抗菌药物的PK/PD参数与优化抗菌治疗

目的概述了抗菌药物药动学/药效学(PK/PD)参数与临床优化抗菌治疗的关系。方法参阅相关文献,进行综合、分析和归纳。结果根据PK/PD参数,抗菌药物大致可分为浓度依赖性、时间依赖性且半衰期较短、时间依赖性且抗菌活性持续时间(如PAE)较长者三类。结论 PK/PD参数对临床优化抗菌治疗和合理应用抗菌药物都具有重要意义。     

The pharmacokinetics and pharmacodynamics of doxazosin compared with atenolol during long-term double-blind treatment

Summary The pharmacodynamics of doxazosin and atenolol were compared on single study days in 39 patients with mild to moderate hypertension receiving long-term double-blind treatment. The pharmacokinetics of doxazosin were investigated in the 20 patients receiving doxazosin. Individually titrated once daily doses of doxazosin were 1, 2, 4, 8 or 16 mg and of atenolol 50 or 100 mg. Patients were first investigated after at least one month on constant dose and then again after at least a further three months. Mean plasma concentrations of doxazosin were proportional to dose and the plasma half-life was 11.5 h and independent of dose. There was low variability of doxazosin plasma concentrations between patients receiving the same dose. Concentrations and half-life were unchanged during the period between investigations. Mean reductions of AUC (0–12 h) blood pressure during the 12-h period post-dose and of blood pressure at 24 h post-dose were not statistically different between doxazosin and atenolol. There was effective control of blood pressure by both drugs at all time points of the day. The pharmacokinetic and pharmacodynamic results obtained in this study are compatible with the use of doxazosin in a once daily dose regimen for the treatment of essential hypertension.     

脉通胶囊药效学实验研究

目的 通过不同的实验方法和动物模型对脉通胶囊的功能进行验证,为临床合理用药提供依据.方法 采用注射胶原蛋白-肾上腺素诱导剂后记录各组小鼠5 min内死亡数和15 min内发生的偏瘫数,观察其体内抗血栓作用;采用大鼠体外血栓形成实验的方法,观察其体外抗血栓作用;采用测定角叉菜胶所致大鼠足趾肿胀度的方法,观察其抗炎作用;采用记录注射醋酸后各组小鼠第一次扭体反应出现时间及15 min内扭体次数的方法,观察其镇痛作用.结果 脉通胶囊可明显减少小鼠5 min内死亡数和15 min内出现偏瘫数(P<0.05);可明显抑制大鼠体外血栓形成(P<0.05);可明显减少致炎大鼠足趾肿胀率(P<0.05或P<0.01);可明显延长致痛小鼠第一次扭体发生时间(P<0.05)及明显减少扭体次数(P<0.05).结论 脉通胶囊具有抗血栓、抗炎镇痛作用.     

The pharmacokinetics and pharmacodynamics of bumetanide in normal subjects

The pharmacokinetics and pharmacodynamics of bumetanide (1 mg) administered either orally or intravenously were studied in a group of normal subjects using high-pressure liquid chromatography. A two-compartment model adequately fitted the intravenous data. Renal clearance (85 ml min^–1 contributed 65% to the total elimination of bumetanide irrespective of whether a model-dependent or model-independent method was used. Oral administration of bumetanide elicited a greater and a more prolonged pharmacological response than did intravenous bumetanide. An attempt is made to relate the pharmacokinetics of the drug to its pharmacodynamics.     

Pharmacokinetics and pharmacodynamics of azosemide

Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

吡硫翁锌乳膏对银屑病样模型小鼠的药效学研究

目的：研究吡硫翁锌乳膏抗银屑病的作用。方法：采用小鼠雌激素期的阴道上皮模型和鼠尾鳞片表皮银屑病样皮损模型,观察吡硫翁锌乳膏抗银屑病的作用。在小鼠雌激素期的阴道上皮模型中,吡硫翁锌乳膏经小鼠阴道给药,连续给药14 d,观察小鼠阴道上皮分裂指数的变化。在鼠尾磷片表皮银屑病样皮损模型中,吡硫翁锌乳膏被涂抹于小鼠尾部,连续给药14 d,观察鼠尾含有颗粒层的鳞片数目的变化,及对小鼠上皮细胞有丝分裂及表皮细胞分化的影响。结果：经吡硫翁锌乳膏处理后,小鼠阴道上皮分裂指数明显降低,鼠尾含有颗粒层的鳞片数目明显增加。结论：吡硫翁锌乳膏能明显抑制阴道上皮细胞分裂,促进尾鳞片表皮颗粒层形成,具有潜在的抗银屑病样的作用。     

