奈替米星体液浓度测定的方法学研究

通过对国产硫酸奈替米星注射后人体血尿中药物浓度测定，建立了奈替米星体液浓度测定的微生物法，该方法的检测限为０．０３７５～０．０７５１μｇ，最低检测浓度为０．２５～０．５μｇ／ｍｌ，回收率为８８．８％±３．６３％～９８％±１４．４０％，重复性试验相对标准差为２．２２％～５．３４％；并对１０例健康受试者用药后血标本１００余份进行了微生物法测定和高压液相色谱法测定，对两种方法测定结果的比较发现：微生物法测定的血药浓度明显高于ＨＰＬＣ法（Ｐ＜０．０１），而ＨＰＬＣ法由于需复杂的样品预处理和特殊的色谱条件，测定的血药浓度较低，回收率仅７１．９８％～７６．９６％。不过，两种方法测定结果的相关性较好。本研究结果提示：微生物法测定奈替米星体液浓度简便、易操作、结果准确可信，适用于体液药物浓度测定。     

The effect of piperacillin dose on elimination kinetics in renal impairment

Summary The effect of drug dose on piperacillin elimination kinetics was examined in 27 adult subjects with varying renal function. Piperacillin, 15 mg/kg or 60 mg/kg, was given by bolus intravenous injection. The elimination half-life (t_1/2) increased five-fold and plasma clearance (Cl_p) decreased by 80% in patients with renal failure. Both parameters were dose dependent in patients with normal renal function, but not in patients with renal insufficiency. Piperacillin dose dependent elimination is due primarily to capacity limited renal excretion.     

Garenoxacin pharmacokinetics in subjects with renal impairment*

ABSTRACT

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL_cr) > 80?mL/min, CL_cr < 30?mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600?mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3?h before HD (phase 1) and immediately after HD (phase 2).

Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed.

Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration–time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7?h vs 14.4 ± 3?h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5–11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated.

Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.     

Mezlocillin dose dependent elimination kinetics in renal impairment

Summary The effect of drug dose on mezlocillin elimination kinetics was examined in six subjects with normal renal function and in six anuric patients. Each subject received mezlocillin 1, 3 and 5 g as single intravenous doses separated by one week. Elimination was not prolonged by increasing the dose in subjects with normal renal function, but elimination kinetics were dose dependent in anuric patients. Therapeutic guidelines are suggested.     

Pharmacokinetics and pharmacodynamics of ranitidine in renal impairment

Objective: The pharmacodynamics and pharmacokinetics of ranitidine were examined in subjects with varying degrees of renal function to determine the effect of this condition on acid-antisecretory activity. Methods: Subjects with creatinine clearances (C_Cr) ranging from 0 to 213 ml · min⁻¹ received single 50-mg and 25-mg i.v. doses of ranitidine. This was followed by determination of serum and urine ranitidine concentrations, and continuous gastric pH monitoring for 24 h. Results: Serum ranitidine concentrations were described by a two-compartment model linked to a sigmoidal E_max model describing gastric pH. Ranitidine renal clearance, ranging from 0 to 1003 ml · min⁻¹, correlated with C_PAH (r ² = 0.707), while non-renal clearance was unaltered. Steady-state volume of distribution decreased by half in severe renal impairment. No changes in the effective concentration at half-maximal response (EC₅₀), maximal response (E_max), or basal response (E₀) were observed. Thus, renal elimination of ranitidine declined in parallel with renal function, while sensitivity to the pharmacologic effect (gastric pH elevation) was unaltered. Ranitidine was well tolerated in these renally impaired subjects. Conclusion: These data indicate that the current recommendation for renal impairment dose reduction (by two-thirds when C_Cr<50 ml · min⁻¹) might result in under-treating moderately impaired patients, and suggests a less conservative dose reduction (by half when C_Cr<10 ml · min⁻¹) to avoid therapeutic failure while remaining within the wide margin of safety for this drug. Received: 10 September 1996 / Accepted in revised form: 7 December 1996     

奈替米星治疗中风病人肺部感染疗效评价

目的　评价奈替米星治疗中风合并肺部感染病人的临床效果和安全性。方法　 12 0例中风合并肺部感染病人随机分为两组 ,奈替米星组 62例 ,男性 3 4例 ,女性 2 8例 ,年龄 ( 64± 8)岁 ,用硫酸奈替米星葡萄糖注射液 4mg·kg-1·d-1,静脉滴注 ,每天 1次或 2次 ,疗程 7～ 10d。头孢曲松钠组 5 8例 ,男性 3 1例 ,女性 2 7例 ,年龄( 64± 8)岁 ,用头孢曲松钠粉针剂 ( 2 0～ 4 0 ) g/d加入氯化钠注射液 2 5 0ml,静脉滴注 ,每天 1次或 2次 ,疗程 7～10d。结果　两组疗效、细菌清除率和不良反应发生率差异均无显著性 (P >0 0 5 )。结论　奈米替星用于治疗中风合并肺部感染病人疗效确切 ,使用安全     

Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally-induced renal impairment

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg^?1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K₁₂, K₁₂, K_a and an increase in V_d and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK₁₃ and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.     

