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Biomedical subjects

Takeshi Ozeki

Publications and source records attributed to Takeshi Ozeki.

16 recordsLinked to original sources
PubMed2007

Analysis of relationship between peak inspiratory flow rate and amount of drug delivered to lungs following inhalation of fluticasone propionate with a Diskhaler.

A Diskhaler is a dry powder type of inhaler that utilizes a breath controlled drug delivery system. The inspiratory flow rate of the patient would have a significant influence on the effects of drugs administered by a Diskhaler. Thus, we investigated the relationship between inspiratory flow rate and amount of drug delivered into the lungs when using a fluticasone propionate dry powder inhaler with a Diskhaler (FP-DH). To investigate the amount of drug inhaled, we used an inhalation simulator, which consisted of a flow recorder placed in a plastic air-tight box that covered the FP-DH equipped with a twin impinger and a vacuum pump. Drugs located in a plastic box, as well as the device, throat, and stage 1 and stage 2, were assayed by HPLC-UV, following in vitro inhalation at the various flow rates ranged from 18.7 to 77.3 l/min for 2 s. The relationship between peak inspiratory flow rate and amount of drug released from the device was analyzed. A positive linear correlation between the dose released from the device and amount of drug deposited in stage 2 was observed (r=0.899, p<0.001). The doses deposited in stage 2 were estimated to be 2.9 microg at a flow rate of 20 l/min, 6.6 microg at 30 l/min, 8.4 microg at 40 l/min, 10.1 microg at 60 l/min, and 11.3 microg at 90 l/min. It was suggested that the amount of drug in the lungs decreased along with a decrease in peak inspiratory flow rate when it was lower than 60 l/min. Our results were found to be very useful to estimate lung deposition by using peak inspiratory flow rate for administration planning, especially in patients with a flow rate of less than 60 l/min.

Administration, Inhalation↗
PubMed2006

Analysis of linkage between lymphotoxin alpha haplotype and polymorphisms in 5'-flanking region of tumor necrosis factor alpha gene associated with efficacy of infliximab for Crohn's disease patients.

Tumor necrosis factor (TNF)alpha is increased in patients with Crohn's disease (CD) and considered to play an important role in the inflammation. Infliximab (IFX) is used as a therapeutic agent for CD. Recently, it was reported that homozygosity for a lymphotoxin alpha (LTA) haplotype (LTA 1-1-1-1) may identify subgroups with a poor response to IFX. In the present study, we characterized the linkage of the LTA haplotype with SNPs in the 5'-flanking region of the TNFalpha gene. In subjects who had homozygosity for each LTA haplotype, 6 nucleotide variations, -857C > T, -522C > G, -357A > C, -261C > G, -159G > T and -96G > T, were found in the 5'-flanking region of the TNFalpha gene. As for linking with the allele, only -857T met the LTA haplotype 1-1-1-1. We concluded that the differences in therapeutic effects of IFX among patients with CD may be explained in part by the induction ability of TNFalpha via the -857C > T polymorphism.

5' Flanking Region↗
PubMed2006

Influence of mouth washing procedures on the removal of drug residues following inhalation of corticosteroids.

