Investigating centre effects in a multi-centre clinical trial of superficial bladder cancer.

This paper examines the amount of variation among centres and estimates the overall effect of therapy in a multi-centre cancer clinical trial with censored failure time data. To investigate the centre effects, the variation in the treatment effect must be taken into consideration in addition to the variation in the baseline risk. We treat centre effects as random ones and extend the penalized partial likelihood approach proposed by McGilchrist to estimate the treatment-by-centre interaction as well as the baseline risk. This method is applied to data from a superficial bladder cancer clinical trial investigating the efficacy of intravesical chemotherapy after transurethral resection. In this trial, although there exists some degree of centre variation, especially in the baseline risk, the treatment is effective in preventing recurrence among the participating centres. This result indicates that the treatment effect is generalizable to the target population.     

The effect of tulobuterol tape on histamine-induced bronchoconstriction in conscious guinea pigs: long duration of action

The objective of the present study was to determine the action duration of tulobuterol tape within a 24-hr period in conscious guinea pigs. The bronchoconstriction induced by histamine-inhalation was significantly inhibited by tulobuterol tape in comparison with its placebo tape 8 and 12 hr after binding, and the inhibitory rate was 50+/-11% and 35+/-13%, respectively. Twenty-four hours after binding, the inhibitory effect of tulobuterol tape gradually diminished, but the inhibitory rate was maintained at 30+/-14%. These results suggest that tulobuterol tape has a long lasting bronchodilatory action.     

The interactions of bromocriptine and lergotrile with dopamine and α-adrenergic receptors

Summary Bromocriptine and lergotrile, which are clinically used as antiparkinsonian (AP) agents, compete for the binding of H³-dopamine, H³-apomorphine, and H³-haloperidol to striatal membrane sites. Lergotrile has a higher affinity for the H³-dopamine binding to bovine striatal membranes than bromocriptine. Lergotrile and bromocriptine are almost equipotent in competing for the binding of H³-apomorphine to rat striatal membranes, but bromocriptine is more potent in competing for the binding of H³-haloperidol than lergotrile. These results indicate that lergotrile and bromocriptine are mixed putative agonist-antagonist with respect to the postsynaptic dopamine receptors. Lergotrile and bromcriptine at higher concentrations inhibit synaptosomal tyrosine hydroxylase activity, and reverse the apomorphine elicited enzyme inhibition. Thus, these ergot alkaloids behave as mixed agonist-antagonist also with respect to the presynaptic dopamine receptors. Bromocriptine and lergotrile, as well as other tested DH-ergot alkaloids and neuroleptics, compete for the binding of the-antagonist H³-WB-4101 to rat cerebral cortical membranes. The displacing potencies of the tested DH-ergot alkaloids and of the neuroleptics indicate that they have a high affinity for the-adrenoreceptors in the CNS.     

A comparative view of Rickettsia tsutsugamushi and the other groups of rickettsiae

Recent researches on the rickettsial group microorganisms are summarized in their comparative aspects of morphology, cultivation and multiplication, susceptibility to chemotherapeutics, chemical structure of envelopes, nucleic acid, protein constitution, and gene structures. From this overview, Rickettsia tsutsugamushi seems to have different properties from the others and should be reclassified into a new genus, and a new species name as Orientia tsutsugamushi is proposed.Presented at the 4th International Symposium on Rickettsiae and Rickettsial Diseases, Pietany, C.S.F.R., 1–6 October, 1990.     

