SHAPE ESTIMATION OF BOWTIE FILTERS BASED ON THE LUMINESCENCE FROM POLYETHYLENE TEREPHTHALATE RESIN BY X-RAY IRRADIATION.

In this study, we devised a novel method estimating the bowtie filter shapes by imaging luminescence from a polyethylene terephthalate (PET) resin with X-ray irradiation in a computed tomography (CT) scanner. The luminescence distribution of the PET resin corresponding to the thickness of bowtie filter was imaged using a charge-coupled device camera. On the assumption that the material of bowtie filter is aluminium (Al), the shape of bowtie filters was estimated from the correlation between Al attenuation curves and the angular-dependent luminance attenuation profiles according to the thickness of bowtie filters. Dose simulations based on the estimated bowtie filter shapes were performed using head and body PMMA phantoms with 16 and 32 cm in diameter. The simulated values of head and body weighted CT dose index (CTDIw) based on bowtie filter shape by the luminescence imaging method agreed within ~9% with the measured values by a dosemeter.

MEASUREMENT OF INTERNAL RADIATION DOSE DISTRIBUTION IN CT EXAMINATIONS USING POLYETHYLENE TEREPHTHALATE RESIN.

This study proposes a new dosimetry method for the estimation of the internal radiation dose distribution of a subject undergoing computed tomography (CT) examinations. In this novel method, dose distribution of a subject by CT scans was estimated based on radiophotoluminance distribution with polyethylene terephthalate (PET) resin which was cut to the average head size of a Japanese 1-year-old child. The difference in dose distribution depending on the type of bowtie filter was visualized by imaging luminance distribution with the PET phantom using a charge-coupled device camera. Dose distribution images simulated from a water phantom of the same size as the PET phantom were compared with the luminance distribution images. The linear correlation was demonstrated between luminance of the PET phantom and the simulated water dose. In comparison with the simulated water doses and the converted water doses from luminance of the PET phantom, the relative differences were within 20%.

Studies on the metabolic fate of M17055, a novel diuretic (6). Assessment for drug-drug interactions of M17055 in metabolism, distribution and excretion.

1. The potential of M17055, a novel diuretic candidate, to affect the activities of human CYP enzymes, alter the plasma unbound fraction and compete with concomitant drugs in renal secretion as part of an assessment for drug-drug interactions in metabolism, distribution and excretion was investigated. 2. The effects of M17055 on the activities of human CYP1A2, CYP2E1, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 were considered negligible at clinically relevant concentrations. 3. The majority of M17055 (99%) was bound to human plasma proteins, but it is unlikely to alter the binding of other clinically relevant drugs. 4. The renal clearance of M17055 (corrected for the plasma unbound fraction in male rats) substantially exceeded the glomerular filtration rate and was markedly reduced by treatment with probenecid, suggesting that the renal excretion of M17055 is controlled predominantly by an active secretion mechanism. 5. The results show that M17055 is unlikely to cause or undergo significant pharmacokinetic interactions with concomitant drugs in metabolism and distribution. However, when it is administered simultaneously with certain organic anions, drug-drug interactions during kidney excretion may be possible.

Metabolic fate of ulinastatin (2); Pharmacokinetics in rabbits following intra-articular administration.

The absorption and distribution of ulinastatin following intra-articular administration of [125I]ulinastatin to rabbits were determined and kinetic analysis using a multi-compartment model was performed. At 4 h after administration, the content of radioactivity in the synovial fluid, which was comparable to that of the immunoreactive ulinastatin, was 14.51% of the dose and decreased in a biphasic manner. The highest level of radioactivity was observed in the synovial membrane, followed by the meniscus, ligament, cartilage and patella, the radioactivities of which also declined biphasically. After intra-articular administration, the plasma concentration of total radioactivity increased slowly and reached maximum at 4.3 h, and then declined slowly in a monophasic manner with a half-life of 10.8 h. The radioactivity of the high molecular weight fraction in plasma, which reached maximum at 1.7 h after administration and then declined with a half-life of 11.8 h, was consistent with the time curve for immunoreactive ulinastatin in the plasma through 24 h after the administration. Within 8 and 24 h after administration, respectively, 1.48 and 4.66% of the administered radioactivity were transferred to the lymphatic fluid. The pharmacokinetics of [125I]ulinastatin after an intra-articular administration could be explained using a multi-compartment model in which a portion of the administered ulinastatin was absorbed via the lymphatic system. This finding suggested that ulinastatin was rapidly distributed and retained for a long period of time in the joint tissues. In addition, the pharmacokinetics of ulinastatin following intra-articular administration indicated typical flip-flop kinetics.

