Effect of angiotensin II and thromboxane A2 on the production of matrix metalloproteinase by human aortic smooth muscle cells.

Angiotensin II (AGII) and thromboxane A2 (TXA2), potent vasoconstrictors, augmented the production of the precursor of tissue procollagenase/promatrixmetalloproteinase-1 (proMMP-1) and DNA synthesis in cultured human aortic smooth muscle cells (SMC) significantly compared with that in untreated SMC. Moreover, AGII and TXA2 stimulated hydrolysis of phosphoinositides and subsequent formation of inositol triphosphate (IP3), leading to an increase in the intracellular free Ca2+ concentration. These results suggest that the production of proMMP-1 increased by AGII and TXA2 in intimal SMC in relation to cell proliferation plays a role in arterial reconstruction in vascular diseases.

Ambient pressure stimulates immortalized human aortic endothelial cells to increase DNA synthesis and matrix metalloproteinase 1 (tissue collagenase) production.

In the present study, we investigated the effect of ambient pressure on [3H]-thymidine incorporation and on the production of matrix metalloproteinase 1 (tissue collagenase/proMMP-1) using human aortic endothelial cells immortalized with simian virus 40 (SE-1). Incubation of cells at ambient pressures of 50 and 100 mmHg for 24 h slightly increased [3H]-thymidine incorporation when directly compared with normal culture conditions. The amount of [3H]-thymidine incorporated in SE-1 reached a maximum at 150 mmHg, while a further increase in pressure to 200 mmHg decreased incorporation. The same ambient pressure slightly stimulated human aortic intimal smooth muscle cells (SMC) to increase [3H]-thymidine incorporation but not medial SMC. Immunoblot analysis also showed that ambient pressure, ranging from 50 to 200 mmHg, like 12-O-tetradecanoyl-phorbol-13-acetate stimulated SE-1 to produce proMMP-1, an effect not seen with either intimal or medial SMC. The amount of proMMP-1 produced also reached a maximum level at 150 mmHg. We postulate that human endothelial cells are ambient pressure sensitive and that relatively lower ambient pressures play an important role in the growth of endothelial cells, while higher pressures injure endothelial cells, resulting in the initiation of atherosclerosis. This cell line may prove useful in the investigation of both the physiological and pathological roles of blood pressure on endothelial cell function.

[Pharmacokinetics and clinical efficacy of flomoxef in neonates].

Clinical pharmacology and efficacy of flomoxef (FMOX) in neonates were investigated. And the following results were obtained. 1. Mean serum concentrations of FMOX at 30 minutes after administration were 24.3 micrograms/ml, 47.6 micrograms/ml, and 85.8 micrograms/ml at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg administered, respectively. 2. Mean serum half-lives of FMOX were 3.4 hours in 0-3 day-old neonates, and 2.6 hours in 4 day-old or older subjects. 3. A dose response was evident among different dose groups given 10 mg/kg, 20 mg/kg, and 40 mg/kg. 4. Urinary recovery rates of FMOX in the first 6 hours after administration ranged between 12.8 and 51.1%. 5. FMOX was effective in 7 out of 8 cases in which causative pathogens were identified. 6. Diarrhea was observed in 1 case as a side effect of the drug, but the symptom was relieved soon after the completion of the treatment. There was no case in which any abnormal laboratory results were observed. 7. FMOX has a broad spectrum of activities against Gram-positive and Gram-negative aerobes and anaerobes. It is stable against most of beta-lactamases. It was demonstrated to be highly effective in our study, and yet without any serious side effects. FMOX is therefore considered to be one of the useful agents of the first choice for the treatment of bacterial infections such as sepsis and urinary tract infections in neonates and infants.

[Pharmacokinetics and clinical safety of aztreonam in neonates].

Clinical pharmacology and safety of aztreonam (AZT) in the neonatal period were investigated. The results obtained are summarized as follows. 1. Serum concentrations of AZT at 30 minutes after administration of 10 mg/kg were 22.1-32.2 micrograms/ml and those of 20 mg/kg 22.5-75.9 micrograms/ml. 2. Serum half-lives of AZT were 3.5-6.6 hours in 0-3 day-old neonates, and 2.0-4.0 hours in neonates 4 day-old or older. 3. A dose response was evident between the 10 mg/kg administration group and the 20 mg/kg group. 4. Urinary recovery rates of AZT in the first 6 hours after administration ranged between 17.8 and 69.9%. 5. No clinical side effects were observed in the administration of AZT alone (6 cases), or in combination with ampicillin (9 cases). Thrombocytosis was observed in 1 case as an abnormal laboratory finding, but it returned to normal within 1 week after the completion of AZT administration. 6. AZT had a potent antimicrobial activity against Gram-negative aerobes and hardly induced beta-lactamase. Furthermore, side effects were not observed in this study. Therefore, AZT is considered to be useful for the treatment of urinary tract infections and other serious infections caused by Gram-negative pathogens even in the neonatal period.

[Pharmacokinetics and clinical efficacy of imipenem/cilastatin sodium in neonates].

Clinical pharmacology and clinical efficacy and safety of imipenem/cilastatin sodium (IPM/CS), a beta-lactam antibiotic with a carbapenem nucleus and a dehydropeptidase-I inhibitor, were investigated in newborns. 1. Peak serum concentrations of IPM/CS at a dose of 20 mg/20 mg/kg were achieved at the end of 60-minute infusion. Maximum serum levels of IPM and CS were 44.2 micrograms/ml and 70.0 micrograms/ml, respectively, in neonates with ages 0-3 days. IPM and CS peak levels in premature infants with ages 0-3 days were 47.2 micrograms/ml and 56.1 micrograms/ml, respectively. IPM and CS peak levels in neonates 4 day-old or older were 35.0 micrograms/ml and 41.5 micrograms/ml, respectively, and in premature infants of similar ages were 45.7 micrograms/ml and 65.3 micrograms/ml, respectively. 2. Mean serum half-lives of IPM and CS in 0-3 day-old neonates were 1.6 hours and 3.1 hours, respectively, and the mean serum half-lives in premature infants were 2.1 hours and 4.6 hours, respectively. In neonates 4 day-old or older, the mean serum half-lives of IPM and CS were 1.6 hours and 2.6 hours, respectively, and in premature infants they were 1.5 hours and 1.9 hours, respectively. 3. A dose response was evident between doses of 10 mg/10 mg/kg and 20 mg/20 mg/kg of IPM and CS. 4. Urinary recovery rates of IPM for the 0- to 6-hour post IPM/CS infusion period ranged between 27.2 and 46.6%. For CS, urinary recovery rates for the 0- to 6-hour post IPM/CS infusion period ranged between 25.3 and 100.8%. 5. Clinical efficacy was evaluated in 9 patients and 7 patients showed excellent or good responses. 6. Of 14 patients who received IPM/CS treatment, 1 patient showed hematuria, leukopenia and thrombocytopenia, and 3 patients showed eosinophilia. However, these adverse reactions improved after the completion of therapy. 7. IPM has excellent antimicrobial activity against aerobic and anaerobic Gram-positive and Gram-negative bacteria. In this study, coadministration of IPM and CS produced good clinical responses and no serious adverse reactions. It is hence concluded that IPM/CS sodium is very useful for the treatment of severe bacterial infections in neonates, especially in the presence of beta-lactamase resistant strains and in polymicrobial infections.