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961.
Shioya T Satake M Sano M Kagaya M Watanabe A Sato K Ito T Ito N Sasaki M Miura M 《European journal of clinical pharmacology》2002,58(3):171-176
STUDY OBJECTIVE: Th2 cytokines play an important role in the pathogenesis of asthma. Our study objective was to determine the effect of suplatast tosilate, a Th2 cytokine inhibitor, on patients with cough-variant asthma. METHODS: Twenty patients with cough-variant asthma (CVA) were assigned to a suplatast tosilate (100 mg three times daily) group or a placebo group for 6 weeks in a double-blind randomized study. The cough scores, medication scores, pulmonary function, bronchial hyperresponsiveness to methacholine, cough threshold for capsaicin, percentage of eosinophils and concentrations of eosinophilic cationic protein (ECP) in hypertonic saline-induced (induced) sputum were evaluated. The main outcome measures were capsaicin cough threshold and concentrations of ECP in induced sputum. RESULTS: In the suplatast group, the cough scores and the medication scores decreased significantly over time. The percentage of eosinophils in induced sputum significantly decreased from 53.5+/-5.6% to 13.6+/-2.6%. The cough threshold for capsaicin improved significantly from 2.72+/-3.41 microM to 39.7+/-22.7 microM in the suplatast group. The concentrations of ECP in induced sputum decreased significantly from 435+/-123 microg/l to 56+/-34 microg/l in the suplatast group. The bronchial responsiveness to methacholine changed from 8.45+/-3.43 units to 11.4+/-3.76 units in the suplatast group. CONCLUSIONS: Suplatast improved the cough scores and the cough threshold for capsaicin in patients with CVA without significant side effects, suggesting the effectiveness of suplatast in the treatment of CVA. Suplatast also decreased the percentage of eosinophils and concentrations of ECP in induced sputum, suggesting improvement in eosinophilic inflammation in patients with CVA. Further pharmacodynamic research is needed to explain the precise mechanism. 相似文献
962.
Development of transdermal formulation of tulobuterol for the treatment of bronchial asthma 总被引:2,自引:0,他引:2
Kato H Nagata O Yamazaki M Suzuki T Nakano Y 《Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan》2002,122(1):57-69
beta 2-Adrenergic agonists have been widely used to treat patients with asthma. Usually, oral dosage forms of beta 2-agonists have been used, but side effects such as palpitation and tremor have been reported because of excessive serum levels around Tmax. It is said that circadian variations exist in the manifestation of asthma with maximum incidence of asthma attacks in early morning at around 4 a.m., the so-called morning dip. Chronotherapy for asthma based on circadian rhythm should be more efficient and have a lower frequency of side effects. Accordingly we developed a transdermal delivery system of the beta 2-agonist tulobuterol adapted to the circadian rhythm. The system is designed to administer the appropriate dose of the drug at an optimal time using the so-called Crystal Reservoir System. The superiority of the transdermal formulation of tulobuterol over the current therapy using oral formulations of beta 2-stimulants was indicated by its excellent pharmacokinetic profile, and confirmed by the results of clinical trials. This formulation is the first transdermal chrono-delivery system reported anywhere in the world, and is expected to provide more effective and safe treatment of asthma and related diseases not only in adults, but also especially in children. 相似文献
963.
