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Y Kotake

Publications and source records attributed to Y Kotake.

At least 73 records · Page 4Linked to original sources
PubMed1996

Chiral spin traps. The spin trapping chemistry of 5-methyl-5-phenylpyrroline-N-oxide (MPPO).

The use of 5,5-dimethylpyrroline-N-oxide (DMPO) as a versatile spin trap was first published in this journal (E.G. Janzen and J.I.-P. Liu, J. Magn. Reson. 9, 510-512 (1973). In this paper, the general use of an improved DMPO-type spin trap, namely 5-methyl-5-phenylpyrroline-N-oxide (MPPO), is proposed. MPPO is more stable than DMPO and has an excellent shelf life. Commonly known artifacts of DMPO are not present in MPPO. The EPR spectra of MPPO spin adducts have the same patterns as DMPO spin adducts which users have become familiar with. The lifetimes of spin adducts are longer for MPPO than for DMPO and the rate constants of spin trapping are similar. An interesting additional feature is associated with the detection of two spin-adduct spectra in some cases. The major component is assigned to the trans addition product (with respect to the phenyl group) in the case of carbon-centered radicals. The minor component is assigned to the cis adduct. In the superoxide/peroxyl radical adduct, however, the reverse appears to be the case. Only one EPR spectrum is detected in the hydroxyl radical adduct of MPPO.

Artifacts↗
PubMed1996

Studies on the stability of oxygen radical spin adducts of a new spin trap: 5-methyl-5-phenylpyrroline-1-oxide (MPPO).

A new spin trap, 5-methyl-5-phenylpyrrolin-1-oxide (MPPO), has been evaluated with respect to the intrinsic stabilities of the hydroxyl and superoxide (or hydroperoxyl) radical spin adducts. Hydroxyl or superoxide radicals were generated using various sources in the presence of MPPO, and the hydroxyl or superoxide radical spin adduct of MPPO was detected by EPR spectroscopy. The time course of spontaneous decay of the EPR signal from hydroxyl or superoxide spin adducts followed first-order kinetics and the half-life was dependent on the pH of the medium. At pH 7.4 the half-life times are 76.4 and 5.7 min for the hydroxyl and hydroperoxyl/superoxide spin adducts, respectively. Structural factors which could influence the decay rates are also discussed.

Drug Stability↗
PubMed1996

In vivo spin trapping of nitric oxide generated in the small intestine, liver, and kidney during the development of endotoxemia: a time-course study.

Spin trapping of nitric oxide (NO.) in vivo in liver, small intestine, kidney, and plasma of intact rats was accomplished using diethyldithiocarbamate (DETC) administered intraperitoneally. DETC combines with Fe2+ to form (DETC)2-Fe and is an excellent trapping agent for nitric oxide. DETC distribution and uptake by the organs of interest was determined and the formation of the active trapping agent (DETC)2-Fe was assayed in the various organs and plasma. The capacity of this spin trap to capture NO. in vivo was demonstrated by administering sodium nitroprusside to the animals. The trapping procedure was then used to assess the course of NO. generation during a 6 h period in animals that had been treated with endotoxin. The rate of NO. generation/gram tissue was determined during the last 15 min of each time period. The results indicate that induction of nitric oxide generation begins earliest in the small intestine, then in the liver, and still later in the kidney and plasma. Nitric oxide production was most intense in the liver and was still increasing at the end of the experiment. Control animals receiving the spin trapping agent showed only little or no evidence of nitric oxide production except for the small intestine. The results show that induction of NO. generation caused by endotoxin begins at different times in different organs.

Animals↗
PubMed1996

[Distribution of irrigating fluid to intracellular and extracellular fluid space during transurethral prostatectomy I--Estimation of irrigating fluid absorbed by measuring serum osmolality].

