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Biomedical subjects

A Hamada

Publications and source records attributed to A Hamada.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effect of JTP-2942, a novel thyrotropin-releasing hormone analogue, on pentobarbital-induced anesthesia in rats.

The effects of a novel thyrotropin-releasing hormone (TRH) analogue, N alpha-((1S,2R)-2-methyl-4-oxocyclopentylcarbonyl)-L-histidyl-L-pro linamide monohydrate (JTP-2942), on pentobarbital-induced anesthesia in rats were investigated and compared with those of TRH. Intravenous administration of both JTP-2942 and TRH caused a dose-dependent decrease in the recovery time from pentobarbital-induced anesthesia. The minimum effective doses of JTP-2942 and TRH were respectively 0.03 and 1 mg/kg. The effect of JTP-2942 was antagonized by intraperitoneal scopolamine (0.5 mg/kg). Intraperitoneal JTP-2942 (1 mg/kg) caused an increase of acetylcholine release and a decrease of choline release in the frontal cortex and hippocampus of pentobarbital-treated rats. In addition, JTP-2942 ameliorated the decrease of hemicholinium-3-sensitive high-affinity choline uptake and the increase of acetylcholine in these brain regions. However, JTP-2942 had no effect on choline acetyltransferase activity or the choline content, which were also not changed by pentobarbital. Our results indicate that the effect of JTP-2942 on pentobarbital-induced anesthesia was about 30 times more potent than that of TRH, and suggest that JTP-2942 may act by accelerating acetylcholine turnover.

Acetylcholine↗
PubMed1995

Inhibition of 5'-deoxy-5-fluorouridine phosphorolysis by acyclopyrimidinenucleosides in intestinal tissue homogenates.

This study examined the inhibitory effect of acyclopyrimidinenucleosides on 5'-deoxy-5-fluorouridine (5'-DFUR) phosphorolysis in intestinal tissue derived from rabbit, rat, mouse, and human. 5-Bromoacyclouridine, 5-fluoroacyclouridine, acyclouridine, and 5-nitroacyclouridine showed little or only moderate effect, but acyclothymidine [5-methyl-1-(2'-hydroxyethoxymethyl)uracil] showed strong inhibitory effect on 5'-DFUR phosphorolysis in intestinal tissue homogenates derived from human. In the absence of inhibitor (acyclothymidine), the Vmax of 5'-DFUR phosphorolysis was 2.66 mumol/min and the Km was 0.57 mM in human intestinal homogenates. The Vmax was unaltered by increased inhibitor concentration. The maximal inhibitory effect of acyclothymidine on 5'-DFUR phosphorolysis in rat homogenates was over 90%. The Ki/Km was 0.63 in human, 2.14 in rabbit, 1.09 x 10(-2) in rat, and 1.71 x 10(-2) in mouse. These data show that acyclothymidine is a competitive inhibitor of 5'-DFUR phosphorolysis, and that it can inhibit not only uridine phosphorylase but also thymidine phosphorylase.

Animals↗
PubMed1995

[Chlorination and ozonation of contaminants in water environment and role of free radicals].

Pollutants in water environment are briefly reviewed concerning the water quality standard, especially the new items listed in the standard. They are disinfection byproducts, organohalogen compounds, and agrochemicals. Effects of chlorination and ozonation in the water treatment process on these contaminants and the contribution of the free radical to their toxicity are also discussed. Chlorination and ozonation in the water treatment process are believed to produce various active oxygen species, which seem to participate in the reaction with fumic acid, pollutants and bacteria. Main active oxygen species generated during the water treatment was a hydroxy radical, because DMPO-OH adduct was detected by the spin-trapping electron spin resonance (ESR) technique using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin-trapping reagent. Besides DMPO-OH, several DMPO adducts detected in both treatments were also described.

Chlorine↗
PubMed1995

In vivo ESR studies of antioxidant activity on free radical reaction in living mice under oxidative stress.

In vivo antioxidant activity seems to be quite complicate due to multiple interaction with biomaterials and differs from results by in vitro experiments. In vivo estimation of antioxidant activity is performed by measuring TBA reactive substances in blood or hydrocarbon gases in breath, but these systems do not measure free radical reaction but the final products of oxidative reaction. In the present study, we applied in vivo ESR to evaluate antioxidant activity by monitoring the redox reaction of nitroxide radical and clearly found that the nitroxide is very susceptible to oxidative stress in vivo and quite useful to evaluate antioxidant activity non-invasively.

