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T Iga

Publications and source records attributed to T Iga.

At least 55 records · Page 3Linked to original sources
PubMed1999

[Quantitative analysis of factors to influence the environment of the clean room and clean bench during preparation of intravenous hyperalimentation (IVH) admixtures].

We quantitatively studied factors influencing the environment cleanliness for intravenous hyperalimentation (IVH) admixing. The environment cleanliness was evaluated by measuring the counts of particles (> 0.5 micron) and bacteria floating in 1 ft3 of the air inside the clean room (23.6 m3) and in the clean bench built in the department of pharmacy, The University of Tokyo Hospital in 1998. The number of particles at the center of the clean room during IVH admixing by 4 pharmacists was higher than that at the medicine passing area (150 +/- 50/ft3 vs. 260 +/- 60/ft3; mean +/- S.D., n = 12). The cleanliness inside the clean room was improved as the measurement point became higher from the floor (600 +/- 180/ft3, 150 +/- 50/ft3, and 35 +/- 15/ft3 at 50, 100, and 150 cm height, respectively) and the number of persons working inside the room decreased. The changes in the counts of floating bacteria were similar to that of floating particles under the same conditions. In addition the effect of disinfection on the counts of bacteria was clearly observed. When the cleanliness of the room became lower by turning off the air conditioning, the particle counts inside the clean bench became lower along with the distance from the front glass becoming deeper (i.e., 1400 +/- 550/ft3, 140 +/- 70/ft3, and 40 +/- 30/ft3 at 0, 5, and 15 cm, respectively). From these lines of evidence, the following items were suggested in order to maintain the environment cleanliness for IVH admixing. First, the number of persons residing in the clean room should be kept to be minimum. Second, the clean bench should be set up in the center of the clean room. Finally IVH admixing operation should be performed at more than 15 cm depth inside the front glass surface of the clean bench. Moreover, the effect of mopping-up of the clean room with 0.1% benzethonium chloride clearly demonstrated the importance of disinfection on a routine basis.

Air Conditioning↗
PubMed1999

[Preparation of ketamine tablets for treatment of patients with neuropathic pain].

Ketamine is known to have distinguished analgesic effects without anesthetic when administered in a low dose. Since ketamine is not commercially available except injection forms, we prepared ketamine tablets for the home-care medication of patients with neuropathic pain. The direct compression or wet granulation method was employed to form 150 mg of tablets containing 50 mg of ketamine. The latter method was superior to the former one in terms of content uniformity, weight variation and disintegration tests of the tablets. Ketamine contents in the tablet prepared by the wet granulation method were unchanged for 12 weeks under the conditions of 25 degrees C and 75% relative humidity (RH). The Cmax and AUC0-3 h values for ketamine after administration of the tablet were slightly smaller than those of the syrup in a healthy volunteer. However, analgesic effects of the tablet was similar to that of the syrup in a patient with neuropathic pain. And the tablet was also effective for another four patients with neuropathic pain. These results indicate that ketamine tablets are useful for the home-care medication of patients with neuropathic pain.

Adult↗
PubMed1999

[Effects of the rational use of corticosteroids eye drops for the prevention of ocular toxicity in high-dose cytosine arabinoside therapy].

Although the use of corticosteroid (CS) eye drops of the use of eye washing by artificial tears was effective for the prevention of ocular toxicity such as keratitis and photophobia in the high-dose cytosine arabinoside (Ara-C) therapy, the toxicity was not prevented perfectly. We studied the effects of the rational use of CS eye drops, and the combined use of CS eye drops and eye washing by physiological saline in order to prevent the ocular toxicity. Before the study, the instillation of 0.1% sodium bethamethazone phosphate (BM) eye drops was carried out at 4-6 times per day during the high-dose Ara-C therapy, and continued for several days after the high-dose Ara-C therapy. However, the rational use of "eyelid closure" and "naso-lacrimal occlusion" after the instillation was not performed Consequently, the ocular toxicity was observed in 3 (19%) of 16 cases of the patients. When the instillation of BM eye drops at 4 times per day was carried out rationally according to the consultation of pharmacist during the high-dose Ara-C therapy and for additional 10 days after the therapy, no ocular toxicity was observed in all cases (0 of 6 cases). Furthermore, the combined use of eye washing by physiological saline and instillation of BM eye drops was effective for the decrease of the risk of ocular toxicity, because no ocular toxicity was observed in the high-dose Ara-C therapy (0 of 34 cases). Our procedure in this study would be effective for the prevention of ocular toxicity in the high-dose Ara-C therapy.

