E4177, 3-(2’-carboxybiphenyl-4-yl)methyl-2-cyclopropyl-7-methyl-3H-imidazo4,5-6pyridine, was characterized by in vitro autoradiography and by examining functional antagonism upon angiotensin II (Ang ...II)-induced contraction of isolated vessels. In rat adrenal cortex and liver, E4177 competitively inhibited the specific binding of 125I-Sar1, Ile8Ang II, with IC50 being (5.2±1.0) × 10-8 M for the adrenal cortex and (1.2±0.3) × 10-7 M for the liver. These IC50 values were similar to those for losartan, which showed an IC50 of (6.0±0.9) × 10-8 M for the adrenal cortex and (1.3±0.5) × 10-7 M for the liver. In contrast, E4177 and losartan had little effect on the binding to rat adrenal medulla where AT2-receptors predominate. These results indicate that E4177 is ΑΤ1-specific as is losartan. E4177 and losartan competitively antagonized the Ang II-induced contraction of human and rabbit arterial strips without any agonistic action. The obtained IC50 values indicated that E4177 was twice as potent as losartan in human arteries and three times more so in rabbit aortic strips. Responses to norepinephrine, serotonin, histamine or KC1 were not affected by E4177. In addition, E4177 (10-5 M) had no effect on angiotensin-converting enzyme activity. These data indicate that E4177 is a potent AT, Ang II-receptor antagonist that may be clinically useful for the treatment of cardiovascular diseases such as hypertension.
Ceftizoxime (CZX), one of the fifth group in cephem-antibiotics classified by FUJII, was administrated intravenously with a one shot dose of 20 mg/kg to neonates and low birth weight infants with ...ages ranged 4-21 day old and plasma and urinary concentrations and urinary recovery rates of the drug were determined. Clinical, prophylactic and bacteriological effects of CZX were evaluated and adverse reactions and effects on laboratory test values due to this drug were studied in 22 neonates and low birth weight infants (0-76 day old) consisting of 16 cases with various bacterial infections including presumptive cases of bacterial infections and 6 cases with prophylactic administration against infectious diseases. An average CZX daily dose of 55.3 mg/kg was given once or divided into 2-4 times daily (twice: 16 cases, 3 times: 3 cases, 4 times: 2 cases) through intravenous one shot administration for 6 days on the average. The results obtained are summarized as follows. 1. Neonates and low birth weight infants were classified into 3 groups by age: 4-7, 8-14, 15-21 day old. Plasma peak levels of CZX were observed at an average of 5 minutes after administration in all 3 groups with mean values of 58.3, 74.9 and 76.9 μg/ml, respectively, and the 4-7 day old-group showed a lower value than with other 2 groups. Mean values of AUC were 218.9, 221.0 and 197.0 μg·hr/ml, respectively, and no notable difference was observed within each group. Mean values of half-lives of CZX were 3.61, 2.72 and 2.37 hours, respectively, and the younger group tended to have the longer value. 2. Urinary concentrations of CZX ranged 10.9-1,190 μg/ml in all of the 3 groups during 0-2, 2-4, 4-6, 6-8 hours after administration. Mean values of urinary recovery rates during 8 hours of the 3 age-groups were 60.1, 68.7, 56.7%, respectively. The oldest group showed the lowest mean value bacause one of the cases had the lowest value of 34.5% for an unknown reason. 3. Clinical effect of CZX in 16 cases with various bacterial infections and presumptive bacterial infections was evaluated with an efficacy rate of 87.5%. The prophylactic effect was recognized in all 6 cases that were given CZX to prevent infectious diseases. 4. The bacteriological effect was evaluated in only one case with an infection due to Escherichia coli, which was eradicated by the treatment. 5. No adverse reactions were observed in any cases and eosinophilia was seen in 1 case (5.3%) as an abnormal laboratory test value, probably due to this drug.
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