1.The renal artery to a lone remaining kidney was constricted in fourteen concious dogs. The following variables were measured in all animals: blood pressure (BP), cardiac rate (CR), plasma renin concentration (PRC), plasma volume (PV), extracellular fluid volume (ECFV) and plasma non-protein nitrogen (NPN). Sodium balance was estimated in eleven dogs. Cardiac output (CO), total peripheral resistence (TPR) and stroke volume (SV) were measured in nine dogs. Angiotensin responsiveness (AR) was measured in six animals.2. Within 2 hr the following changes occurred: a sharp increment of BP, PRC and TPR, with initial reduction or no change in CO and CR; SV and PV were not changed. The linear regression of BP changes on PRC changes did not differ statistically from the one previously obtained during the infusion of exogenous renin in the conscious dog. AR was much depressed at 2 hr.3. After 24 hr a slight but sigdicant sodium retention developed, while PV and ECFV and SV increased, CO remained unchanged owing to a decrease of CR. PRC tended to return toward normal while BP remained high. Thus the linear regression between these two variables disappeared. At this stage AR increased toward normal and in two dogs exceeded normal. 4.On days 3 4 and 6-7 after constriction, CO increased owing to a rise of SV, while TPR decreased. PV and ECFV were expanded while sodium balance was maintained. AR varied very much in the individual dogs according mainly to changes of PRC, sodium balance and PV. 5. On days 12-14 sodium balance became positive again, PRC returned within normal levels in almost all the dogs. PV and ECFV also tended to decrease to normal.CO and AR were measured in only two dogs at this stage.6. It is suggested that the early rise of blood pressure might be produced by the

SUMMARY The possible existence of kinetic interactions between rifampicin and isoniazid and the effect of the concomitant presence of an impaired liver function were investigated in man.In a first study normal healthy subjects and patients with chronic liver disease received, on three different occasions, a single dose of 600 mg rifampicin or isoniazid and of rifampicin and isoniazid associated in randomized sequences. The results have shown that in both groups the serum levels, half-life values, and urinary excretion of each drug given alone are not significantly different from those observed when the other drug is associated. Serum levels and half-life of rifampicin and isoniazid were significantly higher in patients with chronically impaired liver.In a second study, rifampicin and isoniazid were given in combination at the same doses as in the first study over a period of one week. The results have shown a trend to decrease in the serum levels of rifampicin of the healthy subjects and a trend to increase in the patients with chronic liver disease on day 7 of treatment. In both groups a reduction in the half-life of rifampicin was also observed. No changes in serum isoniazid concentrations were observed between day 1 and day 7 in the healthy subjects, whereas a significant increase was observed in the patients. No significant changes in the half-life of isoniazid were observed.

No abstract

No abstract

SUMMARY Rifampicin induces a proliferation of the smooth endoplasmic reticulum in guinea-pig and human hepatocytes. This may support the hypothesis of enhancement of drug-metabolizing enzymes induced by the drug. However, the pattern of proliferation is not similar in man and in guinea-pig hepatocytes. Some caution is needed in the study of enzyme induction in man and in extrapolations fromn animal to human data. Meyer-Brunot, 1968;Curci, Ninni, and Iodice, 1969). On the other hand, repeated administration of rifampicin causes a decrease in the half-life and a fall in blood levels of the drug (Curci, Ninni, and Iodice, 1969;Furesz, 1970) together with an increase in biliary excretion of the antibiotic (Furesz, 1970 suspended in 1 % Methocel at a concentration of 16 mg/ml through a gastric tube. After two days of treatment three animals, after five days five, and after 10 days three animals were killed. Four animals received only 1 % Methocel at a dose of 0.5 ml/100 g body weight: at two days one was killed, at five days two,and at 10days one animal.Two animals did not receive any treatment. These animals were killed by section of the carotid; the abdomen was opened immediately and fragments of liver were processed for light and electron microscopy. PATIENTSTwo patients received 20 mg/kg/day rifampicin (Rifadin, Lepetit-Milan) and four 10 mg/kg/day. A liver biopsy was taken after two days of treatment. A control biopsy before treatment was obtained in three of these patients.One patient received 10 mg/kg/day for five days followed by 16 mg/kg/day for two days. A liver biopsy was taken at the end of the seven days. PROCESSING THE MATERIALFor light microscopy fragments of liver were fixed in 4% formalin, embedded in paraffin, and stained with haematoxylin-eosin. For electron microscopy, 1 mm3 fragments were fixed for one and a half hours in 1 % osmic acid in phosphate buffer pH 7.4. After dehydration with alcohol the fragments were embedded in an Epon/Araldite mixture.The blocks were cut with an LKB Ultrotome III 984