhancement of insulin by co-administering EMS with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) was determined. The w/o/w and o(1)/o(2) emulsion solvent evaporation methods were used to prepare insulin-hydroxypropyl methylcellulose phthalate (HPMCP) EMS. High-performance liquid chormatography determined the drug loading, entrapment efficiency, stability to pepsin, and drug dissolution rate in hydrochloric acid solution (pH 1.2) and phosphate buffer solution (pH 6.8). The hypoglycaemic effect was studied by orally administrating the insulin EMS and SNAC to rats. The particle size of EMS (o(1)/o(2)) and EMS (w/o/w) was about 500 and 30 micro m respectively, and drug loading was 7 and 3% respectively. After being incubated with 18 micro g/mL pepsin solution (pH 1) at 37 degrees C, only 20% of insulin in EMS (o(1)/o(2)) was digested within 4 h, while 60% of the insulin in EMS (w/o/w) was digested within 1 h. In hydrochloric acid solution (pH 1.2), EMS (o(1)/o(2)) had less drug dissolution than EMS (w/o/w). In phosphate buffer solution (pH 6.8), the entire drug release time of EMS (o(1)/o(2)) and EMS (w/o/w) was 75 and 10 min, respectively. After orally administering with SNAC, EMS (o(1)/o(2)) could decrease the blood glucose level of rats remarkably and maintain the hypoglycaemic effect for 4 h, while EMS (w/o/w) had just a weakly hypoglycaemic effect. The results showed that the characteristics-optimized EMS, i.e. EMS (o(1)/o(2)) incorporating SNAC, could enhance insulin absorption significantly in the gastrointestional tract by taking advantage of both protection from enzyme degradation and improvement of drug permeability.  相似文献   

6.
Ten 4-hydroxy and 4-alkoxy benzoic and phenylalkanoic acids have been investigated. Solubilities in aqueous buffer at pH 1·2 were determined, together with distribution coefficients between the buffer and either octanol or isopropyl myristate. When plotted against the total number of carbon atoms in the side chains, log octanol/water distribution coefficients gave two parallel straight lines, one for the substituted benzoic acids, and the other for the substituted phenylalkanoic acids. The slopes approximated to 0·5, the generally accepted value for methylene. Similar plots could be obtained with isopropyl myristate, provided the hydroxy acid results were ignored, and also when log aqueous solubilities were plotted against carbon number, although there was considerable scatter. The differences between the distribution coefficient results were explained in terms of solute-solvent interactions, and the scatter attributed to variations in the heats of fusion of the solutes. Yalkowsky's equation (1977), linking aqueous solubilities and melting points with distribution coefficients, was applied to the results, and found to be of limited predictive value.  相似文献   

7.
Ten 4-hydroxy and 4-alkoxy benzoic and phenylalkanoic acids have been investigated. Solubilities in aqueous buffer at pH 1.2 were determined, together with distribution coefficients between the buffer and either octanol or isopropyl myristate. When plotted against the total number of carbon atoms in the side chains, log octanol/water distribution coefficients gave two parallel straight lines, one for the substituted benzoic acids, and the other for the substituted phenylalkanoic acids. The slopes approximated to 0.5, the generally accepted value for methylene. Similar plots could be obtained with isopropyl myristate, provided the hydroxy acid results were ignored, and also when log aqueous solubilities were plotted against carbon number, although there was considerable scatter. The differences between the distribution coefficient results were explained in terms of solute-solvent interactions, and the scatter attributed to variations in the heats of fusion of the solutes. Yalkowsky's equation (1977), linking aqueous solubilities and melting points with distribution coefficients, was applied to the results, and found to be of limited predictive value.  相似文献   

