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S Higuchi

Publications and source records attributed to S Higuchi.

At least 541 records · Page 30Linked to original sources
PubMed1981

[Studies of D-penicillamine (5): effects on rat adjuvant arthritis (author's transl)].

D-Penicillamine (D-PA), 80-100 mg/kg/day enhanced the early phase of adjuvant arthritis (AA) in rats when it was administered orally for about 4 weeks after the adjuvant injection day, whereas dexamethasone (1 mg/kg/day, p.o.) and chloroquine diphosphate (25 mg/kg/day, p.o.) inhibited AA in the same dosing regimen. On the other hand, subcutaneous injection of sodium aurothiomalate (12.5 mg/kg/day) enhanced AA initially, but inhibited it later. The enhancing effect of D-PA on the early phase of AA was observed also at doses of 50 mg/kg/day and 200 mg/kg/day, but, in the case of 200 mg/kg/day, inhibited the later phase of AA. When the administration of D-PA was started before the adjuvant injection, it showed a tendency to suppress AA on proportion to the dosing period. The effect of D-PA, however, was not observed in the model when the drug administration was started after the establishment of arthritis. The co-administration pyridoxine HCl did not influence the effect of D-PA on AA. A good correlation was not obtained between the inflammatory score and the PPD induced skin reaction, serum metals level and histopathological changes of lymph node in the AA rats treated with D-PA. Thus the effect of D-PA on AA was related to dose, timing and duration of the administration. It was suggested that the enhancing and inhibitory effects of D-PA on AA were not based on vitamin B6, depletion, but rather were caused by inhibition of T1 and T2 lymphocytes which may be regulating this arthritis process.

Administration, Oral↗
PubMed1981

[Effects of anti-inflammatory drugs on the arachidonic acid induced erythema in guinea pigs (author's transl)].

The inhibitory effects of anti-inflammatory drugs on th erythema induced by arachidonic acid in guinea pigs were studied. Values of ED50 (mg/kg, p.o.) were; diclofenac sodium (19.9), indomethacin (28.1), naproxen (52.4), phenylbutazone (67.1), ibuprofen (81.3), aspirin (92.6). These drugs, however, were ineffective on the erythema induced by prostaglandin E2. Basic nonsteroidal and steroidal anti-inflammatory drugs and anti-oxidants were negative in the inhibition of arachidonic acid-induced erythema. Cyproheptadine as an anti-histamine and -serotonin agent and morphine as a CNS acting agent were also negative. Erythema did not occur following treatment with linoleic acid, linolenic acid and gamma-linolenic acid. Bishomo-gamma-linolenic acid-induced erythema was inhibited by diclofenac sodium. The inhibition of acidic nonsteroidal anti-inflammatory drugs in this system seemed to be the result of a block of the enzymatic conversion of arachidonic acid to prostaglandins. The arachidonic acid-induced erythema in guinea pigs can serve as a new animal model for evaluating prostaglandins biosynthesis inhibitors such as anti-inflammatory drugs.

Animals↗
PubMed1980

Application of the stable isotope technique to the elucidation of the saturation phenomenon of nicardipine hydrochloride metabolizing enzyme activity in dogs.

The pharmacokinetics of 2-(N-benzyl-N-methylamino)ethyl methyl 2,6-dimethyl 4-(m-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate hydrochloride (nicardipine hydrochloride) was studied in dogs by using two deuterium labelled compounds (N-[2H3]methyl and N-[2H7]benzyl derivatives). The biological isotope effect of the [2H7]derivative, which was calculated from the half-lives in vivo and the metabolic rates in vitro, was 1.37 and 1.36, respectively, suggesting that debenzylation in the liver was one of the rate limiting steps of elimination of the drug, while the [2H3] derivative did not show this effect. The [2H3] derivative was administered orally or intravenously to dogs 2 h after oral administration of the non-labelled compound, and the plasma concentration of the [2H3] derivative was determined by the selected ion monitoring method. The biological half-lives, AUC and systemic availability increased with increasing doses of non-labelled nicardipine hydrochloride, while plasma clearance decreased, suggesting that the hepatic enzyme activity metabolizing the drug was partly saturated by the drug or its metabolites.

Animals↗
PubMed1980

Comparative pharmacokinetics of nicardipine hydrochloride, a new vasodilator, in various species.

1. The pharmacokinetics of a new potent vasodilator, 2-(N-benzyl-N-methylamino)-ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (nicardipine hydrochloride), were studied after oral and i.v. dosage to rats, dogs, monkeys and humans. 2. The plasma half-life and volume of distribution in humans after i.v. administration did not change with dosage in clinical range. In rats and dogs these parameters increased with higher doses, probably because of the potent vasodilative effect of the drug. 3. The plasma clearance in dogs and humans was not affected by dosage, but in rats tended to increase slightly with higher doses. 4. Systemic availability after oral administration was low in spite of excellent absorption, indicating a marked first-pass effect. Increased systemic availability with increased dose indicates that the metabolic activity of the liver may become partly saturated with the drug or its metabolites. 5. Disappearance of the drug from the plasma after i.v. administration was fastest in rats > dogs approximately monkeys > humans. The terminal half-life of the drug after i.v. administration to humans was about 1 h.