Mouth washing after inhalation of corticosteroids is effective for prevention of local adverse effects such as hoarseness and oropharyngeal candidiasis. To establish an optimal procedure for such mouth washing, we investigated the removal rates of drug residues remaining on the oropharyngeal mucosa using various mouth washing methods following inhalation. A beclomethasone dipropionate metered dose inhaler (BDP-MDI) (100 microg) and a fluticasone propionate dry powder inhaler (FP-DPI) (100 microg) were used. The effects of different mouth washing methods were evaluated by quantification of drugs in the expectorated rinse solution using an HPLC method. The amounts of BDP recovered in the rinse after gargling and rinsing for 5 s each were 47.1+/-13.6 microg, while they were 42.9+/-9.4 microg after rinsing alone for 10 s and 38.7+/-9.2 microg after gargling alone for 10 s. Under the same conditions, FP amounts were 32.9+/-7.3 microg, 28.9+/-2.4 microg, and 27.1+/-7.9 microg, respectively. In a comparison of washing time, the amounts of BDP recovered were 49.8+/-9.7 microg after gargling and rinsing for 2 s each, 53.5+/-10.2 microg after those for 3 s each, and 47.1+/-13.6 microg after those for 5 s each, while the amounts of FP under the same conditions were 36.4+/-2.4 microg, 33.3+/-6.4 microg, and 32.9+/-7.4 microg, respectively. As for the effect of time lag before mouth washing, the amount of BDP recovered decreased by 65.7% with a lag time of 1 min and by 5.6% after 10 min, while that of FP decreased by 51.1% with a lag time of 1 min and by 7.7% after 10 min. Our results suggest that the amount of drugs removed by mouth washing is significantly associated with the time lag between inhalation and mouth washing. We concluded that immediate gargling and rinsing after inhalation is most useful for the removal of drugs following inhalation of corticosteroids.

Administration, Inhalation↗
PubMed2006

[Analysis of the factors associated with drugs remaining in the Diskhaler following inhalation of fluticasone propionate].

Because it is well known that drug remains in the fluticasone propionate Diskhaler (FP-DH) following a single inhalation, the following patient information is recommended. "Please inhale more than once or twice if any drug remains in the device after inhalation". It is believed the inspiratory flow rate of the individual patient has an influence on the amount of drug that remains in the device. If the dosing performance of FP-DH is dependent on inspiratory effort, establishment of a method of inhalation that makes it independent of inspiratory flow rate is important in clinical practice. In the present study, we investigated the influence of various methods of inhalation of drug remaining in the FP-DH. No significant differences were observed regarding the drug remaining in the device among the inhalation times examined (range, 0.5-2.5 s) or the number of inhalations (range, 1-3 times). On the other hand, the amount of drug remaining in the device did decrease by tapping the device before the second inhalation. The results suggest that the amount of drug remaining in the device can be decreased by tapping the device after the first inhalation if the patient's inspiratory flow rate is low.

Administration, Inhalation↗
PubMed2006

[Usefulness of small group discussion using KJ method regarding early exposure for first-year pharmaceutical science students].

We evaluated the usefulness of small group discussion using the KJ method (KJ-SGD) in regards to early exposure for first-year pharmaceutical science students. Fourteen students were divided into 3 groups. They were asked to discuss the societal role of pharmaceutical science faculty members and then write the results of their discussion. Thereafter, each of the groups presented the contents of their written results to all of the students. Discussion sessions were held on two separate occasions, the first prior to early exposure and the second after early exposure. After receiving early exposure, the students were asked to revise their previous written results. Further, a questionnaire was given to the students following each discussion session, which revealed that more than 92% understood the KJ-SGD method and most answered that it was useful. In addition, all answered that their perceptions were changed after early exposure. Our findings showed that KJ-SGD was useful and that the students were able to effectively understand the contents following early exposure.

Education, Pharmacy↗
PubMed2006

[Survey of the attitude of master course students of clinical pharmacy toward clinical trials].

To obtain basic data on the introductory lecture on clinical trials in a School of Pharmacy, we carried out an attitude survey among master course students in the School of Pharmacy of our University. We distributed two types of questionnaire, one before and one after a lecture on the outline of clinical trials and the role of pharmacists in the performance of clinical trials. In the first questionnaire, 67% of respondents were interested in clinical trials, and 89% stated that they had obtained information on clinical trials from lectures at the University. On the other hand, over 92% thought that pharmacists should manage investigational drugs and provide information on those drugs for the rational conduct of clinical trials. Over 80% of respondents hoped that they would receive education on clinical trials in the third or fourth year of study, since that is when basic education ends and clinical education starts. After the first questionnaire and student attendance at an introductory lecture on clinical trials, second questionnaire was distributed. Based on the results of the second questionnaire, almost all of the students hoped to learn more about the actual conduct of clinical trials.