8.
The purpose of this study was to evaluate structure-permeability relationships for chemicals through stratum corneum (SC) and viable epidermis/dermis (VED). In vitro skin permeation of ten compounds through excised rat skin was analyzed based on a two-layer diffusion model and the diffusion coefficients in SC (D(SC)) and VED (D(VED)) were determined. The relationships between the permeation parameters and the physicochemical parameters (octanol-water partition coefficient (log K(o/w)), and hydrogen bond donor number (HBD)) of the compounds were analyzed. D(SC) increased as lipophilicity increased, whereas D(VED) decreased for log K(o/w) > 2. Increases in log K(o/w) caused a decrease in the permeability coefficient from SC through VED (P(VED/SC)) for log K(o/w) > 1. The simulation study suggests that the in vitro skin permeation of a highly lipophilic compound is strongly controlled by skin thickness due to low diffusivity in VED. The present study suggests that VED act as a considerable permeation barrier for highly lipophilic compounds due to low diffusivity.  相似文献   

9.
A parameter that measures hydrogen-bond donor (HBD) strength of solutes is useful in modeling many biological interactions. The solvents octanol and chloroform, have about equal HBD strength and thus will accommodate the hydrogen-bond acceptor (HBA) groups in solutes about equally well. Because the solvent octanol has a strong acceptor oxygen, solutes with HBD groups will favor it over chloroform on that basis. With its eight alkane carbons, octanol also favors solutes with a significant amount of alkane character, a property referred to in this paper as 'excess alkane affinity' (XAA). On the other hand, it is easier to form a cavity in the solvent chloroform, so larger solutes tend to favor that solvent. After allowing for XAA and molecular volume, the difference between log P(oct) and log P(clf) is a measure of the effective sum of HBD. This value is given the symbol epsilonalpha and appears to be on the same scale as Abraham's summation operatoralpha(2)(H).  相似文献   

10.
The microencapsulation vesicle (MCV) method is a liposome preparation technique that reproducibly produces liposomes with homogeneous particle sizes with a high encapsulation efficiency. Liposomes encapsulating water-soluble drugs, lipophilic drugs and an amphiphilic drug were prepared by the MCV method and the encapsulation efficiency of the drugs was examined. Three kinds of egg yolk lecithin with different iodine values, i.e., purified egg yolk lecithin (PEL), partially hydrogenated purified egg yolk lecithin (R-20) and completely hydrogenated purified egg yolk lecithin (R-5), were used for membrane materials in order to explore the possible effects of membrane rigidity or surface area on the encapsulation efficiency of the drug. Water-soluble 5-fluorouracil showed 12-15% encapsulation efficiency, which was higher than those reported in the literature (less than 10%). With the MCV method, theoretically the initial drug-containing water phase was always separated from the dispersion medium by the lecithin-containing oil phase, which was advantageous to maintaining a higher encapsulation efficiency of the water-soluble drug. The encapsulation efficiency of lipophilic ibuprofen and flurbiprofen was around 90%. As for ketoprofen and liposomes were not formed when using hydrogenated egg yolk lecithin R-5, while the encapsulation efficiency using PEL or R-20 was around 80%. Amphiphilic amitriptyline hydrochloride resulted in a slightly higher encapsulation efficiency when dissolved in the water than the chloroform. Among the three kinds of lecithin, the most unsaturated PEL tended to show a higher encapsulation efficiency, probably due to differences in the packing geometry of the hydrophobic carbon chains in the membrane bilayer. The encapsulation efficiency of these drugs strongly correlated to the logP(octanol/water) and also tended to correlate to the logP(chloroform/water) for the order of the logP(chloroform/water) was almost the same as the order of the logP(octanol/water) in the drugs examined. As far as the results of this study, the logP(octanol/water) was considered to be a better indicator of the encapsulation efficiency of a drug in the MCV method.  相似文献   

