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Biomedical subjects

M Kudoh

Publications and source records attributed to M Kudoh.

At least 55 records · Page 3Linked to original sources
PubMed1994

Selectivity of isoprenoid-containing imidazole antifungal compounds for sterol 14-demethylase P450 (P450(14)DM) and 7-ethoxycoumarin O-deethylase P450 of rat liver microsomes.

The imidazole antifungal compound AFK-108 (1-[2-(2,4-dichlorophenyl)-2-((2E)-3,7-dimethylocta-2,6- dienyloxy)ethyl]-1H-imidazole) has been shown to be a potent inhibitor for yeast lanosterol 14 alpha-demethylase (P450(14)DM), interacting specifically with the sterol side-chain recognition part of the substrate site through its geranyl moiety. AFK-108 acted as a potent inhibitor for rat liver P450(14)DM, while its farnesyl (AFK-110) and prenyl (AFK-122) homologues were weak inhibitors. This indicates that AFK-108 interacts with rat liver P450(14(DM in the same manner as with the yeast enzyme. However, the difference between the potency of AFK-108 and the homologues was greater in rat P450(14)DM than in the yeast enzyme. AFK-108 and its homologues partially inhibited 7-ethoxycoumarin O-deethylase activity of rat liver microsomes. The order of potency was AFK-122 > AFK-108 > AFK-110, indicating that some steric hindrance of the isoprenoid moiety might affect their potency. The inhibitory effect of AFK-108 for P450(14)DM was considerably higher than for 7-ethoxycoumarin O-deethylase P450, while the inhibition of AFK-110 and AFK-122 on these enzymes was of the same order of magnitude. These results suggest that azole compounds interacting with the side-chain recognition site of P450(14)DM may be good candidates as antifungal agents selective for fungal P450(14)DM.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1994

Long-term potentiation in the auditory cortex of adult rats.

Long-term potentiation (LTP) in the auditory cortex was studied in slices obtained from adult rats. White matter stimulation produced field potentials in layers II/III, which were composed of two negative waves followed by a slow positivity. The second negative and third positive waves were blocked by a low Ca2+ (0.48 mM) medium or by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM), while the first negativity unchanged. D-2-amino-5-phosphonovalerate (D-AP5, 50 microM) showed no clear effect on the field potentials. Tetanic stimulation of the white matter produced potentiation in the second negativity, and the potentiation was maintained for at least 30 min. D-AP5 blocked this potentiation completely. These data indicate that LTP is evoked by activation of N-methyl-D-aspartate (NMDA) receptors in the auditory cortex of adult rats.

2-Amino-5-phosphonovalerate↗
PubMed1994

An evaluation of a new lactic acid polymer drug delivery system: a preliminary report.

A new drug delivery system, made of a mixture of DL-lactic acid polymer and a copoly (L-lactic acid/delta-valerolactone) polymer (LAP) containing varying concentrations of Ofloxacin, has been evaluated. Results revealed that a LAP drug delivery system containing 0.03% Ofloxacin inhibited the in vitro growth of clinically derived Staphylococcus aureus and Pseudomonas aeruginosa. Further, in an in vivo situation in rats, at 1 week after the wound was inflicted, no infection was macroscopically seen in split-thickness wounds that had been covered by LAP drug delivery system containing 0.5 or 0.03% Ofloxacin, and more than 80% of the wound area had epithelialised.

Animals↗
PubMed1994

[A study on effectiveness of treatment and prevention of relapse using topical administration of terbinafine in a guinea pig model for tinea pedis].

The effectiveness of topical terbinafine (TBF) to tinea pedis was evaluated an animal model in which guinea pigs were experimentally infected through their planta pedis with Trichophyton mentagrophytes, then a 1% TBF or butenafine (BTF) cream was administered topically once daily for 4 consecutive weeks. The therapeutic efficacy was assessed on the basis of recovery of fungal cultures from the planta pedis. The cured guinea pigs were reared in a clean environment that protected the animals from reinfection. The dermal tissues were cultured 2, 4, and 8 weeks post-treatment to examine for relapse of tinea. Complete cure was achieved after 4 weeks of administration of TBF or BTF cream. In animals receiving 4 weeks of treatment with TBF, relapse was not observed up to 8 weeks after the termination of treatment. In animals treated with BTF for 4 weeks, while no relapse occurred 4 weeks after cessation of the treatment, relapse was detected in 2 out of 10 feet at 8 weeks after the termination of treatment. These results suggest that topical TBF is effective in curing the infection and in preventing relapse in a guinea pig model of tinea pedis.

Administration, Topical↗
PubMed1993

Encoding of amplitude-modulated tones by neurons of the inferior colliculus of the kitten.