The effect of decontamination procedures on the pharmacodynamics of venlafaxine in overdose

AIMS

To investigate the relationship between decontamination procedures and seizure events caused by venlafaxine overdose and to estimate the time at which 90% of patients would have had their first seizure in the presence and absence of decontamination.

METHODS

Data were collected from 319 patients who took an overdose of venlafaxine on 436 occasions. Seizures occurred on 24 of 436 occasions (5%). Patients received one of single dose activated charcoal (SDAC), whole bowel irrigation (WBI), a combination of either (SDAC/WBI) or no decontamination. Logistic regression and time to event analysis were used to investigate the influence of dose and decontamination on the probability of seizures and time to 90% (t₉₀) of seizure, respectively.

RESULTS

A linear logistic regression model described the data. Simulation from the model showed that the probability of seizure was 0.05 (0.03–0.08), 0.19 (0.09–0.35) and 0.75 (0.30–0.96) at 1000, 5000 and 10 000 mg, respectively (median and 95% credible interval). At the mean dose of 2100 mg the odds ratios (OR) in the presence of SDAC, WBI and SDAC/WBI were 0.48 (0.25–0.89), 0.71 (0.35–1.22) and 0.25 (0.08–0.62), respectively. A modified Gompertz model described the time to seizure events. Simulations from the Gompertz model showed that the t₉₀ values for first seizure was 26 h and was not affected by dose or decontamination procedure.

CONCLUSION

SDAC/WBI provided greater benefits than the sum of the independent effects of SDAC and WBI. Patients should be observed for at least 24 h for seizures based on the dose and risk of seizure occurring.     

The pharmacokinetics and pharmacodynamics of lignocaine and MEGX in healthy subjects

Lignocaine clearance declines during continuous intravenous infustion in man and in vitrostudies suggest that this may partly be due to inhibition by MEGX, a metabolite of lignocaine, MEGX is pharmacologically active in animals, but this is not yet proven in man. This study examined the pharmacokinetics and pharmacodynamics of lignocaine and MEGX in eight healthy male volunteers given lignocaine HCl 120mg, MEGX HCl 120 mg, lignocaine HCl 120 mg+MEGX HCl 120 mg, and placebo, administered according to a randomized double-blind protocol. One-, two-, or three-compartment models were fitted to drug and metabolite blood concentration-time profiles and clearance, volume (V _ss ), andhalf-life values were calculated and compared by paired t-test. Systolic time intervals and QTinterval were recorded and compared by repeated measures ANOVA. When administered in combination with MEGX, lignocaine clearance was significantly reduced from 58±18 to 48±13 L hr(su–1) (p <0.02). The V(inss) was unchanged and there was a trend toward an increase in terminal half-life. Lignocaine, MEGX, and the combination significantly reduced QTinterval up to 30 min after injection and this was maintained to 2 hr with the lignocaine and the combination. Transient side effects were experienced with all active treatments, but were most pronounced with the combination. Thus, lignocaine clearance was inhibited by MEGX, which was pharmacologically active in man.     

药代动力学药效动力学结合模型研究进展

药代动力学和药效动力学共同构成了现代药理学研究的基础。PK/PD模型是将两者相结合,以说明给予某一剂量后所引起的药理作用的时间过程。研究PK/PD关系不但有助于正确指导临床用药,还可以用于探讨药物作用机制、新药评估以及新制剂的开发等。本文就近些年来PK/PD模型在药理学和毒理学,临床应用以及新药开发等方面的研究进展作一简要的综述。     

