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Gabexate (GB), a serine protease inhibitor that is widely used for the treatment of acute pancreatitis and disseminated intravascular coagulation, has been reported to be partly hydrolyzed by human serum albumin. However, other enzymes responsible for GB hydrolysis in human blood remain unclear. In this study, we examined in vitro metabolism of GB with human blood samples. The hydrolytic activities of the plasma and erythrocytes at 100µM of GB were 167 ± 26 and 151 ± 9n mol/min/ml blood fraction (mean ± S.D., n = 8), respectively. Kinetic analysis indicated that Vmax and Km values were 1.75µmol/min/ml blood fraction and 529µ Mf or the plasma and 10.6µmol/min/ml blood fraction and 7360µ Mf or the erythrocytes, respectively. The activity of human plasma wa si nhibited by ethopropazine, a butyrylcholinesterase inhibitor (27% inhibition at 100µM). Furthermore, the plasma activity was inhibited by 5,5 � -dithiobis(2-nitrobenzoic acid) (DTNB) (40% inhibition at 5000µM), suggesting the involvement of albumin in the plasma GB hydrolysis. The erythrocyte activity was also decreased by DTNB (56% inhibition at 5000µM), implying that this activity was dependent on the presence of sulfhydryl group(s), while little or no inhibition of the activity was seen with phenylmethylsulfonyl fluoride, diisopropyl fluorophosphate, and BW284C51. Butyrylcholinesterase from human serum showed GB hydrolytic activity with Vmax of 363 nmol/min/m gp rotein and Km of 263µM. These results suggest that, in addition to albumin, butyrylcholinesterase and erythrocyte sulfhydryl-dependent enzyme are responsible for GB hydrolysis in human blood.

Metabolism of nafamostat, a clinically used serine protease inhibitor, was investigated with human blood and liver enzyme sources. All the enzyme sources examined (whole blood, erythrocytes, plasma and liver microsomes) showed nafamostat hydrolytic activity. V(max) and K(m) values for the nafamostat hydrolysis in erythrocytes were 278 nmol/min/mL blood fraction and 628 microM; those in plasma were 160 nmol/min/mL blood fraction and 8890 microM, respectively. Human liver microsomes exhibited a V(max) value of 26.9 nmol/min/mg protein and a K(m) value of 1790 microM. Hydrolytic activity of the erythrocytes and plasma was inhibited by 5, 5'-dithiobis(2-nitrobenzoic acid), an arylesterase inhibitor, in a concentration-dependent manner. In contrast, little or no suppression of these activities was seen with phenylmethylsulfonyl fluoride (PMSF), diisopropyl fluorophosphate (DFP), bis(p-nitrophenyl)phosphate (BNPP), BW284C51 and ethopropazine. The liver microsomal activity was markedly inhibited by PMSF, DFP and BNPP, indicating that carboxylesterase was involved in the nafamostat hydrolysis. Human carboxylesterase 2 expressed in COS-1 cells was capable of hydrolyzing nafamostat at 10 and 100 microM, whereas recombinant carboxylesterase 1 showed significant activity only at a higher substrate concentration (100 microM). The nafamostat hydrolysis in 18 human liver microsomes correlated with aspirin hydrolytic activity specific for carboxylesterase 2 (r=0.815, p

