Search PubMed⌕ Search

Biomedical subjects

R Hori

Publications and source records attributed to R Hori.

At least 37 records · Page 2Linked to original sources
PubMed1999

Pharmacokinetics and pharmacological effect of recombinant human granulocyte colony-stimulating factor conjugated to poly(styrene-co-maleic acid) in rats.

A new derivative of recombinant human granulocyte colony-stimulating factor (rhG-CSF) has been synthesized by conjugating rhG-CSF to poly(styrene-co-maleic acid) (poly(styrene-co-maleic acid)-rhG-CSF) to try to avoid glomerular filtration and thus potentiate the neutrophil-proliferating activity of rhG-CSF. Poly(styrene-co-maleic acid)-rhG-CSF was highly bound to bovine serum albumin (BSA) and the molecular weight of the poly(styrene-co-maleic acid)-rhG-CSF-BSA complex was estimated to be about 90000 by gel filtration. Intravenous administration of poly(styrene-co-maleic acid)-rhG-CSF to normal rats resulted in a dose-dependent increase in neutrophil count. The neutrophil-proliferating activity of poly(styrene-co-maleic acid)-rhG-CSF was about 10 times greater than that of rhG-CSF. After intravenous injection at a dose of 5 microg protein kg(-1) the total clearance of rhG-CSF fell from 71.0 to 32.1 mLh(-1) kg(-1) following poly(styrene-co-maleic acid) modification. An isolated perfusion study in rat kidney showed that the filtered fraction of rhG-CSF was reduced by conjugation with poly(styrene-co-maleic acid). These results suggest that poly(styrene-co-maleic acid)-conjugation can potentiate the neutrophil-proliferating activity of rhG-CSF by reducing, at least in part, its renal clearance.

Animals↗
PubMed1998

Transcription: TRF walks the walk but can it talk the talk?

The TBP-related factor TRF binds to a TATA box promoter sequence and mediates basal transcription in vitro. A central question is: does TRF function in vivo to transduce the effects of activators in a tissue-specific fashion?

Amino Acid Sequence↗
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↗
PubMed1997

Relationship between expression level of P-glycoprotein and daunorubicin transport in LLC-PK1 cells transfected with human MDR1 gene.

P-Glycoprotein-mediated transcellular transport and intracellular accumulation of [3H]daunorubicin were examined in cell monolayers with different levels of P-glycoprotein. The porcine kidney epithelial cell line LLC-PK1 was transfected with MDR1 cDNA, and four sublines, LLC-GA5, LLC-GA5-VLB4, LLC-GA5-COL10, and LLC-GA5-COL150, were obtained by culturing the cells in the absence or in the presence of 4 ng/mL vinblastine, 10 ng/mL colchicine, and 150 ng/mL colchicine, respectively. Western blot analysis showed a large difference in P-glycoprotein expression within these sublines. The degree of drug resistance was dependent on the expression level of P-glycoprotein. The amount of the unidirectional transport of [3H]daunorubicin by P-glycoprotein corresponded to the expression level of P-glycoprotein, which was followed by the decrease in intracellular accumulation of the agent. The concentration of cyclosporin A required for the inhibition of P-glycoprotein-mediated transport of [3H]daunorubicin was higher in cells with a high expression of P-glycoprotein. These findings suggest that the transport of daunorubicin by P-glycoprotein and its inhibition by cyclosporin A correspond to the expression level of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Protease footprinting analysis of ternary complex formation by human TFIIA.

Transcription factor (TF) IIA performs two important regulatory functions during RNA polymerase II transcription: it is required for efficient binding of TFIID to a core promoter and it mediates the effects of upstream activators, both through direct interaction with the TATA box binding protein (TBP). To begin studying how TFIIA mediates these effects, we used a highly sensitive protease footprinting methodology to identify surfaces of human TFIIA participating in TFIIA x TBP x TATA ternary complex formation. Chymotrypsin and proteinase K cleavage patterns of TFIIA bearing a 32P-end-labeled gamma subunit revealed that amino acids 59-73 were protected from cleavage both in the context of an immobilized ternary complex and in a binary complex with TBP alone. In contrast, amino acids 341-367 in the beta portion of a 32P-labeled alpha-beta subunit were protected in the ternary but not in the binary complex, implying that those residues interact with promoter DNA. The regions of human TFIIA identified by protease footprinting are homologous to and encompass the yeast TFIIA residues that contact TBP and DNA in the recently solved crystal structure of the yeast ternary complex. The conservation of the regions and residues mediating complex formation implies that yeast and human TFIIA employ the same mechanism to stabilize the binding of TFIID to a core promoter.

Binding Sites↗
PubMed1997

Bactericidal eradication from carious lesions of prepared abutments by an antibacterial temporary cement.

