No abstract

1. A comparison was made on the protective effects of the following: ME3221, a competitive angiotensin AT1 receptor antagonist; losartan, in which a major active metabolite is a non-competitive angiotensin AT1 receptor antagonist; and enalapril, an angiotensin-converting enzyme inhibitor, using the salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP received orally ME3221 (3 and 10 mg/kg per day), losartan (10 mg/kg per day) and enalapril (10 mg/kg per day) from the 6th to the 20th week of age. All the control rats showed rapid elevation of systolic blood pressure (SBP), accompanied by hypertensive complications, and died by 15 weeks of age. 3. ME3221, losartan and enalapril suppressed the elevation of SBP in the salt-loaded SHRSP to a comparable degree. ME3221 and losartan increased the survival rate to > 90%, and diminished hypertensive complications such as cerebral apoplexy (stroke), renal injury (increased proteinuria, and total N-acetyl-beta-D-glucosaminidase activity) and heart failure (cardiac hypertrophy and pleural effusion). 4. Competitive (ME3221) and non-competitive (losartan) angiotensin AT1 receptor antagonists showed comparable efficacy against the complications and mortality of the salt-loaded SHRSP; both were more potent than enalapril in the protective effect.

1.The protective effect of ME3221, a surmountable AT1 antagonist, on the hypertension and its concomitant complications in aged (32 week old) stroke-prone spontaneously hypertensive rats (SHRSP) was studied following long-term (32 weeks) oral administration, and compared with those of losartan (metabolite EXP3174 is an insurmountable AT1 antagonist) and enalapril.2. During the treatment period, ME3221, at a dose of 10 mg/kg per day steadily reduced the systolic blood pressure, and no tolerance was developed to the fall in blood pressure.The reference drugs showed similar activity, but the antihypertensive effect of ME3221 was more potent.3. In the control group, rats began to die from 52 weeks of age and all rats had died by 64 weeks of age. In contrast, no rats treated with ME3221, losartan or enalapril died before 64 weeks of age.4. ME3221, losartan and enalapril suppressed the hypertensive complications observed in control SHRSP, that is, cerebral apoplexy (stroke and cerebral oedema), renal injury (increased proteinuria, total N-acetyl-B-D-glucosaminidase activity and ascites) and heart failure (cardiac hypertrophy and pleural effusion). 5.These results indicate that ME3221 has a stable antihypertensive effect, prevents hypertensive complications and prolongs survival in aged SHRSP equally as well as losartan and enalapril.

No abstract

The efficacy of ME1036, a novel parenteral carbapenem, was compared with that of vancomycin by using a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. Compared with vancomycin, ME1036 reduced the bacterial counts in the vegetations at a lower dosage or over a shorter period of administration when it was used for the treatment of MRSA endocarditis.Recently, methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly prevalent worldwide as both a nosocomial and a community-acquired pathogen (11). Furthermore, nosocomial MRSA infections increase the risk of mortality and prolonged hospitalization. Endocarditis caused by MRSA is a serious infectious disease (1), and MRSA continues to make up a growing share of organisms that cause endocarditis (6, 9). Vancomycin is the most reliable antimicrobial agent for the treatment endocarditis caused by MRSA, but drug tolerance has been correlated with treatment failure (2, 10). ME1036, a novel parenteral carbapenem synthesized at Meiji Seika Kaisha, Ltd., possesses potent activities against gram-positive bacteria (including MRSA and penicillin-resistant Streptococcus pneumoniae) and gram-negative bacteria (4).Rabbit endocarditis was produced by the method of Perlman and Freedman (8). Female New Zealand White rabbits (weight, 1.9 to 2.6 kg) were anesthetized with ketamine and xylazine. A polyethylene catheter was placed across the aortic valves. S. aureus CR1434 (1.3 to 2.9 ϫ 10 6 CFU in 1 ml) was injected into the vein. This strain was isolated from clinical samples in a hospital in Japan. The MICs of methicillin, ME1036, and vancomycin for S. aureus CR1434 are 400, 0.5, and 1 g/ml, respectively. Eighteen hours after bacterial challenge, the antimicrobial treatment was initiated. Either ME1036 (coadministered with cilastatin sodium at 20 mg/kg of body weight/dose) or vancomycin was administered intravenously every 12 h for 5 days. Another experiment was conducted by following the same procedure but for durations of 1, 3, and 5 days. Untreated control animals were killed at the initiation of therapy. Twelve hours after the last treatment, the animals were killed. The vegetations were weighed wet under sterile conditions, homogenized in saline, and serially diluted. The dilutions were plated on Muller-Hinton agar (MHA), and the plates were incubated at 37°C for 24 h. The lower limit of detection was 2.04 to 2.93 log 10 CFU/g.The efficacies of ME1036 and vancomycin in the MRSA endocarditis model are shown in Fig. 1. The cardiac vegetations from controls had a bacterial count of 8.83 Ϯ 0.89 log 10 CFU/g (mean Ϯ standard derivation). ME1036 at 10 and 20 mg/kg/dose reduced the bacterial counts to 3.15 Ϯ 1.57 log 10 CFU/g (P Ͻ 0.01) and 2.58 Ϯ 0.68 log 10 CFU/g (P Ͻ 0.01), respectively. The vegetations were rendered sterile by consecutive treatment with ME1036. Vancomycin at 20 and 40 mg/ kg/dose reduced the bacterial counts to 6.91 Ϯ 3.37 and 3.94 Ϯ 2.69 log 10 CFU/g (P Ͻ 0.01), respectively.To ascertain whether residual MRSA CR1434 i...