Twenty-three patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia were studied. The irrigating fluid widely used in Japan is a hypo-osmolar solution with 3% sorbitol (Uromatic S, 170 mOsm.kgH2O-1, Baxter). The blood loss and the distribution of the irrigating fluid absorbed were computed from serum osmolality, blood urea nitrogen, and hematocrit using the equation we had formulated. The blood loss, the total fluid absorbed (ABS), and the volumes distributed to intracellular space (delta ICF) and extracellular space (delta ECF) were 419 +/- 677 ml, 1,582 +/- 1,446 ml, 384 +/- 348 ml and 778 +/- 1,279 ml (mean+/-SD), respectively. The correlation coefficient of delta OSM (difference between pre- and post-surgical serum osmolality) vs ABS and that of delta OSM vs delta ICF were high (0.98, 0.98) but that of delta Na (difference between pre- and postsurgical serum sodium) vs ABS was low (0.56). The linear regression equations of ABS vs delta OSM and delta ICF vs delta OSM were ABS (L) = 0.362 x delta OSM and delta ICF (L) = 0.088 x delta OSM, respectively. These equations means that one mOsm.kgH2O-1 reduction of the serum osmolality is the result of 362 ml of irrigating fluid absorbed, 88 ml of which shifting into the intracellular space.

Aged↗
PubMed1996

[Distribution of irrigating fluid in intracellular and extracellular spaces during transurethral prostatectomy II--TUR syndrome and hyponatremia].

Thirty four patients undergoing transurethral resection of the prostate (TURP) under spinal anesthesia were assigned to a TUR syndrome (TURS) group (n = 7) or an asymptomatic (ASP) group (n = 27) depending on the clinical manifestations of the TUR syndrome. Blood loss and distribution of absorbed irrigating fluid (3% sorbitol-Uromatic S, 170 mOsm.kgH2O-1, Baxter) were computed together with serum osmolality, blood urea nitrogen and hematocrit. Postoperative serum sodium concentration and hematocrit were significantly lower in the TURS group than in the ASP group (124 +/- 8.7 vs. 133.9 +/- 5.9 mOsm.l-1 and 26. 8 +/- 4.2 vs. 35.0 +/- 4.6%, respectively). Postoperative serum osmotic pressure did not differ between the groups despite the difference in sodium concentration because 3% sorbitol could contribute to osmoles in the serum. The volume of irrigating fluid absorbed and its distribution into the intracellular space (delta ICF) did not differ between the groups. However, blood loss was significantly greater in the TURS group than in the ASP group (1457 +/- 434 ml vs. 173 +/- 450 ml, P < 0.01), and consequently extracellular fluid (ECF) volume was significantly reduced in the TURS group (-354 +/- 1201 ml vs. 802 +/- 1302 ml, P < 0.05). Thus, massive blood loss and reduced ECFs rather than dilutional hyponatremia, are thought to contribute to clinical manifestation of the TUR syndrome.

Aged↗
PubMed1996

[Prediction and the results of postoperative performance status in patients with giant bulla--prospective study of 47 patients].

The discriminant function (Z) for predicting postoperative performance status in patients with giant bulla was addressed in our previous paper. In the present study, patients with dyspnea were classified into Group 1 or Group 2 based on preoperative function, Group 1 showing continuous improvement in dyspnea and Group 2 unchanged or worsened condition after bullectomy. Of the 47 patients in this study, 28 had dyspnea of grade 2 or more, 19 revealing no symptoms prebullectomy. The group predictions for the 28 patients were compared with the postoperative status in dyspnea for over four years following surgery. The predicted grouping in 26 of the 28 (93%) agreed with the postoperative status but in two it did not: one was familial bullous emphysema the other had repeated episodes of pneumonia, both of which were predicted for Group 1. All 19 patients without preoperative dyspnea were studied their symptoms and lung functions before and after bullectomy. After surgery, none showed dyspnea and significant changes of functions. As to preoperative pulmonary function, patients with FEV1.0% of more than 60% and delta N2 of less than 2% were improved, the prediction agreeing with the actual results. Fourteen patients with FEV1.0% of less than 55% showed high delta N2. When delta N2 exceeded 3.5%, deterioration of dyspnea was observed following surgery. Bullectomy is indicated in patients with low pulmonary function, by preoperative FEV1.0% and delta N2.

Adult↗
PubMed1995

Spin trapping agent, phenyl N-tert-butyl nitrone, inhibits induction of nitric oxide synthase in endotoxin-induced shock in mice.

