Why are cadaveric renal transplants so hard to find in Japan? An analysis of economic and attitudinal aspects.

In view of the fact that in Japan treatment of end-stage renal disease depends disproportionately heavily on hemodialysis and almost negligible on transplants from cadaveric donors (hemodialysis 44.4/100,000; renal transplants 0.31/100,000 per year; cadaveric renal transplants 0.11/100,000 per year (1983 data)), we analysed the cost-effectiveness of hemodialysis and renal transplantation, predicted economic gains under expected changes in variables and described attitudes of the Japanese hampering cadaveric renal transplantation. Adjusted life expectancy of transplant recipients (live and cadaveric combined) under the current technical conditions is longer than that of those on hemodialysis (18.3 vs. 14.7 years) and the cost per year for maintaining the transplant is approximately one third of hemodialysis ($12,000 vs $32,000). If the proportion of cadaveric transplant recipients would increase to the levels of the USA (hemodialysis 30.8/100,000; transplants 2.6/100,000 per year; cadaveric transplants 1.9/100,000 per year (1983 data)) along with improvement in graft survival rate, the life expectancy for transplant recipients in Japan could increase by 2 years, thus reducing the annual cost even further. The current number of patients starting hemodialysis (11,500 cases per year) coupled with their life expectancy predicts the number of patients on hemodialysis to reach equilibrium at around 174,000 in a decade (Japanese population 110 million). Based on current price, their annual cost will be about 5.3 billion dollars. Medical expenditure of this magnitude for such a small fraction of people is expected to become an increasingly strong economic incentive for cadaveric renal transplantation. A review of studies on Japanese attitudes toward cadaveric renal transplantation in both urban and rural areas shows that approximately 60% are in favor of donating their kidney after death, though with the majority of cases the donation is contingent upon agreement of their family. It was suggested that the paucity of cadaveric kidney supply stems mainly from the custom of the Japanese to make decisions by consensus. It was also reported that more than 80% of physicians supported the donation of cadaveric grafts while this rate fell to 40% in case of brain death. As the first heart transplantation was carried out in 1968 under both medically and ethically dubious circumstances, distrust toward the diagnosis of brain death appears to be still quite strong. (Not a single heart transplantation has been attempted in Japan in the past 18 years).(ABSTRACT TRUNCATED AT 400 WORDS)

[The risk of colorectal adenomatous polyp in relation to serum total cholesterol levels in Japanese men classified by age group].

In order to investigate the relationship between the risk of colorectal cancer and serum total cholesterol (TC) levels, we studied the relationship between the risk of colorectal adenomatous polyp and high TC levels in Japanese men aged from 40 to 59 at a manufacturing company. We first diagnosed 283 subjects as having adenomatous polyp (AD) or normal (C), identified by means of an immunological fecal occult blood detection test and total colonofiberscopic examination (TCF), and then selected 94 subjects after excluding the patients with diseases possibly influencing TC. We classified the subjects into two age groups (40-49 and 50-59) and conducted a statistical analysis of AD and C groups by means of a two tailed t-test. The mean values for TC (DTC), which had been obtained within 3 months before TCF, were significantly different (p < 0.001 95% CI 15.79-48.49) for those in their 40s, but were not different for those in their 50s. In order to check the stability of the data, we analyzed the mean values for DTC and BTC, which had been obtained within 15 months. The results showed the same trend for those in their 40s (p = 0.001 95% CI 10.76-40.87). The mean DTC and BTC values were again not significantly different for those in their 50s. We further divided the subjects into the lower (-181 mg/dl) and higher (209 mg/dl-) DTC values and conducted further statistical analysis with Fisher's exact test. The results were significant in the 40-49 age group (p = 0.004), in the odds ratio (13.75 95% CI 2.32-81.49), but showed no significant difference in the 50-59 age group. The mean LDL-cholesterol values within 3 months before TCF were significantly different in the 40-49 age group (p < 0.001 95% CI 15.22-47.70) and were not different in the 50-59 age group. There was no statistical difference in the mean values for HDL-cholesterol, triglyceride and body mass index in either age group. From these results, it can be concluded that the risk of colorectal adenomatous polyp was associated with a higher serum total cholesterol level in the 40s, and seemed to indicate a close relationship with the risk of colorectal cancer.

Mechanism of the anti-obesity effects induced by a novel melanin-concentrating hormone 1-receptor antagonist in mice.

BACKGROUND AND PURPOSE: Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists. EXPERIMENTAL APPROACH: To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions. KEY RESULTS: Treatment with the MCH1 receptor antagonist at 30 mg.kg(-1) for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis. CONCLUSIONS AND IMPLICATIONS: Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.

Evaluation of three cervical cancer detection programs in Japan with special reference to cost-benefit analysis.