Effect of β2-microglobulin adsorption column on dialysis-related amyloidosis.Backgroundβ2-microglobulin (β2-m) is considered a major pathogenic factor in dialysis-related amyloidosis (DRA), often seen in long-term dialysis patients. No effective therapy for this severely debilitating disease is currently available. Lixelle™, an adsorption column, has been developed for the elimination of β2-m; the efficacy of this column has been evaluated in this study.MethodsSeventeen hemodialysis patients with DRA were first treated with high-flux dialysis for a minimum of 1 year. This was followed by 1-year treatment with Lixelle™ column connected in series to the high-flux dialyzer. Treatments were used three times a week for both phases of this study. During the study period, β2-m, pinch strength, motor terminal latency, and activities of daily living were evaluated.ResultsAfter 1-year treatment with high-flux dialysis the β2-m level remained unchanged; however, after 1-year treatment with the addition of the Lixelle™ column, β2-m level decreased significantly from 34.5 ± 8.4mg/L to 28.8 ± 7.3mg/L (P < 0.05). After 1 year of Lixelle™ column use, the pinch strength increased from 6.8 ± 4.7 pounds to 9.1 ± 5.5 pounds (P < 0.01), and the median motor terminal latency was significantly reduced from 5.1 ± 1.0 mseconds to 4.5 ± 1.1 mseconds. A significant improvement was also observed in the activities of daily living score of the upper extremities.ConclusionThese results suggest that the addition of Lixelle™ to the high-flux dialyzer is associated with a significant clinical improvement in DRA patients.

We studied the adhesive and sealing effects of sheet style fibrin adhesive, TO-193 (TachoComb), on some tissues and organs, comparing them with those of sheet style collagen agent, collagen sponge, Novacol, and Avitene and liquid fibrin adhesive agent, Beriplast P. TO-193 showed more a potent adhesive effect on liver than the sheet style collagen agents and was more potent on bone and skin than the liquid fibrin adhesive agent. Furthermore, TO-193 had a potent sealing effect at the site of incomplete suture immediately after application on a motile organ such as lung and stomach. These effects may be partly attributable to rapid expression of the effect due to the presence of a high concentration of fibrinogen on coverage. Enhancement of fibrin penetrability to the tissues by compression and inhibition of cleavage of coverage by the collagen sponge also may be participating in the effects of TO-193. These results suggest that TO-193 will be a valuable adhesive and sealing agent.

1. 1. The mechanism of action of a new antiplatelet agent, KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate) and its active main metabolite, desethyl KBT-3022, was investigated. 2. 2. KBT-3022 and desethyl KBT-3022 inhibited cyclooxygenase from ovine seminal gland with IC 50 values of 0.69 and 0.43 μM, respectively. 3. 3. At concentrations higher than those required for cyclooxygenase inhibition, desethyl KBT-3022 inhibited cAMP-phosphodiesterase, specific binding of U46619, and release of phosphatidic acid from thrombin-stimulated platelets. 4. 4. Oral administration of KBT-3022 inhibited the production of thromboxane B 2 during blood coagulation more potently than the production of 6-keto-prostaglandin F 1α from aortic strips in guinea pigs. 5. 5. These findings suggest that KBT-3022 may inhibit platelet activation principally via the inhibition of cyclooxygenase by desethyl KBT-3022.

The effect of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate), a new cyclooxygenase inhibitor, on experimental brain edema was studied. In vitro, KBT-3022 (100 microM) and its metabolite desethyl KBT-3022 (10 and 100 microM), but neither acetylsalicylic acid nor indomethacin, inhibited arachidonic acid-induced swelling of guinea pig cortical slices. KBT-3022 (3-100 microM) and desethyl KBT-3022 (3-30 microM), but neither acetylsalicylic acid nor indomethacin, inhibited lipid peroxidation in guinea pig brain homogenate. In vivo, oral administration of KBT-3022 (1, 3 and 10 mg/kg) and indomethacin (10 and 30 mg/kg), but not acetylsalicylic acid, prevented brain edema induced by bilateral carotid occlusion and recirculation in gerbils. Indomethacin then prevented postischemic hyperthermia, but not KBT-3022. KBT-3022 (10 mg/kg) and indomethacin (30 mg/kg) inhibited lactate accumulation in gerbil brain after ischemia and recirculation. These results suggest that KBT-3022 prevents development of both cytotoxic edema in vitro and vasogenic edema in vivo.