11.
The 3-alkylcarbonyloxymethyl-5-fluorouracil (3-ACOM-5-FU) prodrugs have been characterized by their solubilities in isopropyl myristate (S(IPM)) and partition coefficients between IPM and pH 4.0 buffer (K(IPM:AQ)). Estimated S(AQ) values have been obtained from S(AQ) = S(IPM)/K(IPM:AQ.) The abilities of the prodrugs to deliver total 5-FU species from IPM suspensions through hairless mouse skin (J(i)) have been evaluated in diffusion cell experiments. All of the prodrugs were much more soluble in IPM than 5-FU, and the propionyloxymethyl (C2) member of the series was almost twice as soluble in pH 4.0 buffer. Except for the acetyloxymethyl (C1) member of the series, the 3-ACOM-5-FU prodrugs exhibited greater S(IPM) and S(AQ) values than the corresponding 1-alkylcarbonyloxymethyl (1-ACOM-5-FU) prodrugs. The 3-ACOM-5-FU prodrugs that exhibited greater S(IPM) and S(AQ) values than the 1-ACOM-5-FU prodrugs also exhibited greater J(i) values, except for the C2 member. The C2 member also gave the largest error in predicting J(i) using the transformed Potts-Guy equation. All of the 3-ACOM-5-FU prodrugs delivered more 5-FU as a percentage of J(i) than the 1-ACOM-5-FU prodrugs but were not more effective as a series at targeting dermal as opposed to transdermal delivery.  相似文献   

12.
Physicochemical analysis and Monte Carlo simulations were used to identify structural features which prevent oral absorption of HBED, a potent iron chelator. In water the dominant conformations of HBED involve the hydrophobic collapse of the two aromatic rings. These conformations are favored in polar media because they expose the polar phenolic hydroxy groups to the solvent and partially shield the nonpolar aromatic rings. In a less polar solvent such as chloroform, a symmetrical H-bond network between the carboxylates and the amines dominates the conformational space. This leads to the exposure of the phenolic hydroxy groups to the solvent, which is unfavorable for solvation. The low solubility of HBED in nonpolar solvents was confirmed experimentally by determination of the partition coefficients in octanol, chloroform, and cyclohexane and may explain the poor membrane permeability of this compound. The high conformational stability which disfavors partitioning into phospholipids is mainly due to the symmetrical H-bond network. Potentiometric titrations of a monoester of HBED in MeOH/water indicate that the protonation sequence was changed compared to that of the parent compound, suggesting that the symmetrical H-bond network was disrupted. Conformational analysis in chloroform confirmed that, in contrast to HBED, no symmetric interaction between the carboxylate and the nitrogen amines is possible in the half-ester and a variety of conformations which allow partial shielding of the polar phenolic OH groups are energetically possible. This theoretical model predicting a better solubility of the half-esters in nonpolar solvents was supported by the large increase in the partition coefficients in octanol, chloroform, and cyclohexane measured experimentally. The high absorbability predicted by physicochemical and computer simulation methods was corroborated by in vivo experiments in marmoset monkeys where the monoethyl ester derivative of HBED was well-absorbed orally while the parent compound was nearly ineffective in the same model.  相似文献   

13.
14.
The partition coefficients (Kps) of three N-monodemethylated metabolites of phenothiazines (chlorpromazine (CPZ), triflupromazine, and promazine) between phosphatidylcholine (PC) vesicles (SUV) and water were determined to evaluate their affinity to biomembranes by second-derivative spectrophotometry without any separation procedures. The second derivative spectra showed distinct derivative isosbestic points confirming the entire elimination of the residual background signal effects of the SUV, which were observed in the absorption spectra. From the relationship between PC SUV concentration and the derivative intensity change (DeltaD) of each metabolite induced by its interaction with the PC bilayer, the Kp values were calculated and could be obtained with the R.S.D. of below 10% (n = 5) proving an accuracy of the derivative method. The obtained Kp values were similar to those of the parent drugs (the relative differences were within 15%), although the partition coefficient of N-monodemethylated CPZ measured in an octanol/buffer system was reported to be about 1/18 of CPZ. The results obtained from the PC liposome/buffer system do not contradict with psychoactivity and brain accumulation of N-monodemethylated metabolites of phenothiazines, in contrast to the results of the octanol/buffer system.  相似文献   

