Neurotoxicodynamics of the Interaction between Ciprofloxacin and Foscarnet in Mice

The potential for convulsions induced by the coadministration of ciprofloxacin (CPFX) and foscarnet (PFA) may be due not to a change in the distribution of CPFX to the brain but to a potential CPFX-induced inhibition of γ-aminobutyric acid (GABA)-GABA_A receptor binding in the presence of PFA.     

Investigation of mouth washing by patients after inhaling corticosteroids

We report an effective method for mouth washing after inhalation of corticosteroids for the prevention of local adverse effects such as hoarseness and oropharyngeal candidiasis. This method involves gargling and rinsing immediately after inhalation, repeated at least twice. We performed a questionnaire survey on mouth washing after inhalation of corticosteroids of 19 inpatients who used inhaled corticosteroids at the University of Tokyo Hospital. The questions concerned: 1) awareness of local adverse effects of inhaled corticosteroids; 2) gargling and rinsing habits; 3) repeating mouth washing at least twice; and 4) mouth washing immediately after inhalation. The percentage of patients correctly performing the individual maneuvers were: 1) 63.2%; 2) 36.8%; 3) 36.8%; and 4) 63.2%. The percentage of patients performing our recommended method of mouth washing (all four elements) was 11%. These results suggest that patients receiving inhaled corticosteroids poorly comprehend mouth washing procedures after inhalation of corticosteroids. It is important that pharmacists advise patients on the correct method of mouth washing.     

The relative importance of cytokine gene polymorphisms in the development of early and late acute rejection and six-month renal allograft pathology

BACKGROUND: Acute rejection episodes and 6-month protocol biopsy acute pathology are highly correlated with long-term outcomes in renal transplant recipients. Recurrent, vascular, and late rejections are particularly deleterious. METHODS: We determined the relative contribution of human leukocyte antigen matching, cytokine genotypes, delayed graft function (DGF), and baseline immunosuppression to the development of acute rejection and allograft pathology in 118 renal transplant recipients. RESULTS: Multivariate logistic regression modeling demonstrated that the adjusted odds ratio and 95% confidence interval for recurrent (> or =2) early rejections (0-3 months) increased linearly for high (H) > intermediate (I) > low (L) interferon-gamma (1.8; 1.1-3.2) and tumor necrosis factor (TNF)alpha (3.0; 1.3-6.9) genotype, whereas every 1 microg/L increase in the cyclosporine A level was protective (0.991; 0.984-0.999). The odds ratio for recurrent late rejections (4-6 months) increased for H > I > L TNFalpha (5.1; 1.8-14.7) genotype and DGF (7.1; 1.6-30.2), whereas H > I/L transforming growth factor-beta1 genotype decreased the relative risk (0.09: 0.02-0.49). Vascular rejection was only predicted by H > I > L TNFalpha phenotype (3.0; 1.2-7.9). The odds ratio for the 6-month Banff Acute Score (6A > or= 4) increased for H > I > L TNFalpha (2.7; 1.1-6.7) and interleukin-10 (3.4; 1.2-6.2) genotype, and DGF (3.4; 1.1-11.5). Treatment of early subclinical rejection decreased the relative risk (0.20; 0.07-0.62). CONCLUSIONS: High transforming growth factor-beta1 producer phenotype seems to be protective against acute inflammation, whereas H and I interferon-gamma, TNFalpha, and interleukin-10 producer genotypes correlate with adverse outcomes. Cytokine genotyping identifies individuals who may benefit from more intensive surveillance and treatment posttransplant.     