The effects of KBT-3022 and its metabolite desethyl KBT-3022 on platelet aggregation were determined in rat, guinea-pig, rabbit and human platelets in-vitro and ex-vivo. KBT-3022 and desethyl KBT-3022 inhibited platelet aggregation induced by arachidonic acid and collagen in-vitro more potently than aggregation induced by adenosine diphosphate, platelet-activating factor or thrombin, as well as by acetylsalicylic acid, and their effects were approximately 100 times more potent than those of acetylsalicylic acid. Desethyl KBT-3022, but not KBT-3022 or acetylsalicylic acid, inhibited thrombin-induced aggregation and 5-hydroxytryptamine release from platelets more potently than ticlopidine hydrochloride at higher concentrations. Oral administration of KBT-3022 inhibited both arachidonic acid- and collagen-induced platelet aggregation and reduced platelet retention in a glass-bead column approx. 100 times more potently than acetylsalicylic acid. KBT-3022 showed little or no anti-inflammatory effect on either ultraviolet-induced erythema or arachidonic acid induced ear oedema, and had lower gastro-ulcerogenicity than acetylsalicylic acid. These results suggest that KBT-3022 is a potent inhibitor of platelet activation with weak side-effects.

SummaryUsing guinea pigs, a study was conducted on the effects of KBT-3022, a new anti-platelet agent, on hemorheological properties in various tests including blood filterability, blood viscosity, shear stress-induced red blood cell (RBC) deformability and contents of ATP and 2,3-diphosphoglycerate (2,3-DPG). Oral administration of KBT-3022 at 1 and 10 mg/kg significantly increased blood filterability, and significantly reduced blood viscosity at 10 mg/kg without changing the hematocrit, plasma fibrinogen concentration or plasma viscosity. KBT-3022 (10 mg/kg, p.o.) improved RBC deformability in response to shear stress, which was evoked by passing the blood through a thin tube. This dose of KBT-3022 also increased the contents of ATP and 2,3-DPG in RBC. These findings indicate that KBT-3022 may reduce blood viscosity as a sequel to improvement of RBC deformability through direct action on RBC. The increase in the intracellular levels of ATP and 2,3-DPG was considered to be involved in this improvement of hemorheological properties. These hemorheological effects of KBT-3022 appear to be promising for the treatment of patients with ischemic vascular disease.

The protective effect of KBT-3022 (ethyl 2-[4,5-bis-(4-methoxyphenyl)thiazol-2-yl]pyrrol-1-ylacetate), a new cyclooxygenase inhibitor, in cerebral hypoxia and ischemia was studied and compared with those of indomethacin and acetylsalicylic acid (ASA). Oral administration of KBT-3022 (3-100 mg/kg) and indomethacin (3 and 10 mg/kg) significantly prevented KCN-induced death in mice, while ASA (100mg/kg) had no effect. KBT-3022 (3 and 10 mg/kg, p.o.) and indomethacin (10 mg/kg, p.o.) significantly prolonged the survival time of mice subjected to normobaric hypoxia, while ASA (100 mg/kg, p.o.) had no effect. KBT-3022 (3-30 mg/kg, p.o.) and indomethacin (3 mg/kg, i.p.) significantly ameliorated delayed neuronal death in the gerbil hippocampal CA1 sector after occlusion of bilateral carotid arteries for 5 min, while ASA (300 mg/kg, p.o.) had no effect. KBT-3022 (10 mg/kg, p.o.) significantly inhibited ATP depletion in the gerbil hippocampus after a 1-min occlusion of bilateral carotid arteries, but had no effect on ATP depletion after a 5-min occlusion and the recovery during recirculation. These results show that KBT-3022 exerts protective effects against cerebral anoxia and hypoxia and ameliorates delayed neuronal death in the hippocampus. KBT-3022 may therefore be useful for prophylaxis of ischemic cerebrovascular disorders.

