Pharmacokinetic studies on the concomitant administration of piperacillin and cefazolin, and piperacillin and cefoperazone in rabbits

The pharmacokinetics of each drug on the concomitant administration of piperacillin (PIPC) and cefazolin (CEZ) or cefoperazone (CPZ) were studied in rabbits. When rabbits received the consecutive drip infusion administration of CEZ (0.71 mg/kg/minute) and PIPC (1.38 mg/kg/minute) and likewise of CPZ (0.72 mg/kg/minute) and PIPC (1.54 mg/kg/minute) for 1 hour, respectively, the serum half-lives of CEZ and CPZ were respectively prolonged about 1.8 and 1.6 times during drip infusion of PIPC than administered alone. However, when the sequence of administration were reversed, the serum levels of PIPC were not affected by the consecutive drip infusion administration of CEZ and CPZ. To study these findings in detail, the single intravenous dose of 20 mg/kg of CEZ and CPZ were administered under drip infusion of PIPC (2.65-2.93 mg/kg/minute). The serum half-lives of CEZ and CPZ were also prolonged about 5.4 and 1.9 times, respectively, whereas urinary excretion of CEZ, and urinary and biliary excretion of CPZ were reduced by PIPC. Moreover, when the single intravenous dose of 20 mg/kg of PIPC were administered under drip infusion administration of CEZ (0.96-2.60 2.60 mg/kg/minute), the pharmacokinetics of PIPC was not affected by the presence of CEZ. However, under drip infusion administration of CPZ (2.60-2.70 mg/kg/minute), the PIPC serum half-life was prolonged about 1.4 times, and biliary excretion of PIPC was reduced but urinary excretion was not. From the results of renal clearance experiments, tubular secretion appeared to be the predominant mechanism of renal elimination for these three drugs. These results indicate that PIPC influences the pharmacokinetics of both drugs by the competitively inhibiting tubular secretion in CEZ, and tubular secretion and hepatic transport system in CPZ. Therefore, in this respect PIPC seems to have probenecid-like action.     

Relationship between gastric secretion and serum gastrin levels in dogs anesthetized with morphine and urethane.

The serum levels of immunoreactive gastrin (IRG) and secretion of gastric juice were simultaneously determined in dogs anesthetized with morphine and urethane. There was a significant positive linear correlation between secretion and serum IRG level in these dogs. Serum IRG level and gastric secretion were reduced by bilateral vagotomy at the neck. The amount of gastric juice was reduced dose-dependently by an intravenous injection of atropine (0.001--0.016 mg/kg), hexamethonium (0.064--1 mg/kg) and secretin (2--8 U/kg). The reduction of gastric secretion paralleled that of the serum IRG level. However, the reduction of gastric secretion did not parallel that of serum IRG level under the influence of prostaglandin E1 (0.002--0.008 mg/kg i.v.) and duodenal acidification. Prostaglandin E1 and duodenal acidification reduced gastric secretion without the reducing serum IRG level. These findings were discussed in relation to the mechanism of gastric juice stimulation by morphine, and it is suggested that endogenous gastrin release through the vagal and non-vagal pathways participates in morphine-induced gastric secretion. The difference in inhibitory effect between duodenal acidification and secretin suggests the possibility that substances other than secretin may participate in the regulation of gastric secretion in dogs.     

The introduction of microvascular surgery to hepatic artery reconstruction in living-donor liver transplantation--its surgical advantages compared with conventional procedures.

Microvascular surgery for the reconstruction of the graft artery has been used since the 8th case in our series of 14 liver transplantations using living-related donors, and the clinical results have been compared between the first seven cases (the Loupe group) and the last seven cases (the Micro group). Seven arteries in 7 grafts were reconstructed with the use of loupe magnification in the Loupe group, while 8 arteries in 7 grafts were anastomosed with microscopic techniques in the Micro group. Statistically, there was no difference between the two groups in general background, including age, body weight and primary disease of the recipient, and in medical and surgical factors possibly relating to postoperative thrombosis of the hepatic artery. In two cases in the Loupe group, one or two additional reconstructions were necessary to obtain sufficient blood flow, while 8 arteries were anastomosed in the Micro group without any arterial complication in the postoperative period. There was no difference in time required for completing the arterial reconstruction (45.1 +/- 18.1 min in the Loupe versus 44.4 +/- 6.9 min in the Micro [mean +/- SEM]). Postoperative ultrasonic Doppler duplex study demonstrated a temporary decrease in the arterial flow in 2 cases of the Loupe group, and partial thrombosis of the artery was suspected. Additionally there were two episodes of hepatic artery thrombosis in 1 case of the Loupe group, in which emergent revision for thrombectomy and reanastomosis was performed at the first episode. This illustrated the higher incidence of arterial complications in the Loupe group compared with the Micro group (4 episodes/7 arteries in the Loupe versus 0/8 arteries in the Micro, P less than 0.05). In the present series there were no graft failures or arterial complications in the three deaths in the series. The clinical improvements achieved by microvascular surgery in living-donor liver transplantation suggest an alternative technical strategy for dealing with problematic arterial reconstruction in adult liver transplantation.     

Chronic hepatitis C]

Eleven years have elapsed since the hepatitis type C was first reported and treatment with interferon alone has resulted in about 30% recovery in man. In the case of heavy infection by HCV genotype 1b, 2a, interferon treatment has not been wholly satisfactory and treatment with long term combination of interferon and ribavirin appears to be most effective and a combination of interferon, ribavirin may become the mainstream of the treatment. A duration of one year appears to be most satisfactory. Even when this combination therapy is going, heavy infection by HCV genotype 1b recovery is about 50% and in order to prevent the occurrence of carcinoma, long term treatment with a small dose of interferon must be considered. New agent other than ribavirin must be developed.