Animals↗
PubMed1993

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Antioxidant activity of nitroxide radicals in lipid peroxidation of rat liver microsomes.

Inhibition of lipid peroxidation by nitroxide radicals in rat liver microsomes was studied using several nitroxide compounds which have various lipophilicities. Addition of NADPH to microsomes in an oxygen atmosphere induced lipid peroxidation as indicated by the increase of thiobarbituric acid (TBA)-reactive substances, hydroperoxide, conjugated diene, and oxygen consumption. Lipid peroxidation was inhibited by nitroxides located in both water phase and membrane. Oxygen consumption and the generation of active oxygens were inhibited by water-soluble nitroxides but not by intramembranous ones. Intramembranous nitroxides significantly prevented the production of conjugated dienes and lipid hydroperoxides. The facts suggest that water-soluble nitroxides interfere with the generation of active oxygens as preventive antioxidants, while intramembranous nitroxides inhibit the formation of lipid alkyl radical as chain-breaking antioxidants. The intensity of ESR signals due to intramembranous nitroxide radicals remained constant during the inhibition reaction of lipid peroxidation, suggesting that the prevention of lipid peroxidation is coupled with the reversible redox reaction between nitroxides and the reduced nitroxides in microsomes. The reduced forms of nitroxides, which were prepared by the reduction of intramembranous nitroxides, also inhibited the generation of TBA-reactive substances as well as the parent nitroxide. These facts indicate that either intramembranous nitroxide radicals or their reduced forms, "hydroxylamines," may be useful lipophilic antioxidants.

Animals↗
PubMed1993

Aging retards spin clearance from mouse brain and food restriction prevents its age-dependent retardation.

After the nitroxyl radical 3-carbamoyl-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (carbamoylPROXYL) was intraperitoneally administered to mice, the time courses of changes in the intensity of signals in L-band electron spin resonance spectra from their brains were measured. The spin clearance rate of old, ad libitum-fed mice was lower than that of young, ad libitum-fed mice. The rate of old, food-restricted mice was significantly higher than that of old, ad libitum-fed mice and was comparable to that of young, ad libitum-fed mice. The spin clearance was found to be due to the one-electron reduction of the nitroxyl radical, because a decreased spin intensity of it in serum was restored to the original level by potassium hexacyanoferrate (III) oxidation in vitro. These results suggest that reducing capacity in the cardiovascular system of mice is decreased with advancing age, and that food restriction prevents an age-dependent decrease in the reducing capacity.

Aging↗
PubMed1993

Acrylamide; induction of DNA damage, chromosomal aberrations and cell transformation without gene mutations.

The genotoxic potential of acrylamide monomer (AA), a compound familiar as a raw material of polyacrylamide electrophoresis gel, was extensively investigated in vitro. The results were clear cut: AA did not induce any gene mutations in Salmonella/microsome test systems (TA98, TA100, TA1535, TA1537), Escherichia coli/microsome assay (WP2 uvrA-) up to a dose of 50 mg AA/plate, or in HPRT-locus in Chinese hamster V79H3 cells (AA, 1-7 mM, 24 h treatment). On the other hand, AA showed a strong positive response: (a) in a Bacillus subtilis spore-rec assay (DNA damage) at 10-50 mg/disc, (b) to a chromosomal structural change test (AA, 2-5 mM, 24 h treatment), (c) to a polyploidy test (AA, 1-5 mM, 24 h treatment) in Chinese hamster V79H3 cells, (d) to a cell transformation assay in mouse BALB/c3T3 cells (AA, 1-2 mM, 72 h treatment). Sister chromatid exchange was also weakly but significantly induced by AA (AA, 1-2.5 mM, 24 h treatment) in Chinese hamster V79H3 cells. Carcinogenic potential of AA was reported in mice and rats several years ago. AA thus seems to be a typical clastogenic rodent carcinogen without any gene mutation potential. Furthermore, this experiment showed for the first time positive response of AA to a microbial test system (B. subtilis spore-rec assay).

