Pharmacokinetics of intravenous omeprazole in critically ill paediatric patients

The proton pump inhibitors are first-line drugs for the treatment of a number of gastrointestinal diseases. These drugs have a good safety profile, making it possible to use them in paediatric patients. Although their pharmacokinetics in children has not been extensively studied, research performed suggests that the dose used should be varied as a function of age, as this factor affects the drug’s metabolism. Proton pump inhibitors can be used in critically ill children for the prophylaxis and treatment of gastrointestinal haemorrhage, although there is still little experience with this. The most widely used proton pump inhibitor at the present time is omeprazole. As there are specific characteristics of these patients that could alter the pharmacokinetics of the drugs, studies need to be performed to determine the most suitable dose and dosage interval.     

核糖霉素高产菌株核苷链霉菌筛选

以核苷链霉菌09-15为出发菌株,采用氮离子束注入、甲基磺酸乙酯、紫外线诱变,耐抗生素的筛选等手段育种,以期获得高产菌株.测定了09-15菌对8种抗生素的敏感性,并讨论了菌株对自身代谢产物低耐受性的原因.比较了多种方法的诱变效应,氮离子束注入的诱变效应好,正变率高;紫外线正变率低.经过多种方法复合处理,获得St-150菌株,摇瓶发酵单位比亲株09-15提高20%,发酵液的杂质含量明显降低,并在20吨发酵罐得到验证.     

Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients

BACKGROUND: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. METHODS: We investigated the pharmacokinetics of free platinum (Pt) in 12 children (25 courses) receiving cisplatin (75-120 mg/m2) either as a continuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusions. Plasma and urinary Pt concentrations were analysed using atomic absorption spectroscopy. Cisplatin-induced nephrotoxicity was determined using creatinine clearance and several glomerular and tubular marker proteins. RESULTS: Using a two-compartment model the pharmacokinetic parameters for free Pt were: initial half-life 21.6 +/- 9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/- 4.97 (microg/ml) x h/(100 mg/m2) and cumulative renal elimination(infinity) 41.7 +/- 6.6% of dose. Higher cisplatin delivery rates led to higher peak concentrations of free Pt in plasma and urine and to lower cumulative renal Pt elimination (P < 0.01). During all courses, increases of urinary albumin and alpha1-microglobulin excretion were documented. The creatinine clearance decreased significantly to 70% of baseline values. Correlations were found between both peak free Pt concentrations in plasma and in urine and the maximum of urinary excretions of albumin and of N-acetyl-beta-D-glucosaminidase and the nadir of the glomerular filtration rate (P < 0.05). CONCLUSIONS: With respect to nephrotoxicity, long-term infusions of cisplatin seem to be preferable over intermittent bolus administration in paediatric patients. The best predictive pharmacokinetic parameters for cisplatin-associated nephrotoxicity in children are peak free Pt concentrations in plasma and urine.     

Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery

AIMS: This paper describes the pharmacokinetics and effects of propofol in short-term sedated paediatric patients. METHODS: Six mechanically ventilated children aged 1-5 years received a 6 h continuous infusion of propofol 6% at the rate of 2 or 3 mg kg-1 h-1 for sedation following cardiac surgery. A total of seven arterial blood samples was collected at various time points during and after the infusion in each patient. Pharmacokinetic modelling was performed using NONMEM. Effects were assessed on the basis of the Ramsay sedation score as well as a subjective sedation scale. RESULTS: The data were best described by a two-compartment pharmacokinetic model. In the model, body weight was a significant covariate for clearance. Pharmacokinetic parameters in the weight-proportional model were clearance (CL) = 35 ml kg-1 min-1, volume of central compartment (V1) = 12 l, intercompartmental clearance (Q) = 0.35 l min-1 and volume of peripheral compartment (V2) = 24 l. The interindividual variabilities for these parameters were 8%, < 1%, 11% and 35%, respectively. Compared with the population pharmacokinetics in adults following cardiac surgery and when normalized for body weight, statistically significant differences were observed the parameters CL and V1 (35 vs 29 ml kg-1 min-1 and 0.78 vs 0.26 l kg-1P < 0.05), whereas the values for Q and V2 were similar (23 vs 18 ml kg-1 min-1 and 1.6 vs 1.8 l kg-1, P > 0.05). In children, the percentage of adequately sedated patients was similar compared with adults (50% vs 67%) despite considerably higher propofol concentrations (1.3 +/- 0.10 vs 0.51 +/- 0.035 mg l-1, mean +/- s.e. mean), suggesting a lower pharmacodynamic sensitivity to propofol in children. CONCLUSIONS: In children aged 1-5 years, a pharmacokinetic model for propofol was described using sparse data. In contrast to adults, body weight was a significant covariate for clearance in children. The model may serve as a useful basis to study the role of covariates in the pharmacokinetics and pharmacodynamics of propofol in paediatric patients of different ages.     