15.
Retention (capacity) factors (k′ values) of immunosuppressive drugs were determined in microemulsion electrokinetic chromatography (MEEKC) systems as a tool for the indirect estimation of partition coefficients (POW) between 1-octanol and water. The microemulsions were based on phosphatidylcholine (PC) and bile acids (BAs) as biosurfactants and isopropyl myristate (IPM) as oil. Immunosuppressants were azathioprine (AZA), mycophenolate mofetil (MMF), tacrolimus (FK506) and cyclosporine A (CyA). Capacity factors of the analytes were determined from electrophoretic mobilities using an aqueous phosphate buffer (20 mM; pH 7.5) for all the systems. Retention was compared with that in the most commonly used microemulsion based on sodium dodecyl sulphate (SDS). log POW versus log k′ calibration lines were constructed using reference compounds with known POW. In addition, data of log POW of the immunosuppressants were determined by partitioning between octanol and water, and were calculated by the aid of computer program. A different sequence of log POW for two analytes was found in the biosurfactant-based systems compared with the SDS-containing one. Excellent agreement was observed between the log POW values derived from the microemulsions containing deoxycholate compared with the data determined by partitioning between octanol and water. It was concluded that the retention factors in the systems with biosurfactants are good estimators for the partitioning in biological systems.  相似文献   

16.
The aim of this study was to employ the novel skin sandwich system in order to quantify the influence of the octanol-water partition coefficient on follicular drug absorption in human skin. To this end, seven different drugs - estradiol, corticosterone, hydrocortisone, aldosterone, cimetidine, deoxyadenosine and adenosine - exhibiting a wide range of log octanol-water partition coefficients (logK(o/w)) but relatively similar molecular weights were selected as candidate solutes. Application of the skin sandwich technique yielded an interesting relationship between % follicular contribution and logK(o/w). The follicular contribution to total flux was small (4 and 2%) for the two most lipophilic drugs but varied between 34 and 60% for the remaining drugs of intermediate and low logK(o/w) values. Lipophilicity seems to be an important modulator of drug absorption into follicular orifices only above a critical logK(o/w) threshold. Below this critical logK(o/w) value, lipophilicity does not apparently influence the follicular contribution in an obvious way and the process is probably governed by other molecular properties. Identification of these other active properties would require performing this kind of a study on a much larger set of candidate drugs.  相似文献   

17.
PURPOSE: To determine whether the delivery of a phenolic parent drug by its alkyloxycarbonyl (AOC) prodrugs through hairless mouse skin would show similar dependencies on water and lipid solubilities that similar prodrugs of more polar heterocyclic amide and imide parent drugs have shown. METHODS: Flux through hairless mouse skin from suspensions in isopropyl myristate (J(MIPM)), solubilities in IPM (S(IPM)) and water (S(AQ)), and partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K(IPM:4.0)) were measured for two series of AOC derivatives of acetaminophen (APAP); their solubilities in pH 4.0 buffer (S4.0) were estimated from S(IPM)/K(IPM:4.0). Log J(MIPM) values were calculated from the n = 43 coefficients for the parameters in the transformed Potts-Guy (Roberts-Sloan) equation, and the average error of prediction (delta log J'(IPM)) was calculated. The J(MIPM), S(IPM), S4.0, and molecular weight (MW) data for this series and two other series were combined with the n = 43 database to give a n = 61 database, and new best fit coefficients were determined for the Roberts-Sloan equation: log J(MIPM) = x + y log S(IPM) + (1 - y) log S4.0 - z MW. RESULTS: All of the 4-AOC-APAP derivatives underperformed based on their predicted log J(MIPM) (delta log J'(MIPM) = 0.275 +/- 0.147 log units) and, although the two more water soluble members of this more lipid soluble series were more effective than APAP, they were only marginally so: <2 times. Addition of three new series to the n = 43 database for the Roberts-Sloan equation did not substantially change the coefficients to the parameters: x, y, z, and r2 = -0.322, 0.530, 0.00337 and 0.92, respectively. CONCLUSIONS: The topical delivery of a model phenolic drug by its AOC prodrugs through hairless mouse skin from IPM shows the same dependence on S(IPM), S4.0, and MW as the delivery of polar heterocycles by their similar prodrugs.  相似文献   