Evaluation of applying drug dose adjustment by physicians in patients with renal impairment

ObjectiveTo determine whether appropriate dose adjustment was taken into account or not by the physicians when prescribing drugs in patients with renal impairment.DesignA retrospective chart review was performed and included 98 adult in-patients, diagnosed with renal impairment based on clinical evaluation and laboratory data, in King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia, who was admitted to the hospital from September 2005 to January 2011. Data of the patients were noted and recorded including baseline demographics, clinical data, laboratory data, renal state, treatment data and medications.ResultsThe initial number of the patients was reduced to 80 where a total of 502 drugs were investigated in the present study with an average of six drugs per patient. Of these 502 studied drugs, 196 (39%) required dose adjustment where 92 (46.9%) were adjusted and 104 (53.1%) were not adjusted. It was found also that most of the drugs requiring dose adjustment were antibiotics (39.8%).ConclusionThe current study confirms that physicians still do not take into account sufficiently patients’ renal function when prescribing drugs. Continuous medical education and collaboration with clinical pharmacist should be encouraged for quality improvement in patients with renal impairment.     

瑞舒伐他汀联合厄贝沙坦对原发性高血压早期肾损伤患者肾脏功能及其他实验室指标的影响

目的 探讨瑞舒伐他汀联合厄贝沙坦对原发性高血压早期肾损伤患者肾脏功能及实验室指标的影响。方法 将原发性高血压早期肾损伤患者60例随机分为两组,分别给予厄贝沙坦单用(对照组)和与瑞舒伐他汀联用(试验组);比较两组患者肾功能及实验室指标,评价其临床疗效。结果 对照组患者治疗后总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白(LDL-C)及高密度脂蛋白(HDL-C)水平分别为(5.65±1.36)mmol/L、(2.18±0.85)mmol/L、(3.70±0.97)mmol/L、(1.18±0.63)mmol/L;试验组患者治疗后TC、TG、LDL-C及HDL-C水平分别为(3.94±0.80)mmol/L、(1.62±0.46)mmol/L、(2.26±0.64)mmol/L、(1.45±0.73)mmol/L;对照组患者治疗后血肌酐(Scr)、血尿素氮(BUN)及24 h尿白蛋白定量水平分别为(79.15±17.25)mmol/L、(5.37±1.07)mmol/L、(73.54±16.34)mmol/L;试验组患者治疗后Scr、BUN及24 h尿白蛋白定量水平分别为(75.70±14.84)mmol/L、(4.92±0.98)mmol/L、(57.32±12.94)mmol/L;试验组患者治疗后血脂和肾脏功能指标均显著优于对照组,差异有统计学意义(P<0.05);试验组患者治疗后β2-MG、Cys-C、hs-CRP及ET-1水平均显著低于对照组,差异有统计学意义(P<0.05)。结论 瑞舒伐他汀联合厄贝沙坦治疗原发性高血压早期肾损伤患者效果确切。     

盐酸克林霉素和克林霉素磷酸酯致肾损害的比较

克林霉素是临床常用的抗菌药物,近年来其肾损害的不良反应备受关注.通过对国内文献报道的分析表明,与克林霉素磷酸酯比较,盐酸克林霉素引起肾毒性的时间早、程度严重,是需要临床密切关注和进一步研究的风险信号.     

The effect of renal function on the pharmacokinetics of ranitidine

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg iv infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied.Renal function was assessed in each patient by ⁵¹Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC.Patient groups with renal impairment had significantly increased AUC and t_1/2 with corresponding decreases in CL_p and _z when compared with normal subjects. There was also a significant increase in t_max but not in C_max. There was a high linear correlation between the degree of renal impairment and ranitidine clearance.In patients with GFR 20 ml min^–1, the AUC mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20–50 ml min^–1, the average AUC ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR 20 ml min^–1.     

Population pharmacokinetics of rosuvastatin: implications of renal impairment,race, and dyslipidaemia

ABSTRACT

Objectives: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters.

Methods: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test.

Results: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F?) was estimated to be 257?L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR?) of 30?mL/min (moderate renal impairment) and of 50?mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94?mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively.

Conclusions: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.     