Pharmacokinetics of antipyrine in epileptic patients.

The pharmacokinetics of antipyrine were examined after oral and intravenous administration to 20 epileptic subjects receiving antiepileptic drug therapy. Bioavailability was essentially complete (mean bioavailability 101.2% +/- 14.4 (s.d.] indicating that even in enzyme induced subjects, antipyrine behaves as a restrictively eliminated compound with negligible presystemic elimination in the gut or liver. Of the generally used measures of enzyme induction (oral clearance, oral half-life and intravenous half-life) oral clearance was the most closely related to the intravenous clearance of antipyrine (r = 0.919, P less than 0.001). Oral antipyrine administration is an alternative to intravenous administration in epileptic subjects who are enzyme-induced.     

Pharmacokinetics of loracarbef in pediatric patients.

Loracarbef is an investigational oral antibiotic but its pharmacokinetics have not been studied after multiple oral doses in pediatric patients. The pharmacokinetics of loracarbef were determined in 18 pediatric patients after multiple oral doses. 8 patients with streptococcal pharyngitis received 7.5 mg/kg every 12 h, and 10 patients with otitis media were given 15 mg per kg every 12h. Multiple blood and urine samples were collected to measure loracarbef concentrations. In patients with streptococcal pharyngitis, the mean maximum serum concentration (Cmax), the time to achieve maximum concentration (Tmax), area under the serum concentration-time curve (AUC) and elimination half-life (t1/2) were 10.6 +/- 3.6 mcg/ml, 0.78 +/- 0.21 h, 21.4 +/- 7.2 mcg.h/ml, and 1.2 + 0.4 h, respectively. The mean Cmax, Tmax, AUC and t1/2 were 18.0 +/- 5.4 mcg/ml, 0.83 +/- 0.44 h, 35.6 +/- 9.4 mcg.h/ml, and 1.1 +/- 0.5 h, respectively, in patients with otitis media. The Cmax exceeded the minimum inhibitory concentration of common susceptible pathogens causing pharyngitis and otitis media by severalfold. Nearly 60% of the dose was excreted unchanged in the urine during the dosage interval. The pharmacokinetics were independent of dose. Loracarbef was well tolerated in all patients. These data suggest that loracarbef may be used safely at doses of 7.5 mg/kg every 12 h in pediatric patients with streptococcal pharyngitis and 15 mg/kg every 12 h in those with otitis media.     

Pharmacokinetics of cefoxitin in patients undergoing hemodialysis.

The parmacokinetics of Cefoxitin were studied after an i.v. administration of 15 mg/kg body weight in 17 patients with terminal renal impairment, 10 of which were undergoing 6 hr hemodialysis sessions. The average pharmokinetic parameters obtained from this kind of patient were the following: alpha = 2.88 hr-1 beta = 0.18 hr-1 K12 = 1.43 hr-1 K21 = 1.04 hr-1 K13 = 0.53 hr-1 Vc = 8.23 l Vp = 11.61 l Vdss = 19.84 l. The amounts of the antibiotic in the central and peripheric compartments are established together with the amount of the antibiotic eliminated as a function of time. The pharmacokinetic parameters are significantly different from those established in the period between dialysis sessions, and thus, the elimination constant reaches a value of 0.28 h-1. The degree of plasma protein binding of Cefoxitin is 41.46% during the hemodialysis sessions. A dosage regimen is programmed as a function of the pharmacokinetic parameters established for this kind of patient. It is recommended that an i.v. dose of 15 mg/kg body weight should be administered at the beginning and end of each dialysis session lasting 6 hours, when the periods between the sessions are 48 hours.     

Pharmacokinetics of ranitidine in critically ill patients.