Spin trapping agent, phenyl N-tert-butyl nitrone (PBN) significantly reduces mortality due to lipopolysaccharide (LPS)-induced shock in Balb/c mice as had previously been shown in rats. We hypothesized that PBN decreases mortality by directly or indirectly inhibiting nitric oxide (NO) generation. Therefore, we determined the effect of PBN administration on LPS-induced NO generation in mice. NO generation was monitored in the mouse liver after administration of LPS by an in vivo NO-spin trapping, followed by ex vivo EPR measurement. When the mice was treated with PBN 0.5hr before LPS administration, NO generation in the liver was reduced by 80%. However, when PBN was given 3hrs after LPS, NO generation did not change. Both pre- or post-administration of NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine inhibited the NO generation. Western blotting of inducible NOS (iNOS) in mouse liver cytosol obtained from PBN-pretreated animals demonstrated a decreased expression of iNOS, indicating the reduction in NO generation was caused by the decrease in the amount of enzyme present but not by the inhibition of iNOS enzyme activity per se.

Animals↗
PubMed1995

1-Benzyl-1,2,3,4-tetrahydroisoquinoline as a parkinsonism-inducing agent: a novel endogenous amine in mouse brain and parkinsonian CSF.

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) was detected as a novel endogenous amine in mouse brain and parkinsonian CSF by using the gas chromatography-selected ion-monitoring method. The level of 1BnTIQ was very high in CSF of some parkinsonian patients compared with that of controls with other neurological diseases, the mean value being three times higher (parkinsonians: 1.17 +/- 0.35 ng/ml of CSF, n = 18; vs. controls: 0.40 +/- 0.10 ng/ml of CSF, n = 11; mean +/- SEM, not significantly different). The pole test, a toxicological examination to evaluate behavior abnormalities related to Parkinson's disease, was used to examine the pharmacological effect of 1BnTIQ in mice. Repeated administration of 1BnTIQ induced behavior abnormalities, which pretreatment with 1-methyl-1,2,3,4-tetrahydroisoquinoline could prevent. We suggest that 1BnTIQ may be related to the idiopathic Parkinson's disease.

Animals↗
PubMed1995

Novel 6-5 fused ring heterocycle antifolates with potent antitumor activity: bridge modifications and heterocyclic benzoyl isosters of 2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidine antifolate.

Structural modifications of an extremely potent inhibitor of dihydrofolate reductase (DHFR) activity and tumor cell growth, N-[4-[3-(2,4-diamino-6,7-dihydro-5H-cyclopenta[d]pyrimidin-5- yl)propyl]benzoyl]-L-glutamic acid (1), have led to the synthesis of new cyclopenta[d]pyrimidine-based antifolates, including those with low alkyl substituted trimethylene bridges (2a, b) and isosterically modified bridges (ethyleneoxa, 2c; ethyleneamino, 2d; the N-methyl- and N-ethyl derivatives of 2d, 2e, f) and those in which the benzene ring of 1 has been replaced by heterocyclic isosters (indole, 2g; indoline, 2h; thiophene, 2i). These new analogs are highly potent as DHFR and cell growth inhibitors, and most of them are more potent than methotrexate (MTX) and 10-ethyl-10-deazapterin (10-EDAM) in inhibiting tumor cell growth (P388 MTX-sensitive and MTX-resistant, colon 26 and KB) on 72 h drug exposure. Among them, 2a (the 10-methyl derivative of 1) and 2i were most potent, being 2- to 3-fold more potent than 10-EDAM. On 4 h drug exposure, the growth-inhibitory activity of these analogs was radically influenced by even minor structural changes. Compounds 1, 2a--e, g--i were much more cytotoxic in colon 26 cell line than were MTX and 10-EDAM, with 2d and 2i being most potent, followed by 2a. Structure-activity relationships and their possible significance are discussed.

Animals↗
PubMed1995

Can spin trapping compounds like PBN protect against self-inflicted damage in polymorphonuclear leukocytes?

Polymorphonuclear leukocytes (PMNs) have been suggested to be damaged by superoxide radical generated on their own. The protective capacity of a spin trapping compound, phenyl-N-tert-butyl nitrone (PBN) was evaluated for this damage which occurs after the induction of superoxide generation. The life span of PMNs after superoxide generation was measured in the presence of PBN using the cell counting method, and effects of PBN on the amount of superoxide generated were quantitated using both cytochrome c reduction and spin trapping with DMPO. Results indicated significant extension of life span when PBN was present, and the extension was dose dependent. However, the magnitude of life span extension was not as large as expected from the decrease of superoxide generation. Possible mechanisms for the protection of PMNs by PBN are discussed.

