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Y Inada

Publications and source records attributed to Y Inada.

At least 73 records · Page 4Linked to original sources
PubMed1993

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids.

A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects affected the potency of the AII antagonistic action. Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect. The representative compound, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 1.1 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0 x 10(-10) M). Oral administration of CV-11974 to conscious normotensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.

Angiotensin Receptor Antagonists↗
PubMed1993

Inhibition of rabbit aortic angiotensin II (AII) receptor by CV-11974, a new nonpeptide AII antagonist.

The angiotensin II (AII) antagonistic action of CV-11974 (2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl] benzimidazole-7-carboxylic acid) was investigated in an AII-receptor binding assay using rabbit aortic membranes and an AII-induced contraction assay using rabbit aortic strips. A single class of [125I]AII-(Sar1,Ile8) binding sites was found in the membranes with a dissociation constant (Kd) of 0.15 nM and a receptor concentration (Bmax) of 86.9 fmol/mg protein. CV-11974 markedly reduced Kd without affecting Bmax. The specific binding of [125I]AII-(Sar1,Ile8) in this preparation was inhibited completely by CV-11974 [the inhibition constant (Ki) = 0.64 nM], DuP 753 [an angiotensin II type I (AT1) receptor-selective antagonist] (Ki = 51 nM) and EXP3174 (an active metabolite of DuP 753) (Ki = 6.8 nM), but was not affected by PD123177 (an AT2 receptor-selective antagonist). These results suggest that the single binding site in rabbit aortic membranes is an AT1 receptor subtype. The affinity of CV-11974 to these AT1 receptors was approximately 80 and 10 times higher than that of DuP 753 and EXP3174, respectively. CV-11974 showed no appreciable affinity for the AT2 receptors found in bovine cerebellum. In the in vitro functional study, CV-11974 markedly reduced the AII-induced maximal contractile response of rabbit aortic strips (pD'2 = 9.97). In contrast, Compound 7-H, which lacks the carboxyl group at the benzimidazole ring of CV-11974, inhibited the contraction in a competitive manner. The inhibition by CV-11974 was long lasting. These results suggest that CV-11974 is a potent and long-acting AT1 receptor-selective, competitive antagonist. The carboxyl group at the benzimidazole ring plays an important role in the interaction between CV-11974 and the AT1 receptor.

Angiotensin II↗
PubMed1993

Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles.

A series of substituted 2-butylbenzimidazoles bearing a biphenylylmethyl moiety at the 1-position was prepared via three synthetic routes and evaluated for angiotensin II (AII) receptor antagonistic activity (in vitro and in vivo). Binding affinity was determined using bovine adrenal cortical membrane. Substitution at the 4-, 5-, or 6-position reduced the affinity relative to that of the unsubstituted compound (13a). However, most of the compounds with a substituent at the 7-position showed binding affinity comparable to that of DuP 753 (losartan). In functional studies, a carboxyl group was found to be very important for antagonistic activity against AII. Comparison of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-4-, -5-, -6-, and -7-carboxylic acids (15a-d) in an AII-induced rabbit aortic ring contraction assay clearly demonstrated the importance of the substitutional position of the carboxyl group. In an in vivo assay, oral administration of benzimidazole-7-carboxylic acids caused long-lasting inhibition of the AII-induced pressor response in rats. The optimum substituent at the 7-position of the benzimidazole ring was found to be a carboxyl or an ester group. The representative compound, 2-butyl-1-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxy lic acid (15d, CV-11194), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 5.5 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11194 (IC50 value, 5.5 x 10(-11) M), while the compound had no effect on the contraction induced by norepinephrine or KCl. Orally administered CV-11194 at doses of 0.3-10 mg/kg dose-dependently inhibited the AII-induced pressor response in rats and dogs. CV-11194 at 1 mg/kg po reduced blood pressure in spontaneously hypertensive rats (SHR). The three-dimensional molecular structure of CV-11194 was determined by X-ray diffraction.

Adrenal Cortex↗
PubMed1993

"Plasmatic imbibition" in the rat musculocutaneous pedicled venous flap: enzymatic proof using horseradish peroxidase.