In this study, we investigated the effects of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)-thiazol-2-yl]pyrrol-1-ylacetate), a potent and long-lasting anti-platelet agent, in several experimental thrombosis models and compared them with those of other anti-platelet drugs. Oral administration of KBT-3022 prevented arachidonic acid-induced death due to pulmonary embolism in mice and rabbits with respective ED50 values of 0.29 and 0.12 mg/kg. The protective effect of acetylsalicylic acid (ASA) against mortality was weaker than that of KBT-3022, and ticlopidine hydrochloride (TP) showed no such effect in these models. In a guinea pig arterio-venous shunt model, the inhibition by KBT-3022 of thrombus formation on a silk thread inserted into the shunt was dose-dependent and 300 and 30 times more potent than the inhibition obtained with ASA and indomethacin, respectively. In a model of aortic thrombosis induced by perivascular application of 20% silver nitrate solution, KBT-3022 (1 mg/kg, p.o.) inhibited thrombus formation significantly, ASA (100 mg/kg, p.o.) tended to inhibit it, and TP had no effect. However, in a stasis-induced venous thrombosis model in guinea pigs, TP inhibited thrombus formation significantly, but KBT-3022 and ASA were ineffective. These results suggest that KBT-3022 may be a useful drug for the treatment and/or prophylaxis of thrombus formation in shunts and aortic thrombosis.

By developing 6-amidino-2-naphthyl 4-guanidinobenzoate (I, FUT-175) as a basic structure, its various derivatives were synthesized and their inhibitory activities on trypsin, plasmin, kallikrein, thrombin, C1r and C1s as well as on complement-mediated hemolysis were examined. The protective effect of these compounds on complement-mediated Forssman shock was also examined in guinea pigs. 6-Amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-benzoate (41, FUT-187) was found to be a suitable compound for oral administration with anti-complement activity superior to that of compound I.

To clarify whether monoaminergic inputs to the subfornical organ (SFO) area participate in fluid regulatory systems, we examined the effects of body fluid depletion on monoamine turnover in the region of the SFO using microdialysis techniques in rats. An iso-osmotic reduction of fluid volume following subcutaneous treatment with polyethylene glycol (PEG) significantly increased dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the SFO area. 5-hydroxytryptamine (5-HT) in the SFO area could be detected after the PEG treatment, while 5-HT was undetectable before the treatment. The data imply that both dopaminergic and serotonergic systems in the SFO area may be involved in controlling body fluid balance.

Although the authors recently reported that nafamostat, a clinically used serine protease inhibitor, was mainly hydrolysed by carboxylesterase in human liver microsomes, the involvement of human liver cytosol has not been elucidated. The current study examined the in vitro metabolism of nafamostat with human liver cytosols. Kinetic analysis indicated that the Vmax and Km values in the liver cytosols were 9.82 nmolmin(-1) mg(-1) protein and 197 microM for a liver sample HL-1, and 15.1 nmolmin(-1) mg(-1) protein and 157 microM for HL-2, respectively. The Vmax/Km values in both cytosols were at least threefold higher than those in the corresponding microsomes. The liver cytosolic activity for nafamostat hydrolysis was inhibited by phenylmethylsulfonyl fluoride (PMSF) (43% inhibition at 100 microM), whereas diisopropyl fluorophosphate (DFP) and bis(p-nitrophenyl)phosphate (BNPP) failed to inhibit the activity. Furthermore, the hydrolytic activity was also reduced by palmitoyl-CoA (67% inhibition at 100 microM) but not by acetyl-CoA. Effects of PMSF, DFP and BNPP on cytosolic palmitoyl-CoA hydrolytic activity were comparable with those of the cytosolic nafamostat hydrolytic activity. In addition, the palmitoyl-CoA hydrolytic activity was competitively inhibited by nafamostat with the apparent Ki value of 164 microM for the liver cytosol from HL-2. These results suggest that an isoform of long-chain acyl-CoA hydrolase may be responsible for the nafamostat hydrolysis in human liver cytosol.

