Application of Akaike information criterion to evaluate warfarin dosing algorithm.

INTRODUCTION: Several factors responsible for inter-individual differences in response to warfarin have been confirmed; however, unidentified factors appear to remain. The purpose of this study was to examine a simple method to evaluate whether optional variables are appropriate as factors to improve dosing algorithms. MATERIALS AND METHODS: All patients were Japanese. Genotyping of selected genes was conducted, and other information was obtained from medical record. Dosing algorithms were constructed by multivariate linear regression analyses and were evaluated by the Akaike Information Criterion (AIC). RESULTS AND CONCLUSIONS: Multivariate analysis showed that white blood-cell count (WBC), concomitant use of allopurinol, and CYP4F2 genotype are apparently involved in warfarin dose variation, in addition to well-known factors, such as age and VKORC1 genotype. We evaluated the adequacy of these variables as factors to improve the dosing algorithm using the AIC. Addition of WBC, allopurinol administration and CYP4F2 genotype to the basal algorithm resulted in decreased AIC, suggesting that these factor candidates may contribute to improving the prediction of warfarin maintenance dose. This study is the first to evaluate the warfarin dosing algorithm by AIC. To further improve the dosing algorithm, AIC may be a simple and useful tool to evaluate both the model itself and factors to be incorporated into the algorithm.

Effect of diabetes on aortic nitric oxide synthesis in spontaneously hypertensive rats; does captopril modulate this effect?

Nitric oxide (NO) is a potent regulator in the cardiovascular system; it is generated by the nitric oxide synthase (NOS) family of proteins. NO produced in endothelial cells plays a crucial role in vascular functions. The aim of this study was to clarify the effect of diabetes on aortic NO synthesis in a model of genetic hypertension and determine whether captopril modulates this effect. Diabetes was induced in ten weeks old spontaneously hypertensive rats (SHR) by streptozotocin injection. The rats were allocated into 3 groups: control group 1, non-diabetic SHR; group 2, diabetic SHR; group 3, diabetic SHR group receiving captopril at 80 mg/kg in drinking water for 4 weeks. Mean blood pressure (MBP) was measured once a week by tail-cuff method. Aortic NO metabolities (nitrite/nitrate) and endothelial NOS (NOS-3) were assayed by Griess reaction and by immunoblotting and immunohistochemistry, respectively. There was a significant decrease in nitrite/nitrate (NOx) in aortas of diabetic SHR compared with controls. The decrease of aortic NOx in diabetic SHR was accompanied by a decrease in NOS-3 expression. Captopril treatment reduced MBP without affecting either NOx level or NOS-3 expression in aortas of diabetic SHR. We conclude that STZ-induced diabetes decreased NO in aortas of SHR that may reflect endothelial cell dysfunction; captopril administration decreased MBP without affecting NO level in aortas of diabetic SHR which suggest that the blood pressure-lowering effects of captopril were independent of NO.

Prediction of iopromide reduction rates during haemodialysis using an in vitro dialysis system.

BACKGROUND: In clinical studies, it has been difficult to evaluate the influence of haemodialysis (HD) parameters on HD clearance (CL(HD)) and reduction rate (RR) of non-ionic contrast medium during HD sessions. We therefore predicted clinical values of CL(HD) and RR of iopromide, a non-ionic contrast medium, from findings obtained from in vitro experiments, and confirmed that these predictive values were comparable with the actual values in clinical cases. METHODS: We developed a correlation equation for predicting CL(HD) on the basis of in vitro HD experiments by varying blood flow rates between 100 and 200 ml/min with a cuprammonium rayon dialyser (AM-SD-10H). Total body clearance of iopromide (CL(PT)) was estimated by the Cockroft-Gault equation. The volume of distribution (V(d)) was obtained from the reported value. By using the HD and three pharmacokinetic parameters (CL(HD), CL(PT) and V(d)), we predicted CL(HD) and RR for seven patients undergoing HD after the administration of iopromide. RESULTS: In the in vitro study, the mean values (+/-SD) of iopromide clearance at blood flow rates of 100, 150 and 200 ml/min were 45.35 (2.54), 53.88 (6.46) and 57.61 (4.72) ml/min, respectively. There were highly significant correlations between clearance and blood flow rate (r = 0.975). Although the predicted CL(HD) showed a tendency towards underestimation, a good correlation was found. Predicted RR values were similar to observed values except for one case. CONCLUSION: The in vitro model used in the present study provides pertinent information about CL(HD) and is helpful for predicting RR during HD in individual patients undergoing HD.