To determine the reason for survival of a pedicled venous flap in which only a draining vein is preserved, it is important to clarify what kind of blood flow is present in the preserved draining vein. Pedicled venous flaps were prepared on the dorsum of the rat and histologically evaluated using horseradish peroxidase (HRP). HRP was applied between the flap and recipient bed in one group. In the other group, HRP was injected into the femoral vein after the flap was turned over (to prevent contact with the recipient bed). The flaps in these HRP-treated groups were compared with untreated control groups. HRP applied between the flap and recipient bed was imbibed into the flap and subsequently transferred into the preserved draining vein. HRP that was injected into the femoral vein was also found in the draining vein of the flap. These results suggest that (1) plasmatic imbibition occurs in pedicled venous flaps; and (2) antegrade and retrograde blood flow are present in the draining vein.

Administration, Topical↗
PubMed1993

The arterialised venous flap: experimental studies and a clinical case.

It is accepted that small arterialised venous flaps (AVF) can survive on a recipient bed with poor blood supply but survival of larger flaps is not always satisfactory. Possible reasons for this include the flap anatomy, particularly the pattern of the venous network, or factors at the recipient site. To investigate the possible factors in the flap design and the recipient site of an arterialised venous flap, we studied the relationship between (1) size of the artery used to arterialise the flap at the recipient site and the survival rate and (2) the number of draining veins and the survival rate, using rabbit ear skin flap models. Our results suggest that AVFs may become necrotic in the presence of a relative excess of arterial blood inflow, and that two exit veins are more effective than one. We also report a case where a 10 x 15 cm sized free AVF harvested from the lower extremity survived on the forearm.

Adult↗
PubMed1993

The pedicled venous flap. Clinical applications.

Experimental findings of survival of pedicled venous flaps were clinically applied in seven cases for traumatic skin defects on digits. Five flaps which were transferred to or on digits other than the thumb survived, but two flaps from the index to the thumb developed partial necrosis. In order to prevent flap necrosis, the draining vein should be short.

Adult↗
PubMed1993

The pedicled venous flap. An experimental study.

Musculocutaneous pedicled venous flaps on the dorsum of rats survived at a statistically significantly higher rate than musculocutaneous composite grafts (p < 0.01). With a Silastic sheet (Dow Corning) beneath, both composite grafts and pedicled venous flaps necrosed. When a Silastic sheet with holes in it to allow some revascularisation from the bed was placed beneath, the survival rate was significantly better than with a complete Silastic sheet (p < 0.01). These results demonstrate that pedicled venous flap survival depends both on the draining vein, and revascularisation from the underlying bed.

Animals↗
PubMed1993

Non-radioactive coloured microsphere measurement of regional tissue blood flow for axial pattern flaps in rabbits.

We administered non-radioactive coloured microspheres (NRACM) to measure the regional tissue blood flow (RTBF) of eight axial pattern flaps and four kidneys in four rabbits using four repeated injections into each animal. As a control, we used radioactive microspheres (RAM) for six kidneys in three rabbits. There were no significant differences for RTBF values between NRACM and RAM, between the numbers of microspheres used (2 x 10(6) and 4 x 10(6)), or between the number of injections. These results showed that NRACM is a useful and safe laboratory method.

Animals↗
PubMed1993

Blood flow through prefabricated flaps--an experimental study in rabbits.

Prefabricated flaps were created by femoral vessel implantation beneath the abdominal skin in rabbits. The area of survival and blood flow through the prefabricated flap were measured after 1, 2, 4, 6, 8, and 12-week intervals. The parameters at 6, 8 and 12-week intervals were significantly larger than those for random pattern flaps (p < 0.01), but were significantly smaller than those for axial pattern flaps (p < 0.01). The minimum interval at which the prefabricated flap could be transferred successfully was between 6 and 8 weeks in this model. Microangiography demonstrated that neovascularisation began at the distal end of the implanted vascular bundle and spread throughout the flap by 8 weeks.

Abdominal Muscles↗
PubMed1993

Fabrication of vascularized bone grafts using ceramic chambers.