Cell Death↗
PubMed1995

Spin trapping isotopically-labelled nitric oxide produced from [15N]L-arginine and [17O]dioxygen by activated macrophages using a water soluble Fe(++)-dithiocarbamate spin trap.

The unique capabilities of EPR spin trapping of nitric oxide based on a ferrous-dithiocarbamate spin trap have been demonstrated in a study verifying the source of the nitrogen and oxygen atoms in nitric oxide produced from activated macrophages. Spin trapping experiments were performed during nitric oxide generation from activated mouse peritoneal macrophages using the ferrous complex of N-methyl D-glucamine dithiocarbamate as a spin trap. When 15N-substituted arginine was given to the activated macrophages in the presence of the spin trap, a characteristic EPR spectrum of the nitric oxide spin adduct was obtained, which indicates the presence of the 15N atom in the nitric oxide molecule. The hyperfine splitting (hfs) constant of the 15N nucleus was 17.6 gauss. When 17O-containing dioxygen (55%) was supplied to the medium, an EPR spectrum consistent with the 17O-substituted nitric oxide spin adduct was observed in the composite spectrum. The hfs of 17O was estimated to be 2.5 gauss. The 14NO spin adduct observed after prolonged incubation in the medium which contains [15N]L-arginine as the only extracellular source of arginine demonstrates that arginine is recycled through its metabolite in activated macrophages.

Animals↗
PubMed1995

Mutual contact of adherent polymorphonuclear leukocytes inhibits their generation of superoxide.

Superoxide generation by polymorphonuclear leukocytes (PMNs) in suspension, or adherent to glass or plastic, after stimulation with N-formylmethionyl-leucyl-phenylalanine or phorbol myristate acetate was measured by cytochrome c reduction and spin trapping. Amounts of superoxide generated by adherent PMNs were inversely related to cell density. The generation of hydrogen peroxide was also inhibited at higher cell densities. In contrast to adherent cells, superoxide released by PMNs in suspension linearly increased with respect to cell number over a wider range. Microscopic observation indicated that the number of cells in mutual contact increased rapidly at cell densities higher than 4 x 10(4) cells/cm2, and inhibition of superoxide became apparent at higher cell densities. Mediators which could be released by PMNs, such as NO and adenosine, were not the cause of inhibition. These data suggest that mutual contact of PMNs suppresses their generation of superoxide. Survival rates of PMNs after stimulation increased at higher densities, indicating that the mutual contact-induced inhibition of superoxide generation by PMNs may be physiologically relevant at sites of inflammation.

Cell Adhesion↗
PubMed1994

Synthesis and antitumor activities of novel 6-5 fused ring heterocycle antifolates: N-[4-[omega-(2-amino-4-substituted-6,7-dihydrocyclopenta [d]pyrimidin-5-yl)alkyl]benzoyl]-L-glutamic acids.

Novel antifolates with a 6-5 fused ring system, 6,7-dihydrocyclopenta [d]pyrimidine, (3a,b and 4a,b) were synthesized on the basis of combined modification of the heterocycle and bridge regions of the folate molecule. The synthetic method involves (1) synthesis of key intermediates of tert-butyl 4-[omega-(2-substituted-3-oxocyclopentanyl) alkyl]benzoates (8a,b and 9a,b) by a carbon-carbon radical coupling of tert-butyl 4-(omega-iodoalkyl)benzoates (7a,b) with 2-substituted-2-cyclopenten-1-ones (5 and 6) utilizing tributyltin hydride, (2) cyclization of either the methyl enol-ethers derived from the 2-cyanocyclopentanones (8a,b) or the 2-(methoxycarbonyl)cyclopentanones (9a,b) themselves by treatment with guanidine which leads to 6,7-dihydrocyclopenta [d]pyrimidines with a 4-(tert-butoxycarbonyl)phenylalkyl group (11a,b and 14a,b), (3) deprotection to the corresponding carboxylic acids (12a,b and 15a,b), and (4) amidation with diethyl glutamate and deesterification. Potent dihydrofolate reductase inhibition and highly potent cell growth inhibition were found with 2,4-diaminopyrimidine-fused cyclopentene compounds containing the trimethylene (3a) or ethylene bridge (3b) but not with the corresponding 2-amino-4-hydroxy analogs (4a,b). Compounds 3a and 3b were more growth inhibitory to several tumor cell lines (P388, colon 26, colon 38, and KB) than was methotrexate, with 3a being the most potent. Both 3a and 3b gave increases in the lifespan of P388 leukemic mice comparable to that observed with MTX. Both compounds were therapeutic against colon 26 colorectal carcinoma in mice. Compound 3a was highly effective against LC-6 non-small cell lung carcinoma in nude mice.