TO-193 (TachoComb) is a new fibrin adhesive agent that consists of a collagen sheet coated with fibrin glue. We compared the hemostatic effect of TO-193 in several experimental models with Beriplast P as a fibrin adhesive agent, Avitene and Novacol as a microfibrillar collagen hemostat, and a sponge-like collagen sheet as the constitutional parts of TO-193. In the in vitro bleeding model in which blood leaks out through cotton cloth, the pressure of TO-193 when blood leakage was observed was higher than those of Beriplast P, Avitene, Novacol and the collagen sheet, indicating that TO-193 possessed a strong adhesive effect on the bleeding surface. On the kidney resection surface, TO-193 showed a more potent adhesive effect than those of Beriplast P and the collagen sheet, suggesting that TO-193 has a potent hemostatic effect. In the liver resection, TO-193 significantly reduced the bleeding volume compared with that of Novacol in normal rats. Furthermore, the bleeding volume of TO-193 was about half that of Beriplast P and equivalent to that of Novacol even in anticoagulant-treated rats. From these data, it is expected that TO-193 would be a valuable hemostatic agent for clinical use since TO-193 possesses a potent adhesive ability on the bleeding resection surface and would certainly stop bleeding in both patients with normal coagulation and those with a low blood coagulation condition.

We devised a method for evaluating polymorphonuclear leukocyte (PMN) infiltration in vivo employing an air bleb technique combined with measurement of myeloperoxidase (MPO) activity, and the effects of some anti-platelet agents were evaluated. KBT-3022 (ethyl 2-[4,5-bis (4-methoxyphenyl)thiazol-2-yl] pyrrol-1-ylacet ate) and cilostazol inhibited the increase in MPO activity in the connective tissue around the air bleb induced by leukotriene B4 (LTB4) and formyl-methionyl-leucyl-phenylalanine (fMLP). Indomethacin inhibited only the fMLP-induced increase in MPO activity, but ticlopidine hydrochloride and acetylsalicylic acid had no effect. Histologic observation confirmed the inhibition of PMN infiltration by KBT-3022. These results indicate that KBT-3022 may be a potent inhibitor of both LTB4- and fMLP-induced infiltration of PMNs.

Inhibitory activities of FUT-187 on trypsin-like serine proteases were compared using camostat mesilate (camostat), and 4-(4-guanidino benzoyloxy)-phenyl acetic acid methanesulfonate (GBPA) known as an active metabolite of camostat in the blood. Ki values of FUT-187 on the competitive inhibition mechanism were 0.097 microM for trypsin, 0.029 microM for pancreatic kallikrein, 0.61 microM for plasma kallikrein, 0.57 microM for plasmin, 2.5 microM for thrombin, 20.4 microM for factor Xa and 6.4 microM for C1r. However, FUT-187 acted as a noncompetitive inhibitor for factor XIIa and an uncompetitive inhibitor for C1s, and Ki values for these proteases were 0.021 and 0.18 microM, respectively. Ki values of camostat for these proteases were in the range of 0.037 to 96.4 microM, and those of GBPA for the above proteases except trypsin and plasma kallikrein were higher than those of FUT-187. The inhibitory activity of FUT-187 on trypsin was not reduced by the addition of the serum at 10%, whereas, that of GBPA was reduced (4.3 fold) in terms of IC50 values. The concentration of FUT-187 required to double APTT (activated partial thromboplastin time) was 1.09 microM, while GBPA, by concentrations up to 1 mM failed to double APTT. The kinin formation by glandular kallikrein in the rat plasma was inhibited by FUT-187 with IC50 value of 0.024 microM, while camostat revealed no inhibition by concentrations up to 1 microM. The complement-mediated hemolyses in the classical and alternative pathways were also inhibited by FUT-187 with IC50 values of 0.17 and 3.5 microM, respectively, the corresponding values for camostat being 350 and 150 microM, respectively. It is concluded that FUT-187 is a potent and selective inhibitor of trypsin-like serine proteases, and its inhibitory activities are stronger than those of camostat on glandular kallikrein, factor XIIa and C1s in complement pathway.

