[Effect of itraconazole on digoxin clearance in patients with congestive heart failure].

We showed a digoxin-itraconazole interaction in three patients in whom digoxin serum concentrations were increased. Their electrocardiograms revealed arrhythmias such as ventricular premature contraction, atrioventricular block, and ST depression. The elimination half-life of digoxin in case 3 patient who continued itraconazole therapy was 8.4 days, which was estimated by nonlinear least squares method from the serum concentrations of digoxin versus time curve. In order to evaluate the influence of itraconazole on pharmacokinetic parameters of digoxin, we estimated digoxin clearance by the Bayesian method using the population pharmacokinetic parameters in Japanese patients. During the concomitant use of itraconazole and digoxin, the digoxin clearance in all patients decreased to 50.5 +/- 8.8% (mean +/- S.D.) of the clearance without itraconazole. When digoxin and itraconazole are used concomitantly, careful monitoring of digoxin serum concentrations is necessary. Based on our results of digoxin clearance evaluation, the dose of digoxin should be reduced to 50% of original dose after itraconazole is started, and digoxin serum concentration might be controlled at the same level before the concomitant use.

Control of plasma cholesterol-lowering action of probucol with various lipid carrier systems.

In order to explore the relationship between the pharmacokinetic properties and pharmacological actions of lipophilic drugs injected with lipid carrier systems, probucol was selected as a model drug with high lipophilicity, and the effect of disposition control on cholesterol-lowering activities was evaluated. Both large emulsion, with mean diameter of 280 nm, and long-circulating type small emulsion containing egg sphingomyelin with mean diameter of 100 nm, showed stable incorporation of probucol. The former produced rapid accumulation of probucol in the liver, while the latter demonstrated prolonged systemic circulation and gradual hepatic uptake. On the other hand, injection of a micellar solution with HCO-60 (polyoxyethylene hydrogenated castor oil) showed a rapid decrease in plasma concentration and a high hepatic uptake of probucol, similar to injections with serum, suggesting the rapid release of the drug from the micelles. However, probucol in a micellar solution showed higher cholesterol-lowering action than that in emulsion formulations. These results suggested that the pharmacological action of probucol in the liver might be affected by the uptake mode and sequential disposition in the organ, depending on the drug retention properties of the lipid carrier particles.

Effect of particle size and charge on the disposition of lipid carriers after intratumoral injection into tissue-isolated tumors.

PURPOSE: Pharmacokinetic properties of various lipid carriers (liposome and emulsions) after intratumoral injection were studied in perfusion experiments using tissue-isolated tumor preparations of Walker 256 carcinosarcoma. METHODS: Four types of lipid carriers, large emulsion (254 nm), small emulsion (85 nm), neutral liposomes (120 nm) and cationic liposomes (125 nm) were prepared. We quantified their recovery from the tumor, leakage from the tumor surface and venous outflow after intratumoral injection into perfused tissue-isolated tumors, and analyzed venous appearance curves based on a pharmacokinetic model. RESULTS: In contrast to the small emulsion and neutral liposomes, which immediately appeared in the venous outflow perfusate following intratumoral injection, the appearance of the cationic liposomes and the large emulsion was highly restricted, clearly demonstrating that intratumoral clearance of these formulations can be greatly retarded by the cationic charge and large particle size, respectively. The venous appearance rate-time profiles were fitted to equations derived from a two-compartment model by nonlinear regression analysis. When the calculated parameters were compared among these four formulations, the venous appearance rate did not exhibit such a large difference; however, the rate of transfer from the injected site to the compartment which involves clearance by venous outflow was all very different. CONCLUSIONS: The results of this study indicate that the determining factor which alters the pharmacokinetic properties of these lipid carriers after intratumoral injection is not the rate of transfer from the interstitial space to the vascular side but the rate of intratumoral transfer from the injection site to the well-vascularized region.

Thyrotrophin-binding inhibitory immunoglobulins and HLA-DRW3-two prognostic factors in Graves' disease.

Thyrotrophin-binding inhibitory immuno-globulin (TBII) activity and HLA typing were performed in 38 Chinese patients with Graves' disease to find out the relationship among TBII activity, HLA antigen and relapse. Twelve out of 13 patients who were TBII-positive at anti-thyroid drug withdrawal relapsed. All seven patients with HLA-DR3 antigen relapsed, whereas all ten patients in remission did not have DR3. Therefore, both TBII activity at drug withdrawal and DR3 antigen could predict subsequent relapse. However, a larger patient sample is required to determine the precise relationship between TBII activity and HLA-DR3 antigen.

Relations between the HLA-antigens and immune responsiveness to SK/SD in healthy Japanese subjects.

A possible association between the HLA antigens and immune responsiveness to SK/SD was studied in 90 healthy Japanese volunteers. No association was found between the HLA antigens, including B5, and SK/SD stimulated blastoid transformation. There was a week indication of an association between Bw22 and responses to SK/SD. But this was not statistically significant as far as the corrected P value was concerned.