Adolescent↗
PubMed1999

[Effects of mouth wash on the removing beclomethasone dipropionate delivered by pressurized aerosol metered-dose inhaler in the mouth].

Effects of mouth wash (mouth rinsing and gargling) on the removal of drug residues in both mouth and pharynx after the use of pressurized aerosol metered-dose inhaler (MDI) were studied. The concentration of beclomethasone dipropionate (BM) in mouth wash after a splay of Becotide inhaler was measured by the method using HPLC. The total amount of the removed BM was measured by a sum of the concentrations of BM in 4 or 5 times of mouth washes in the following 4 kinds of methods. In method 1, mouth wash was done with 5 times of water change after a splay of MDI on wetted mouth. In method 2, mouth wash was done with 5 times of change water on dried mouth. In method 3, mouth wash was done with 4 times of change saliva on wetted mouth. In these methods, the actual inhalation of BM was not done. In method 4, mouth wash was done with 5 times of change water after a splay and a inhalation on wetted mouth. The mouth wash procedures removed totally 47.9%, 51.1%, 31.3%, and 33.3% of a splayed amount of BM in each method, respectively. It was required for the removal of 90% of the totally recovered BM to do one time of mouth wash in method 1, two times in method 2, three times in method 3, and two times in method 4, respectively. These data suggest that the mouth wash procedure is shown to have prophylactic benefit for candidiasis induced by steroid delivered by MDI.

Administration, Inhalation↗
PubMed1999

[Kinetic analysis of therapeutic doses of beta-blockers for angina pectoris based on receptor occupancy theory--relationship between beta 1-receptor occupancy or vasodilative action and dose].

Beta-adrenoceptor blocking agents (beta-blockers) have been widely used for the treatment of angina pectoris. The average/standard therapeutic doses vary widely among beta-blockers with the maximum of about a 120-fold difference. In order to clarify the mechanism of this difference, we analyzed retrospectively the pharmacological effects of beta-blockers in consideration of the beta 1-receptor binding affinity and the vasodilative activity on the basis of pharmacokinetics and the receptor occupancy theory. The analysis was performed on eight beta-blockers without a vasodilative effect and on four beta-blockers with a vasodilative effect. The beta 1-receptor occupancies at the steady-state condition after oral administration of standard doses were calculated by the use of the data on the concentration of unbound agents in plasma and on the dissociation constant of receptors. The estimated receptor occupancies were 87 +/- 6% or 88 +/- 10% for the beta-blockers with or without a vasodilative effect, respectively, and a significant difference was not observed between these groups. These results suggest that the beta 1-receptor occupancies may be a principal indicator for the therapeutic effects for angina pectoris regardless of their vasodilative effects.

Administration, Oral↗
PubMed1999

Quantitative prediction of metabolic inhibition of midazolam by itraconazole and ketoconazole in rats: implication of concentrative uptake of inhibitors into liver.

To evaluate the extent of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio of midazolam (MDZ) by itraconazole (ITZ) or ketoconazole (KTZ) in rats. MDZ was administered at a dose of 10 mg/kg through the portal vein at 60 min after bolus administration of 20 mg/kg ITZ or during 0.33 mg/h/body of KTZ infusion. The ratio values in the area under the plasma concentration curve of MDZ in the presence of ITZ and KTZ was 2.14 and 1.67, respectively. The liver-unbound concentration to plasma-unbound concentration ratios of ITZ and KTZ were 11 approximately 14 and 1.3, respectively, suggesting a concentrative uptake of both drugs into the liver. ITZ and KTZ competitively inhibited the oxidative metabolism of MDZ in rat liver microsomes, and Ki values of ITZ and KTZ were 0.23 microM and 0.16 microM, respectively. We predicted the ratio values of MDZ in the presence of ITZ and KTZ, using Ki values and unbound concentrations of both drugs in the plasma or liver. The predicted ratio values in the presence of ITZ or KTZ calculated by using unbound concentration in the plasma were 1.03 approximately 1.05 and 1.39, whereas those calculated using unbound concentration in the liver were 1.73 approximately 1.97 and 1.51, respectively, which were very close to the observed ratio values. These findings indicated the necessity to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of the drug-drug interactions concerning metabolic inhibition in the liver.