The present study was designed to create a vascularized bone graft combining the osteogenetic potential of bone marrow cells, and vascular bundle implantation in a hydroxyapatite chamber, using New Zealand white rabbits. A hydroxyapatite chamber was molded into a cylindrical shape, and hydroxyapatite fillers were soaked in an autogenous bone-marrow-cell suspension at a concentration of 1.6 x 10(8)/ml. In one group, the implant was packed with allogenic demineralized bone matrix powder (DBM) and implanted in the mid-thigh subcutaneously, with the epigastric vessels running through the chamber. In a second group, the chamber with bone marrow cells and DBM was implanted subcutaneously, without vascular bundle implantation. The control group consisted of a chamber without DBM, soaked in venous blood and implanted in the opposite thigh, with the epigastric vessels running through the chamber. Cross-sectional bone area and mineral apposition rate were measured, in addition to newly-formed vessels. After 3 weeks, chambers implanted with bone marrow cells and DBM demonstrated consistent bone formation in the pores of the chamber walls and within the chambers. No evidence of bone formation was noted in the chambers soaked with venous blood. The results indicated that vascular-bundle implantation promoted earlier bone formation with neovascularization in the chambers with bone-marrow cells and DBM. Microangiograms revealed vascular connections between the vascular bundle and soft tissue surrounding the chamber through newly-formed vessels in the chamber wall. These findings support the concept of creating a preformed vascularized bone graft, to reconstruct segmental bone defects.

Animals↗
PubMed1993

Pharmacological profile of a highly potent and long-acting angiotensin II receptor antagonist, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4- yl]methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974), and its prodrug, (+/-)-1-(cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5- yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate (TCV-116).

The angiotensin II (AII) antagonistic action of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzi mid azole-7 - carboxylic acid (CV-11974) was examined in in vitro assay systems, including AII receptor binding assay using membrane fractions of bovine adrenal cortex or rabbit aorta and AII-induced contraction assay using rabbit aortic strips, and CV-11974 and its prodrug, (+/-)1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylate (TCV-116), were examined in an in vivo system of AII-induced pressor response in conscious rats. DuP 753 or EXP3174 (the main active metabolite of DuP 753) was used as the reference compound. CV-11974 inhibited the binding of [125I] AII to the bovine adrenal cortical membrane and rabbit aortic membrane with IC50 values of 1.12 x 10(-7) and 2.86 x 10(-8) M, respectively. Similar results were obtained with EXP3174. CV-11974 interacted with AII in these membrane fractions with subtype 1 receptor in a competitive manner. CV-11974 at 10(-5) M did not affect the binding of [125I]AII to subtype 2 (AT2) receptor in bovine cerebellum. CV-11974 selectively inhibited the AII-induced contraction of rabbit aortic strips in a noncompetitive manner (pD' 2, 9.97); it had no effects on the contraction induced by norepinephrine, KCl, serotonin, prostaglandin F2 alpha or endothelin. EXP3174 showed a pD'2 value of 8.95 for the AII-induced contraction. CV-11974 given intravenously and TCV-116 given orally inhibited the AII-induced pressor response in rats with ID50 values of 0.033 mg/kg and 0.069 mg/kg, respectively. These effects of CV-11974 and TCV-116 were 12 and 48 times more potent than those of EXP3174 and DuP 753, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1993

Vascularized fibular grafts in the treatment of osteomyelitis and infected nonunion.

From 1976 to 1989, 33 patients with osteomyelitis and infected nonunion of lower extremity bones were treated with vascularized fibular grafts. There were 30 males and three females, and the ages at operation ranged from 17 to 69 years. There were 24 tibial lesions and nine femoral lesions. The fibular graft was performed immediately after lesional debridement in eight patients, but in 25 it was done secondarily after debridement and successful subsidence of inflammation. The mean interval between the last debridement and fibular grafting was ten weeks. Thirty of 33 grafts survived. The mean periods required to obtain radiographic bone union was 6.2 months at the proximal site and 6.3 months at the distal site. Local recurrence of infection occurred in four patients; all but one healed well with saucerization. Vascularized fibular graft is an effective procedure for the treatment of destructive osteomyelitis and infected nonunion.

Adolescent↗
PubMed1992

Synthesis and thromboxane A2/prostaglandin H2 receptor antagonistic activity of phenol derivatives.