Responses of single neurons of the central nucleus of the inferior colliculus (ICC) of kittens 4-43 days of age were studied using sinusoidally amplitude-modulated (AM) tones delivered monaurally or binaurally via sealed and calibrated earphones. The carrier frequency of the AM signal was set to the CF of the neuron. CFs ranged from 2-26 kHz. During the about first 2 weeks of postnatal life, ICC neurons responded to sound with periodic bursts of activity. In response to AM tones, discharges of ICC neurons at all ages studied were phase-locked to the envelope of the modulation waveform over a wide range of stimulus level and modulation depth. A linear relationship, independent of SPL, was found between the average phase of discharge on the modulation cycle and modulation frequency. The slope of the line represents a time delay, which was highly correlated with the first-spike latency to tone onset, and hence with the age of the animal. The mean effective phase of the discharge remained relatively constant with age. There was little systematic change in average phase of discharge with changing stimulus level or modulation depth, although the number of spikes evoked and the temporal pattern of the spikes within a modulation cycle could vary. The sensitivity function relating spike synchrony or spike count to modulation frequency was typically band-pass in nature. The most effective modulation frequency (MEMF) was, on average, 15 Hz, far below that reported for adult cat ICC cells. When AM tones were delivered binaurally, the discharge was a periodic function of the interaural phase difference of the stimulus envelopes. The results indicate that prior to the time the cochlea is able to respond to most environmental sounds, monaural and binaural circuits involving the ICC faithfully transmit information pertaining to amplitude-modulated signals in the rate and timing of their discharges. During the next several weeks, when neural thresholds fall to adult levels, ICC circuits are activated by amplitude modulated sounds at levels encountered in the normal acoustic environment even though they are restricted to modulation frequencies below those encoded by the adult.

Acoustic Stimulation↗
PubMed1992

Inhibition by a novel azole antifungal agent with a geranyl group on lanosterol 14 alpha-demethylase of yeast.

AFK-108 (1-[2-(2,4-dichlorophenyl)-2-((2E)-3,7-dimethylocta-2,6- dienyloxy)ethyl]-1H-imidazole) is a new imidazole derivative characterized by a geranyl substituent showing strong antifungal activity. Azole antifungal agents are known to be potent inhibitors of lanosterol 14 alpha-demethylase (P450(14)DM) of fungi. The role of the geranyl group of AFK-108 on interaction of AFK-108 with the target was studied by using Saccharomyces cerevisiae P450(14)DM as the model enzyme. AFK-108 and some of its derivatives bound to oxidized P450(14)DM with one-to-one stoichiometry and inhibited the demethylase activity. AFK-108 derivatives having the longer farnesyl or the shorter prenyl group showed lower affinity than AFK-108 for the enzyme. AFK-108 caused 100% inhibition at the equivalent concentration to P450(14)DM in the reaction mixture (0.07 microM), while the farnesyl derivative inhibited the activity by 60% at the same concentration. AFK-108 interfered with the binding of CO to the ferrous P450(14)DM. However, the interfering effect of the prenyl derivative was lower than that of AFK-108. Another AFK-108 derivative having the saturated 3,7-dimethyloctyl group was also a weaker inhibitor than AFK-108. These experiments suggest that the geranyl group of AFK-108 interacts with the substrate binding site of P450(14)DM that recognises the side chain of the substrate. AFK-108 is the first example of an azole derivative interacting with the side chain recognising region of the substrate binding site of P450(14)DM.

Antifungal Agents↗
PubMed1992

Analysis of the leukotriene D4 receptor in the granulation tissue of allergic inflammation in rats.

Leukotriene (LT) D4 receptor in the granulation tissue formed in the air pouch-type allergic inflammation model in rats was analyzed. Membrane preparation of the granulation tissue obtained 3-9 days after the antigen challenge has specific binding sites of [3H]LTD4. Scatchard analysis showed that the affinity (Kd) and the density (Bmax) were not changed among the granulation tissue obtained 3-9 days after the antigen challenge. The Kd value in the granulation tissue (0.90 +/- 0.12 nM) was close to that in the rat lung (1.00 +/- 0.24 nM) and the guinea pig lung (0.86 nM). On the other hand, Bmax (62 +/- 8 fmol/mg protein) in the granulation tissue was higher than that in the rat lung (21 +/- 4 fmol/mg protein) but was far less than that in the guinea pig lung (405 fmol/mg protein). LTC4 and LTE4 inhibited the binding of [3H]LTD4 to the membrane preparation of the granulation tissue in a concentration-dependent manner. IC50 of LTC4 and LTE4 were 1 x 10(-7) and 2 x 10(-7) M, respectively. A guanine nucleotide, guanyl-5'-yl-imido-diphosphate (GppNHp), reduced [3H]LTD4 binding to the membrane preparation of the granulation tissue suggesting that LTD4 receptors in the granulation tissue are associated with G proteins. These results indicate that LTD4 binding sites in the granulation tissue are high affinity receptors for LTD4. A possible role of LTD4 in the recurrence of allergic inflammation in the chronic phase is discussed.

Animals↗
PubMed1992

[A modified technique in total cavopulmonary connection].

We have used an alternative technique in Total Cavopulmonary Connection without using any prosthetic material. The technique is a modification of Senning operation in which a flap of right atrial wall is used to create a tunnel between inferior vena cava and superior vena cava. We used this modified technique in two cases, and they showed excellent postoperative convalescence.