Animals↗
PubMed1999

Correlation between in vivo and in vitro hepatic uptake of metabolic inhibitors of cytochrome P-450 in rats.

To predict the degree of accumulation of hepatic metabolic inhibitors in the liver from the in vitro data, we investigated the relationship between cell/medium concentration ratios (C/M ratios) in isolated rat hepatocytes and liver/blood unbound concentration (K(Bf)) after i.v. administration of various metabolic inhibitors such as itraconazole, ketoconazole, verapamil, diltiazem, enoxacin, ciprofloxacin, clarithromycin, cimetidine, and nizatidine. The C/M ratios of itraconazole were approximately 6,000 and 200 at the concentrations of 0.1 and 10 microg/ml, respectively, and the uptake of ketoconazole and verapamil into the hepatocytes also showed a concentration dependence, although the degree was smaller than that of itraconazole. The uptake of diltiazem, enoxacin, ciprofloxacin, and clarithromycin into the hepatocytes showed linear profiles on concentration dependence. There was an excellent correlation between C/M ratios and K(Bf) values of all nine drugs with a slope of 1. This finding suggested the possibility of predicting drug concentrations in the liver (C(H)) from C/M ratios, the blood concentrations of drugs (C(B)) and unbound fraction in blood (f(B)), which was expressed by C(H) = (C/M). C(B). f(B). It may be possible to predict the drug concentrations in human liver from K(Bf) values estimated with isolated human hepatocytes and concentrations in the blood in a similar manner as in rats.

Animals↗
PubMed1998

Quantitative determination of domperidone in rat plasma by high-performance liquid chromatography with fluorescence detection.

A sensitive and selective analytical method for the determination of domperidone in rat plasma is described. The procedure involves liquid-liquid extraction followed by reversed-phase high-performance chromatographic analysis with fluorometric detection at 282 nm for excitation and 328 nm for emission. The detection limit was 1 ng ml(-1) using 1 ml of plasma. This assay procedure should be useful for the pharmacokinetic study of domperidone in small animals such as rats.

Animals↗
PubMed1998

Catalepsy induced by calcium channel blockers in mice.

It is known that calcium channel blockers induce Parkinsonism. In this study, amlodipine-, diltiazem-, and verapamil-induced catalepsy was investigated in mice. All of these three calcium channel blockers induced catalepsy. Dopamine D1, D2, and mACh receptor occupancies were estimated under the same conditions, and the affinities of these drugs for each receptor were also estimated in vitro. Intensity of catalepsy was predicted by dopamine D1, D2, and mACh receptor occupancies with the dynamic model which had already been constructed and was compared with the observed values. The predicted and the observed values were comparable (r = 0.98, p < 0.001). In conclusion, the dynamic model considering D1, and D2, and mACh receptor occupancy may be useful for quantitative prediction of drug-induced catalepsy.

Amlodipine↗
PubMed1998

Simvastatin-tacrolimus and simvastatin-cyclosporin interactions in rats.

The effect of simvastatin (SV)-tacrolimus (TL) and simvastatin-cyclosporin (CyA) interactions on creatine phosphokinase levels and renal and hepatic function were investigated in rats. Animals were divided into seven groups; (1) SV (150 mg kg-1 oral) alone, (2) SV + TL (150 mg kg-1 oral + 0.5 mg kg-1 intraperitoneal (i.p.)), (3) TL (0.5 mg kg-1 i.p.) alone, (4) SV + CyA (150 mg kg-1 oral + 10 mg kg-1 oral), (5) CyA (10 mg kg-1 oral) alone, (6) control vehicle for oral administration, and (7) control vehicle for i.p. administration. A marked reduction in body weight and mortality was observed in the (SV + CyA) and (SV + TL) groups. Plasma creatine kinase levels in the (SV), (TL), (SV + CyA) and (SV + TL) groups, 7 days postadministration, were significantly higher compared with those before administration (p < 0.05). The plasma urea nitrogen levels in the (TL), (SV + CyA) and (SV + TL) groups after 7 days of administration were significantly higher than those of the controls. In addition, a marked increase in the plasma levels of alanine and aspartate amino transferases were observed in the (SV + CyA) groups.