原发性高血压患者动态脉压和昼夜节律异常对早期肾损害的预测价值

目的探讨原发性高血压患者24h动态脉压（24hPP）、血压昼夜节律对早期肾损害的预测价值。方法将146例原发性高血压病患者按24hPP分为4组,A组：PP≤40mmHg（1mm-Hg=0.133kPa）（28例）,B组：41～60mmHg（1mmHg=0.133kPa）（43例）,C组：61～80mmHg（1mmHg=0.133kPa）（51例）,D组：大于80mmHg（1mmHg=0.133kPa）（24例）;按血压昼夜变化率（△MBP）分为2组,杓型组：△MBP≥10%（65例）,非杓型组：△MBP〈10%（81例）,分别进行2h动态血压监测和检测血、尿β2微球蛋白（β2-MC）和尿α1微球蛋白（α1-MG）、尿微量白蛋白（mALB）并比较各组的检测值。结果各组间性别、年龄、体质量指数、空腹血糖、血肌酐、总胆固醇、甘油三酯水平均差异无显著意义（P〉0.05）。随着24hPP增高,早期肾损害程度越严重,D组〉C组〉B组〉A组（P〈0.05）;非杓型组夜间收缩压、舒张压及早期肾损害程度明显高于杓型组（P〈0.05）。结论 24hPP增大及血压昼夜节律异常可作为高血压患者早期肾损害的预测指标。     

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses

The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (C_max) and area under the curves (AUC) of buspirone and 1-PP on Days D 5 and 10 were higher than on Day D 1. The trough levels (C_min) and AUCs (D 5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher C_max and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers. There was no correlation between the average plasma concentrations of buspirone ( ) and the degree of renal impairment judged by creatinine clearance. An excellent correlation was observed between of buspirone and serum albumin (r=0.862, and P<0.0001) as well as between and bromsulphalein clearance (r=0.678, P<0.0003).In view of high intra-and inter-subject variability in buspirone concentrations, definitive dosing recommendations for patients with compromised renal or hepatic function could not be made, but such patients should initially be dosed cautiously with buspirone.     

Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

Objective: Assuming linear kinetics, the mean CSF concentrations of an antibacterial in steady state (C_ssCSF) can be estimated, when the area under the concentration-time curve in CSF after the first dose is known. For this purpose we propose the function C_ssCSF=AUC_CSF·Anticipated dose/Dosing Interval·Applied dose. Results: Together with the MIC and MBC of the causative pathogen, the estimate is of value in the choice of antibacterial drug and the dosing regimen in central nervous system infections.     

慢性心力衰竭患者肾脏损害与成纤维细胞生长因子23的相关性分析

目的 探讨慢性心力衰竭患者肾脏损害与成纤维细胞生长因子23（FGF23）的相关性.方法 289例慢性心力衰竭患者,根据肾小球滤过率（eGFR）结果将入选的289例患者分为3组：肾功能正常组,肾功能轻度下降组和肾功能中、重度下降组.入院时采血测定患者血清FGF23水平、N末端B型钠尿肽（NT-proBNP）及肾功能指标肌酐、尿素氮和计算eGFR,心脏彩色超声测定左室射血分数（LVEF）和左心室舒张末内径（LVEDD）等.结果 3组患者心肾功能的恶化趋势一致.FGF23水平随着肾功能的恶化明显升高,肾功能中重度下降的患者血清FGF223明显高于肾功能轻度下降和正常组患者（P＜0.05）.在慢性心力衰竭患者中,血清FGF23水平与肾功能指标尿素氮、肌酐和eGFR均呈正相关,相关系数分别为0.532、0.686、0.783,差异具有统计学意义（P＜0.05）.血清FGF23水平与心功能指标NT-proBNP呈正相关（r=0.652,P＜0.05）,与射血分数呈负相关（r=-0.521,P＜0.05）.结论 心力衰竭程度、心力衰竭肾脏损伤程度与血清高水平FGF23有关.     

Influence of food on the kinetics of 8-methoxypsoralen in serum and suction blister fluid in psoriatic patients

Summary The influence of food on the kinetics of 8-methoxypsoralen (8-MOP) in serum and suction blister fluid was evaluated in a cross-over study in 19 psoriatic patients under PUVA treatment. The peak serum concentration of 8-MOP was reached 1.5 h after ingestion on an empty stomach, and in suction blister fluid the maximum concentration was already present in the first sample taken after 2 h, the time when UVA radiation was given. The postprandial kinetics of 8-MOP in serum and suction blister fluid differed, the highest levels being reached, respectively, at 2.4 and 3 h after intake, i.e. in both body fluids after irradiation had started. The side effects of 8-MOP, such as nausea and dizziness, in the two groups were similar. The present results indicate that to optimize the therapeutic effect of PUVA in individual patients, 8-MOP should be given on an empty stomach.     

Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment

The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects 55 years of age (YNG), 12 elderly subjects 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), Cl_CR 20–60 ml·min^–1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method.Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and <1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t_1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not.Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.     

Pharmacokinetics of oral acetyl-L-carnitine in renal impairment

Summary Acetyl-L-carnitine 1.5 g and 3.0 g was administered as three divided doses on each of two occasions to 24 people with varying renal failure (creatinine clearance 127 – 8 ml·min^–1). Plasma and urinary concentrations of total-L-carnitine, free (non-esterified) carnitine, short-chain esters and acetyl-L-carnitine were measured.The baseline (pre-study) concentrations of all four substances were related to renal function. Patients whose creatinine clearance was below about 30–40 ml·min^–1 were had the highest concentrations.Renal elimination of all four substances was related to dose and to renal function. There was evidence for dose-related elimination, with greater elimination of the larger dose.