Effect of chlorpromazine on hepatic transport of indocyanine green in rats

The effect of chlorpromazine hydrochloride (CPZ) on the hepatic transport of indocyanine green (ICG) was studied in the rat, in an attempt to elucidate the mechanisms of hepatotoxicity of CPZ in vivo, by comparing the pharmacokinetic parameters of ICG after bolus and chronic administration of CPZ. Delays were shown in both plasma disappearance and biliary excretion of ICG in the CPZ-treated rats (10 and 15 mg/kg intraportal bolus administration). Significant decreases were observed in the pharmacokinetic parameters, V₂ and total body clearance (CL_tot) in CPZ 10 mg/kg treated rats and k₃₄, V₂ and CL_tot in CPZ 15 mg/kg treated rats, while a significant increase was observed in k₂₁ in both CPZ-treated groups; V₁ was not altered. The apparent liver-to-plasma concentration ratio (K_p,app) of ICG at 50 min after i.v. administration was decreased significantly in CPZ 15 mg/kg treated rats when compared to control rats, suggesting an alteration in the distribution of ICG to the liver by CPZ. Bile flow rates decreased immediately after bolus intraportal administration of CPZ in both CPZ-treated groups, and they then returned progressively to the basal levels. The output of bile acids was also inhibited by CPZ in a time-dependent and reversible manner and the bile acid independent fraction of bile flow was decreased significantly in both CPZ-treated groups. Chronic treatment with CPZ (10 or 20 mg/kg, i.p., per day for 3 weeks) did not alter either the pharmacokinetic parameters or the bile secretion profile of ICG, although there were significant decreases in body and liver weights in CPZ-treated groups. This may have been due to the rapid metabolism and excretion of CPZ in the rat when compared to humans. It is proposed that the acute toxic effect of CPZ on hepatic transport of ICG in the rat may be due mainly to the time-dependent and reversible cholestasis induced by CPZ, and that chronic treatment with CPZ may not alter the hepatic transport of ICG in the rat.     

Frequency distribution of thiopurine S-methyltransferase activity in red blood cells of a healthy Japanese population

Thiopurine S-methyltransferase (TPMT), which exhibits a genetic polymorphism, plays an important role in the metabolism of thiopurine drugs such as mercaptopurine, thioguanine, and azathioprine. To determine the frequency distribution of TPMT activity in 157 Japanese subjects with different TPMT genotypes, ie, TPMT*1/*1 and TPMT*1/*3, the authors measured levels of 6-methylmercaptopurine formed from 6-mercaptopurine in red blood cells lysates by HPLC. The TPMT activities in our Japanese subjects ranged from 11.0 to 42.6 pmol/h/mgHb. Although the mean value of TPMT activities in 6 subjects with TPMT*1/*3C (20.3 +/- 8.1 pmol/h/mgHb) was 25% lower than that in 151 subjects with TPMT*1/*1 (27.0 +/- 5.1 pmol/h/mgHb), there was overlap. The ranges of TPMT activity in subjects with TPMT*1/*1 and those with TPMT*1/*3C were similar. The median values in TPMT*1/*3C and TPMT*1/*1 individuals were 20.1 (11.0-31.2) and 26.8 pmol/h/mgHb (15.7-42.7), respectively (Mann-Whitney U-test: median difference 6.7 pmol/h/mgHb, 95% CI 0-25.5, P < 0.05). This observation may have relevance for the use of 6-mercaptopurine and azathioprine as therapeutic agents in Japanese patients.     

Pharmacokinetic/pharmacodynamic analysis of neutrophil proliferation induced by rhG-CSF in patients receiving antineoplastic drugs

In the present study, we analyzed the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on neutrophil counts in cancer patients undergoing chemotherapy using a previously developed pharmacokinetic/pharmacodynamic model.(7)) The time profiles of neutrophil counts in blood after repeated administration of rhG-CSF to lung cancer patients undergoing chemotherapy could be analyzed by this model by considering the inhibition of neutrophil production by antineoplastic drugs. Although deviation was observed between the predicted and observed neutrophil counts in ovarian cancer patients, it may be possible to use this model for determining a rational dosage regimen of rhG-CSF for patients undergoing chemotherapy.     