国产氯苯扎利的药效学研究

氯苯扎利（Ｌｏｂ，２５，５０与１００ｍｇ·ｋｇ－１）对大鼠角叉菜胶足肿胀、棉球内芽肿均无明显抑制作用。而Ｌｏｂ三种剂量与二种给药方案对佐剂性关节炎（ＡＡ）大鼠的多发性关节肿胀均有明显的防治作用，并能使ＡＡ大鼠低下的脾细胞ＣｏｎＡ增殖反应恢复正常，还能使ＡＡ大鼠腹腔巨噬细胞（ＰＭΦ）升高的ＩＬ－１水平降低。在环磷酰胺（Ｃｙ）诱导溶血素抗体生成低下或增高的小鼠模型上，Ｌｏｂ均呈现反向调节作用。Ｌｏｂ（０．００１～１００μｍｏｌ·Ｌ－１）对正常小鼠脾细胞的ＣｏｎＡ增殖反应具有低浓度促进和高浓度抑制的双向调节作用。     

The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers

The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing.The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l^–1 and t1/2_z increased to 4.0 h (NS).There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.     

Pharmacokinetics and pharmacodynamics of sofosbuvir and ledipasvir for the treatment of hepatitis C

Introduction: The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications.

Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration.

Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.     

喹诺酮类抗菌药物的药动学和药效学研究进展

喹诺酮类是目前临床普遍使用的一类抗菌药物.现从体外实验、动物实验和人体试验等方面对其药动学/药效学(PK/PD)研究进行了综述,并对PK/PD与细菌耐药及其在临床上的应用进行了简介.     

The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis

AIM

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis.

METHODS

Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg⁻¹. Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis.

RESULTS

Steady-state volume of distribution was determined to be 111 ± 71 ml kg⁻¹ and plasma clearance was 5.2 ± 1.8 ml min⁻¹ kg⁻¹ in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml⁻¹) was larger than previously described.

CONCLUSIONS

This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.     

β-内酰胺类抗生素的药动学/药效学研究进展

综述了β-内酰胺类抗生素的药动学/药效学(PK/PD)研究进展,主要阐述了PK/PD综合参数确立的实验证据,掌握PK/PD参数有助于抗菌药物的合理应用,提高疗效,减少不良反应.     

氟卡胺的药代动力学与药效动力学

氟卡胺是抑制心脏传导间期AH,HV,QRS,QT的抗心律不齐新药。犬iv 2,4 mg/kg氟卡胺后呈二室型代谢动力学特点,其t_(1/2)为60～70min。健康人po 200 mg/kg与小鼠sc 10 mg/kg氟卡胺后呈一级吸收一室型,t_(1/2)为60～76 min。 以抑制传导间期为药效指标,犬iv 4 mg/kg氟卡胺后测各传导间期变化,计算药效动力学,公式为:△％=(△_(max)％)c~(-kt)。以血药浓度对数对相应时间传导间期变化(△％)作图呈线性相关,计算公式为:C=ae~b(△％)。     

新型抗血栓药物作用机制研究进展

根据已有文献报道 ,综述了血栓形成和新型抗血栓药物作用机制的研究进展。血栓形成的病理生理涉及内皮细胞功能异常和细胞黏附功能异常。新型抗血栓药物主要有FⅩa抑制剂、GPⅡb/Ⅲa受体抑制剂、以内皮细胞为靶点的抗血栓药物。     

国产尼美舒利的药效学研究

本文研究了国产尼美舒利在小鼠、大鼠及家兔体内的抗炎、镇痛和解热作用.结果表明.尼美舒利抑制巴豆油致小鼠耳廓肿胀(ED_(50)为49.2mg·kg~(-1));抑制角叉菜胶致大鼠足肿(ED_(50)为2.75mg·kg(-1));0.6mg·kg~(-1)剂量对大鼠佐剂关节炎有显著预防和治疗作用。100mg·kg~(-1)对小鼠醋酸扭体法的抑制率为68％;对热板法致痛的痛阈提高率为55％。ip给药对蛋白胨致家兔发热的解热作用.其最小有效剂量为2mg·kg~(-1);5mg·kg~(-1)ig可显著降低啤酒酵母致大鼠升高的体温.证实国产尼美舒利具有很强的抗炎、镇痛和解热作用。     

头孢哌酮的药物动力学及药效学

对比国产和进口头孢哌酮的药物动力学，为临选药提供依据。结果两组的药学参数、ＭＩＣ值及有效率均无统计学差异。结论：国产和进口头孢哌酮的药物动力学及药效学相似。