The plasma pharmacokinetics of ranitidine (50 mg i.v.) have been studied in 17 critically ill patients in an intensive care unit. Measurements of gastric aspirate pH were also made in 16 of these patients. Ranitidine therapy was part of the patients' normal drug regimen. Ranitidine plasma concentration was measured by high performance liquid chromatography and appropriate polyexponential equations were fitted to concentration-time data to enable calculation of relevant pharmacokinetic parameters. Values of the volume of the initial dilution space (median = 89 ml kg-1) and volume of distribution at steady state (median = 1.54 l kg-1) were about 60% of corresponding mean literature values for healthy controls. Plasma clearance (median = 4.22 ml min-1 kg-1) and terminal half-life (median = 4.7 h) were about 2-3 fold less and 2-3 fold greater, respectively, than values for healthy controls. There was wide interpatient variation in all the pharmacokinetic parameters. Renal impairment was considered to be largely responsible for the low plasma clearance. Gastric aspirate pH was measured at 0, 1 and 7 h after ranitidine administration and 58% of samples were found to be above pH 4. Four patients had gastric pH values which were consistently below pH 4 despite average trough plasma ranitidine concentrations equal to or greater than those required for a 50% suppression of gastric acid secretion in normal volunteers.     

Pharmacokinetics of cefamandole in patients undergoing hemodialysis.

The pharmacokinetics of Cefamandole was studied in 17 patients with terminal renal impairment, 10 of which were undergoing sessions of hemodialysis while 7 were in the period between dialysis sessions. An open two-compartment kinetic model was used to describe the bi-phasic decrease of the plasma concentrations of Cefamandole thus establishing the amounts of the antibiotic in the peripheral and central compartments together with the amount eliminated. All patients received an i.v. bolus injections of 15 mg/kg body weight. During the hemodialysis sessions, the pharmacokinetic parameters of Cefamandole were the following: alpha = 5.006 hr-1 beta = 0.182 hr-1 K12 = 2.598 hr-1 K21 = 2.147 hr-1 K13 = 0.441 hr-1 Vc = 5.700 l Vp = 6.190 l Vdss = 11.94 l It may be seen that there is a decrease in the overall elimination constant compared with that obtained during the periods between the dialysis sessions. A dosage regimen of multiple doses is established as a function of the pharmacokinetic parameters of the antibiotic for patients with terminal renal impairment undergoing periodic sessions of hemodialysis.     

核糖霉素的选择性环氨基甲酸酯保护

目的发展一种新的选择性环氨基甲酸酯保护策略，用以合成具有环氨基甲酸酯结构的新型核糖霉素衍生物。方法全苄氨羰基保护的核糖霉素在氢化钠作用下环合，通过控制反应条件选择性在不同位点引入环状氨基甲酸酯保护基。将苄氧羰基催化氢化脱除可得含有环氨基甲酸酯结构的核糖霉素衍生物。结果通过反应条件的控制成功地实现了核糖霉素的选择性环氨基甲酸酯保护。脱保护得到了的核糖霉素衍生物，但并没有预期的抗菌活性。结论含有环氨基甲酸酯的核糖霉素衍生物的合成表明选择性环氨基甲酸酯保护策略是方便可行的。具有环氨基甲酸酯结构的核糖霉素衍生物可能并不具有抗菌活性。     

Pharmacokinetics of primaquine in patients withP. Vivax malaria

Summary The pharmacokinetics of primaquine (PQ) and its major carboxylic acid metabolite (PQC) have been studied in seven Indian patients withP. vivax malaria following PQ 15 mg/day p.o. for 14 days. After a single oral dose on Day 1, a mean peak blood concentration of 50.7 ng/ml PQ was attained after 2.3 h, which declined monoexponentially with a half-life of 5.6 h. The mean total body clearance was 37.6 l/h and the volume of distribution was 2921. The mean renal excretion (0–24 h) of the drug was only 0.54% of the dose and renal clearance was 0.189 l/h. Following chronic administration, none of the pharmacokinetic parameters was affected, and a steady state blood concentration of 2.5–4.2 ng/ml PQ was attained. After the first dose of PQ, PQC had a mean area under the blood concentration — time curve 11-fold higher than that of the parent drug. In contrast to the rapid distribution and elimination of PQ, the metabolite showed a longer mean residence time and accumulation in the body. The mean C_max and AUC of the metabolite on Day 14 were 48 and 40% higher than the corresponding Day 1 values. The metabolite could not be detected in urine at any time in any patient. PQ and its metabolite did not show any accumulation in blood cells.Communication No.797 from Hindustan CIBA-GEIGY Limited, Research Centre     