Antigenicity study of 6-amidino-2-naphthyl 4-[(4, 5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187), a new protease inhibitor, was investigated in guinea pigs and mice and the following results were obtained. 1. In guinea pigs immunized with FUT-187 plus adjuvant by intramuscular / subcutaneous routes, ASA, ACA and PCA reactions challenged intraveneously or intradermally were positive. 2. In guinea pigs immunized with FUT-187 plus adjuvant by intramuscular / subcutaneous routes, ASA and PCA reactions challenged orally were negative. 3. In guinea pigs immunized with FUT-187 by the oral route, ASA, ACA and PCA reactions were negative. 4. In guinea pigs immunized with IABA and AN plus adjuvant by intramuscular / subcutaneous routes, ASA and PCA reactions were negative. 5. 48-hr PCA reactions were elicited with sera obtained from BALB / c and C3H / He mice immunized with FUT-187 plus adjuvant by the intraperitoneal route, responses were negative. 6. From the results of hapten inhibition tests using anti-FUT-187 guinea pig serum, it is suggested that the antigenicity of FUT-187 is attributable to the its benzoic acid.

MK-0521 and captopril were orally administered to acute (6 to 8 days after unilateral renal artery constriction) and chronic (2 to 2.5 months after the constriction) 2-kidney Goldblatt hypertensive dogs for 7 to 21 days. MK-0521 lowered the blood pressure to similar extents in the acute and chronic stages of hypertension. The antihypertensive effect of MK-0521 was dose-dependent and persistent even after its cessation. Captopril also produced an antihypertensive effect, although the effect in the chronic stage of hypertension was less prominent than that in the acute stage of hypertension. MK-0521 was more inhibitory on the renin-angiotensin system than captopril. In the acute stage of hypertension, the dogs treated with MK-0521 had increased angiotensin converting enzyme (ACE) activity, while they had decreased plasma angiotensin II level and elevated plasma angiotensin I level and plasma renin activity. These results clarified the inhibitory effect of MK-0521 on ACE. In contrast, in the chronic stage of hypertension, MK-0521 showed no depression of plasma angiotensin II. There were no significant changes in daily urinary volume, and renal clearances of sodium, potassium and creatinine. These results suggest that the major mechanism of the antihypertensive effect of MK-0521 in 2-kidney Goldblatt hypertensive dogs is an inhibition of the ACE. In addition, the different effects in the acute and chronic hypertensive dogs suggest that some differences exist in the mechanisms of maintaining blood pressure between the two stages of 2-kidney Goldblatt hypertensive dogs.

1. The effects of FUT-175 on the development of adjuvant arthritis in rats were studied and compared with those of indomethacin. FUT-175 inhibited both primary and secondary paw lesions in the adjuvant arthritic rats when it was administered orally on a daily basis from the day before through 18th day after adjuvant injection. 2. In addition, FUT-175 inhibited the increase in hemolytic complement in adjuvant arthritic rats in a dose-dependent manner. 3. Indomethacin also showed an inhibitory effect on the development of arthritic lesion, but had no effect on the increase in hemolytic complement in the adjuvant arthritis in rats. 4. Furthermore, FUT-175 inhibited the activities of various proteases in vitro , and then strongly inhibited complement-mediated hemolysis via the classical and alternative pathways, while indomethacin had no effect on them. 5. These results suggest that the anti-inflammatory activity of FUT-175 may differ from indomethacin in the mechanisms of action and, at least in part, due to the anti-complement activity.

FUT-175 inhibited the zymosan-induced rat paw edema in a dose-dependent manner, while indomethacin exhibited no significant activites in this model. FUT-175 also inhibited the decrease in hemolytic complement (CH50) induced by zymosan in vitro, and indomethacin was inactive. These results suggest that FUT-175 has potent in vitro and in vivo nhibitory activity against the activation of the complement system induced by zymosan.

