Shigehiko Shimada

Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates

ABSTRACT Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CLarbekacin = 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CLarbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, Varbekacin = 0.54 liters/kg, CLvancomycin = 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CLvancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, Vvancomycin = 0.66 liters/kg, CLpanipenem = 0.0832 for PCAs of <33 weeks and CLpanipenem = 0.179 × BW for PCAs of ≥33 weeks, and Vpanipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

Extremely prolonged elimination of cibenzoline at toxic plasma concentrations in patients with renal impairments

Three patients (age: 36, 68, and 80 years) treated with a standard oral dose of cibenzoline (300 mg/d) developed clinical symptoms being compatible with cibenzoline toxicity (e.g., prolonged QTc, wide QRS, arrhythmias, hypotension and hypoglycemia). Their plasma cibenzoline concentrations (i.e., 1944–2580 &mgr;g/L) were 5 to 10 times greater than the expected therapeutic levels. All patients had severe renal dysfunction (i.e., creatinine clearance: 10–16 mL/min) but had no severe liver damages. They received no drugs that might have inhibited hepatic drug metabolism. Intentional or accidental overdosing of the drug was ruled out in each patient. The elimination half-lives of cibenzoline monitored immediately after its withdrawal (i.e., 69, 116 and 198 hours) were 3–10 times longer than those reported in patients with end-stage renal failure of about 20 hours. In addition, two patients exhibited biphasic plasma drug decay curves. Our report indicates that not only reduced renal excretion but also non-linear kinetics of the drug via non-renal elimination at toxic concentrations may render renal failure patients more susceptible to cibenzoline toxicity.

Disopyramide concentrations in human plasma and saliva: Comparison of disopyramide concentrations in saliva and plasma unbound concentrations

AbstractObjective: This study was performed to investigate whether it is possible to use saliva instead of blood usually used for therapeutic drug monitoring (TDM) of disopyramide. Methods: Six healthy male volunteers ingested 200 mg of disopyramide base, and the disopyramide concentrations in saliva and plasma (total and unbound) were determined by the HPLC. Results: Disopyramide concentration-time profiles for the saliva were nearly equal to those for the plasma unbound concentrations. A large variation for absorption time of the drug was observed among the subjects. Disopyramide concentrations (Cs) in saliva did not correlated well with plasma total concentrations (Cp), r = 0.799, but did well with unbound concentrations (Cpu), r = 0.969, for the 3–12 h period on the elimination phase. The mean ratio of disopyramide concentrations in the saliva against the plasma unbound concentrations was almost constant (1.02(0.10), CV = 9.7%) for the period. The pharmacokinetic parameters (tmax, t1/2, AUC, AUMC and MRT values) for disopyramide calculated from the saliva data were nearly equal to those from the unbound data. Conclusion: Disopyramide concentrations in saliva correlated well with plasma unbound concentrations on the elimination phase.

Pharmacokinetics of amoxapine and its active metabolites in healthy subjects

Abstract Therapeutic drug monitoring for antidepressants is problematic because the blood concentration is usually poorly correlated with the dose. We have developed a simple method to simultaneously determine the pharmacokinetics of amoxapine (AMX) and its active metabolites 7-hydroxyamoxapine (7-OHAMX) and 8-hydroxyamoxapine (8-OHAMX). Using this method, we studied the pharmacokinetics of AMX and its metabolites in six male and six female healthy volunteers. The subjects received 25-mg and 50-mg single doses of AMX. After each dose, the pharmacokinetic parameters were determined according to their serum concentration-time curves. The area-under-the-curve value for 8-OHAMX was three to five times greater than that for AMX. Serum concentrations of AMX and 8-OHAMX 12 hours after administration were closely associated with the doses of AMX per body weight. This association was even more apparent when AMX and 8-OHAMX were combined. Consequently, AMX may be a useful marker for therapeutic drug monitoring, although the pharmacologic action attributable to its active metabolites should be taken into account.

Survey on the Actual Status of Use of Antiseptics in Our Hospital

Prevention of nosocomial infections is an important task for any medical institution. Although it is important to administer antibiotics prophylactically during the perioperative period, the proper use of antiseptics should have top priority. We carried out a survey to show the actual status of antiseptic use in our hospital in order to determine their proper use. The survey was carried out considering two aspects: the expense situation on the basis of the order slips and the status of use in each department and ward. It was conducted by questionnaire, and the pharmacist of each department asked questions to the nursing staff there. It was found that disinfectants and antiseptics are used almost correctly in our hospital. However, some improper uses were also found. In the future, on the basis of the findings of this study by questionnaire, we would like to give instructions from the standpoint of the pharmacist in the proper use of disinfectants and antiseptics and in the control of nosocomial infections.

Study on Microbial Contamination of Burette Chambers after Clinical Use.

The microbial contamination of burette chambers after clinical use was examined. Sixty-one burette chambers were collected from the gastroenterology ward, the gastroenterological surgery ward and the neurology ward at Kitasato University East Hospital. Each burette chamber was filled with 20 ml of thioglycollate medium (fluid) and incubated at 37°C for 7 days. These burette chambers were investigated for the number of doses and the days of use.The results on these burette chambers, indicated that only one was contaminated. The isolated bacteria were identified as Propionibacterium spp. In addition, the burette chambere were administered about 13 doses, on average, were used for about 5 days, on average.

Awareness of pharmacy students about the practical training at hospital pharmacies.

A questionnaire was used to ascertain the awareness of pharmacy students (below: p.students) about the practices and business in their field at hospitals.The subjects of this survey were 513 p.students who had participated in practical training at the Pharmacy Department of Kitasato University Hospital during the last 5 years.1.Most of the students participated in practical training at hospital pharmacies were hoping to become hospital pharmacists, and their experience through the practical training was a basis for their choice of occupation.2.Their comprehensions of pharmacist and job content at hospital pharmacies were low. 3.Through their experience at hospital pharmacies, most students realized the heavy responsibility of pharmacists and the necessity of applied pharmaceutical knowledge. 4.It is necessary to add practical training at hospital to the curriculam at pharmacy school for students hoping to work at hospital pharmacies.5.Cooperation of the specialists in this field is expected to reduce the heavy duty of the pharmacists at the hospital.

Simplified Pyrogen Test

Japanese Pharmacopoeia (J. P.) requires that the pyrogen test is essential for parenteral solutions. But, in hospital pharmacy, it is practically impossible to perform the official test because of the difficult control of test animals, limited laboratory facilities and timeconsuming procedures. In the study for a simplified checking, a method better than the J. P. pyrogen test was found. The method requires Limulus Lysate, a blood component of Limulus, which is presently applied for the quantitative analysis of endotoxin. The result of this study indicates the possibility of checking pyrogens in parenteral solutions prepared at a hospital pharmacy.