Yoshinobu Goto

Improved Oxidation of Active Methyl Group of N-Heteroaromatic Compounds by Selenium Dioxide in the Presence of tert-Butyl Hydroperoxide

The oxidation of active methyl group of N-heteroaromatic compounds including both of bicyclic and monocyclic compounds using SeO 2 was considerably improved in the presence of tert-butyl hydroperoxde in dioxane to give the corresponding aldehyde or carboxylic acid in the moderate to good yields. The present oxidation proceeds more mildly and more selectively to form aldehyde rather than carboxylic acid, compared with conventional SeO 2 oxidation without tert-butyl hydroperoxide.

Pharmacoepidemiologic investigation of a clonazepam-valproic acid interaction by mixed effect modeling using routine clinical pharmacokinetic data in japanese patients

Non‐linear Mixed Effects Modeling (NONMEM) was used to estimate the effects of clonazepam–valproic acid interaction on clearance values using 576 serum levels collected from 317 pediatric and adult epileptic patients (age range, 0·3–32·6u2003years) during their clinical routine care. Patients received the administration of clonazepam and/or valproic acid. The final model describing clonazepam clearance was CLu2003=u2003144·0 TBW−0·172u20031·14VPA, where CL is total body clearance (mL/kg/h); TBW is total body weight (kg); VPAu2003=u20031 for concomitant administration of valproic acid and VPAu2003=u2003zero otherwise. The final model describing valproic acid clearance was CL (mL/kg/h)u2003=u200317·2u2003TBW−0·264u2003DOSE0·159 0·821CZPu20030·896GEN, where DOSE is the daily dose of valproic acid (mg/kg/day); CZPu2003=u20031 for concomitant administration of clonazepam and CZPu2003=u2003zero otherwise; GENu2003=u20031 for female and GENu2003=u2003zero otherwise. Concomitant administration of clonazepam and valproic acid resulted in a 14% increase in clonazepam clearance, and a 17·9% decrease in valproic acid clearance.

Population pharmacokinetics of digoxin in Japanese patients: a 2-compartment pharmacokinetic model.

ObjectiveTo clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population.DesignRetrospective analysis of clinical pharmacokinetic data.Patients and participantsData were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females).MethodsDigoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM.Results246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 □TBW + 0.112 □CLCR) □0.77SPI □0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CLCR is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance.ConclusionsThe estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.

ObjectiveTo clarify the observed variability of haloperidol disposition in patients with psychiatric disorders.DesignRetrospective population pharmacokinetic study.Participants218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations.MethodsRoutine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program.ResultsThe final pharmacokinetic model was CL = 42.4 • (TBW/60)0.655 • 0.814AGE≥55 • (DOSE/200)0-236 • 1.32ANTIEP and Vd = 34.4 • TBW • 0.336 AGE≥65, where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (μg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE≥55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE≥65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and anti-parkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance.ConclusionApplication of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.

Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis

Abstract. Objective: The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. Method: The data (n=448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. Results: Estimates generated using NONMEM indicated that clearance of digoxin (l·h–1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error –0.04xa0ng·ml–1; mean absolute prediction error 0.20xa0ng·ml–1).

Electrophilic reaction of quinoline 1-oxide through base-induced deprotonation

Lithiation of quinoline 1-oxide-BF 3 complex (3) with LTMP and TMEDA in ether at −78°C followed by treatment with benzaldehyde or cyclohexanone affords the corresponding 2-substituted derivatives (4, 5 or 6), while the reaction of quinoline 1-oxide (1) itself under the same conditions results in the formation of 2,2-biquinoline 1-oxide (2)

Nitrosation of 1-alkylisoquinolines and their N-oxides and configurational assignments of their oximes

Nitrosation of 1-methyl-, 1-ethylisoquinoline and their N-oxydes with alkyl nitrite was studied under various conditions, and the following three systemes, (t-BuONO and n-BuLi-t-BuOK in THF), were found to be generally effective for nitrosation of not only isoquinolines but also pyridine and quinoline derivatives

Reinvestigation of nitrosation of methylpyridines and their 1-oxides and deoxygenation of 3-pyridinecarbaldehyde 1-oxide oxime

Treatment of methylpyridines and their 1-oxides with t-butyl nitrite in the presence of potassium t-butoxide in liquid ammonia afforded the corresponding aldoximes in good yields except for the case of 3-methylpyridine. The reaction of 3-methylpyridine with t-butyl nitrite in the presence of lithium 2,2,6,6-tetramethylpiperidide and N,N,N,N-tetramethylethylenediamine in tetrahydrofuran at -78°C led to 3-(3-methyl-4-pyridyl)methylpyridine. Deoxygenation of 3-pyridinecarbaldehyde 1-oxide oxime was effected in 78% yield by the action of t-butyldimethylsilyl chloride-imidazole-sodium iodide-zinc followed by desilylation with tetrabutylammonium fluoride to give 3-pyridinecarbaldehyde oxime

Interindividual variation of serum haloperidol concentrations in Japanese patients – clinical considerations on steady-state serum level–dose ratios

Objective:u2002 Marked interpatient variability in haloperidol (HAL) level–dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations.

Preparation and antibacterial activity of 3-methyl-1-p-substituted phenylpyrazole-5-thiol.

3‐Methyl‐1‐phenylpyrazole‐5‐thiol (3a) and its p‐nitro‐(5) and p‐fluorophenyl (8) derivatives were prepared as potential antimicrobial agents in relatively good yields. Compounds 3a and 8 showed good antibacterial activities against MRSA, S. aureus, S. epidermidis, E. faecalis, E. faecium, and S. pyogenes. Moreover, compound 3a also showed a synergistic effect with some aminoglycosides.