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N Katsutani

Publications and source records attributed to N Katsutani.

9 recordsLinked to original sources
PubMed2000

Hepatic drug metabolizing enzymes induced by clofibrate in rasH2 mice.

Hepatic drug metabolizing enzyme activities were determined, after treatment with clofibrate, in transgenic mice carrying human c-Ha-ras (rasH2 mice). Changes in the drug metabolizing enzyme activities in these mice by gene integration were also evaluated. Male and female rasH2 mice (Tg) and the litter mates not carrying the gene (non-Tg) received orally 500 mg/kg of clofibrate or the vehicle for 12 consecutive days. Liver homogenate and microsomes were prepared and the contents and activities of cytochrome P450 (CYP), cytochrome b5 content and enzyme activities related to peroxisome proliferation were determined. Relative liver weights, CYP4A and activities of catalase and carnitine palmitoyl transferase increased to the same extent in Tg and non-Tg mice treated with clofibrate. In Tg and non-Tg groups that received vehicle, contents and activities of CYP and cytchrome b5 contents were comparable. It was concluded that gene integration did not alter drug metabolizing enzymes and responses to clofibrate.

Animals↗
PubMed1999

[General toxicity study of gadobenate dimeglumine formulation (E7155) (4)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in dogs].

Gadobenate dimeglumine formulation (E7155), at doses of 0 (physiological saline), 0.25, 0.5, 1 and 2 mmol/kg/day of body weight, was administered intravenously to male and female beagle dogs once daily for 4 consecutive weeks in order to evaluate the subacute toxicity of the test article. Reversibility of toxicity was evaluated during a 4-week recovery period at 1 and 2 mmol/kg/day. No toxicologically significant changes were observed at 0.25 and 0.5 mmol/kg/day. In animals receiving 1 or 2 mmol/kg/day, transient swelling and redness of the facial and eye areas, lethargy, decreased activity, emesis, retching, watery or unformed stool, decreased body weight or body weight gain, decreased food consumption, decreased hematocrit and hemoglobin concentration, increased APTT, increases in plasma ALP, GPT or gamma-GT, decreased plasma inorganic phosphorus, total protein or albumin, increased liver or kidney weight, subacute inflammatory infiltrates, loss of centrilobular hepatocytes or hepatocellular cytoplamic vacuolation in the liver, vacuoles in the epithelial cells of the renal tubles and/or hypocellularity in the bone marrow were seen. The results of toxicokinetic analysis showed that systemic exposure was similar in males and females, and there was no accumulation of the test material over the treatment period, although AUC tended to be enhanced by slightly more than the proportionate dose increase. These effects were recovered or tended to be reversed after a post-dosing period for 4 weeks. In conclusion, the No Observed Adverse Effect Level (NOAEL) was 0.5 mmol/kg/day.

Animals↗
PubMed1994

Dynamic properties of nucleic acids in biosupramolecular systems, as studied by 31P NMR.

The dynamic properties of nucleic acids in five different types of intact supramolecular systems, namely, chicken erythrocyte chromatin, the wild type and a deletion mutant of the lambda phage, lipid-containing phage PM2, and Alteromonas espejiana ribosomes, were investigated by means of 31P solid-state NMR. The nucleic acids in the different supramolecular systems showed unique dynamic properties, which are closely connected with their functions. The total anisotropy of the phosphorus chemical shift (delta sigma = sigma 33-sigma 11) of the ribosomes was 210 ppm at 5 degrees C. This anisotropy was much larger than those of any DNA complexes, suggesting the highly rigid structure of ribosomal RNA. In contrast, 160 ppm was the largest chemical shift anisotropy at 5 degrees C for B-form DNA in the supramolecular systems. This flexibility would be essential for DNAs to exert their functions. The involvement of a condensation protein in the PM2 phage was supported by the chemical shift anisotropy. The spin-lattice relaxation time in the proton rotating frame [T1 rho(H)] of the nucleic acids became shorter with the increase in the effective field in the rotating frame for all systems examined, showing that the motions of the nucleic acids effective for the relaxation are in the slow motional regime or in the range of omega 1 tau c = 1 at 5 degrees C. The motional state of DNA of the lambda phage was found to change at about 20 degrees C on the basis of the temperature dependence of the spin-lattice relaxation time of phosphorus (T1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Immunogenicity of various beta-lactam antibiotic-protein conjugates and cross-reactivity of the antibodies produced in guinea pig.

Immunogenic properties of bovine serum albumin (BSA) conjugates of various beta-lactam antibiotics (ABs) and cross-reactivity of the produced antibodies were investigated in guinea pigs. Each AB-BSA conjugate was immunized with complete Freund's adjuvant. Following the second injection, AB-specific antibodies were detected with high titers. Produced antibodies showed concentration-dependent inhibition by the corresponding AB. Cross-reactivity between the produced antibodies and ABs was evaluated with two methods, i.e. by testing for reactivity with the various AB-ovalbumin conjugates, and by assaying for inhibition of enzyme-linked immunosorbent assay (ELISA) by the various ABs. The latter method could detect minor cross-reactions more sensitively than the former one. The results suggested that similarity of the acyl side chain of a cephalosporin nucleus or a penicillin nucleus contributes to immunological cross-reactivity.

Animals↗
PubMed1992

Drug-specific immune responses induced by procainamide, hydralazine and isoniazid in guinea-pigs.