A novel quinolinone diuretic, M12285, and its activation mechanism through sulfate conjugation.

The diuretic activity of a quinolinone oxime diuretic, M12285, was examined after renal arterial, i.v. and portal injection in rats. M12285 injected into the renal artery at a dose of 1 mg/kg caused no diuretic effect, whereas i.v. and portal injections induced marked diuresis dose dependently. The minimum effective dose with portal injection was lower (1 mg/kg) than that with i.v. injection (3 mg/kg) and the start of the effect was faster with portal injection. These results indicated that some metabolic modification in the liver is necessary for the diuretic activity to appear. Accordingly, we performed in situ rat liver perfusion with M12285 and obtained several metabolites. Renal arterial injection of each fractionated metabolite of M12285 revealed that all the diuretic activity derived from one of these metabolites. From IR and 1H-nuclear magnetic resonance (1HNMR) measurements, the chemical structure of this active metabolite was assumed to be a sulfate-conjugated form of M12285 at the oxime moiety. Based on this tentative chemical structure, we synthesized the oxime sulfate of M12285 (potassium salt, M17000) and confirmed the identity of IR and 1HNMR spectra. Administration of M17000 into the renal artery induced apparent diuresis in a dose-dependent manner in both rats and dogs. These results indicate that the oxime sulfate of M12285 is responsible for the diuretic activity of M12285. Therefore, we synthesized several derivatives of M17000 and confirmed their possible therapeutic value as a novel family of diuretics, namely quinolinone oxime sulfonic acids.

Metabolic disposition of ethyl eicosapentaenoate and its metabolites in rats and dogs.

When orally administered to rats, 14C-labelled ethyl eicosapentaenoate (14C-EPA-E) was hydrolyzed and, in the lymph, incorporated mainly into triglycerides (TG) in chylomicrons. In plasma and other tissues, eicosapentaenoic acid (EPA) and its metabolites, such as docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA), were detected in TG and phospholipid fractions. In plasma, EPA and its metabolites were found to be integrated into lipoproteins. Tissue distribution of these metabolites showed characteristic patterns from one tissue to another, as did their compositional distribution in lipids. EPA, DPA and DHA were found to be metabolized via beta-oxidation in in vitro experiments with mitochondrial fraction.

[Effects of ulinastatin on experimental arthritis].

Effects of the urinary enzyme inhibitor ulinastatin on experimental arthritis were investigated. Ulinastatin at the dose of 30,000 units/kg/day, i.v., significantly restored the swelling of hind paw, inflammatory score and bone damage in adjuvant arthritic rats. Intraarticular administration of ulinastatin at 3000 units/site x 3, significantly suppressed the articular swelling and the elevated inflammatory parameters in the synovial fluid of carrageenin-induced arthritic rabbits. Moreover, ulinastatin at the dose of 50000 units/kg/day, i.v., significantly prevented the elevation of serum rheumatoid factor and articular lesions in MRL/l mice. In addition, ulinastatin significantly inhibited human granulocyte elastase and cathepsin G. These findings indicate that ulinastatin may be a useful therapeutic agent for arthritis.

[Effect of urinastatin on disseminated intravascular coagulation].

Effect of urinary enzyme inhibitor urinastatin (MTI) on disseminated intravascular coagulation (DIC) was investigated. The prolongation of PTT and increase in FDP in endotoxin-induced DIC in rats were restored by the intravenous infusion of MTI. The reduction in platelet counts, decrease in fibrinogen level and prolongation of PT were partially suppressed by the drug. Furthermore, in vitro addition of MTI prevented the decrease in r and k values and increase in ma and m epsilon values in the thromboelastogram of whole blood in endotoxin-induced DIC in rabbits. It is suggested that MTI might prevent DIC in vivo and in vitro through the inhibition of Factor XII activity and through the prevention of thromboplastin release caused by endotoxin.