Attitude of Health Personnel↗
PubMed2006

[Subject making and evaluation method for objective structured clinical examination (OSCE) in pharmaceutical practice].

The aim of this study was to discuss subject selection and the evaluation method for an objective structured clinical examination (OSCE) in pharmaceutical sciences. We designed the OSCE to assess pharmaceutical students' clinical ability. In this trial, there are three stations (ST1 in circle: dispensing powdered medicine, ST2 in circle: patient reception, ST3 in circle: drug counseling), and 25 students and six instructors participated. Each student took an examination at two stations, and evaluated other students at the other station. Each instructor evaluated the student at two stations. Before the evaluation, we developed a checklist that contained the items "evaluation of the quantity" of the action, "evaluation of the quality" of the skill and the attitude, and "overall evaluation" to ensure the standardization of scoring. After the OSCE trial, we calculated and analyzed each examinee's evaluation score. In ST1 in circle and ST3 in circle, the average time for performance exceeded the time limit (5 min). There was no significant relationship between the each examinee's evaluation score and the time at all stations. The evaluation point "evaluation of the quantity" did not differ among evaluators, but a difference was seen in the "evaluation of the quality." In addition, in the quantitative evaluation, there was a difference in the evaluation of the item for which the evaluator's judgment was necessary. Instructors' evaluations were more severer than students'. In the "overall evaluation," there was no significant relation between the quantitative evaluation score and the score of the overall impression. However, there was a significant relationship with the qualitative evaluation. From these results, for assignment making, it is necessary for examinees to finish the work within the time limit, and that the evaluation not affect the performance time. Additionally, it is necessary to standardize the evaluation to reduce differences among evaluators, who should be trained. Moreover, it was suggested that the selection of an appropriate evaluation system for each evaluation item is important in OSCE stations.

Education, Pharmacy, Graduate↗
PubMed2005

The Val158Met polymorphism of the catechol-O-methyltransferase gene is associated with the PSA-progression-free survival in prostate cancer patients treated with estramustine phosphate.

OBJECTIVE: The aim of our study is to find out the good responders for estramustine phosphate (EMP) therapy in patients with prostate cancer. We have focused on the metabolism of EMP and studied the association between a functional single-nucleotide polymorphism in the catechol-O-methyltransferase gene (Val158Met of COMT) and PSA-progression-free survival in Japanese patients with prostate cancer treated by EMP. METHODS: Seventy-two Japanese patients with previously untreated prostate cancer who were found to be eligible for low-dose EMP therapy were enrolled in the study. Genotyping of the Val158Met polymorphism of COMT was conducted by both the polymerase chain reaction-based restriction fragment length polymorphism method and TaqMan assay. RESULTS: Patients with the Val/Val genotype of COMT had a significantly higher PSA-progression-free rate as compared to those with the Val/Met or Met/Met genotype (p=0.027). The adjusted hazard ratio of biochemical PSA failure for the Val158Met genotype of COMT was 2.164 (95% CI, 1.111 to 5.525). CONCLUSIONS: The Val158Met polymorphism of COMT is associated with the PSA-progression-free rate of EMP-treated patients in prostate cancer.

Aged↗
PubMed2005

Effects of the CYP3A5 genetic polymorphism on the pharmacokinetics of diltiazem.

BACKGROUND: The cytochrome P450 (CYP) 3A subfamily plays an important role in the metabolism of various endogenous and exogenous compounds. Among CYP3A subfamily members, CYP3A5 is polymorphically expressed and the CYP3A5*3 and CYP3A5*6 alleles are known not to express functional CYP3A5. Thus, these mutant alleles are thought to be responsible for interindividual variability of CYP3A activity. METHODS: Subjects possessing CYP3A5*1/*1, *1/*3 or *3/*3 received oral administration of diltiazem hydrochloride (60 mg), and plasma and urinary concentrations of diltiazem and its metabolite N-desmethyldiltiazem were measured. Before drug intake, cortisol metabolic clearance in each subject was measured to estimate in vivo CYP3A4 activity. RESULTS: The mean values of total oral diltiazem clearance of subjects with *1/*1, *1/*3 and *3/*3 were 183.4 +/- 39.4, 197.9 +/- 49.6 and 293.6 +/- 141.1 (l/h), respectively, and were not significantly different among the 3 genotype groups. The cortisol metabolic clearance was not significantly different among the three genotype groups, indicating that the CYP3A4 activity is not significantly different. CONCLUSION: The results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem. Although our results did not indicate significance of CYP3A5, the effects of CYP3A5*3 on the metabolism of other CYP3A substrates remain to be investigated.