The drug-induced graft vs host reaction (GVHR) hypothesis requires, as its first step, specific T-cell immune responses to the drug-modified self. Procainamide, isoniazid and hydralazine are known to provoke various allergic reactions including GVHR-like adverse effects in man. We now report that drug-specific immune responses can easily be induced by these drugs in guinea-pigs. Twenty-five milligrams of each of these drugs and penicillin G, which is known to make covalent bonds with proteins and to also induce drug-specific immune responses, were mixed with complete Freund's adjuvant (CFA) and subcutaneously (s.c.) injected twice at an interval of 2 weeks into female Hartley guinea-pigs. The antibodies to these drugs were assessed by means of an enzyme-linked immunosorbent assay (ELISA). Two weeks after the last injection, all animals treated with isoniazid, hydralazine and penicillin G produced high titers of antibodies to these drugs. Antibodies to procainamide were also detected, although their antibody titers were low. The specificity of the antibodies produced were tested by the inhibition of ELISA and concentration-dependent inhibition was observed. Delayed type hypersensitivity (DTH) reactions were also observed in the animals treated with procainamide, isoniazid and hydralazine 2 weeks after the last injection. These results suggest that the allergic reactions observed in clinical use are related to the inducing potential of drug-specific immune responses in an animal system. Therefore, immunization of guinea-pigs with test drugs and CFA may give useful information for predicting the occurrence of allergic reactions in man.

Animals↗
PubMed1992

Popliteal lymph node enlargement induced by procainamide.

The ability of procainamide (PA) to induce primary local popliteal lymph node (PLN) reactions has been investigated. We employed an in vitro drug-metabolizing system, based on the hypothesis that the negative result for PA in a PLN assay (PLNA) was due to insufficient metabolizing activity at the reaction site. PA was incubated previously in vitro with the S-9 mixture derived from rat liver. The reactants were ultrafiltered in order to eliminate high molecular-weight molecules, and then the low molecular-weight fraction was subcutaneously (s.c.) injected into the hind footpad of mice. PLN reactions were assessed by weighing the popliteal lymph node of the injected side. The reactants of more than 5 mg of PA and S-9 mixture induced PLN enlargement in C3H/He mice 8 days after injection. BALB/c and C57BL/6 mice were also susceptible to PLN reaction in response to the reactants of PA (10 mg) and S-9 mixture. PLN reactions to PA were induced 2 days after the injection and sustained until 18 days. Contact of PA with the S-9 mixture for 30 min at 37 degrees C was sufficient to induce PLN enlargement. However, contact for 24 h reduced the peak reaction. On the other hand, PA which had not been incubated with the S-9 mixture and acetylprocainamide (acetylPA) gave little or no reaction. Local PNA has not been considered to be suitable for the detection of drugs with the potential to induce immune disorders in cases where a metabolite contributes to the adverse reaction. However, the employment of an in vitro drug-metabolizing system may overcome that defect.

Animals↗
PubMed1992

Immunogenic properties of structurally modified human tissue plasminogen activators in chimpanzees and mice.

Immunogenic properties of second generation human tissue plasminogen activator (tPA) derivatives were examined in chimpanzee and mouse systems. Five species of modified tPAs (mtPAs) (designated 2660, 2663, 2810, 8000, and 9200), recombinant native tPA or bovine serum albumin (BSA) as a positive control were subcutaneously injected nine times at suitable intervals into chimpanzees, genetically the closest species to man. These animals were tested for antigen(Ag)-specific antibodies to the corresponding proteins by means of enzyme-linked immunosorbent assay and Western blot analysis. Neither 9200, one of the five mtPAs tested, nor tPA was immunogenic, although BSA and the other four mtPAs were immunogenic under these conditions. Thus, an antigenic determinant was not exposed by the modification on 9200 and this modified tPA is expected not to be immunogenic in humans. In the mouse studies, mice were immunized with mtPAs. Serum samples from these animals were tested for antibodies to the mtPAs which did not concomitantly recognize native tPA by immune adsorption of the antibodies to tPA. The amount of such antibodies after the elimination of native tPA-reactive antibodies was little or none when the serum samples from 9200 and from the other mtPAs, except 8000, were tested. Taking into consideration the results of the chimpanzee studies, it can be concluded that Ag-specific antibodies are dominantly produced to unchanged epitopes present in modified proteins in the mouse system, in which the native protein is immunogenic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Drug-specific immune responses induced by immunization with drugs in guinea pigs and mice.

In order to develop a system for evaluating the allergenicity of drugs in clinical use, we tested drugs for the ability to induce drug-specific immune responses in guinea pigs and mice. Test drugs were benzylpenicillin, procainamide, hydralazine, isoniazid, alpha-methyldopa, D-penicillamine, captopril, sulfamethoxazole and 2,4-dinitrochlorobenzene (DNCB), which are known to induce allergic responses in man including hypersensitivity reactions and drug-induced auto-immune responses. Guinea pigs were immunized with an emulsion of complete Freund's adjuvant (CFA) and 25 mg of each drug. Mice were immunized with an emulsion of CFA and 2 mg of each drug or a mixture of aluminum hydroxide gel and 2 mg of each drug. In order to examine drug-specific immune responses, we employed detection of antibodies by enzyme-linked immunosorbent assay (ELISA) and passive cutaneous anaphylaxis tests, active systemic anaphylaxis (ASA) tests and delayed type hypersensitivity (DTH) tests. In guinea pigs, drug-specific antibodies were detected following immunization with benzylpenicillin, procainamide, hydralazine, isoniazid, captopril, sulfamethoxazole or DNCB. Some of these drugs were also positive in DTH tests and/or ASA tests. In mice, however, only DNCB gave positive results. Therefore, our system involving immunization of guinea pigs with CFA emulsion of a drug and detection of drug-specific immune responses is considered to be an effective test method for evaluating drug allergenicity.

Animals↗