Pharmacokinetic differences between morning and evening administration of cyclosporine and tacrolimus therapy.

We performed 24-hour monitoring of cyclosporine (NEO) and tacrolimus (TAC) blood concentrations, evaluating pharmacokinetic parameters and characterizing circadian variations. The monitoring was performed in 10 instances on nine patients administered NEO and 12 out of 11 patients administered TAC. All cases were administered equally divided doses of drugs twice daily orally. Blood samples were taken before and 1, 2, 3, 4, 6, and 12 hours after NEO or TAC administration in the morning and evening. The pharmacokinetic parameters were compared between morning and evening administrations of both drugs. AUC0-12, AUC0-4, C(max), C2, and C(max)/C(min) of NEO and TAC were significantly lower during the evening compared with morning administrations. C(min) values were significantly higher in the evening. T(max) of NEO was longer in evening, although there was not a significant difference; T(max) of TAC was significantly longer in the evening. We found that NEO and TAC administrations in the evening resulted in reduced bioavailability and delayed absorption when compared with drug administrations in the morning. It was thought that the difference in bioavailability between morning and evening administrations was smaller with TAC, because TAC shows lower peak levels and a flatter blood concentration curve than NEO. C(min) was higher after evening administration than morning because of delayed absorption, though the bioavailability of both drugs decreased in the evening. These results suggest that we have to appreciate apparently high trough levels.

Radial flow bioreactor for the creation of bioartificial liver and kidney.

A radial flow bioreactor (RFB) is used for a three-dimensional perfusion culture of hepatocellular carcinoma (HCC) cells and renal cells, to create a bioartificial liver and kidney. The cylindrical reactor is filled with porous cellulose microcarrier. RFB can be characterized as a system in which the medium flows from the periphery toward the center of the reactor, thereby delivering an adequate supply of oxygen and nutrients to cells at the center as well as at the periphery. HCC cells incubated in the RFB system at high density maintained viability for long periods of time. Proximal tubular cells (LLC-PK1) as well as HCC cells, but not human immortalized mesangial cells (HMC) were cultured in the RFB for more than 14 days. The mRNA expression of some enzymes involved in the urea cycle, cytochrome P450s in HCC cells, and the 1-alpha-hydroxylase (CYP27B1) in LLC-PK1 cells was higher than that in monolayer cultures. These results suggest that the RFB system composed of HCC cells or renal cells may be useful for a bioartificial liver and kidney.

A new model for production of chronic gastric ulcer by duodenogastric reflux in rats.

We have established an experimental model of chronic gastric ulcer, in rats which transection of the lower horizontal portion of the duodenum and anastomosis of the forestomach to the upper part of the jejunum caused regurgitation of all duodenal juice into the stomach. After 3, 6, 12, and 30 wk, all treated rats developed an ulcer in the prepyloric region on the lesser curvature of the stomach. More than half of the antrum was finally involved in the ulcer. Histologic studies revealed chronic ulcers quite similar to human ones. As a control series, transection at the pylorus failed to produce an ulcer. Although many papers have appeared regarding the experimental production of chronic gastric ulcer, most of the studies reported have applied chemicals, drugs, or mechanical injury to the gastric mucosa. Our model produced chronic regurgitation of duodenal juice as a natural phenomenon, and uniformly resulted in ulcer formation. Intragastric total bile acid concentrations were significantly elevated in the reflux group. Serum gastrin levels, the thickness of the fundic mucosa, and the height of fundic gland were also significantly increased. Thus, the detergent action of bile acids and the increased acid secretion were assumed to play an important role in ulcer formation. Further studies using this model are warranted on the pathogenesis of chronic peptic ulceration.

A clinicopathological study of post-bulbar duodenal ulcer--analysis of 6 cases and comparison to usual chronic duodenal ulcer.

We investigated the functional and morphological aspects of acid secretion in 6 patients with post-bulbar duodenal ulcer and compared the findings with the events of 40 patients with the usual chronic duodenal ulcer. The post-bulbar ulcer patients showed a much higher acidity, and a biphasic, prolonged acid secretion pattern, presumably representing an enhanced parietal cell function. Histological study of antrectomized specimens revealed that 4 of those with the post-bulbar ulcer had a small antrum in which the fundic gland area expanded distally. The proximal border of the pyloric gland area was within 4 cm of the pylorus. This would suggest the presence of a large parietal cell mass. On the contrary, however, there was no such instance in those patients with the usual duodenal ulcer. Hyperacidity, due to a large parietal cell mass and an enhanced parietal cell function, may play an important role in the pathogenesis of post-bulbar duodenal ulcer.

Clinical diagnosis of minute gastric cancer less than 5 mm in diameter.

When 58 minute gastric cancers less than 5 mm in diameter from 55 patients were classified into 22 of the single group (minute gastric cancer alone) and 36 of the multiple group (associated with other large gastric cancers), the preoperative correct diagnostic rate by x-ray was 22.7% and 11.1% in the single group and in the multiple group, respectively, with a total rate of 15.5%. The diagnostic rate by endoscopy, aided by endoscopic biopsy, was 95.5%, 13.9%, and 44.8%, respectively. Therefore, it appears that endoscopy and endoscopic biopsy are most efficient diagnostic tools for the detection of such minute gastric cancers. Since the detection of the depressed type (IIc) of minute gastric cancers is considered most significant because of their frequent submucosal invasion, their characteristic endoscopic findings are emphasized: (1) irregular and polygonal shape, (2) distinct depression, (3) clear demarcation, (4) nodular margins, and (5) moth-eaten appearance and abrupt thinning of the mucosal folds.

Minute gastric cancers less than 5 mm in diameter.

Minute gastric cancers with maximum dimensions of less than 5 mm were studied clinicopathologically. There were 49 intramucosal cancers among 46 patients and nine submucosal cancers among nine patients. No lymph node metastasis was found. Macroscopically, eight (13.8%) were evaluated, 12 (20.7%) were flat, and 38 (65.5%) were depressed. Most submucosal cancers were of the depressed type (8/9, 88.9%). Classification of cancers according to association with other large cancers into single group (22 cases) and multiple group (33 cases) revealed that (1) the majority of the minute gastric cancers (20/22, 90.9%) in the single group were the depressed type and (2) submucosal cancers in the single group were 8/22, accounting for 36.4%, a much higher incidence as compared with 1/36 (2.9%) in the multiple group. These facts indicate that gastric cancers should be detected when they are about 5 mm in maximum dimension and before they invade beyond the submucosal layer, especially in single and depressed type.