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During the past few years, we have been impressed by the observation that our patients with pre-eclampsia and eclampsia usually demonstrate sulfobromophthalein sodium (BSP) retention in blood in the 45-minute BSP test. On the basis of these findings, we undertook a study of hepatic BSP-removal mechanisms during the course of normal pregnancy. Increased BSP retention in 45 minutes was not detected in normal pregnancy when compared to results obtained in a group of nonpregnant women of comparable age. When hepatic BSP-removal mechanisms were appraised quantitatively by a prolonged-infusion method (1, 2), however, significant changes in both hepatic uptake and excretion of BSP were observed. The following study presents in detail such data obtained from women in various stages of normal pregnancy and in the early postpartum period, and compares these findings with data obtained in a separate group of control nonpregnant women. METHODSThe method used in the present studies was devised by Wheeler and his associates (1,2) and is based on the observations that removal of BSP from plasma depends on the simultaneous operation of at least two separate hepatic mechanisms: 1) uptake of BSP into a hepatic * This work was supported by research grants from the U. S. Public Health Service (H-3439, A-6082), and frcm Parke, Davis & Co. Part of this work has appeared in abstract form (Clin. Res. 1962, 10, 189; 1963, 11, 58) and was presented at the Annual Meeting of the American Association for the Study of Liver Diseases, Chicago, Ill., November, 1962, and "storage compartment," and 2) active secretion into bile (1-8). The quantity of BSP taken up into the "storage compartment" appears to be directly proportional to plasma concentration (1). Thus, uptake into storage during a period of changing plasma concentration can be represented in symbols as S X AP/At, where the "relative storage capacity" S, a proportional factor, is defined as the number of milligrams of BSP stored in the liver per milligram per 100 ml of plasma concentration, and AP/At signifies the rate of change of plasma concentration in milligrams per 100 ml per minute. Secretion of BSP into bile is a rate-limited process characterized by a maximal excretory rate or Tm (1, 2, 8), defined in terms of milligrams per minute. The maximal rate of BSP secretion into bile is achieved when plasma BSP concentration is maintained in excess of 2 to 3 mg per 100 ml during prolonged infusions of BSP (1, 8). At these plasma concentrations, the general equation for the hepatic removal rate of BSP (1), RH, in milligrams per minute, is as follows: RH = S X (AP/At) + Tm.Values for RH and AP/At obtained during two or more different rates of BSP infusion are substituted in the formula, providing a set of simultaneous equations that can be solved for both S and Tm. In practice, values for RH and AP/At were obtained during three separate infusion rates of BSP, each given for an hour. As indicated by Wheeler, when the corresponding values for RH and AP/At are plotted on the ordinate an...

Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.

This study demonstrated that the current criteria employed by JRC have a low risk, but the background rates of HBV and HCV infections in Japanese patients are significant.

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Serum transaminase (AST and ALT) values were monitored after administration of placebo to 104 healthy male volunteers for a phase I study. Both values remained within normal ranges in most of them. However, AST or ALT was above the normal range in 13 volunteers (12.5%) . Their clinical features were ALT>AST, high serum rglutamyl trans peptidase, high serum triglyceride, high obesity index, or a combination of any of the four. We concluded that AST or ALT is likely elevated in volunteers showing these clinical signs; this should be noted in the evaluation of drug toxicity in future phase I studies.

The pharmacokinetics of DP-1904, a new potent and selective thromboxane synthetase inhibitor and its effects on ex-vivo prostanoid formation were studied in Japanese normal male volunteers, who received orally a single 10, 20, 50, 100, 200, 400 or 800 mg dose. The drug was well tolerated by all subjects without evidence of any adverse reactions. The absorption of DP-1904 from gastro-intestinal tract was rapid. After oral doses of 10-800 mg of the drug given to volunteers in the fasted state, the mean maximum drug concentrations in plasma (Cmax) (mean +/- s.e., n = 5) of 0.215 (+/- 0.041), 0.399 (+/- 0.037), 1.47 (+/- 0.22), 2.86 (+/- 0.22), 4.66 (+/- 0.58), 7.28 (+/- 0.72) and 16.9 (+/- 2.6) micrograms mL-1 were reached within 1 h. DP-1904 concentrations declined monophasically after Cmax with half lives of 30-40 min. These half lives were independent of the administered doses. The mean area under the concentration-time curves (AUCs) increased from 0.398 (+/- 0.038) to 30.0 (+/- 2.7) micrograms h mL-1 as the dose increased from 10 to 800 mg. Linear relations between the doses and Cmax and AUCs were observed. The correlation coefficients for Cmax and AUC were 0.930 and 0.960, respectively. The apparent oral clearance (CL/F) and renal clearance (CLR) did not change significantly as dose increased from 10 to 800 mg. The kinetics of DP-1904 proved to be linear in the dose range studied.(ABSTRACT TRUNCATED AT 250 WORDS)