The effects of sphincteroplasty on manometric profile of common bile duct and the duodenum (author's transl)

A simultaneous manometric monitoring of the common bile duct (CBD) and the duodenum were performed 2 weeks after choledocholithotomy on 15 patients whose common bile ducts were explored without sphincteroplasty and 30 patients with sphincteroplasty. These manometric studies were carried out by open-tip catheters intubated into the CBD and duodenum through the T-tube at the operation. In patients without sphincteroplasty, no effects of the duodenal pressure on a CBD pressure profile were recognized, while a synchronized pressure profile of the CBD and the duodenum was obtained in patients with sphincteroplasty. By stimulation with morphine (Morphine sulfate; 0.17 mg/Kg iv bolus), waxing and waning of the pressured in the CBD without sphincteroplasty were observed with 20 cmH2O in maximum at about 13 minutes after injection. However, in the CBD with sphincteroplasty, scale-over increase of the pressure curve was seen immediately after duodenal contraction caused by morphine stimulation. A direct infusion of 5 ml of 0.1 N hydrochloride to the duodenum causes hyperperistalsis of the duodenum, which made a synchronized pressure profile in the CBD with sphincteroplasty but made no remarkable change in a pressure profile of the CBD without sphincteroplasty. These findings conclude that the sphincter of Oddi plays an important role as a "pressure barrier" between the CBD and the duodenum, and that with the destruction of this sphincter by sphincteroplasty, a pressure profile of the CBD becomes close to that of the duodenum. This simultaneous manometric study of the CBD and the duodenum might be one of most valuable methods for evaluation of completeness of the sphincteroplasty.     

Factors influencing the outcome of Chiari pelvic osteotomy: a long-term follow-up

We have reviewed 103 of 126 Chiari osteotomies carried out in our department between 1956 and 1987. The cases were graded radiologically, using the Japanese Orthopaedic Association (JOA) system, into a pre/early osteoarthritis (OA) group and an advanced OA group. In the pre/early group there were 86 hips. The mean follow-up was for 17.1 years (4 to 37). Preoperatively, 51 hips had an average JOA clinical score of 78.6+/-8.4 points and the final mean JOA clinical score was 89.4+/-12.5 points. Advanced degenerative change developed in 33.7% and one hip required a total replacement arthroplasty (TRA). Chiari osteotomy alone, without accompanying intertrochanteric osteotomy, was performed on 62 hips. For these the median survival time was 26.0+/-2.5 years, using as the endpoint progression to advanced OA. Differences in survivorship curves related significantly to the severity of the preoperative OA, the shape of the femoral head and the level of osteotomy. In the advanced OA group, we followed up 17 hips for a mean of 16.2 years (1 to 27). Before operation, the mean JOA clinical score in 13 hips was 63.2+/-7.9 points and the final score 84.0+/-12.0 points. TRA was eventually carried out on four hips. Our findings suggest that the Chiari osteotomy remains radiologically effective for about 25 years. The procedure is best suited to subluxated hips with round or flat femoral heads and early or no degenerative change. Intra-articular osteotomy can lead to osteonecrosis, and should be avoided. In hips with advanced OA, the Chiari procedure creates an acetabulum which facilitates later TRA, and may delay the need for this procedure in younger patients.     

In vitro metabolism of fenthion and fenthion sulfoxide by liver preparations of sea bream, goldfish, and rats.

The in vitro metabolism of fenthion and its sulfoxide (fenthion sulfoxide) in sea bream (Pagrus major) and goldfish (Carassius auratus) was investigated and compared with that in rats. Fenthion was oxidized to fenthion sulfoxide and the oxon derivative, but not to its sulfone, in the presence of NADPH by liver microsomes of sea bream, goldfish, and rats. These liver microsomal activities of the fish were lower than those of rats but were of the same order of magnitude. The NADPH-linked oxon- and sulfoxide-forming activities of liver microsomes of the fish and rats were inhibited by SKF 525-A, metyrapone, alpha-naphthoflavone, and carbon monoxide. The oxidizing activity to fenthion sulfoxide was also inhibited by alpha-naphthylthiourea. Several cytochrome P450 isoforms and flavin-containing monooxygenase 1 exhibited these oxidase activities. Fenthion sulfoxide was reduced to fenthion with liver cytosol of the fish and rats upon addition of 2-hydroxypyrimidine, N(1)-methylnicotinamide, or butyraldehyde, each of which is an electron donor of aldehyde oxidase, under anaerobic conditions. The activity was inhibited by menadione, beta-estradiol, and chlorpromazine, which are inhibitors of aldehyde oxidase. The activities in the fish livers were similar to those of rat liver. Aldehyde oxidase purified from the livers of sea bream and rats exhibited the reducing activity. Thus, fenthion and fenthion sulfoxide are interconvertible in fish and rats through the activities of cytochrome P450, flavin-containing monooxygenase, and aldehyde oxidase.     

