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Y Sawada

Publications and source records attributed to Y Sawada.

At least 145 records · Page 8Linked to original sources
PubMed1998

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a] pyridine moiety.

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1, 2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50's of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant.

Administration, Oral↗
PubMed1998

Interaction of p27 with E1A and its effect on CDK kinase activity.

The interaction of p27 with adenovirus (Ad) E1A was investigated to study its possible role in cell-cycle regulation and transformation by E1A. In in vitro binding assays, recombinant p27 proteins were shown to bind 12S and 13S E1A products of both Ad12 and Ad5. The amino-terminal region of p27, but not the carboxyl-terminal region, was responsible for the E1A binding. In the Ad12 E1A proteins, the C-terminal region showed relative importance in p27 binding. Phosphorylation of histone H1 or E1A proteins by CDK2 complex was inhibited by p27, but, in contrast, p27 stimulated the phosphorylation of E1A proteins by CDK4. Thus, the interaction of p27 and E1A proteins may modulate the function of E1A in cell-cycle control by regulating E1A phosphorylation.

Adenoviridae↗
PubMed1998

Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1.

Apoptosis signal-regulating kinase (ASK) 1 was recently identified as a mitogen-activated protein (MAP) kinase kinase kinase which activates the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathways and is required for tumor necrosis factor (TNF)-alpha-induced apoptosis; however, the mechanism regulating ASK1 activity is unknown. Through genetic screening for ASK1-binding proteins, thioredoxin (Trx), a reduction/oxidation (redox)-regulatory protein thought to have anti-apoptotic effects, was identified as an interacting partner of ASK1. Trx associated with the N-terminal portion of ASK1 in vitro and in vivo. Expression of Trx inhibited ASK1 kinase activity and the subsequent ASK1-dependent apoptosis. Treatment of cells with N-acetyl-L-cysteine also inhibited serum withdrawal-, TNF-alpha- and hydrogen peroxide-induced activation of ASK1 as well as apoptosis. The interaction between Trx and ASK1 was found to be highly dependent on the redox status of Trx. Moreover, inhibition of Trx resulted in activation of endogenous ASK1 activity, suggesting that Trx is a physiological inhibitor of ASK1. The evidence that Trx is a negative regulator of ASK1 suggests possible mechanisms for redox regulation of the apoptosis signal transduction pathway as well as the effects of antioxidants against cytokine- and stress-induced apoptosis.

Animals↗
PubMed1998

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 1. Construction of the basic framework.

A novel class of potent, selective, and orally active non-peptide bradykinin (BK) B2 receptor antagonists were designed and synthesized starting from 8-benzyloxyimidazo[1,2-a]pyridine derivative 2. The unique screening lead (2) was discovered by a two-step intentional random screening process, involving recognition of the relationship between BK and angiotensin II (Ang II) and the common structural features. Systematic chemical modification of 2 elucidated the structural requirements essential for B2 binding affinity leading to the identification of 8-[[3-(N-acylglycyl-N-methylamino)-2,6-dichlorobenzyl]oxy]-3-halo- 2- methylimidazo[1,2-a]pyridine skeleton as the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2,6-dichlorobenzene ring to allow these compounds to adopt the characteristic active conformation. The representative lead compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors, with nanomolar IC50S and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at an oral dose of 1 mg/kg. Pharmacokinetic studies of compounds 47c and 50b in rats highlighted their excellent oral bioavailabilities, indicating that they represent the first orally active non-peptide B2 antagonists reported to date.

Administration, Oral↗
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

[Removal of the endocardial pacemaker leads--experience with 16 leads in 10 patients].

Recent advances in pacemaker leads have contributed to the improvement of their stability at the anchored sites. However, we sometimes have difficulty in removing them. We have experienced the removal of 16 leads in 10 patients (male: 7, female: 3) in the last 5 years. The age of patients ranged from 48 to 87 years, and the average was 60. The reasons for the removal were as follows; pocket infection in 6 cases, sepsis in 1 case, ischemic skin erosion in 1 case, retained fractured ventricular lead in 1 case, fracture of Accufix atrial lead in 1 case. The methods of removal consisted of using the removal kit, the snare or the basket snare transvenously, direct surgical approach or a combination of them. We used the removal kit alone in 12 electrodes (6 atrial, 6 ventricular), and removal of 5 atrial and 3 ventricular leads were successfully by this method only. The removal of 4 leads by kits alone failed, so that 2 ventricular leads were removed transvenously, one atrial and one ventricular lead were removed surgically, and 1 ventricular lead was left untreated. Finally, we were able to remove 15 of 16 leads (93.3%) successfully. This experience indicates that these interventions should be performed as less invasively as possible, yet we should give an explanation to the patients as to the options we may employ when we have failed in the intended procedure.

