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Biomedical subjects

Y Yamada

Publications and source records attributed to Y Yamada.

At least 253 records · Page 14Linked to original sources
PubMed2001

CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver.

Combination chemotherapy consisting of 5-fluorouracil (5-FU) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carboxycamptothecin (CPT-11) is a promising regimen for gastrointestinal cancer. The circadian-dependent efficacy and toxicity of 5-FU are related to the circadian variation in the activity of dihydropyrimidine dehydrogenase (DPD), which is a rate-limiting enzyme in the pyrimidine catabolic pathway. To optimize the schedule of the CPT-11 plus 5-FU combination, we investigated the effect of CPT-11 on the circadian rhythm of DPD in vivo. In control mice, the DPD mRNA level in the liver was significantly higher at 14:00 than that at 02:00. After intravenous administration of CPT-11 (30 mg / kg) at 20:00, the circadian rhythm of the DPD mRNA level in the liver was no longer observed 18 h later (14:00), but it was unaffected 6 and 18 h later (at 14:00 and 02:00) when CPT-11 was given at 08:00. In addition, a dose-dependent lengthening of the period of the circadian rhythm of DPD was observed for 42 h after intravenous injection of CPT-11 at 20:00. The levels of DPD protein and activity at 21 h after administration of CPT-11 (at 17:00) were significantly higher than at 9 h (at 05:00). These results suggest that CPT-11 may influence the circadian rhythm of DPD at the transcriptional level. Modulation of the circadian rhythm of DPD by CPT-11 may be a factor in optimizing the combination of 5-FU and CPT-11.

Animals↗
PubMed2001

Suppression of occurrence and advancement of beta-catenin-accumulated crypts, possible premalignant lesions of colon cancer, by selective cyclooxygenase-2 inhibitor, celecoxib.

Suppression of occurrence and advancement of premalignant lesions is important for cancer prevention. Our previous studies clarified that beta-catenin-accumulated crypts, independent of aberrant crypt foci (ACF), are probably direct precursors of colon cancers in rats. Here we investigated the effects of a selective cyclooxygenase-2 inhibitor, celecoxib, on the development of beta-catenin-accumulated crypts in comparison with those on ACF. Male F344 rats were divided into 4 groups. Groups 1 - 3 were administered azoxymethane (AOM) s.c. at a dose of 15 mg / kg body weight, once weekly for 3 weeks to induce beta-catenin-accumulated crypts. Groups 2 and 3 also received experimental diet containing celecoxib (500 and 1500 ppm, respectively) for 8 weeks, starting a week before the first dosing of AOM. At termination, the frequency and crypt multiplicity (number of crypts / lesion) of beta-catenin-accumulated crypts of groups 2 and 3 were significantly less than that of group 1. Furthermore, numbers of silver-stained nucleolar organizer regions (AgNORs) / nucleus in beta-catenin-accumulated crypts were also decreased by exposure to celecoxib. In this study, celecoxib had greater effects on the frequency and growth of beta-catenin-accumulated crypts than on those of ACF. These findings represent additional evidence that beta-catenin-accumulated crypts are premalignant lesions of colon cancer. The results also suggest that beta-catenin-accumulated crypts could be a novel target for evaluation of possible chemopreventive agents against colon carcino-genesis, and indicate that possible chemopreventive effects of celecoxib on the initial stage of colon carcinogenesis may be related to modulation of cell proliferation activity in such early lesions.

Animals↗
PubMed2001

A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells.

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity. Based on these findings we here examined the antiangiogenic effects of TAC-101. Oral administration of TAC-101 (2-8 mg/kg/day) resulted in a drastic suppression of the AZ-521 cell-induced angiogenesis in a mouse dorsal air sac assay system, compared to the vehicle alone. Immunohistochemical analysis with antibody against the endothelial marker CD31 revealed a significant reduction in microvessel density in liver metastases from animals treated with TAC-101 (8 mg/kg p.o.), compared to liver metastases from the untreated control animals. The ability of TAC-101 (8 mg/kg p.o.) to prevent experimental liver metastasis of AZ-521 cells in athymic nude mice was comparable with that of the known angiogenesis inhibitor TNP-470 (30 mg/kg s.c.). TAC-101 also affected angiogenesis in chorioallantoic membranes and some functions of endothelial cells associated with angiogenesis, whereas the retinoid failed to suppress AZ-521 cell proliferation directly. These data suggest that the TAC-101 is an orally active antiangiogenic agent and that this antiangiogenic property may contribute to its efficacy against liver metastasis of human stomach cancer cells.