Acrylamide↗
PubMed1993

Cutaneous leishmaniasis in mast cell-deficient W/Wv mice.

Genetically mast cell-deficient W/Wv mice infected with Leishmania amazonensis showed progressive development of ulcerative skin lesions. However, no significant differences between the W/Wv mice and the normal littermates with respect to size of the lesions, anti-Leishmania immunoglobulin E antibody, and the number of eosinophils accumulated in the lesions were observed.

Animals↗
PubMed1993

Differential effects of acyclothymidine, a potent pyrimidine nucleoside phosphorylase inhibitor, on the pharmacokinetics of doxifluridine in rabbits via oral administration.

Acyclothymidine (AcyT, 5-methyl-1-(2'-hydroxyethoxymethyl)uracil), a potent inhibitor of pyrimidine nucleoside phosphorylase (PyNPase), was co-administered with 5'-deoxy-5-fluorouridine (5'-DFUR), a PyNPase activating prodrug of 5-fluorouracil (5-FU), to rabbits. The absorption and pharmacokinetic parameters of 5'-DFUR and its active metabolite 5-FU, after administration of 5'-DFUR in combination with AcyT, were evaluated in the animals. Animals were given an oral or intravenous administration of 5'-DFUR (50 mg/kg) in combination with an equimolar dose of AcyT (40 mg/kg). The half-lives (t1/2) of 5'-DFUR and 5-FU in plasma were 16.8 and 11.5 min, respectively. AUC (area under the plasma concentration-time curve) of 5'-DFUR and 5-FU following the oral administration of 5'-DFUR (50 mg/kg) was 1710 and 24.3 micrograms.min/ml, respectively. After the oral co-administration of 5'-DFUR and AcyT (at a molar ratio of 1:1), the AUC values for 5'-DFUR and 5-FU increased to 2680 and to 121.1 micrograms.min/ml, respectively. However, this combination had little effect on the t1/2 of 5'-DFUR.

Administration, Oral↗
PubMed1993

In vivo EPR measurement of radical reaction in whole mice--influence of inspired oxygen and ischemia-reperfusion injury on nitroxide reduction.

In vivo EPR measurements were carried out with whole mice to evaluate the influence of inspired oxygen and ischemia-reperfusion injury on spin-clearance of the nitroxide radicals which were administered intravenously or intramuscularly. Nitroxide radicals in head, abdomen, or muscle domains were composed of sharp triplet lines. The peak heights decreased gradually with time. The reduction of nitroxide radicals depended both on the inspired oxygen concentration and on the domains. Femoral ischemia-reperfusion injury also affected spin-clearance of the nitroxide radical in the thigh. The results were discussed with regard to the generation of active oxygen species.

Animals↗
PubMed1993

Whole mouse measurement of paramagnetism-loss of nitroxide free radical in lung with a L-band ESR spectrometer.

Paramagnetism-loss of nitroxide radical in lung of whole mouse was characterized using L-band ESR technique. The nitroxide, hydroxy-TEMPO, which had been injected trans-tracheally into mouse lung was confirmed to lose its paramagnetism in one electron reduction. The reduction activity remained even after lavage of lung. The reduction was inhibited by N-ethylmaleimide, a membrane-permeable sulfhydryl-blocker, though direct reduction of the radical by sulfhydryls was not observed in vitro. Sulfhydryl-blockers floating in membranes also inhibited the reduction, depending on their chain length. The results indicate that the reduction may be done within plasma membranes of alveolar epithelial cells.

Animals↗
PubMed1992

Synthesis of halogenated trimetoquinol derivatives and evaluation of their beta-agonist and thromboxane A2 (TXA2) antagonist activities.

The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate beta 1 (guinea pig atria) and beta 2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both beta-adrenergic systems and gave a rank order of stimulatory potency of 1 much greater than 6 greater than or equal to 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 greater than 6 much greater than 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On beta-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5-position of TMQ completely abolished both beta 1- and beta 2-adrenergic agonist activities while imparting weak antagonist activity on beta 1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8-(trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on beta-adrenergic systems and TXA2 systems. On beta-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)-8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.