Aged↗
PubMed1998

[Coronary artery bypass graft surgery in dialysis patient].

To determine the operative outcome of coronary artery bypass graft surgery (CABG) for severe coronary artery disease in long-term hemodialysis patients, we analyzed a group of 16 patients who underwent CABG over a ten-year period in our institution. Hospital mortality was 12.5% (2 of 16 patients). These two patients died of ischemic colitis and perioperative myocardial infarction, respectively. There were five late deaths: one patient died from myocardial infarction, one from uremia, one from gastro-intestinal bleeding, one from gastric cancer and one from unknown cause. There were four significant postoperative complications (morbidity 25%), consisted of one pulmonary tuberculosis, one sternal dehiscence secondary to mediastinitis, one mediastinal hematoma secondary to late bleeding from the LITA dissection area and one A-V shunt trouble. Graft patency rate within the first two months was 93% (30 to 42 in 13 patients). Hospital survivors experienced complete relief from angina. Actuarial survival was 68.8% at 3 years, 57.3% at 5 years and 28.6% at 7 years. This rate is not significantly different from the survival of all dialysis patients, but seems to be better than that of dialysis patients with not operated coronary artery disease. We concluded that CABG in dialysis patients can be accomplished with acceptable morbidity and mortality and effective relief of symptoms.

Cause of Death↗
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

A study of the concentration of orally administered sparfloxacin found in exudates from suture wounds beneath occlusive dressings.

The concentration of orally administered sparfloxacin (SPFX), an antimicrobial agent, in exudates from the suture wounds beneath occlusive dressings has been measured. Twenty-one patients who received oral therapy with 100 mg of SPFX prior to surgery and 200 mg/day of SPFX after surgery were studied. During the operations, the suture wounds were covered by occlusive film. 48h post-operation, wound exudates under the dressings were drawn and measured using high performance liquid chromatography. SPFX values were 0.801+/-0.340 microg/ml (mean+/-SD). The results suggest that wound exudates beneath the occlusive dressing have concentrations of SPFX high enough to prevent infection in most cases when administered orally.

Administration, Oral↗
PubMed1998

Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist, FR165649, and agonist, FR190997.

1. The nonpeptide bradykinin (BK) B2 receptor antagonist, FR165649 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methylquinoline), and agonist, FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl) cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridyl methoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2-pyridylmethoxy group is the only structural difference between them. 2. Both FR165649 and FR190997 displaced [3H]-BK binding to B2 receptors in guinea-pig ileum membranes, with an IC50 of 4.7 x 10(-10) M and 1.5 x 10(-9) M, respectively. They also displaced [3H]-BK binding to B2 receptors in human lung fibroblast IMR-90 cells, with an IC50 of 1.6 x 10(-9) M and 9.8 x 10(-10) M, respectively. 3. In guinea-pig isolated ileum-preparations, FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration-response curves to BK on contraction. Analysis of the data produced a nominal pA2 value of 9.2+/-0.1 (n=5) and a slope of 1.4+/-0.1 (n=5). On the other hand, FR190997 induced concentration-dependent contraction of guinea-pig ilea with a pD2 of 7.9+/-0.2 and the contraction was inhibited by a specific peptide bradykinin B2 receptor antagonist, Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]BK) in a non-competitive manner. 4. In IMR-90 cells, FR165649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10(-7) M) of the concentration-response curves to BK on PI hydrolysis. FR190997 induced concentration-dependent PI hydrolysis in IMR-90 cells with a pD2 of 8.4+/-0.1, and this effect was inhibited by Hoe 140. 5. These results indicate that FR165649 and FR190997 are, respectively, a potent bradykinin B2 receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. FR165649 and FR190997 may be useful tools for studying the relationship between ligands and receptors.

Animals↗
PubMed1998

Non-traumatic rhabdomyolysis with gluteal ulcer.