Administration, Oral↗
PubMed2001

Possible involvement of interferon regulatory factor 4 (IRF4) in a clinical subtype of adult T-cell leukemia.

Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the overexpression of IRF4 caused the transformation of Rat-1 fibroblasts in vitro. Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax. Similarly, constitutive expression of IRF4 was demonstrated in freshly isolated peripheral blood mononuclear cells (PBMC) from patients with either acute or chronic ATL. However, the high-level expression of IRF4 was specifically associated with acute ATL. With mitogen-activated PBMC from healthy donors, cell cycle analyses revealed that the induction of IRF4 occurred prior to cell cycle progression and the cells that had entered the cell cycle were predominantly IRF4-positive cells. In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2 / M phase population significantly. Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.

Adult↗
PubMed2001

[Gonococcal abscess in the prepuce: a case report].

We reported a case of gonococcal abscess in the prepuce not accompanied with urethritis. As initial therapy fluoroquinolone was ineffective, the abscess spread to the subcutaneous tissue around the penile root. After intravenous administration of cefodizime, the clinical symptoms improved, and Neisseria gonorrhoeae was eradicated.

Abscess↗
PubMed2001

Outbreak of cefozopran (penicillin, oral cephems, and aztreonam)-resistant Neisseria gonorrhoeae in Japan.

We have previously reported that the Neisseria gonorrhoeae isolates from clinical failure cases treated with cefdinir and aztreonam, beta-lactams exhibited high MICs. These resistant isolates were clearly separated from the isolates exhibiting a low level of resistance to beta-lactams as shown by the MIC distribution of cefozopran. Restriction fragment length polymorphism DNA typing revealed that the outbreak of cefozopran-resistant isolates in Kitakyushu, Japan, occurred as a result of clonal spread.

Adult↗
PubMed2001

Gene replacement analysis of the butyrolactone autoregulator receptor (FarA) reveals that FarA acts as a Novel regulator in secondary metabolism of Streptomyces lavendulae FRI-5.

IM-2 [(2R,3R,1'R)-2-1'-hydroxybutyl-3-hydroxymethyl gamma-butanolide] is a gamma-butyrolactone autoregulator which, in Streptomyces lavendulae FRI-5, switches off the production of D-cycloserine but switches on the production of a blue pigment and several nucleoside antibiotics. To clarify the in vivo function of an IM-2-specific receptor (FarA) in the IM-2 signaling cascade of S. lavendulae FRI-5, a farA deletion mutant was constructed by means of homologous recombination. On several solid media, no significant difference in morphology was observed between the wild-type strain and the farA mutant (strain K104), which demonstrated that the IM-2-FarA system does not participate in the morphological control of S. lavendulae FRI-5. In liquid media, the farA mutant overproduced nucleoside antibiotics and produced blue pigment earlier than did the wild-type strain, suggesting that the FarA protein acts primarily as a negative regulator on the biosynthesis of these compounds in the absence of IM-2. However, contrary to the IM-2-dependent suppression of D-cycloserine production in the wild-type strain, overproduction of D-cycloserine was observed in the farA mutant, indicating for the first time that the presence of both IM-2 and intact FarA are necessary for the suppression of D-cycloserine biosynthesis.

Bacterial Proteins↗
PubMed2001

Identification of the varR gene as a transcriptional regulator of virginiamycin S resistance in Streptomyces virginiae.

A gene designated varR (for virginiae antibiotic resistance regulator) was identified in Streptomyces virginiae 89 bp downstream of a varS gene encoding a virginiamycin S (VS)-specific transporter. The deduced varR product showed high homology to repressors of the TetR family with a conserved helix-turn-helix DNA binding motif. Purified recombinant VarR protein was present as a dimer in vitro and showed clear DNA binding activity toward the varS promoter region. This binding was abolished by the presence of VS, suggesting that VarR regulates transcription of varS in a VS-dependent manner. Northern blot analysis revealed that varR was cotranscribed with upstream varS as a 2.4-kb transcript and that VS acted as an inducer of bicistronic transcription. Deletion analysis of the varS promoter region clarified two adjacent VarR binding sites in the varS promoter.