Hamdy SI Hiratsuka M Narahara K El-Enany M Moursi N Ahmed MS Mizugaki M 《European journal of clinical pharmacology》2002,58(1):29-36
OBJECTIVE: The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the Egyptian population and compare them with the frequencies in other ethnic populations. METHODS: A sensitive real-time polymerase chain reaction assay was developed and successfully applied for genotyping of the consensus (wild-type) alleles plus five variants of four genes: DCP1 [the insertion allele ( I) versus the deletion allele ( D)], CETP*TaqI ( B1 versus B2), ADRB2*R16G, ADRB2*Q27E, and HTR2A*102T>C. This study was carried out in 242 unrelated Egyptian subjects and is the first to describe these allelic variants in the Egyptian population. RESULTS: The frequencies of the tested alleles were found as: DCP1 ( I: D, 0.32:0.68), CETPTaqI ( B1: B2, 0.65:0.35), ADRB2*R16G ( Arg16: Gly16, 0.57:0.43), ADRB2*Q27E ( Gln27: Glu27, 0.76:0.24), and HTR2A*102T>C ( T102: C102, 0.53:0.47). The common Arabian ancestors of the Egyptians, Spanish, Saudi, and Emirate had created a common pattern of distribution of some allelic variants ( DCP1 and CETP). However, in the genotyping of ADRB2, the frequency of the polymorphism at codon 16 was found to be similar to the Chinese population, whereas that at codon 27 was similar to African-Americans with significant differences than other Caucasian populations. The frequency of the HTR2A*102T>C variant appeared to be similar to many Caucasian populations and African-Americans. CONCLUSIONS: We have explored the frequencies of important allelic variants DCP1, CETP, ADRB2, and HTR2A among the Egyptian population focusing on the ethnic diversity in the distribution of the tested mutant alleles. Our results may help in better understanding the observed ethnic variation in angiotensin-converting enzyme inhibition and atherosclerosis therapy. It also may contribute to better characterization of interethnic differences in isoprenaline and clozapine response, which will have implications for the cost effective and rational prescribing of these drugs. 相似文献
964.
To investigate the usefulness of serum alpha 2u-globulin changes as a new parameter for detecting endocrine-mediated effects, we performed a 28-day repeated-dose toxicity study using the administration of bisphenol A (BPA) or ethynyl estradiol (EE) in male rats, based on the draft protocol of the 'Enhanced OECD Test Guideline 407 (enhanced TG 407)'. BPA at doses of 0, 40, 200 and 1000 mg/kg per day or EE at doses of 0, 15, 75 and 375 microg/kg per day were orally administered to SD rats. The highest dose of BPA was reduced to 600 mg/kg per day from the second week of the study onwards because a male rat given 1000 mg/kg per day of BPA died within the first week, showing toxic clinical signs. In the assay using BPA, a reduction in the level of alpha 2u-globulin was detected in the group receiving a dose of 600 mg/kg per day. Reductions in the absolute and relative ventral prostate weights were only observed in the 600 mg/kg per day group. In the assay using EE, the alpha 2u-globulin level decreased significantly in the 375 microg/kg per day group. A reduction in the absolute and relative dorsolateral prostate weights was also observed in the 75 and 375 microg/kg per day groups, morphologically abnormal sperm were observed in the 375 microg/kg per day group. Furthermore, atrophic changes in the prostate and seminal vesicle and degenerative changes in the testis were observed in the 375 microg/kg per day group. Although the alpha 2u-globulin level was reduced in this assay using BPA and EE, further studies are necessary before this assay becomes a useful method for detecting endocrine-mediated effects. 相似文献
965.