Animals↗
PubMed1998

Pharmacokinetics and pharmacodynamics of FK143, a nonsteroidal inhibitor of steroid 5 alpha-reductase, in healthy volunteers.

The pharmacokinetics and pharmacodynamics of FK143, a new nonsteroidal inhibitor of steroid 5 alpha-reductase, were investigated in healthy volunteers, with use of plasma FK143 concentrations and serum dihydrotestosterone levels as an index for pharmacologic effects. The area under the plasma concentration-time curve from zero to infinity [AUC(0-infinity)] and maximum plasma concentration [Cmax] were increased dose proportionally after oral administration (100 to 500 mg) while subjects were in the fed state. The AUC(0-infinity) and Cmax after 500 mg oral administration during fed conditions were significantly larger than those during the fasted state, suggesting an increase of the absorption of FK143. Dihydrotestosterone concentrations after a single administration of FK143 (100 to 500 mg) during fed conditions decreased to about 65% of predose values and thereafter slowly recovered to the same levels as predose values at 168 hours. A combined pharmacokinetic-pharmacodynamic model was constructed with use of changes in dihydrotestosterone concentrations. The pharmacokinetic-pharmacodynamic profiles of FK143 after repeated administration were predictable with use of the pharmacokinetic-pharmacodynamic parameters obtained after a single administration of FK143.

5-alpha Reductase Inhibitors↗
PubMed1998

Effects of hypokalaemia on arrhythmogenic risk of quinidine in rats.

Plasma potassium concentration plays an important role in the induction of arrhythmia and is closely related to the arrhythmogenicity of various drugs. We quantitatively analyzed the influence of plasma potassium concentration on QT intervals before drug administration and on drug-induced QT prolongation, to estimate the risk of drug-induced arrhythmia under hypokalaemic conditions. The hypokalaemic models were produced by intraperitoneal administration of furosemide and hydrochlorothiazide in male Sprague-Dawley rats. The relationship between the changes in QT intervals and time profiles of plasma quinidine (QND) concentration were analyzed during constant intravenous infusion of QND (10 or 30 mg/kg/h) and post infusion in normal and hypokalaemic rats. The plasma QND concentration reached the therapeutic range (3-7 microg/ml) at the high infusion rate (30 mg/kg/h). No pharmacokinetic differences between normal and hypokalaemic rats were observed. QND induced QT prolongation in parallel with the plasma concentration without hysteresis. Although the potency of QND for QT prolongation was not affected by hypokalaemia, the QT intervals before drug administration were significantly prolonged in hypokalaemic rats (65.90 +/- 1.40 vs 56.60 +/- 0.748 msec, mean +/- SEM, p < 0.0001). Thus, the prolongation of QT intervals before drug administration may act as a risk factor of arrhythmia under hypokalaemic conditions.

Animals↗
PubMed1998

Effect of cilastatin on renal handling of vancomycin in rats.

To provide insights into the possibility of reducing the nephrotoxicity of vancomycin (VCM) by cilastatin, the effect of cilastatin on the renal handling of VCM, as well as on glomerular filtration rate (GFR) and plasma protein binding of VCM, were studied using rats. After a bolus intravenous (iv) dose of VCM (100 mg/kg), concomitant cilastatin administration (100 mg/kg, iv) resulted in a significant increase in the total VCM clearance and significant decrease in the kidney uptake clearance of VCM, defined as kidney VCM concentration vs AUC ratio. Moreover, after a 3-h continuous iv infusion of VCM (18 or 90 mg/h/kg), significant decrease in the kidney uptake clearance of VCM was observed with concomitant cilastatin iv infusion (300 mg/h/kg). On the other hand, GFR and VCM plasma protein binding did not show any significant change with cilastatin. From the observation that cilastatin decreased the kidney uptake clearance of VCM and enhanced its urinary excretion, it was suggested that cilastatin inhibited the reabsorption of VCM in the renal proximal tubular cells. Thus, it may be possible that cilastatin alleviates the nephrotoxicity of VCM due to reduced accumulation and accelerated renal excretion of VCM.