FUT-175, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate (nafamstat mesilate), a novel synthetic protease-inhibiting agent, was studied to determine its in vitro effects against various proteases and other enzymes, as well as to determine its in vivo protease inhibitory effects. FUT-175 was found to inhibit, in an intense, specific and reversible way, the enzyme activities of trypsin, C1r, C1s, thrombin, kallikrein and plasmin with IC50 values of the order of 10(-6)-10(-8) M. FUT-175 also inhibited complement-mediated hemolysis, including both classical and alternative pathways, sites of inhibition being on C1r and C1s as evidenced by the intermediate-cell technique. In animal model reactions in which the complement system is known to be involved as pathogenetic factors, e.g., Forssman shock, Forssman cutaneous vasculitis, zymosan-induced paw edema, endotoxin shock and local Shwartzman reaction, FUT-175 was highly effective in that, for example, intravenous dosing at 3 mg/kg could completely protect guinea pigs from the lethal Forssman shock. FUT-175 was also found to be effective in trypsin-induced shock in mice, in lethality due to thrombin-thrombosis in mice and in kinin formation in the inflammatory process in rats.

Angiotensin converting enzyme (ACE) inhibitory activity of MK-0521 in dogs and the effects of its single oral administration on blood pressure and the renin-angiotensin system in 2-kidney Goldblatt hypertensive dogs were compared with those of captopril and MK-421. MK-0521 at 0.001-0.1 mg/kg, i.v., or 0.01-1 mg/kg, p.o., attenuated the pressor effect of angiotensin I without affecting that of angiotensin II and augmented the depressor effect of bradykinin. The potency of MK-0521 to reduce the pressor effect of angiotensin I was 9.8 times that of captopril by intravenous administration, and by oral administration, it was 15.9-32.1 times that of captopril and approximately 3 times that of MK-421. When administered orally, the onset of action and the time to peak effectiveness were more rapid than those of MK-421, but slower than those of captopril. Duration of the action of MK-0521 was longer than that of captopril and equal or longer than that of MK-421. The inhibition of ACE was well correlated with serum MK-0521 levels. MK-0521 produced a dose-dependent antihypertensive effect in 2-kidney Goldblatt hypertensive dogs at over 0.3 mg/kg, p.o., without affecting the heart rate. The antihypertensive effect of MK-0521 was persistent and approximately 3 times more potent than that of captopril. MK-0521 inhibited the serum ACE activity and increased the plasma renin activity, while it had a tendency to decrease plasma aldosterone level. These changes were parallel to the time course of the antihypertensive effect. These results suggest that the main mechanism of the antihypertensive effect of MK-0521 is the suppression of angiotensin II production due to the inhibition of the ACE.

On the basis of my experience in the X-ray astronomy, and on some typical highlights of multi-wavelength observations, I emphasize the importance of collaboration between space astronomy and ground-based astronomy.

FUT-175 has been reported by S.Fujii et al.1) to inhibit strongly Clr, Cls, trypsin and thrombin as well as kallikrein and plasmin. In the present study, effects of FUT-175 on the complement and kallikrein system were investigated in vitro and in vivo. The in vitro complement-mediated hemolysis via classical pathway activation was performed as described by Mayer et al., and the systemic Forssman shock in guinea pigs was induced by the method of Glovsky et al. The in vitro kinin formation was performed with glass powder in rat plasma. The anti-inflammatory effects of FUT-175 were also studied on kaolin- and scald-induced edema of rat paws. FUT-175 markedly inhibited the complement-mediated hemolysis, the IC50 being 4.5 × 10−8 M, and protected the guinea pig from the systemic Forssman shock at doses of 0.3 - 3 mg/kg, i.v., in a dose-dependent manner. FUT-175 also inhibited the in vitro kinin formation with the IC50 of 1.1 × 10−7 M (glass powder) and reduced the kaolin- and scald-induced edema formation at doses of 30 - 300 mg/kg, p.o..