PURPOSE: The aim of this study was to observe the antibacterial potential of polycarboxylate temporary cement containing a mixture of metronidazole, ciprofloxacin, and cefaclor on carious lesions of prepared abutments that were designed to leave caries on the abutments. MATERIAL AND METHODS: Antibacterial efficacy was estimated in vitro and in vivo by measuring bacterial recovery from the lesions. Bacteria counts ranged from 10(4) to 10(7) both in vitro (nine samples) and in vivo (five samples) in time-zero samples, just before the application of the antibacterial cement. RESULTS: No bacteria were recovered from carious lesions in vitro (six samples) or in vivo (four samples) after the lesions were covered by the antibacterial temporary cement. For the remaining samples, some bacteria (5 to 80 counts per sample) were recovered, with one notable exception in which marginal leakage provided a bacteria count of 10(3). Bacteria counts ranging from 10(3) to 10(5) occurred in carious lesions covered by temporary cement without antibacterial agents, which indicated that temporary cement alone was not a potent disinfectant. CONCLUSIONS: The results of this study indicated that the antibacterial temporary cement can be useful for eradicating bacteria from carious lesions of prepared abutments.

Adult↗
PubMed1997

T-8581, a new orally and parenterally active triazole antifungal agent: in vitro and in vivo evaluations.

T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml. For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.

Animals↗
PubMed1997

Determining the optimum dose for the intravenous administration of nicardipine in the treatment of acute heart failure--a multicenter study. The Nicardipine Heart Failure Study Group.

Nicardipine is a potent arteriolar vasodilator with a negligible negative inotropic effect. Although intravenous administration of this drug has been reported to be effective in the treatment of heart failure, the optimal dose by this route is not clear. This study was designed to determine the optimum dose for the intravenous infusion of nicardipine in the treatment of heart failure. In Trial 1, nicardipine was administered intravenously at a dose of 0.5 microgram/kg per min to 14 patients with acute heart failure. The dose was increased to 1.0 microgram/kg per min in 13 cases with marked improvement at 2 h. In Trial 2, nicardipine was administered in a double-blind manner to 53 patients at 3 different rates of infusion for 2 h: 1.0 (Group 1, n = 19), 2.0 (Group 2, n = 15), and 3.0 (Group 3, n = 19) micrograms/kg per min. Neither heart rate nor mean right atrial pressure changed in any of the 3 groups. Favorable hemodynamic effects were evident in all groups beginning 30 min after the start of infusion, with an increase in cardiac index (control vs 2 h after infusion, L/min per m2) (Group 1: 2.2 +/- 0.4 vs 3.1 +/- 0.8, Group 2: 2.2 +/- 0.4 vs 2.9 +/- 0.5, Group 3: 2.3 +/- 0.3 vs 3.1 +/- 0.7, all p < 0.01 compared to the control) and a decrease in diastolic pulmonary artery pressure (Group 1: 26 +/- 10 vs 19 +/- 7, Group 2: 27 +/- 10 vs 20 +/- 8, Group 3: 26 +/- 7 vs 18 +/- 5 mmHg, all p < 0.01). The decrease in systolic pressure was greatest in Group 3 (Group 1: 141 +/- 31 vs 119 +/- 18, Group 2: 149 +/- 25 vs 118 +/- 17, Group 3; 147 +/- 27 vs 107 +/- 14 mmHg, all p < 0.01 compared to control, and p < 0.05 between Groups 1 and 3). The intravenous drip infusion of nicardipine is effective in the treatment of heart failure by inducing an increase in cardiac output and a decrease in pulmonary artery wedge pressure. The optimal dose in this study was 1.0 microgram/kg per min.

Acute Disease↗
PubMed1997

Stress fracture of the medial malleolus.

It is difficult to assess the healing of the medial malleolar stress fracture. We describe a case of medial malleolar stress fracture which was monitored its healing with repeated magnetic resonance images.

Adolescent↗
PubMed1996

Effect of cyclosporin analogues and FK506 on transcellular transport of daunorubicin and vinblastine via P-glycoprotein.

PURPOSE: P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated. METHODS: The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506. RESULTS: Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D > cyclosporin A > FK506 > cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity. CONCLUSIONS: In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Association between type A behavior pattern and coronary artery spasm in Japanese patients.

The relations between the Jenkins Activity Survey (JAS) Type A score and coronary atherosclerosis and spasm were examined in 192 patients (115 men and 77 women) undergoing coronary angiography. Thirty-nine men (34%) and 12 women (16%) had significant (>or=75%) coronary stenosis. In 97 patients (54 men and 43 women) with no significant coronary stenosis, a coronary spasm provocation test by 0.2 to 0.4 mg of ergometrine was performed, by which a significant focal spasm (>or=75% reduction of luminal diameter) was induced in 22 men (40%) and 5 women (12%). Men who showed a significant focal spasm had a higher Type A score than men who showed no such spasm (1.9 +/- 8.4 vs. -2.4 x 8.3, p < 0.05). Discriminant analysis in male patients revealed that the induction of coronary spasm can be predicted by the JAS Type A score and smoking habit (p = 0.04). No such association was found for female patients. These results suggest that the Type A behavior pattern as assessed by the JAS may be associated with coronary spasm in Japanese men without significant coronary stenosis.

Journal Article↗
PubMed1995

Protease footprinting reveals a surface on transcription factor TFIIB that serves as an interface for activators and coactivators.