Animals↗
PubMed1998

Population pharmacokinetics of vancomycin in Japanese adult patients.

Population pharmacokinetic parameters of vancomycin (VCM) in Japanese adult patients infected with methicillin-resistant Staphylococcus aureus (MRSA) were estimated using 1253 items of serum concentration data from 190 patients obtained in routine drug monitoring. The two-compartment linear model was adopted, and VCM clearance (CL) was correlated with the creatinine clearance (CLcr), which was observed or estimated by the Cockcroft-Gault equation. The population pharmacokinetic analysis program NONMEM with first-order conditional estimation method was used. The results showed VCM clearance to be linearly correlated with CLcr (CL [ml/min] = 0.797 x CLcr) when the estimated CLcr was <85 ml/min, but no linear relationship at higher than this level because of the lack of accuracy in the CLcr estimates. The interindividual variability of CL was 38.5%; K12 and K21 were 0.525 hr(-1) and 0.213 hr(-1), respectively. The distribution volume at steady state (V[SS]) was 60.71, with no significant dependence on the actual body weight. The interindividual variability of Vss was 25.4%. The calculated half-life (t1/2,beta) in a typical patient with CLcr of 85 ml/minute was 12.8 hours. Residual variability was 23.7%. These results were compared to those of healthy volunteers, and guidelines for dosage adjustment in VCM therapy are discussed.

Adult↗
PubMed1998

Population pharmacokinetics of vancomycin in Japanese pediatric patients.

The population pharmacokinetic profile of vancomycin (VCM) in Japanese pediatric patients infected with methicillin-resistant Staphylococcus aureus was analyzed using 181 samples of serum concentration data from 49 patients obtained in routine drug monitoring. The one-compartment linear model was adopted, where the VCM clearance (CL) and the distribution volume (Vd) were correlated with covariates such as postnatal age (AGE) and body weight (BWT). The population pharmacokinetic analysis program NONMEM with the first-order conditional estimation method was used. The results showed that the population mean clearance normalized by BWT increases with AGE up to 1 year of age [CL(L/hour per kg) = 0.1 19 + 0.0619 x (AGE - 1)] and decreases with age over 1 year old [CL(L/hour per kg) = 0.119 + 0.00508 x (1 - AGE)]. The population mean of the distribution volume normalized by BWT was independent of AGE (Vd (L/kg) = 0.522). The interindividual variability of CL was 39.6%, and that of Vd was 18.8%. The intraindividual, residual variability was 34.6%. These results were compared with those in other articles, and a guideline for dosage adjustment in VCM therapy is discussed.

Adolescent↗
PubMed1998

P-glycoprotein-mediated transport of itraconazole across the blood-brain barrier.

The mechanism for the accumulation of itraconazole (ITZ) in its elimination from the brain was studied in rats and mice. The concentration of ITZ in liver tissue declined in parallel with the plasma ITZ concentration until 24 h after intravenous injection of the drug (half-life, 5 h); however, the ITZ in brain tissue rapidly disappeared (half-life, 0.4 h). The time profiles of the brain/plasma ITZ concentration ratio (Kp value) showed a marked overshooting, and the Kp value increased with increasing dose; these phenomena were not observed in the liver tissue. This finding indicates the occurrence of a nonlinear efflux of ITZ from the brain to the blood. Moreover, based on a pharmacokinetic model which hypothesized processes for both nonlinear and linear effluxes of ITZ from the brain to the blood, we found that the efflux rate constant in the saturable process was approximately sevenfold larger than that in the nonsaturable process. The Kp value for the brain tissue was significantly increased in the presence of ketoconazole or verapamil. The brain Kp value for mdr1a knockout mice was also significantly increased compared with that of control mice. Moreover, the uptake of vincristine or vinblastine, both of which are substrates of the P glycoprotein (P-gp), into mouse brain capillary endothelial cells was also significantly increased by ITZ or verapamil. In conclusion, P-gp in the brain capillary endothelial cells participates in a process of active efflux of ITZ from the brain to the blood at the blood-brain barrier, and ITZ can be an inhibitor of various substrates of P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