Adult↗
PubMed2005

Single-nucleotide polymorphisms in the 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side-effects of estramustine phosphate sodium in prostate cancer patients.

BACKGROUND: Estramustine phosphate sodium (EMP) frequently causes side-effects such as gastrointestinal discomfort, nausea, and edema in extremities. We analyzed single nucleotide polymorphisms (SNP) in the 17beta-hydroxysteroid dehydrogenase (HSD17B) genes, which are involved in the metabolism of EMP, to predict the risk of EMP side-effects in prostate cancer patients. METHODS: We performed genotyping of SNP in the HSD17B genes of 44 Japanese patients with newly diagnosed prostate cancer. The association of SNP and individual EMP side-effects was evaluated. RESULTS: Peripheral edema occurred more frequently in patients with C/C genotype of IMS-JST123219 than in those with C/G genotype (OR: 5.47, 95% CI: 1.27-23.64). Haplotype analysis showed that appetite loss was associated with the G allele of IMS-JST123219 and the T allele of IMS-JST123218 (OR: 9.13, 95% CI: 1.15-72.76). CONCLUSIONS: These preliminary data demonstrated that analyses of SNP in the HSD17B genes might predict the occurrence of side-effects from EMP.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Receptor occupancy theory-based analysis of antiemetic effects and standard doses of 5-HT3 receptor antagonists in cancer patients.

PURPOSE: The aim of this study was to determine the usefulness of receptor occupancy theory-based analysis using pharmacokinetic and pharmacodynamic parameters for predicting the average receptor occupancy (PhiB) in humans of each of five 5-HT3 antagonists administered at standard doses. METHODS: The relationship between the PhiB value and the complete vomiting inhibition rate after a single intravenous administration of cisplatin (not less than 50 mg/m2) was analyzed. RESULTS: The predicted PhiB values after intravenous administration and oral administration of 5-HT3 antagonists were more than 65% and 50%, respectively, suggesting that relatively high receptor occupancy is required to elicit sufficient antiemetic effects of 5-HT3 antagonists. Moreover, significant ( P<0.05) linear relationships were found between PhiB values and complete vomiting inhibition rates of 5-HT3 antagonists in preventive cisplatin therapy, with correlation coefficients higher than 0.9, suggesting that the 5-HT3 receptor occupancy is an appropriate index of clinical efficacy of 5-HT3 antagonists, with higher receptor occupancy indicating more extensive antiemetic action. CONCLUSION: The receptor occupancy theory-based analysis of the antiemetic effect of a 5-HT3 receptor antagonist used in this study should be very useful for not only estimating a rational dosage regimen but also determining the standard dose of a new drug using experimental data obtained in a preclinical study.

Antiemetics↗
PubMed2004

Identification of a novel polymorphic enhancer of the human CYP3A4 gene.