Amino Acid Sequence↗
PubMed2001

Acquired subglottic stenosis caused by methicillin resistant Staphylococcus aureus that produce epidermal cell differentiation inhibitor.

Local infection of the trachea in intubated neonates is one of the main risk factors for development of acquired subglottic stenosis, although its role in the pathogenesis is unclear. Methicillin resistant Staphylococcus aureus (MRSA) is often the cause of critical illness in neonatal patients. Two cases are reported of acquired subglottic stenosis following bacterial infection of the trachea, suggesting an association with the staphylococcal exotoxin, epidermal cell differentiation inhibitor (EDIN). EDIN-producing MRSA were isolated from purulent tracheal secretions from both infants. Acquired subglottic stenosis in both cases was probably caused by delayed wound healing as the result of EDIN inhibition of epithelial cell migration.

Epidermal Growth Factor↗
PubMed2001

Ileal neobladder for urinary bladder replacement following total pelvic exenteration for rectal carcinoma.

OBJECTIVE: The aim of this study was to determine the feasibility of using the ileal neobladder as a substitute for the urinary bladder following total pelvic exenteration for rectal carcinoma. PATIENTS AND METHODS: Between 1992 and 1998, we performed total pelvic exenteration with ileal neobladder in 5 men with rectal carcinoma. Four patients had primary tumors, and one had recurrent disease after low anterior resection for rectal carcinoma. Histological types were adenocarcinoma in 4 and squamous cell carcinoma in 1. Invaded organs were: the urinary bladder in 1, the urinary bladder and prostate in 2, the prostate and seminal vesicle in 1, and the prostate in 1. RESULTS: There was no operative death. In 1 patient, an ileal conduit was needed because of partial necrosis of the neobladder. Minor leakage on the dorsal wall of the neobladder occurred in 2 patients, which was successfully stopped with simple closure and a gluteus maximus fasciocutaneous flap, respectively. All except one patient with the ileal conduit could void via the urethra. Complete daytime urinary continence was achieved, but nocturnal continence was maintained with voiding once or twice per night. As the urodynamic state, the mean maximum flow rate was 20.9 ml/s (range 9.0-34.1), the mean average flow rate was 7.7 ml/s (range 3.0-11.0), and the mean voided volume was 285.5 ml (range 160-432). The mean length of follow-up was 47.8 months. One patient died of local recurrence 38 months postoperatively, and 1 died of pneumonia 10 months postoperatively. Both patients could void via the urethra until death. The other three patients are currently alive without any evidence of recurrence. CONCLUSIONS: Although total pelvic exenteration is a laborious surgical procedure, an ileal neobladder could be a good alternative to the urinary bladder enabling the patients to void via the urethra with urinary continence.

Adenocarcinoma↗
PubMed2001

Expression of VLA-4 on eosinophils decreases in patients with eosinophilia.

BACKGROUND: It is assumed that the very late antigen-4 (VLA-4) plays a key role in selective migration and accumulation of eosinophils to the allergic inflammatory focus. The regulatory mechanism for VLA-4 expression is poorly understood, as is its relationship between other adhesion molecules. OBJECTIVE: The aim of the study was to elucidate the relationship between VLA-4 expression and the activation of eosinophils. METHODS: The surface expression of VLA-4, Mac-1, ICAM-1, CD4, CD25, CD69, CD89, IL-5 receptor and GM-CSF receptor on eosinophils isolated from the peripheral blood of 15 patients with eosinophilia and 16 healthy volunteers was measured. RESULTS: The surface expression of VLA-4 presented in mean fluorescent intensity by flow-cytometric analysis showed a significant decrease in the patients with eosinophilia (>700 eosinophils/microl) compared to that of the subjects without eosinophilia. On the other hand, the surface expression of Mac-1 was significantly increased in the patients with eosinophilia. There was an inverse correlation between the expression of VLA-4 and that of Mac-1 (r = -0.81) on the eosinophils obtained from the patients with eosinophilia. CONCLUSION: The changes on the surface expressions of Mac-1 and VLA-4 may be indicating the activation of eosinophils in the patients with eosinophilia and may contribute to their migration to the allergic inflammatory focus.

Adult↗
PubMed2001

Effect of roxithromycin on eotaxin-primed reactive oxygen species from eosinophils.