8例中国病人茶碱代谢物的药物动力学

目的：研究病人常规剂量茶碱治疗后代谢物的动力学。方法：病人静滴茶碱（６．６μｍｏｌ·ｋｇ＾－１）。ＨＰＬＣ法测定给药前后２４ｈ茶碱及其代谢物：１，３－二甲基尿酸（ＤＭＵＡ），３－甲基黄嘌呤（３－ＭＸ），１－甲基尿酸（ＭＵＡ），中间代谢产物１－甲基黄嘌呤（１－ＭＸ）的浓度。结果：ＤＭＵＡ是代谢物中浓度最高的。３－ＭＸ的清除速率最低。１－ＭＸ很快转化成ＭＵＡ，体内浓度很低，但是，翌晨，１－ＭＸ又回升到     

Pharmacokinetics of midazolam in critically ill pediatric patients.

Midazolam is frequently used to produce sedation in critically ill pediatric patients. We studied the pharmacokinetics of midazolam in 22 patients (age 8 days to 16 years). The intravenous infusion rate to produce sedation ranged from 49-385 mcg/kg/hr. The blood samples were obtained at steady-state and midazolam was measured by gas chromatography with electron capture. The steady-state plasma concentrations of midazolam ranged from 49-385 ng/mL. The total clearance, apparent volume of distribution, and elimination half-life ranged from 0.1-3.1 L/kg/hr, 0.2-3.5 L/kg, and 0.3-10.9 hours, respectively. The marked interpatient variability in pharmacokinetics explains in part, the substantial variation in dosage requirements of midazolam to produce sedation in critically ill pediatric patients.     

Pharmacokinetics of metoclopramide in patients with liver cirrhosis.

The pharmacokinetics of metoclopramide were investigated after intravenous and oral administration in eight patients with severe alcoholic cirrhosis and in eight healthy volunteers. As a consequence of a 50% lower clearance (0.16 +/- 0.07 vs 0.34 +/- 0.09 l h-1 kg-1, plasma drug concentrations and the half-life of metoclopramide were greater in patients following both routes of drug administration. Volume of distribution (3.1 +/- 0.8 vs 3.4 +/- 1.2 l kg-1) and absolute bioavailability (79 +/- 19 vs 84 +/- 15%) were similar in the two groups. The adverse effects of metoclopramide observed in patients with marked hepatic impairment are likely to result from increased accumulation of the drug as a result of impaired clearance. Consequently a reduction in dose of 50% is recommended in patients with severe liver cirrhosis.     

Pharmacokinetic studies in paediatric patients. Clinical and ethical considerations.

Important advances in paediatric clinical pharmacology have been made over the past 2 decades. However, there remains a reluctance to pursue pharmacodynamic and pharmacokinetic studies in children and, consequently, many important therapeutic agents have not been adequately studied in this population. Age-related pharmacokinetic/pharmacodynamic studies are not only essential to provide optimal drug therapy for children, but are quite feasible. Usually, paediatric pharmacokinetic studies are conducted in children receiving treatment for a specific medical condition. The approach to soliciting participation of paediatric subjects requires special sensitivity to the fears and anxieties of the child and the parents. Factors influencing subject enrollment and suggestions to enhance enrollment into study protocols are discussed. Pharmacokinetic/pharmacodynamic studies require repeated measurements over time and often entail obtaining multiple blood and urine samples. Techniques for reducing sample volume and number of necessary samples while minimising the discomfort and fear associated with obtaining multiple samples include the development of highly sensitive analytical methods to measure drug concentrations in small volume samples. The number of samples obtained from individual subjects can be minimised by using pharmacokinetic analytical approaches such as the nonlinear mixed effect model (NONMEM) which allows estimation of pharmacokinetic characteristics of a population using limited data from each subject. In addition, less invasive methods to measure drug metabolism/elimination such as salivary sampling, transcutaneous collection and breath analysis have been applied to the study of certain drugs. Children are a particularly vulnerable population because of their limited cognitive abilities and dependence on adults. Thus, they must be afforded greater protection from exploitation as research subjects than that provided to adults.     

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.