Adrenergic beta-Agonists↗
PubMed1992

Effects of the stereochemical orientation of phenethylamines and imidazolines on alpha-adrenergic receptor-mediated DNA synthesis in primary cultured rat hepatocytes.

The hepatic alpha 1-adrenergic receptor mediates a variety of hepatic functions including respiration, glycogenolysis, gluconeogenesis, and growth. We have utilized a rat primary hepatocyte culture system to show that the alpha 1-adrenergic receptor can be activated in a stereoselective manner by a series of phenethylamines and catecholimidazolines resulting in the stimulation of DNA synthesis as determined by [3H]thymidine incorporation. The phenethylamines adhered to the Easson-Stedman hypothesis with a rank order of potency of (-)-(R)-norepinephrine (NE) greater than (+)-(S)-NE greater than the desoxy analog dopamine (DA) for the stimulation of DNA synthesis. However, the 2-substituted catecholimidazolines did not follow this trend and demonstrated an order of potency of the desoxy analog 3,4-dihydroxybenzyl imidazoline (DHT) greater than or equal to (-)-(R)-2-(3,4,alpha-trihydroxybenzyl)imidazoline (TBI) greater than (+)-(S)-TBI. 4-Substituted catecholimidazolines were less potent as inducers of DNA synthesis than the corresponding 2-substituted analogs with an order of potency of (+)-(R)-4-(3,4-dihydroxybenzyl)imidazoline (DBI) greater than (+,-)-(R,S)-DBI greater than (-)-(S)-DBI. When the beta-hydroxyl moiety of NE is replaced with an amino group as in 3,4-dihydroxyphenylethylenediamine, the isomers are less active than the beta-hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic alpha 1-adrenergic receptor can recognize various isomeric forms of these compounds and that hepatocellular growth can be modulated in a stereoselective manner by phenethylamines and imidazolines.

Animals↗
PubMed1992

Occurrence and characteristics of hypodense eosinophils in rats infected with Trichinella spiralis.

Hypodense eosinophils are observed in peripheral blood and tissue from patients with eosinophilia due to helminthic infections. In this study, the variation in eosinophil density was examined in rats during Trichinella spiralis infection. Hypodense eosinophils were observed in the peripheral blood in association with Trichinella infection. In peritoneal fluid, which was representative of tissue fluid, a majority of eosinophils were hypodense regardless of the infection. During the course of tissue eosinophilia after the infection, there was a particular increase in the lowest dense cells in the population of hypodense eosinophils. Eosinophils with lower density, demonstrated larger diameters and had more potent cytotoxic activity.

Animals↗
PubMed1991

Diversity of the pharmacological actions of some tolazoline analogues in human platelets and rat aorta.

Tolazoline and two 4'-substituted benzyl analogues, 2-(4'-aminobenzyl) imidazoline (ABI) and 2-(4'-isothiocyanatobenzyl)imidazoline (IBI) were synthesized and evaluated for adrenoceptor activity in human platelets (alpha 2) and rat aorta (alpha 1), respectively. IBI was prepared as an affinity label for alpha-adrenoceptors and compared with chloroethylclonidine. Tolazoline, IBI, ABI and chloroethylclonidine inhibited the primary and secondary waves of epinephrine-induced human platelet aggregation. In aspirin treated platelets, primary wave aggregatory responses to epinephrine were blocked in a competitive manner by tolazoline, ABI. IBI and chloroethylclonidine giving pA2 values of 6.33, 6.12, 4.71 and 5.70, respectively. Only IBI blocked the aggregation responses to ADP (secondary wave only) arachidonic acid and U46619 (a thromboxane A2 agonist). Arachidonic acid-induced serotonin release and malondialdehyde formation and thrombin-induced release of [3H]arachidonic acid from membrane phospholipids were also blocked by IBI. These data indicate that IBI blocks arachidonic acid release, prostaglandin biosynthesis and the action of thromboxane A2. One hour exposure of aspirin treated platelets with IBI abolished inhibitory effects against epinephrine induced aggregation. In contrast to human platelets, both ABI and IBI produced contractions of rat aorta; however, only the responses to ABI were blocked in a competitive manner by the alpha-antagonists, phentolamine, prazosin, and SKF 104078. Moreover, idazoxan blocked the stimulatory actions of IBI, cirazoline and phenylephrine on rat aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