Acute nephrotoxicity of aristolochic acids in mice.

Aristolochic acids (AA), present in Aristolochia plants, are the toxin responsible for Chinese herbs nephropathy (CHN), a rapidly progressive tubulointerstitial nephritis (TIN). To clarify the mechanisms of the development of CHN, we tried to induce TIN in mice using AA. Three strains of inbred mice, BALB/c, C3H/He and C57BL/6, received 2.5 mg kg(-1) of AA or AA sodium salt (AANa) daily by intraperitoneal or oral administration, 5 days a week for 2 weeks. Serum and renal tissue were obtained at sacrifice. Twelve-hour urine samples were individually collected in a metabolic cage at one-week intervals. In the AA-injected groups, severe tubular injury, with the appearance of acute tubular necrosis, and rare cell infiltration into the interstitium, were seen in BALB/c mice. C3H/He mice also developed TIN with prominent cell infiltration into the interstitium and interstitial fibrosis. In C57BL/6 mice, only mild and focal tubulointerstitial changes were seen. Serum creatinine and blood urea nitrogen increased in BALB/c and C3H/He mice. Immunofluorescent study revealed no deposition of immune components in kidneys. In the AANa-treated groups, TIN was also seen in all groups, but even more severe tubulointerstitial changes were induced by intraperitoneal injection. Further examination using purified AAI, AAII, AAIVa and aristolactam I (ALI) revealed that AAI induced strong nephrotoxicity in mice, and that AAII resulted in mild nephrotoxicity. However, AAIVa and ALI caused no nephrotoxicity in this experimental system. There are strain differences in mice in their susceptibility to AA nephropathy. AAI exerted the strongest nephrotoxic effect in mice.

[Pilot study of the practical use of Internet in medical services: the questionnaire for pharmacists in Japan].

We performed a questionnaire survey to 260 pharmacists as a pilot study, in order to know the actual application of IN to medical services in Japan. The response rate of our questionnaire was 40% (105 persons), and 91% of the answers were from pharmacists who works in hospitals, community pharmacies, or clinics. According to the results, 90 of the 105 pharmacists had had some experience of using IN, and 68% of whom (58% of respondents) use IN daily as a means of problem solution on their works. IN was probably used as a relatively reliable information source something like text-books in such cases as acquiring the medical information for patients or other medical staffs. In addition, IN may have been esteemed its facilities and the informational usefulness and reliability. However, since this survey is just a pilot trial, the result dose not necessarily reflect a general situation around IT use. Consequently, this study result could be need by still further research.

Induction of nephrotoxic serum nephritis in inbred mice and suppressive effect of colchicine on the development of this nephritis.

Accelerated nephrotoxic serum (NTS) nephritis is successfully produced in C57BL/6 mice, using anti-murine glomerular basement membrane (GBM) rabbit antiserum. Anti-murine GBM rabbits antiserum was obtained by immunization of New Zealand white rabbit with trypsinized GBM antigen from normal C57BL/6 mice. Preimmunization with normal rabbit IgG and injection with 150 microl of NTS induced typical NTS nephritis with cellular proliferation in glomeruli, occlusion of glomerular loops, crescents, tubulointerstitial changes and hyperazotemia within 14 days. Polymorphonuclear leucocytes (PMN) have an important role in induction and development of NTS nephritis. Furthermore, clinically used colchicine is thought to suppress functions of PMN. Therefore, the therapeutic effect of colchicine on NTS nephritis was examined. The histological score (HS) of the group treated with 60 microg kg (-1) of colchicine (2.8 +/- 0.5) was significantly lower than that of positive control group (4.03 +/- 0.3).The direct immunofluorescent microscopic study revealed that there is no quantitative difference in the deposition of rabbit IgG, mouse IgG and C3 in GBM between these two groups. Urinary protein excretion and hyperazotemia were significantly suppressed by treatment with 60 microg kg (-1) of colchicine. A NTS nephritis model was established, it was found that colchicine may have a suppressive effect on the development of glomerular nephritis.