Platelet activation in patients with obstructive sleep apnea syndrome and effects of nasal-continuous positive airway pressure 总被引:3,自引:0,他引:3
Shimizu M Kamio K Haida M Ono Y Miyachi H Yamamoto M Shinohara Y Ando Y 《The Tokai journal of experimental and clinical medicine》2002,27(4):107-112
OBJECTIVE: Our study was undertaken to determine whether increased platelet activation occurs in patients with obstructive sleep apnea syndrome (OSAS) and whether a therapy with nasal-continuous positive airway pressure (N-CPAP) alters this activation. METHODS: We measured the positive rate of activated platelets using activation-dependent monoclonal antibodies (MoAb) and flow cytometry in whole blood from 94 patients with OSAS, and from 31 age-matched controls. Thrombotic vascular diseases were surveyed as a background of alternative of platelet activation. RESULTS: The positive rate for activated platelets was significantly higher in patients with OSAS ( PAC1 52.6 +/- 22.9 %, CD62P 6.8 +/- 7.1%, mean +/- SD), as compared with healthy control subjects ( PAC1 16.7 +/- 8.6 %, CD62P 0.7 +/- 0.5 %, p < 0.001). The activation indexes were significantly reduced after 1 month with N-CPAP treatment as a whole (PAC1; from 52.6 +/- 22.9 to 44.2 +/- 22.4, p < 0.05, CD62P; from 6.8 +/- 7.1 to 5.3 +/- 5.5, p < 0.05). In nearly 60 % of patients, platelets activation remained high despite significant improvement of sleep apnea-episodes after N-CPAP. These patients had significantly higher incidence of previous myocardial infarction and/or cerebral infarction and abnormalities of head MRI and carotid sonograpy; indicating that the platelet activation appears to be induced by existing atheroma plaque and not by sympathetic activity in OSAS. CONCLUSION: In conclusion, patients with OSAS have increased percentages of activated platelets as assessed by flow cytometrical analysis of activation dependent surface markers, and were divided into two groups, one group with response to N-CPAP treatment in the reduction of platelet activation and the other without. One possible reason of no response to N-CPAP treatment in the reduction of platelet activation was suggested to be thrombotic diseases. 相似文献
966.
Kominami G Agou T Kanda A Ohno M 《Journal of pharmaceutical and biomedical analysis》2002,30(3):733-738
Immunoassay for recombinant methioninase (rMETase), an anti-cancer agent, in biological sample was developed. Antisera were produced by immunizing rabbits with rMETase. The antisera were evaluated using radioiodine-labeled rMETase and good antisera for sensitive immunoassay were obtained. Horseradish peroxidase (HRP) was coupled to reduced IgG of K232 antiserum through bridging agent, N-(epsilon -maleimidocaproyloxy) sulfosuccinimide ester (sulfo-EMCS), to prepare enzyme-labeled antibody. IgG fraction of K231 antiserum was immobilized on microplate well. Two-site sandwich immunoenzymometric assay (IEMA) was developed using these antibodies and had good standard curve between 0.4 and 12 ng per well. For determination of rMETase in mouse plasma, sample was diluted 100-fold with dilution buffer containing protease inhibitors, because about 10% of rMETase immunoreactivity was lost for 2 h at room temperature. rMETase in mouse plasma could be determined by the proposed method in the range of 0.5-8 microg/ml and the method was validated. This novel IEMA, in substitution for the measurement of its enzyme activity, should be very useful not only for preclinical studies of rMETase but also for the clinical studies. 相似文献
967.
Stimulation of beta(3)-adrenoceptors causes phosphorylation of p38 mitogen-activated protein kinase via a stimulatory G protein-dependent pathway in 3T3-L1 adipocytes 下载免费PDF全文
1. This study deals with phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) via beta(3)-adrenoceptor (AR) and the signal transduction pathway in 3T3-L1 adipocytes. 2. beta(3)-AR agonist BRL37344A (10 nM) caused phosphorylation and activation of p38 MAPK in 3T3-L1 adipocytes but not in fibroblasts. BRL37344A and also the other beta(3)-AR agonists, CGP12177A and SR58611A, caused p38 MAPK phosphorylation in dose-dependent manners. 3. The p38 MAPK phosphorylations by BRL37344A (10 nM), CGP12177A (100 nM), and SR58611A (10 nM) were not antagonized by beta(1)- and beta(2)-ARs antagonist 1-propranolol (100 nM) but blocked by beta(3)-AR antagonist SR59230A (10 microM), suggesting the phosphorylation was caused via beta(3)-AR. 4. The phosphorylations of p38 MAPK were completely abolished by treatment with cholera toxin (CTX) but not pertussis toxin (100 ng ml(-1), 24 h). Activation of Gs by CTX (100 ng ml(-1)) and adenylyl cyclase by forskolin mimicked p38 MAPK phosphorylation. 5. p38 MAPK phosphorylation by BRL37344A was reduced to almost 50% by cyclic AMP-dependent protein kinase (PKA) inhibitors such as H89 (10 microM) and PKI (10 microM). A src-family tyrosine kinases inhibitor PP2 (1 microM) also halved the p38 MAPK phosphorylation. Combined use of H89 (10 microM) and PP2 (10 microM) did not bring about further inhibition. 6. These results suggest that beta(3)-AR caused phosphorylation of p38 MAPK via Gs protein and partly through a pathway involving PKA and src-family kinase(s), although the contribution of the unidentified pathway remains to be clarified. 相似文献
968.