Administration, Oral↗
PubMed1980

Metabolic fate of nicardipine hydrochloride, a new vasodilator, by various species in vitro.

1. The metabolic fate of nicarpidine hydrochloride by rats, dogs and monkeys in vitro has been compared with previously reported in vivo studies. 2. The rate of metabolism of the drug in rat liver was 1.76 mumol/g tissue per 20 min, while the values in the intestine, kidney, lung and blood were less than 0.1 mumol/g tissue per 20 min, suggesting that the first-pass effect observed in vivo was due mainly to metabolism of the drug in the liver. 3. The rates of liver metabolism were 1.76, 0.45 and 0.55 mumol/g tissue per 20 min in rats, dogs and monkeys, respectively. This species difference correlates well with the differences in plasma clearance values, which were 197, 37 and 27 ml/min per kg in rats, dogs and monkeys, respectively, after i.v. administration of nicardipine hydrochloride (0.4 mg/kg). 4. Urinary metabolites were qualitatively similar, but the proportions of each were slightly different, among rats, dogs, monkeys and humans. The most abundant urinary metabolite was derived from debenzylation of the N-benzyl-N-methylaminoethyl ester side-chain in dogs and humans, and from hydrolysis of the same side-chain to the carboxylic acid, together with oxidation of the dihydropyridine nucleus to pyridine, in rats and monkeys. The metabolites produced in vitro were also qualitatively similar in the animal species examined. 5. More than 90% of the drug was reversibly bound to the plasma protein at 0.1 microgram/ml in the three animal species and humans. The extent of binding decreased with increased drug concentration in rats and humans, but not in dog and monkeys.

Animals↗
PubMed1980

Pharmacokinetic studies on nicardipine hydrochloride, a new vasodilator, after repeated administration to rats, dogs and humans.

1. Various doses of [14C]nicardipine HCl were administered orally at different intervals for different periods to rats and dogs, and cumulative excretion, plasma concn. of unchanged drug, plasma clearance, tissue distribution, and AUC determined. 2. Plasma concn. in 12 patients with cerebrovascular disease receiving 20 mg three times per day for 28 (6 patients) or 365 days (6 patients) was determined on various days 1 h after the third dose. 3. In tissues of rats receiving 3 mg/kg/day for 21 days, distribution 1 h after administration on day 14 was 1.4-2.5 times higher than on day one; there was no statistical difference between day 14 and 21, suggesting that a steady state had been established within 14 days. 4. In rats receiving 3 mg/kg/day for seven days, cumulative excretion was 97.3% administered drug, indicating no tendency to accumulation. 5. Doses of 10 mg/kg three times at 3 h intervals to dogs significantly increased the plasma concn. on repeated administration, but this was not the case if the drug was administered at 6 h intervals or if the dose was decreased to 2 mg/kg. These non-linear pharmacokinetics may be ascribable to saturation of the hepatic drug-metabolizing enzyme activity. 6. In dogs given 5 mg/kg three times per day at 3 h intervals for seven days, max. plasma concn. and AUC on day 4 were 1.8 and 1.6 times higher, respectively, than on day 1. On days 4 and 7, these values were similar, suggesting that a steady state had been established within 4 days. 7. In six patients receiving the drug for 28 days, the mean plasma concn. on day 1, 7, 14, and 28 was approx. 0.1 microgram/ml, similar to the value on day 365 in the other six patients. This indicates that during long periods of administration, the plasma concn. of the drug shows no tendency to increase.

Adult↗
PubMed1980

Macrophage functional heterogeneity in vivo. Macrolocal and microlocal macrophage activation, identified by double-staining tissue sections of BCG granulomas for pairs of enzymes.