18.
Formulation of electrically conducting microemulsion-based organogels   总被引:3,自引:0,他引:3  
Gelatin-containing, electrically conducting, rigid water-in-oil (w/o) microemulsion-based organogels (MBG), both with and without the presence of a model drug, have been prepared using pharmaceutically acceptable oils and surfactants. As a precursor to MBG formation, preliminary formulation work was carried out investigating the factors affecting the preparation of w/o microemulsions containing large amounts of dispersed aqueous phase. From these studies isopropyl myristate (IPM) was favoured as oil due to its ability to support w/o microemulsion formation over a wide range of compositions. The single most effective surfactant for stabilising the w/o microemulsions was found to be Aerosol-OT (AOT), although synergistic effects on the extent of w/o microemulsion formation were observed upon its combination with a variety of non-ionic surfactants. Upon addition of gelatin to the w/o microemulsion, MBG could be formed when using AOT as stabiliser with most of the oils investigated (with the exception of the medium and large triglyceride oils, Miglyol 812 and soybean oil, respectively) and with a number of AOT/non-ionic surfactant/IPM combinations (both in the presence and absence of model drugs such as sodium salicylate). MBG could not however be formed with non-ionic surfactants alone, or when used in combination with another non-ionic surfactant (regardless of the oil used). This latter observation was found to be not only a result of the inadequate level of water available for hydration of the surfactant head group and any gelatin present but also a consequence of the inability of these systems to form, upon heating, the percolated microstructures necessary to facilitate the supramolecular assembly of gelatin at the macroscopic level, a pre-requisite for MBG formation.  相似文献   

19.
The partitioning of six phenothiazines was determined between phosphate buffer (pH 6.0) and the lipid phases of cyclohexane, n-octanol and dimyristoyl phosphatidylcholine (DMPC). For DMPC liposomes studies were carried out both below and above the phase transition temperature (Tc) of the liposomes. The partitioning of chlorpromazine hydrochloride between n-octanol and phosphate buffer was both pH and concentration-dependent. A linear relationship between the absolute temperature (T–1) and the logarithm of the equilibrium partition coefficient (ln K) was derived. The temperature dependence of the partition coefficient (K) over the temperature range 20–40° C in cyclohexane and n-octanol, and 5–40° C in DMPC liposomes, permitted the calculation of free-energy (G), enthalpy (H) and the entropy (S) of partitioning. Both the entropy and the enthalpy of partitioning of phenothiazines were positive in the three systems studied. In general, the partitioning of phenothiazines in cyclohexane, n-octanol and DMPC liposomes (both above and below the phase transition temperature (Tc)) is entropically controlled. Correlation was not however found between the free-energy of oil-water partitioning and liposome-water partitioning which may be attributed to the formation of surface associated phenothiazine in high concentrations at the liposome water interface. The concentration dependent partitioning of chlorpromazine in DMPC liposomes may be attributed to the adsorbed fraction of drug.  相似文献   

20.
孙进  程刚  何仲贵  王淑君 《药学学报》2003,38(10):791-794
磷脂膜色谱 (immobilizedartificialmembranechromatography,IAMC)是 2 0世纪 90年代初发展起来的一个高通量筛选药物与磷脂膜相互作用和具有适宜体内药代动力学特征候选药物的工具[1~ 4 ] 。近年来 ,研究结果[5,6 ] 表明 ,由于磷脂膜色谱能较好的模拟细胞膜有序磷脂层的空间环境 ,因此 ,它通常要比正辛醇 水系统更能准确的评价药物与生物膜的相互作用和获得更精确的药物亲脂性参数。因为尚未见磷脂膜色谱和正辛醇 水系统亲脂性测量尺度的系统性比较研究 ,所以本文选择了 2 7个不同化学结构类型药物的集合 ,包括酸性、碱性、中性和两性化合物 ,分别使用正辛醇 水系统和磷脂膜色谱两种生物膜相互作用评价系统对这一系列化合物的亲脂性参数进行考察 ,进而比较这两种不同的生物膜模拟系统。材料与方法药品与试剂 格帕沙星、环丙沙星、左氧氟沙星和OPC 1 72 0 3由日本大冢制药株式会社提供 ;HSR 90 3和NR 762由日本北陆制药株式会社提供 ;奎尼丁、普萘洛尔、阿莫西林、对氨基水杨酸、吡哌酸、利多卡因、普鲁卡因酰胺和正辛醇 (SigmaChemCo,StLouis,...  相似文献   

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