CYP3A4, the most abundant form of cytochrome P450 in the human adult liver, shows wide interindividual variation in its activity. This variability is thought to be caused largely by transcriptional and genetic factors, yet the underlying mechanisms are poorly understood. The purpose of this study was to clarify the mechanisms controlling the CYP3A4 gene transcription and to search for genetic polymorphisms in the 5'-flanking region of the CYP3A4 gene. Transient transfection of human hepatoma HepG2 cells and of normal human hepatocytes with a series of CYP3A4 promoter-luciferase reporter plasmids revealed that a region from -11.4 to -10.5 kilobases, designated the constitutive liver enhancer module of CYP3A4 (CLEM4), was important for the constitutive activation of the CYP3A4 gene. Gel shift assay using nuclear extracts prepared from HepG2 cells showed that HNF-1alpha, HNF-4alpha, USF1, and AP-1 interacted with CLEM4. Furthermore, the introduction of mutations into their binding sites demonstrated that essentially all sites were required for the maximal enhancer activity. Screening for genetic polymorphisms within CLEM4 in genomic DNA from French persons, we identified the novel variant, TGT insertion between -11,129 and -11,128 (-11,129_-11,128insTGT), whose allele frequency was 3.1%. The -11,129_-11,128insTGT resulted in the disruption of USF1 binding and a 36% reduction of the enhancer activity. These results suggest that CLEM4 is a constitutive enhancer of the CYP3A4 gene in the liver and that -11,129_-11,128insTGT may at least partly contribute to the interindividual variability of CYP3A4 expression.

5' Flanking Region↗
PubMed2003

Hepatocyte nuclear factor-4 alpha/gamma and hepatocyte nuclear factor-1 alpha as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers.

Human dihydrodiol dehydrogenase (DD) catalyses the oxidation of trans-dihydrodiols of polycyclic aromatic hydrocarbons and the reduction of several ketone-containing drugs. About 40-fold interindividual difference in DD activities has been noted. Recently, we found that transcriptional factors, hepatocyte nuclear factor (HNF)-1 alpha, HNF-4 alpha and HNF-4 gamma were essential for the expression of DD4 mRNA, which is a major form of DDs. Thus, to clarify a possible mechanism(s) underlying the interindividual difference in DD activities, we investigated the sequences of genes and the expression levels of mRNA for DD4 and HNFs in human livers. We found no clear relationship between the genotypes of DD4 and HNF genes and the expression levels of DD4 mRNA in the subjects. The expression level of DD4 mRNA significantly correlated with that of HNF-1 alpha, HNF-4 alpha or HNF-4 gamma. These results suggest that the expression level of DD4 mRNA is cooperatively regulated by the amounts of HNF-1 alpha, HNF-4 alpha and HNF-4 gamma.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2003

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%.

Journal Article↗
PubMed2002

Hepatocyte nuclear factor (HNF)-4 alpha/gamma, HNF-1 alpha, and vHNF-1 regulate the cell-specific expression of the human dihydrodiol dehydrogenase (DD)4/AKR1C4 gene.

Recently, we found a region A (a hepatocyte nuclear factor (HNF)-4-binding site from nucleotides -701 to -684) and a region B (an HNF-1-binding site from nucleotides -682 to -666) as cis-acting elements necessary for the transcriptional activation of the human dihydrodiol dehydrogenase (DD)4 gene in human hepatoblastoma HepG2 cells, which express DD4 mRNA. Thus, to investigate the mechanism(s) responsible for the cell-type-specific expression of DD4 mRNA, we constructed a reporter plasmid, pDD4 Foot A+B: -95/+28, in which regions A and B were linked to the human DD4 minimal promoter (-95 to +28) fused to the luciferase gene. The luciferase activity was detectable in HepG2 cells but not in human renal adenocarcinoma ACHN cells transfected with the pDD4 Foot A+B: -95/+28, which do not express DD4 mRNA. A supershift assay using antibodies to HNF-4 alpha, -4 gamma, -1 alpha, or valiant HNF (vHNF)-1 revealed that HNF-4 alpha, -4 gamma, and -1 alpha recognized regions A and B in HepG2 cells and that only vHNF-1 bound to regions A and B in ACHN cells. Semiquantitative reverse-transcribed polymerase chain reaction showed that a large amount of vHNF-1-C, which lacked transcriptional activation domain, was expressed in ACHN cells. Transfection of ACHN cells with an expression plasmid of vHNF-1-C did not activate the pDD4 Foot A+B: -95/+28 reporter gene. Taken together, we conclude that the cell-type-specific expression of DD4 mRNA is regulated by vHNF-1-C.

Adenocarcinoma↗