969.
Surgical operations often induce acute hyperglycemia, which is known to affect endothelial functions. In this study, we examined the effects of propofol, a commonly used general anaesthetic, on bovine aortic endothelial cell (BAEC) dysfunction induced by glucose overload. 2 D-glucose overload (23 mM) induced an accumulation of superoxide anion (O2-), assessed by MCLA chemiluminescence, to a similar extent as that generated by 233 microU ml(-1) xanthine oxidase (XO) and 100 micro M xanthine. Propofol inhibited this accumulation with an IC50 of 0.21 micro M, whereas much higher concentrations of propofol were required to scavenge O2- generated by 250 microU ml(-1) XO and 100 microM xanthine (IC50: 13.5 micro M). 3 D-glucose overload attenuated ATP-induced NO production which was detected using diaminofluorescence-2 (DAF-2). The inhibition was reversed by propofol with an EC50 of 0.60 microM. In contrast, inhibitions caused by xanthine/XO were not altered by propofol (1 microM). 4 D-glucose overload suppressed ATP-induced Ca2+ oscillations and capacitative Ca2+ entry (CCE), which were both restored by superoxide dismutase, indicating that O2- was responsible. Propofol restored these attenuated Ca2+ oscillations and CCE with EC50 of 0.31 and 1.0 microM, respectively. 5 D-glucose overload (23 mM) increased the intracellular glucose concentration 4 fold, compared with cells exposed to 5.75 mM glucose, and 1 micro M propofol reduced this increase to 2.8 fold. 6 We conclude from these results that anaesthetic concentrations of propofol prevent the impairment of Ca2+-dependent NO production in BAEC induced by glucose overload. This effect is mainly due to the reduction of O2- accumulation, and involves, at least in part, the inhibition of cellular glucose uptake. 相似文献
970.
Miura S Fujino M Tanigawa H Matsuo Y Saku K 《Nihon yakurigaku zasshi. Folia pharmacologica Japonica》2002,120(1):104P-105P
BACKGROUND: Endothelial cells (ECs) are believed to be critical cellular elements responsible for postnatal angiogenesis. Vascular endothelial growth factor (VEGF) stimulates angiogenesis via the activation of KDR/Flk-1 receptor, which is mainly expressed in ECs. Transactivation of KDR/Flk-1 receptor by bradykinin (BK) B2 receptor contributes to the activation of endothelial nitric-oxide (NO) synthase. Therefore, we examined whether transactivation by BK induced angiogenesis. METHODS AND RESULTS: We developed an in vitro model of human coronary artery ECs (HCECs) tube formation on a matrix gel. We demonstrated that BK dose-dependently induced tube formation. Although a lower concentration of BK did not induce tube formation, the combination of a lower concentration of BK and VEGF did. These effects blocked specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NO synthase. In addition, BK induced the tyrosine phosphorylation of KDR/FlK-1 receptor (transactivation), as did VEGF itself. This transactivation was also blocked by Tki. CONCLUSIONS: Transactivation of KDR/Flk-1 by BK through B2 receptor is a potent signaling in angiogenic phenotype in HCECs. 相似文献