Consideration of possible structural similarities between thromboxane A2 and the hydroquinone form of (R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid (R-(+)-AA-2414) led to the development of a new series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists, namely 7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (I). These compounds were found to be potent TXA2/PGH2 receptor antagonists. Compounds having either a carbonyl or a hydroxymethyl group at the para-position of the phenolic hydroxy group exhibited most potent activities in this series. Compounds 14, 15, 18, and 26 inhibited the specific binding of [3H]U-46619 to guinea pig platelet membranes (IC50 = 4.4, 80, 32, and 13 nM, respectively), and also inhibited U-46619-induced human platelet aggregation (IC50 = 310, 69, 79, and 78 nM, respectively). Comparison of the UV spectra of the compounds with a carbonyl group at the para-position of phenolic hydroxy group revealed that the activity tended to increase in accordance with a decrease in the torsional angle between the carbonyl group and the phenol ring. These results suggested that the spacial location of the carbonyl and hydroxymethyl oxygen are important for significant increase in activity and that the carbonyl and hydroxymethyl oxygen at the para-position of the phenolic hydroxy group might interact with one of the TXA2/PGH2 receptor sites.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Chemical modification of L-asparaginase with a comb-shaped copolymer of polyethylene glycol derivative and maleic anhydride.

L-Asparaginase from Escherichia coli, an anti-tumor enzyme, was chemically modified with two types of maleic anhydride copolymers with a comb-shaped form, the one composed of polyoxyethylene allyl methyl diether with the molecular weight of 13,000 (activated PM13) and the other of polyoxyethylene 2-methyl-2-propenyl methyl diether with 100,000 (activated PM100). The modified asparaginases (PM13- and PM100-asparaginases) exhibited the complete loss of immunoreactivity towards anti-asparaginase serum. The enzymic activity of PM100-asparaginase without immunoreactivity was well retained by 85% of non-modified one, while that of PM13-asparaginase was retained 46%. These results were discussed in relation to the chemical structure of modifying reagents including chain shaped-polyethylene glycol derivatives.

Amino Acids↗
PubMed1992

Continuous local intraarterial infusion after prolonged arterial stasis in the fingers and toes.

Seven patients with trauma to eight digits and one toe went untreated for arterial stasis, with subsequent development of posttraumatic changes in skin coloration. In two patients involving two digits, a daily dose of 2,000 ml containing 240,000 U urokinase, 80 micrograms prostaglandin E1, and 10,000 U heparin in lactated Ringer's solution was administered by intravenous infusion for 10 consecutive days; one of the two digits became necrotic. In all subsequent patients, a daily dose of 80 ml containing 240,000 U urokinase, 40 micrograms prostaglandin E1, 10,000 U (maximum) heparin, and low-molecular-weight dextran was administered by continuous local intraarterial infusion for 10 consecutive days. These seven extremities survived, even in the case of two digits and one toe with over 50 hr of arterial stasis. We believe that revascularization of extremities following prolonged periods of arterial stasis may be possible by means of continuous local intraarterial infusion of antithrombotic agents.

Aged↗
PubMed1992

Existence of lipid vesicles containing platelet-activating factor in endothelial cell lysate.

Platelet aggregation activity due to platelet-activating factor (PAF) was detected at high molecular weight (HMW) and low molecular weight fractions after gel-filtration chromatography of cell lysate of endothelial cells. [3H]PAF added to the cell lysate was similarly distributed after chromatography. The radioactivity associated with HMW fraction was not reduced by digesting the lysate with trypsin, suggesting that PAF was not making complexes with proteins but was included in lipid vesicles in cell lysate. Further evidence showed that an unknown specific factor(s) was needed to form these PAF-containing lipid vesicles. Radioactivity was not found in HMW fraction when [3H]PAF was mixed with cell lysate of vascular smooth muscle cells. When monomeric PAF was added to endothelial cell lysate, the specific activity of aggregation decreased to the level exerted by endogenous PAF-containing lipid vesicles due to incorporation into lipid vesicles. PAF in the form of lipid vesicles was more stable in plasma than monomeric form.

Animals↗