Transcriptional stimulation by the model activator GAL4-VP16 (a chimeric protein consisting of the DNA-binding domain of the yeast activator GAL4 and the acidic activation domain of the herpes simplex virus protein VP16) involves a series of poorly understood protein-protein interactions between the VP16 activation domain and components of the RNA polymerase II general transcription machinery. One of these interactions is the VP16-mediated binding and recruitment of transcription factor TFIIB. However, TATA box-binding protein (TBP)-associated factors (TAFs), or coactivators, are required for this interaction to culminate in productive transcription complex assembly, and one such TAF, Drosophila TAF40, reportedly forms a ternary complex with VP16 and TFIIB. Due to TFIIB's central role in gene activation, we sought to directly visualize the surfaces of this protein that mediate formation of the ternary complex. We developed an approach called protease footprinting in which the broad-specificity proteases chymotrypsin and alkaline protease were used to probe binding of 32P-end-labeled TFIIB to GAL4-VP16 or TAF40. Analysis of the cleavage products revealed two regions of TFIIB protected by VP16 from protease attack, one of which overlapped with a region protected by TAF40. The close proximity of the VP16 and TAF40 binding sites on the surface of TFIIB suggests that this region could act as a regulatory interface mediating the effects of activators and coactivators on transcription complex assembly.

Amino Acid Sequence↗
PubMed1995

Simulation for population analysis of Michaelis-Menten elimination kinetics.

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug.

Computer Simulation↗
PubMed1995

In vitro and in vivo effects of somatostatin on the growth of A431 cells.

We previously reported that the octapeptide somatostatin (SS) analogue SMS 201-995 (SMS) unexpectedly stimulates the growth of A431 human epidermoid carcinoma cells in vitro. In the present study, we found that both SS-14 and SS-28 also stimulated the growth of A431 cells in vitro. The proliferative effect of SS-28 also stimulated the growth of A431 cells in vitro. The proliferative effect of SS-28 was greater than that of SS-14. In contrast, there was no difference in A431 cell tumor weight or area between the SMS-treated or untreated athymic, tumor-bearing mice. The serum epidermal growth factor (EGF) level of the SMS-treated mice was significantly lower than that of the untreated mice. Decreases in serum EGF may attenuate the proliferative effect of SMS in vivo.

Animals↗
PubMed1995

Population pharmacokinetics of theophylline. III. Premarketing study for a once-daily administered preparation.

The population pharmacokinetic parameters for a once-daily administered preparation, Uniphyl were estimated from data collected in the premarketing clinical trial. Altogether, 2772 serum theophylline concentrations were obtained from 131 normal subjects and 306 patients suffering from chronic asthma or chronic obstructive pulmonary disease who participated in the phase I, II, and III clinical trials in Japan. The serum concentration profile was described by a linear one-compartment model with first-order absorption. The factors affecting the pharmacokinetics of this drug were examined by the likelihood ratio test using a nonlinear mixed effect model (NONMEM). The first-order absorption rate constant (Ka) for a 200-mg tablet in a fasting condition was obtained as 0.0773 (1/h), which was smaller than the elimination rate constant (0.168 1/h), indicating the flip-flop characteristic of this preparation. Food indigestion increased the Ka by 17% and the absorption lag time by 5-fold but did not affect the extent of absorption. The 400-mg tablet showed a Ka value 19%, smaller than the 200-mg tablet. Children not older than 15 years showed 58% longer absorption lag time. The inter-individual variability in Ka was 19%, suggesting small variability in the vivo release process. The total body clearance was related to hepatic function, smoking habits, and age. Furthermore, clearance decreased in association with the severity of illness. The findings obtained here are useful not only for the initial dosage adjustment for patients with a variety of backgrounds but also for doses individualization based on serum concentration monitoring with or without the Bayesian feedback method.

Adolescent↗
PubMed1995

Premarketing population pharmacokinetic study of levofloxacin in normal subjects and patients with infectious diseases.

The population pharmacokinetics of levofloxacin (LVFX), the l-enantiomer of ofloxacin, were studied in 522 subjects, including normal subjects and patients with infectious diseases. Altogether, 1572 LVFX serum concentrations were obtained following a single oral administration during clinical trials. The influences of renal function, age, meals and concurrent drug administration on the pharmacokinetic parameters of LVFX were examined by the likelihood ratio test using a nonlinear mixed-effect model (NONMEM). In patients with renal insufficiency, the total body clearance (CL) of LVFX was related to creatinine clearance (Ccr) and body weight (WT), as expressed by CL = 0.0836 Ccr + 0.013 WT. The CL with normal renal function was 0.178 (l/h/kg). The apparent volume of distribution (Vd) was calculated to be 1.46 (l/kg). The elderly subjects, aged 65 years old or over, exhibited, on average, a 32% reduction in CL and 6% greater Vd. LVFX was rapidly absorbed in the gastrointestinal tract, but the concurrent administration of antacids (magnesium, aluminum, etc.) decreased the bioavailability of LVFX by 15-52%. The recommended dose of LVFX was decided on the basis of current pharmacokinetic information and the minimum inhibitory concentrations. Population pharmacokinetic parameters are also useful for the individualization of a dosage regimen by means of the Bayesian forecasting method.

Age Factors↗