Animals↗
PubMed1994

Novel 6,5-fused ring heterocyclic antifolates: biochemical and biological characterization.

Six novel antifolates with 2,4-diaminopyrimidine-fused five-membered rings containing either pyrrole or cyclopentene rings were characterized at the cellular and biochemical level. Five of these antifolates were more growth inhibitory to the CCRF-CEM human leukemia cell line than methotrexate [MTX; drug concentration effective at inhibiting cell growth by 50% relative to untreated control (EC50), 12 nM], the antifolate used in the clinic, and two were more potent than 10-ethyl-10-deazaaminopterin (EC50, 2.7 nM); similar patterns of response were obtained in the FaDu and A253 squamous carcinoma cell lines. In addition, the growth inhibitory potency of these antifolates was generally less dependent on exposure time than was MTX. Growth inhibitory effects could be reversed by leucovorin, indicating an antifolate mechanism. These antifolates targeted dihydrofolate reductase (DHFR) based on direct human DHFR inhibition assays [drug concentration inhibiting enzyme activity by 50% (IC50), 0.6-28 nM; MTX IC50, 0.8 nM] and the cross-resistance of MTX-resistant CCRF-CEM cells containing elevated DHFR. Inhibition of human thymidylate synthase was generally weak. These 6,5-fused ring heterocyclic antifolates utilized the reduced folate/MTX transporter for uptake, based on the cross-resistance of MTX uptake-impaired CCRF-CEM cells, and were efficient substrates for this uptake system, based on inhibition of [3H]MTX uptake (IC50, 0.3-5.8 microM; aminopterin IC50, 2.6 microM). These analogues were substrates for CCRF-CEM folylpolyglutamate synthetase, with several being among the most active substrates now known (highest Vrel/Km 0.73; MTX and 10-ethyl-10-deazaaminopterin, 0.013 and 0.24, respectively). Substrate activity for murine intestinal folylpolyglutamate synthetase was also assayed, and a different specificity pattern was observed. These new antifolates are apparently not substrates for aldehyde oxidase. Analogues containing the fused cyclopentene ring are preferred to those containing the fused pyrrole ring based on growth inhibitory potency, effectiveness against decreased uptake mutants and apparent affinity for transport, and inhibition of DHFR. In addition, fused cyclopentene-containing analogues are efficiently polyglutamylated. The data indicate that antifolates with 2,4-diaminopyrimidine-fused five-membered rings, especially those containing the fused cyclopentene ring, are an important new class of antifolates which warrant further exploration at the synthetic and preclinical levels.

Aminopterin↗
PubMed1994

Mediastinal ultrasonography for the assessment of mediastinal lymph node metastases in lung cancer patients.

Using an ultrasonic probe inserted into the mediastinum during cervical mediastinoscopy, mediastinal ultrasonography (USM) was performed on 63 patients with lung cancer. The patients with a small peripheral mass of less than 2 cm in diameter, according to the chest X-ray results, and with mediastinal lymph nodes smaller than 1 cm in their short axes as determined by computed tomography (CT), were excluded from this study. An analysis of the areas under the receiver operating characteristic curves derived from CT and USM showed that USM was superior (P = 0.043) to CT in terms of the diagnosis for mediastinal lymph node metastases, when the short axis dimension of mediastinal lymph nodes was employed for the diagnosis of metastases. The reason for this is that 97% of the mediastinal lymph nodes imaged by USM were located vertically along the body axis of the patient, and hence USM imaged the true short axis of the node in many cases. Our results indicate that USM is useful for performing a safe biopsy of lymph nodes during mediastinoscopy as well as for obtaining a clear imaging of the subcarinal nodes, which are inaccessible by normal cervical mediastinoscopy.

Adult↗