Antihypertensive effect of bopindolol on stroke-prone spontaneously hypertensive rats (SHRSP)

The antihypertensive effect of bopindolol, a long-acting beta-adrenoceptor blocking agent, was investigated in stroke-prone spontaneously hypertensive rats (SHRSP). One group received tap water during the period of 8 to 32 weeks of age. The average dose of bopindolol administered was calculated from water intake to be approximately 1.4 mg/kg/day. The lowering effect in blood pressure of bopindolol was apparent at the age of 14 weeks, and this continued up to the end of the experiment. Bopindolol significantly reduced the heart rate. Plasma levels of urea nitrogen (BUN), triglyceride, and phospholipid of SHRSP treated with bopindolol were lower than those of the control SHRSP. One of the 8 control SHRSP died, and no rats treated with bopindolol died during the experiment. The histopathological study revealed that three of the control SHRSP had cerebral apoplexy, whereas there was no evidence of cerebral apoplexy in the treated SHRSP. Chronic treatment of bopindolol clearly alleviated myocardial fibrosis and hypertrophic changes in the left ventricular wall of the heart. Decreases in the incidence of proliferative arteritis and malignant nephrosclerosis in the kidney and necrotizing arteritis of the mesenteric arteries were observed in SHRSP treated with bopindolol. The data presented indicate that bopindolol is a powerful antihypertensive agent.     

Accumulation and declination of chlordane congeners in mice

A metabolic experiment involving technical chlordane in mice was carried out in vivo by single and repeated oral administration. In the single oral dose group, residues of trans- and cis-chlordane in mouse whole body showed a maximum content at 5 hours after administration; thereafter, the body content decreased rapidly. For other congeners, the residues of trans- and cis-nonachlor reached a maximum at 10 hours, the residual levels forming a plateau. The intermediate metabolite oxychlordane was detected 1 hour after the administration of technical chlordane, the content in the mouse body increasing with time. In the repeated oral dose group, although technical chlordane was administered repeatedly, increases in trans- and cis-chlordane content were not observed for 29 days. On the other hand, the nonachlor and oxychlordane content increased gradually throughout the observation period. These findings suggest that the accumulation of nonachlors and oxychlordane in the animal body must be high and sufficient attention must be paid to their toxic effect.     

Sister chromatid exchange induction by benzo(a)pryene in cultured peripheral blood lymphocytes of lung cancer patients and healthy individuals with or without familial history of neoplasms

The inducibility of sister chromatid exchanges (SCEs) by benzo(a)pyrene (BP) was studied in cultured peripheral blood lymphocytes of 15 untreated lung cancer patients and 25 healthy persons including 11 high- and 14 low-cancer-risk individuals tentatively classified by the familial history of lung cancer and other neoplasms. The baseline SCE frequency in cultured lymphocytes was significantly high in lung cancer patients, as compared with all healthy persons or low-cancer-risk individuals. Following exposure to BP, the lymphocytes of lung-cancer patients and high-cancer-risk individuals exhibited significantly greater SCE yields than those of persons at low risk, although no significant difference was observed in the lymphocyte SCE yields when the levels of lung cancer patients were compared with those of all healthy persons. A comparison of the net SCE increase (delta SCE) in BP-exposed lymphocytes among the study groups, however, revealed a significant difference in delta SCE values only between high- and low-cancer-risk individuals. The present findings on both the observed SCE yields and delta SCE values suggest that lymphocytes of high-risk individuals may be more susceptible to BP-induced DNA damage than those of persons at low risk, and that such a chromosomal hypersensitivity to genotoxins may be associated with a high risk of neoplasms.     

MECHANISM OF FIBROPLASIA IN CHRONIC ACTIVE HEPATITIS AN IMMUNOHISTOCHEMICAL STUDY OF VARIOUS COLLAGEN TYPES, FIBRONECTIN AND LAMININ IN HUMAN LIVER

The cytoplasm of human bile ductule epithelia was found to be Type V collagen positive, demonstrating that the epithelia were able to generate this type of collagen. The ductules proliferated greatly with Type V collagen positive cytoplasm in piece-meal necrosis of chronic active hepatitis (CAH). The capillary-like bile ductules inside human hepatic lobules were identified. Our findings might explain the mechanism of fibroplasia in CAH.     