Blood Vessel Prosthesis↗
PubMed1990

Ultracytochemical localization of Ca(2+)-ATPase in the mouse taste bud during the early postnatal period.

Calcium-ATPase (Ca(2+)-ATPase) in the cells of the taste bud in the mouse vallate papilla was detected by the electron microscopic cytochemical procedure. In the mature taste bud, the enzyme was intensively located on the plasma membrane of various cell types and at the periphery of nerve fibers, but not in the subcellular organelles such as mitochondria, rough endoplasmic reticulum (rER) and the Golgi apparatus. Probably, plasma membrane Ca(2+)-ATPase plays primary role in determining the cytosolic Ca2+ concentration of the taste bud cell and nerve at a very low range about 10(-7) M. In the developing taste bud during the early postnatal period, on the other hand, CA(2+)-ATPase was apparently located in the lumen and cisternae of the rER. Golgi apparatus and small vesicles in the gustatory epithelial cells. These results suggest that Ca(2+)-ATPase synthesized in the rER passes through the Golgi apparatus to the plasma membrane, mediated by transport vesicles.

Animals↗
PubMed1987

Partial and complete adenine phosphoribosyltransferase deficiency associated with 2,8-dihydroxyadenine urolithiasis: kinetic and immunochemical properties of APRT.

We have studied adenine phosphoribosyltransferase (APRT) in the hemolysates from the families of 2,8-dihydroxyadenine urolithiasis associated with partial deficiency of APRT (the Japanese type) and complete deficiency of APRT (the null type). The APRT in the control subjects was found to be heat-stable at the physiological concentration of phosphoribosylpyrophosphate (PRPP), which was close to the value of its Km for PRPP. The APRT in the Japanese type showed 10 times higher Km values for PRPP and needed a comparably increased level of PRPP for stability in vitro. No change in red cell PRPP was found in the Japanese type of APRT deficiency. The content of APRT enzyme protein was decreased in the hemolysates of the Japanese type, probably due to its lability at the level of PRPP present in the cells. The heterozygote of the null type also had labile enzyme molecules at the physiological PRPP concentration.

Adenine↗
PubMed1985

Isolation of a protein labeled with diisopropyl fluorophosphate on stimulation of polymorphonuclear leukocytes with immune complexes.

As demonstrated by others, diisopropyl fluorophosphate (DFP) markedly inhibits the O2- generation from guinea-pig polymorphonuclear leukocytes (PMN) stimulated by an antibody complex with ovalbumin (Ag-Ab complex), and also the intracellular uptake of antibody-sensitized erythrocytes by the cells. However, when PMN were treated with DFP and washed to remove the inhibitor, they again became able to exhibit the O2- -generating and phagocytic activities. The [3H]DFP-labeling of intact PMN followed by solubilization with Triton N101, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed the existence of several [3H]DFP-labeled proteins with different mol. wts, which disappeared on pretreatment of cells with cold DFP. However, stimulation of DFP-pretreated PMN with Ag-Ab complex in the presence of [3H]DFP resulted in the appearance of a [3H]DFP-labeled, membrane-bound protein with a mol. wt of 40,000. This protein was isolated by affinity chromatography of the solubilized PMN and phagosomes on anti-Ig antibody-Sepharose 4B. Although the enzymatic properties of the protein are not clear, the results so far obtained suggest that it is a putative, stimulus-activated serine protease participating in the triggering events leading to the activation of NADPH oxidase responsible for the respiratory burst and the formation of phagosomes.

Animals↗
PubMed1984

Toxicology of mabuterol.

The acute, subacute and chronic toxicity of dl-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butyl-amino-ethanol hydrochloride (mabuterol), a new beta 2-selective adrenoceptor stimulant, was studied in mouse, rat, rabbit and dog. The acute oral LD50 was between 199.9 and 319.3 mg/kg in all four species used and did not differ significantly between the sexes. Intravenous LD50 was between 18.3 and 51.1 mg/kg (four species), i.p. between 60 and 78.3 mg/kg and s.c. between 113 and 125.7 mg/kg (mouse and rat only). In subacute and chronic studies in Wistar rats, mabuterol was dosed by gavage at 0, 10, 20, 40, 80 and 120 mg/kg for 1 month, and 0, 1, 2.5, 10 and 40 mg/kg for 3 (interim) and 6 months or in food at 0, 2.5, 10 and 40 mg/kg for 6 (interim) and 12 months. Beagle dogs were dosed by gelatine capsule with 0, 0.05, 0.5, 5 and 50 (25) mg/kg for 6 (interim) and 24 months. In rats, 1 and 2.5 mg/kg were well tolerated. At 10 mg/kg and above, irritability and hypersalivation were seen dependent on dose. Two males and one female given 120 mg/kg died from the test substance. In dogs, 0.05, 0.5 and 5 mg/kg were well tolerated. 50 mg/kg caused vomiting, diarrhoea, tonic-clonic convulsions and increased salivation. One male had to be killed because of severe convulsions. At term, 3 of 56 female rats of the one-year study had benign mesovarian leiomyomas. No other substance-related changes were discovered but all findings belonged to the spontaneous pathology of rat and dog, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