Three screening programs for early cervical cancer currently in use in Japan were evaluated according to the following criteria: (1) economic effectiveness; (2) screening efficiency; and (3) access to medical care. The mobile program has the highest benefit-cost ratio (BCR, 1.20) and is hence most cost-effective; its detection rate, rescreening rate, and early cancer detection rate (proportion of Stage-O patients to all patients with cancer) are moderately high (0.09%, 2.07%, 55%, respectively). It is obviously suited to rural areas, especially where residents have a positive attitude toward local health services. The detection center program is less cost-effective than the mobile program (BCR, 0.83) but diagnostically the most effective with highest detection, rescreening, and early cancer detection rate (0.15%, 5.08%, 61%, respectively). It is suitable to large cities (population over 1 million) with efficient public transportation. The private physician program is economically and in terms of screening efficiency least effective of the three; its BCR being 0.40 and detection, rescreening, and early cancer detection rate being the lowest (0.08%, 0.29%, 33%, respectively). However, the private physician program is increasingly employed, presumably because of easy access to medical care, better rapport between the patient and physician, and, in addition, successful lobbying by private physicians.

Absorption of a novel prodrug of L-dopa, L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355). In vitro and in situ studies.

Absorption mechanism and absorption site of a prodrug of L-DOPA, L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355, 1) was investigated using rats. Prodrug 1 (0.5 mM) was taken up by intestinal tissue segments time-dependently in vitro at pH 6.0. However, the rate of uptake was less than that of L-dopa. Inhibitors of the amino acid active transport system (L-Phe, dinitrophenol, ouabain) had no effect on the uptake of prodrug 1. In the intestinal tissue segments, prodrug 1 was extensively hydrolyzed by diisopropylfluorophosphate-sensitive esterase(s). To characterize the absorption site, gastrointestinal tracts were ligated to make acute loops in situ and prodrug 1 or L-dopa was injected into the loops. L-dopa disappeared rapidly from the lumen of the jejunum. In contrast, prodrug 1 disappeared rapidly from the ileum rather than the duodenum or jejunum. From these results, it was suggested that prodrug 1 was slowly absorbed primarily from the lower small intestine.

Quantification of L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355) by high-performance liquid chromatography using o-phthalaldehyde/N-acetyl-L-cysteine derivatization.

A new and rapid high-performance liquid chromatographic assay has been developed for the determination of L-3-(3-hydroxy-4-pivaloyloxyphenyl)alanine (NB-355,I), a novel prodrug of L-DOPA. The method involves precolumn derivatization of the drug in biological samples with o-phthalaldehyde (OPA) and N-acetyl-L-cysteine (NAC) in a triethanolamine buffer (pH 8.0), giving a fluorescent compound that is stable for 2 h at 4 degrees C. Use of an internal standard improved the assay in accuracy and reliability. A programmable injector allowed automatic derivatization of large numbers of samples. Chromatographic separation was performed on a reversed-phase column (Capcell Pak C18) in which the silica gel was coated with silicone polymer. The peaks corresponding to compound I and the internal standard were eluted within 16 min with a mobile phase of acetonitrile-phosphate buffer (pH 7.1). The reliable limit of quantification was 0.5 pmol per injection (0.05 micrograms equivalents of L-DOPA per ml in plasma). The method was successfully applied for the measurements of dog plasma concentrations after oral dosing of compound I.

Diagnostic significance of serum angiotensin-converting enzyme activity in biochemical tests with special reference of chronic liver diseases.

To assess the degree of the differential ability of serum angiotensin-converting enzyme (ACE) activity as compared with 13 conventional biochemical tests, we studied 76 healthy subjects and 107 patients with chronic liver diseases. It was found that the mean values of serum ACE activity were significantly different between the healthy group and groups with liver disease. According to discriminant function analysis, the diagnostic accuracy reached 82.2% in 14 tests. In order to analyze the extent of contribution of each test to the entire diagnostic accuracy, we made an indicator of the relative decrease rate expressed as a percentage, which is 100-100 x (13-test diagnostic accuracy less one test/14-test diagnostic accuracy). The relative decrease rate of serum ACE activity was 11.4%, the largest in value. In conclusion, serum ACE activity may be one of the best discriminators to characterize chronic liver disease.

Simultaneous determination of a new anticancer agent (NB-506) and its active metabolite in human plasma and urine by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic method with ultraviolet detection has been developed to quantify NB-506 and its active metabolite in human plasma and urine. This method is based on solid-phase extraction, thereby allowing the simultaneous measurement of the drug and metabolite with the limit of quantification of 0.01 microgram/ml in plasma and 0.1 microgram/ml in urine. Standard curves for the compounds were linear in the concentration ranges investigated. The range for the drug in plasma was 0.01-2.5 micrograms/ml, and for the metabolite 0.01-1 microgram/ml. In urine, the range for both compounds was 0.1-10 micrograms/ml. The method was validated and applied to the assay of plasma and urinary samples from phase I studies.

In vitro metabolism of a new anticancer agent, 6-N-formylamino-12, 13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo+ ++[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (NB-506), in mice, rats, dogs, and humans.