Development and evaluation of pharmaceutical services in the ICU/CCU by medical staffs

Questionnaires were sent out to the staffs (13 physicians, 52 nurses and 5 medical engineers) of the ICU/CCU at the University of Tokyo Hospital, to evaluate pharmaceutical services by analyzing problems in the services offered. Four components of pharmaceutical services were evaluated: inventory control of drugs, check of drug usage and doses, mixing of injections, and offering drug information. Almost all responses from medical staffs evaluated pharmaceutical services overall as "good". The high response rate (96%) from the nursing staff was attributed to the fact that they were familiar with the pharmacist's role with drug inventory, and mixing injections, when nursing was not available for these tasks. Although 50% of physicians rated the pharmaceutical services of providing drug information as "good", this value was lower than responses on other items of the questionnaires, which suggests some dissatisfaction. The occurrences of drug information obtained by passive offering (121 subjects) was 4 times as common as drug information obtained by active offering (30 subjects). From this finding, and comments on the questionnaires from physicians, it suggests that physicians require more drug information for dosage regimens, and prefer the drug information to be provided more actively. Further, an important comment from physicians and nurses was that the services of pharmacists are not available on all shifts/all days of the week to provide consultation for drug information and mixing of injections. Although having a pharmacist available daily around the clock is desirable and ideal to the medical team, the number of pharmacists under the present system cannot support this. As a solution, we think that it is crucial that pharmacists educate medical staff when they are present to in order to optimize therapy and patient care over time.     

CYP3A4*18: it is not rare allele in Japanese population

We sequenced all 13 exons of the CYP3A4 gene derived from 48 Japanese subjects. One subject possess the 20070 T>C mutation in the exon 10 (result in leu293Pro substitution, namely CYP3A4(*)18), as heterozygote. Thus, we investigated the frequency of CYP3A4(*)18 in 118 Japanese population using polymerase chain reaction-restriction fragment length polymorphism with Msp I and determined that the frequency of the CYP3A4(*)18 allele was 1.3%.     

Effects of CYP2D6 genotypes on plasma concentrations of risperidone and enantiomers of 9-hydroxyrisperidone in Japanese patients with schizophrenia

It has been shown that risperidone (+)-9-hydroxylation is enantioselectively catalyzed by the polymorphic CYP2D6 in human liver. This study aimed to examine the effect of CYP2D6 genotype on (+)-9-hydroxylation of risperidone in schizophrenic patients. Subjects were 38 Japanese schizophrenic inpatients receiving 6 mg/day of risperidone. Plasma concentrations of risperidone and (+)- and (-)-9-hydroxyrisperidone at steady state were quantified using LC/MS/MS and HPLC with alpha 1 acid-AGP chiral column, respectively. The CYP2D6*5(*5) and *10 alleles were identified using polymerase chain reaction (PCR) methods. Twenty patients had no mutated allele, 14 had one mutated allele, and 4 had two mutated alleles. There were significant differences in the steady-state plasma concentrations of risperidone (ANOVA; p < 0.0001) among the three genotype groups, while the CYP2D6 genotype did not affect the steady-state plasma concentrations of (+)-9-hydroxyrisperidone (p = 0.314) or (-)-9-hydroxyrisperidone (p = 0.957). The concentration ratio of risperidone to 9-hydroxyrisperidone was strongly dependent on the CYP2D6 genotypes. This study suggests that CYP2D6 activity strongly influences the steady-state plasma concentrations of risperidone and risperidone/9-hydroxyrisperidone concentration ratios but is unlikely to determine enantio-selectivity in the steady-state plasma concentrations of 9-hydroxyrisperidone in the clinical situation.     

Pharmacokinetic/pharmacodynamic analysis of anti-hyperprolactinemic effect of terguride based on dopamine D2 receptor occupancy

Terguride has been widely used for the treatment of hyperprolactinemia via partial agonistic action on dopamine D2 receptors in the pituitary. The present study analyzed retrospectively the dopamine D2 receptor binding occupancy (phi) of terguride. The average phi value was estimated to be 14.1% after oral administration of the average/standard therapeutic dose of terguride. Taking the intrinsic activity (alpha) into consideration, the value of alpha. phi was 2.33%. These results suggest that the antihyperprolactinemic effect of terguride was elicited despite the low receptor occupancy. Furthermore, we developed a pharmacokinetic/pharmacodynamic model for ascertaining the serum prolactin-lowering effect of terguride, considering both the reversible binding to D2 receptors and the effect on the increase rate in the prolactin level. The developed model fit well with the actual data. Although this model could be improved, it could explain the long duration of the antihyperprolactinemic activity of terguride and might be useful for designing its rational dosage regimen.