Double-blind randomised trial comparing the non-steroidal aromatase inhibitors letrozole and fadrozole in postmenopausal women with advanced breast cancer.

BACKGROUND: To compare the efficacy, safety and tolerability of letrozole, an advanced non-steroidal aromatase inhibitor, and fadrozole hydrochloride, an older-generation drug in this class, we conducted a randomised double-blind trial in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: One hundred and fifty-seven postmenopausal women with advanced breast cancer were enrolled and randomly assigned to receive letrozole or fadrozole in a multicentre, randomised double-blind trial in Japan. One hundred and fifty-four eligible patients were treated with either letrozole 1.0 mg once daily (n = 77) or fadrozole 1.0 mg twice daily (n = 77), for a minimum of 8 weeks. RESULTS: Letrozole showed a significantly higher overall objective response rate [complete response (CR) + partial response (PR)] than fadrozole (31.2% and 13.0%, respectively; P = 0.011, Fisher's exact test). Clinical benefits defined as CR, PR and stable disease (no change in status for more than 24 weeks) were also higher in patients treated with letrozole (50.6%) than fadrozole (35.1%). Letrozole was significantly superior to fadrozole in terms of the dominant lesion in soft tissue, bone and viscera (P = 0.011, stratified Mantel-Haenszel test). Median time to progression was 211 days in the letrozole group and 113 days in the fadrozole group with no significant difference (P = 0.175, log-rank test). Letrozole markedly reduced the estradiol, estrone and estrone sulfate levels in peripheral blood within 4 weeks. The suppressive effect of fadrozole on these hormone levels was insufficient. Adverse drug reactions were observed in 35.9% of the patients treated with letrozole and in 39.5% of those treated with fadrozole with no significant difference between the two groups (P = 0.74, Fisher's exact test). Most of the adverse drug reactions were rated as grade 1 or 2. CONCLUSIONS: The results show letrozole at a dose of 1.0 mg once daily to be more effective in treating postmenopausal women with advanced breast cancer than fadrozole at 1.0 mg twice daily, with similar safety and tolerability profiles.     

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.     

Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan

BACKGROUND: Whether the type of diabetes, race, and year and age of diagnosis affect the incidence of diabetic vascular complications is unknown. That both type 1 and type 2 diabetes occur in the young Japanese population prompted us to investigate whether the type of diabetes and the year of diagnosis are related to the incidence of nephropathy. METHODS: Of the 17,256 diabetic patients who visited the outpatient clinic at our diabetes center between 1965 and 1990, 1578 (9.1%) had early-onset diabetes (diagnosed before the age of 30); of these, 620 (39%) had type 1, and 958 (61%) had type 2 diabetes. The incidence of nephropathy was analyzed in the patients according to postpubertal duration and year of diagnosis. RESULTS: The cumulative incidence of nephropathy after 30 years of postpubertal diabetes was significantly higher (P < 0.0001) in type 2 diabetic patients (44.4%, 95% CI, 37.0 to 51.8%) than in type 1 diabetic patients (20.2%, 95% CI, 14.9 to 25.8%). The incidence of nephropathy among type 1 diabetic patients has declined during the past two decades, whereas it has not among type 2 diabetic patients. The rate ratio for type 2 diabetic patients diagnosed between 1980 and 1984 relative to type 1 diabetic patients diagnosed in the same period was 2.74 (95% CI, 1. 17 to 6.41). CONCLUSIONS: The incidence of nephropathy has declined in Japanese patients with type 1 but not in those with type 2 diabetes. In young Japanese patients, because of the higher incidence of nephropathy in type 2 diabetes and the higher prevalence of type 2 than type 1 diabetes, type 2 diabetes is likely the major cause of diabetic nephropathy.