Phase II trials in cancer: present status and analysis methods

Sixty-seven recent phase II studies are reviewed with respect to their design, conduct and analysis. The review shows that in the majority of studies: (i) eligibility criteria are not clearly defined; (ii) no statistical method is applied in interpreting the results; (iii) not all the patients are considered evaluable. Negative conclusions are drawn from two-thirds of the studies. Very few studies give any statistical rationales for their design, and only nine studies are randomized studies. A review of all 17 phase II studies in breast cancer, reported in Cancer Treatment Reports between 1981 and 1983, shows that: (i) all the studies with 20 or more patients are negative; (ii) all the inconclusive studies are of small size; (iii) the distribution of patients according to prior chemotherapy is not comparable or the terminology used for prior therapy is not uniform. Review of all 19 studies in colorectal cancer, reported in Cancer Treatment Reports between 1981 and 1983, reveals, in addition to the above problems, that the 20% response rate to 5-FU in previously untreated patients is not supported. Proposals are made to improve the design, conduct and analysis of phase II studies. Methods for analysing phase II study data are reviewed and two-stage designs appropriate for phase II trials in cancer are discussed.     

Nucleolus-associated J chains in myeloma cells: clinical significance

Bone marrow aspirates from 20 patients with multiple myeloma (MM), 4 with smoldering multiple myeloma (S-MM), 1 with idiopathic Bence Jones proteinuria (I-BJP), and 6 with primary macroglobulinemia (PMG) were examined for nucleolus-associated J chain. The incidence of nucleolar J chain-positive (J+) cells among nucleolated cells producing M-component was measured. This incidence (94.0-100%) in terminal MM was significantly higher than that (0-58.0%) in non-terminal MM. Judging from a low incidence in the remission phase, chemotherapy might cause a selective elimination of less differentiated myeloma cells with J+ nucleoli and might have some effect on J chain synthesis. The incidence of nucleolar J+ cells was very low in S-MM. The IgM cells in PMG, where J chain is present in a disulfide-linked form, had no or few J+ nucleoli. No correlation between the incidence of nucleolar J+ cells among nucleolated plasma cells and the percentage of nucleolated cells or that of J+ cells was found. Large J+ nucleoli seemed to be another morphological feature indicating anaplastic myeloma cells. A high incidence of nucleolar J+ cells may be one of the indicators for progressive disease.     

Steady-state fluctuation and variability of betaxolol and atenolol plasma levels

Twenty-four nonsmoking male volunteers took 50 mg atenolol or 10 mg betaxolol orally once a day for 9 days in a two-period, four-sequence, randomized, crossover study. Plasma concentrations reached steady state after day 5. Percent fluctuation in plasma concentration defined as (Cmax-Cmin)/Cavg (% fluctuation 1) was 97% on day 9 for betaxolol and 343% for atenolol; thus atenolol fluctuation was more than threefold that of betaxolol. A 10-fold difference in plasma level fluctuation was observed when fluctuation was defined as (Cmax-Cmin)/Cmin (% fluctuation 2). The intersubject variances for % fluctuation 1 and % fluctuation 2 were 4.1 and 85.5 times greater for atenolol than for betaxolol; these differences were marginally statistically significant for % fluctuation 1 and significant for % fluctuation 2. The intrasubject variabilities for area under the curve and plasma level fluctuations were statistically greater for atenolol than for betaxolol. Atenolol intrasubject variances were 25 and 271 times greater than for betaxolol for % fluctuation 1 and % fluctuation 2, respectively. Thus, betaxolol exhibited less fluctuation in plasma levels with substantially less intersubject and intrasubject variability. These factors would be expected to provide a more consistent therapeutic response and more dependable dosage adjustment.