The case is presented of a 34-year-old woman with rhabdomyolysis due to massive intake of nimetazepam, a benzodiazepine hypnotic. On admission, the patient had numerous blisters all over the body. One of the blisters in the gluteal region developed into a deep ulcer accompanied by muscle necrosis although it was not at a pressure point. The ulcer needed surgical intervention. Rhabdomyolysis is caused by the lysis and necrosis of muscle due to direct or indirect injury, high fever, ischaemia, hypoxia or enzyme defects. Release of myocyte components into the circulation then may induce major problems, especially acute renal failure associated with hypermyoglobinaemia. However, there have been few reports of cutaneous ulcer formation in non-traumatic rhabdomyolysis.

Adult↗
PubMed1998

Rapid patterning of Dictyostelium discoideum cells under confined geometry and its relation to differentiation.

The following was recently reported by Bonner et al. (1995): (1) Rapid differentiation occurred into two zones in Dictyostelium discoideum cells confined in a fine glass capillary. The cells in the anterior zone exposed to the air appear similar to prestalk cells, while the posterior zone isolated from the air mimics prespore cells. (2) The volumes of the two zones are proportional to each other for different sized cell masses, and the proportion is the same as that in normal migrating slugs. We investigated the nature of this newly discovered rapid differentiation in a slightly modified geometry. Exponentially growing cells were harvested, washed to remove external nutrients, and pelleted by centrifugation. Subsequently, a small drop of the pelleted (starved) cells was placed on a slide glass and then confined in a two-dimensional space between the slide glass and a coverslip, with help of spacers whose thickness varied from 25 to 100 microm. As a result, a dark zone, which looked optically different, emerged within several minutes in the periphery of the disc of the confined cells, corresponding to the zonation in a capillary as previously reported. When the width of the peripheral zone was measured for more than 30 samples of different diameters for each thickness of the spacers, the width was found to be always about 100 microm, irrespective of the size difference of the cell mass placed. This seems to be contradictory to the previous observation made by Bonner et al. (1995). We also examined oxygen concentration dependence on the zone width. The zone width was found to be independent of the oxygen concentration at low concentrations, but increased rapidly at high concentrations. A reaction-diffusion mechanism for formation of the zone and possible involvement of atmospheric oxygen (O2) in the initial steps of cell differentiation and pattern formation is discussed.

Animals↗
PubMed1998

Increased production of nitric oxide stimulated by interleukin-1beta in peripheral blood mononuclear cells in patients with systemic sclerosis.

OBJECTIVE: Nitric oxide (NO) is an important mediator of immune and inflammatory responses, and has recently been suggested to play some role in the pathogenesis of autoimmune disorders. In this study, we have examined whether peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (SSc) produce higher levels of NO spontaneously or in response to several stimulations in vitro. METHODS: PBMC were obtained from 14 patients with SSc and 15 normal volunteers. Release of NO after stimulation with lipopolysaccharide (LPS), interleukin-lbeta (IL-1beta), tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) was determined by Griess reagents. RESULTS: PBMC from SSc patients exhibited a higher level of spontaneous release of NO (13.4+/-3.8 microM) than those from control subjects (8.9+/-1.6 microM), but without significance. Incubation of PBMC for 24 h with stimulants caused an increase in NO production both in normal subjects and SSc patients. Stimulation with 10 U/ml IL-1beta induced a significantly increased NO production in SSc patients (22.1+/-6.6 microM) compared with normal subjects (12.3+/-4. microM) (P < 0.05); however, in contrast, incubation with other stimulants showed no significant differences in NO production between SSc patients and normal subjects. CONCLUSION: These results suggest the abnormal regulation of NO production in PBMC of scleroderma patients in response to IL-1beta, which might contribute, in part, to the fibrotic process in SSc.

Adult↗
PubMed1998

An auricular paper model.

We have devised a paper model of the auricle that is simple to design and easily fabricated. An oval-shaped sheet of paper is folded so that the prominent and hollow parts center around a helical crus and concha. Most parts of the human auricle can be created by using this model. Studies of the model show that a large skin area is required for the helical crus. The model is considered to be useful in simulating total or partial auricular reconstruction. It also reveals new possibilities in reconstructive methods using tissues composed of cartilage and skin, which are flat and large. Furthermore, it is interesting that the formation of our paper model by forward rotation and folding is compatible with the process of auricle embryonic development.

Animals↗