The metabolism of 6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3, 4-c]carbazole-5,7(6H)-dione (NB-506), a potent inhibitor of DNA topoisomerase I, was characterized in mice, rats, dogs, and humans in vitro. NB-506 was deformylated to ED-501 in mouse and rat plasma with enzyme activity of 140 and 116 pmol/min/mg protein, respectively. The enzyme activity in dog and human plasma was found to be less than 1.7 pmol/min/mg protein. In liver S9 and small intestine S9 samples from mice and rats, activity of the enzyme was very low. Also, there was no activity in the liver or small intestine of dogs and humans. The enzyme involved in the conversion of NB-506 to ED-501 in rat plasma is a rodent-specific serine enzyme with a molecular mass of 138KDa. The Vmax and Km values were 6.3 nmol/min/ml plasma and 54 microM at an optimum pH of 7.4, respectively. Although NB-506 was converted to ED-551 in dog and human plasma in vitro, no conversion was observed in mouse and rat plasma. In human plasma this conversion was not affected by heat treatment (100 degreesC for 1 min), but was inhibited completely by 50 mM EDTA, indicating that the reaction is a chemical reaction catalyzed by metal ions. Although NB-506 was not metabolized by cytochrome P-450 isozymes in liver, this drug was glucuronized in mice, rats, and humans, but not in dogs. These results suggest that a species difference in the metabolism of NB-506 occurred in the liver as well as in plasma. There appeared to be species differences in the metabolism of NB-506 in vitro, correlating well with the species-dependent pharmacokinetics of this drug in vivo.

In vivo metabolism of a new anticancer agent, 6-N-formylamino-12, 13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (NB-506) in rats and dogs: pharmacokinetics, isolation, identification, and quantification of metabolites.

6-N-formylamino-12,13-dihydro-1, 11-dihydroxy-13-(beta-D-glucopyranosil)5H-indolo [2,3-a]pyrrolo [3, 4-c]carbazole-5,7(6H)-dione (NB-506), a potent inhibitor of DNA topoisomerase I, is currently under development for the treatment of cancer. We investigated the pharmacokinetics of NB-506 after i.v. administration in rats and dogs. The plasma concentration of NB-506 decreased biexponentially in rats and dogs with terminal half-lives of approximately 2 h. The area under the curve increased nonlinearly with increasing dose in rats. In contrast, there was a linear relationship between the area under the curve and the dose in dogs. In rats, the plasma clearance decreased with increasing dose up to 187.5 mg/m2 but remained virtually unchanged at the highest dose. The Vdss of NB-506 in rats and dogs was much greater than the plasma volume, indicating that NB-506 is highly distributed to tissue from plasma in these animals. There were marked species differences in the plasma concentrations of ED-501 after i.v. administration of NB-506 to rats and dogs. To better understand the mechanisms of nonlinear pharmacokinetics in rats, in vivo metabolites were determined. After i.v. administration of [14C]NB-506 to rats, two unknown metabolites (RBM-1 and RBM-2), deformyl metabolite (ED-501), and unchanged drug (NB-506) were identified. Mass and NMR spectra analysis revealed that RBM-1 is an 11-O-glucuronide of NB-506 (ED-594) and that RBM-2 is an 11-O-glucuronide of ED-501 (ED-595). In this study, the pharmacokinetics of NB-506 was demonstrated to be nonlinear in rats, probably because of saturation of the enzyme systems catalyzing the deformylation and glucuronidation of NB-506 in rats.

Pharmacokinetic and pharmacodynamic analysis of a novel leukotriene biosynthesis inhibitor, MK-0591, in healthy volunteers.

1. The pharmacokinetic and pharmacodynamic properties of a novel 2-indolealkanoic acid derivative (MK-0591), a potent inhibitor of leukotriene biosynthesis, were investigated in healthy male Japanese volunteers. Single oral doses of 50, 125, 250 and 500 mg and multiple oral doses of 125 mg twice daily for 9.5 days and 250 mg once daily for 10 days were administered. 2. After the single-dose administration following overnight fasting, Cmax and AUC of MK-0591 in plasma increased in a dose-dependent manner, while elimination half-life remained constant (11.2-13.2 h) irrespective of dose. Food intake decreased Cmax and AUC by 71% and 68%, respectively, at a dose of 250 mg. With respect to multiple-dose administration before meals, there were no significant differences in the pharmacokinetic parameters between the first and last days, indicating a lack of significant accumulation of MK-0591 in plasma. Urinary recovery as the unchanged form was negligible throughout the study. 3. Ionophore-stimulated production of leukotriene B4 (LTB4) in blood ex vivo was inhibited significantly from 1 h until 12 to 48 h after single-dose administration as compared with predose value. In parallel, the urinary excretion of endogenous leukotriene E4 (LTE4) was significantly decreased from 4 to 8 h until 48 to 72 h after drug administration. Reduction of ionophore-stimulated LTB4 biosynthesis and urinary excretion of LTE4 following single administration of MK-0591 was statistically significant as compared with placebo group, and the duration of inhibition of LTB4 biosynthesis was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)