BACKGROUND: The CC chemokine eotaxin not only attracts eosinophils to inflamed sites but also promotes adhesion, degranulation and reactive oxygen species production of eosinophils. Reactive oxygen species released from eosinophils are believed to injure epithelial cells at inflamed sites, resulting in airway hyperresponsiveness. Roxithromycin has been reported to have antiasthmatic effects, although its mechanism of action is not thoroughly understood. Therefore, the effect of roxithromycin on eotaxin-primed reactive oxygen species production from eosinophils was studied. METHODS: Reactive oxygen species production by eosinophils cultured with or without roxithromycin was evaluated using luminol-dependent chemiluminescence. RESULTS: Roxithromycin inhibited the release of reactive oxygen species from eosinophils evoked with the calcium ionophore A23187, regardless of pretreatment with or without eotaxin. CONCLUSION: Roxithromycin may protect epithelial cells at inflamed sites, at least partly by inhibiting the release of reactive oxygen species from eosinophils.

Adolescent↗
PubMed2001

Pharmacokinetic and pharmacodynamic analysis of the antihypercalcemic effect of incadronate disodium in rats.

Incadronate concentrates into the bone as a target organ after intravenous administration of incadronate disodium. Mature osteoclasts has take up incadronate from the bone surface and convert it from an active to an inactive form. As a result, incadronate decreases the plasma calcium concentration by suppressing bone resorption. In this study, the pharmacokinetic and pharmacodynamic (PK/PD) analysis model for ascertaining the antihypercalcemic effects of incadronate disodium was developed in rats. Data on both the concentration of incadronate in bone and that of free calcium in blood after intravenous administration from our previous study were used for analysis. To estimate the concentration in the surface layer of bone, data on the concentration of incadronate in bone after single intravenous administration were analyzed based on the PK model considering three-compartments. The estimated concentrations in the surface layer in bone were applied to the PD model as an input function. The PD model was developed to analyze the changes in the plasma calcium concentration after a single intravenous administration considering an irreversible inhibition of osteoclast activity. The obtained fitted curves were in good agreement with the observed data. The model could explain the long duration of the antihypercalcemic effect of incadronate disodium and should be useful for planning rational dose regimens for effective antihypercalcemic therapy.

Animals↗
PubMed2001

[Effect of mouth wash on the removing fluticasone propionate delivered by dry powder inhaler in mouth].

The effect of mouth wash on the removal of drug residues in both mouth and pharynx after the use of fluticasone propionate dry powder inhaler (FP-DPI) was studied. The concentration of FP in mouth wash after sprinkle and inhalation of Flutide 50, 100, 200 Rotadisk was determined by HPLC-UV. The total amount of the removed FP was measured by the sum of the concentration of FP in 5 times of mouth washes. The mouth wash procedures removed totally 79.3 +/- 4.4% (50 micrograms), 68.5 +/- 3.6% (100 micrograms), 69.3 +/- 3.4% (200 micrograms) of sprinkled amount of FP and 29.5 +/- 11.1% (50 micrograms), 35.6 +/- 6.6% (100 micrograms), 31.6 +/- 8.3% (200 micrograms) of inhaled, respectively. It was required for the removal of 90% of the totally recovered FP to do two times of mouth washes in each case. These data suggest that the mouth wash is an effective precaution for candidiasis induced by FP delivered by DPI.

Administration, Inhalation↗
PubMed2001

[The roles of pharmacists on prior review of clinical trials].

A prior review system for clinical trials was introduced into The University of Tokyo Hospital in March 1999, for the purpose of supporting the Institutional Review Board (IRB). In this study, we investigated the effect of this system on IRB, and evaluated roles of pharmacists involved in utilizing this prior review system. An average period from the acceptance of regular application of each protocol to the approval of IRB was 1.7 months, and the period was significantly shorter than that before the introduction of this system (2.3 months). On the other hand, the number of instructions given to applicants increased to be 2.8 times before the introduction of this system, suggesting the improvement of the quality of this prior review system. In the prior review, the number of instructions pointed out from pharmacists concerning pharmacokinetics, pharmacodynamics, drug-interactions, adverse reactions, and the other matters related to investigational drugs was greater than that from doctors or nurses. According to the results of the surveys for doctors, nurses, and other clerical employees, pharmacists were indicated to review from a pharmaceutical point of view and their review was found to be very important. In conclusion, the prior review system was considered to be useful for the rational practice of clinical trials and pharmacists were recognized to be indispensable as reviewers on the prior review.

Clinical Trials as Topic↗