BCG lesions were produced in the skin of rabbits, and biopsies were performed at 7, 21, and 42 days, when they were developing, maximal in size, and almost healed, respectively. Tissue sections were prepared and stained histochemically for several enzymes. The percentage of cells stained for a given enzyme and the distribution of such cells within lesions of various ages were determined. Seven-day BCG lesions contained few esterase- and beta-galactosidase-positive macrophages, but 21-day lesions contained many, especially in the viable and nonviable tuberculous granulation tissue at the edge of the now prominent caseous necrotic center. Both 7-day and 21-day lesions contained many acid phosphatase- and cathepsin-D-positive macrophages, which were numerous in the more peripheral parts of the lesion, where little or no necrosis was present. Enzyme patterns in 42-day lesions resembled those in 21-day lesions. The role of each of these enzymes in the development and regression of the BCG lesion is unknown. Nonetheless, these studies clearly demonstrate that this macrophage population is heterogeneous and that macrophages carry out different functions in different parts of the lesion at different times. Histochemical techniques were developed to stain two enzymes in the same tissue section. The first stain usually contained a naphthol substrate and produced a red color; the second stain contained an indoxyl substrate and produced a blue color. A cell staining with both was colored purple. The peroxidase-antiperoxidase immunocytochemical technique for cathepsin D (producing a red color) was also employed. 1) Red esterase (hydrolyzing naphthol AS-D acetate) and beta-galactosidase, and 2) red esterase and blue esterase (hydrolyzing 5-bromo-4-chloro-indoxyl acetate), probably the same enzyme, were usually present in the same macrophage. In contrast, each of the following enzyme pairs was usually present in a different macrophage: 3) cathepsin D and beta-galactosidase, 4) cathepsin D and blue esterase, 5) acid phosphatase and beta-galactosidase, and 6) acid phosphatase and blue esterase. Roughly 10% of the macrophages stained for one enzyme existed side by side with macrophages stained for a different enzyme. These results suggest that local macrophage activation is under two levels of control. The first, macrolocal control, would determine the overall enzyme distribution in the lesion; whereas the second, microlocal control, would determine enzyme distribution on a cell-by-cell basis, ie, how two neighboring macrophages can each be rich in a different enzyme.

Animals↗
PubMed1980

Structure and stability of complexes between poly-5-bromouridylic acid and 2,9-dimethyladenine or 2-methyladenosine.

The complexes formed between poly-5-bromouridylic acid (poly(BU)) and 2,9-dimethyladenine (m2m9A) or 2-methyladenosine (m2Ado) were investigated. The stoichiometry of the m2m9A-poly(BU) complex was found to be 1:1 as determined by equilibrium dialysis measurements. The CD spectra of the complexes showed the formation of helically ordered structure. This is also confirmed by the sharp melting profiles. A comparison of the CD spectra with that of poly(m2A) . poly(BU) complex revealed a close relationship of the helical structures for these three types of complexes. It was observed that the m2m9A was able to form a thermally more stable complex with the poly(BU) than the m2Ado did.

Adenine↗
PubMed1979

Simplified determination of lorazepam and oxazepam in biological fluids by gas chromatography-mass spectrometry.

Lorazepam and oxazepam in plasma and urine were measured by gas chromatography-mass spectrometry. Oxazepam was used as an internal standard in the assay of lorazepam and vice versa. After removal of interfering substances with n-hexane, the drugs were extracted with benzene and converted to N1,O3-bistrimethylsilyl derivatives. Glucuronide forms of the drugs were extracted after hydrolysis with beta-glucuronidase. A common fragment ion at m/e 429 was used to monitor the two drugs. The sensitivity was 2 ng/ml for both drugs, which was sufficient to determine plasma and urine concentrations after therapeutic doses to humans.

Anti-Anxiety Agents↗
PubMed1979

Histochemical demonstration of enzyme activities in plastic and paraffin embedded tissue sections.

Histochemical staining for enzymes is usually performed on frozen sections. This report lists the longer incubation times required to demonstrate esterase, acid phosphatase, beta-galactosidase, and cytochrome oxidase in plastic embedded and ruotine paraffin embedded tissues. The sections embedded in plastic, i.e. water soluble methacrylate (Polyscience's JB-4) and cut at 2 micrometers, were far superior to frozen sections and paraffin embedded sections both in tissue detail and in the localization of the histochemical reaction product.

Acid Phosphatase↗
PubMed1978

Quantitative determination of nifedipine in human plasma by selected ion monitoring.

A highly sensitive and specific method for the determination of nifedipine in plasma is described. Nifedipine was oxidized to its pyridine analogue with nitrous acid and determined by selected ion monitoring. Deuterium labeled nifedipine was used as an internal standard. Plasma levels as low as 5 ng ml-1 were measured. The usefulness of the method was demonstrated by obtaining plasma concentration curves for humans after an oral dose of 10 mg.

Humans↗
PubMed1978

The effect of cortisone on the accumulation, activation, and necrosis of macrophages in tuberculous lesions.

Rabbits were injected intramuscularly with cortisone acetate (2 mg/kg) on alternate days. Six days after the first injection these rabbits and controls were injected intradermally in multiple sites with BCG (the vaccine strain of tubercle bacillus). Periodically, over the next 2 months, the resulting lesions were measured and surgically biopsied, and the animals were tuberculin-tested. Macrophage activation in the BCG lesions was evaluated histochemically by staining for beta-galactosidase activity. Both BCG lesions (and tuberculin reactions) in the cortisone-treated group were considerably smaller than those in the control group. Cortisone was highly effective in reducing the number of infiltrating mononuclear cells (MN), the amount of caseous necrosis and ulceration, and the percent of NM that were beta-galactosidase-positive. The decreased activation and reduced number of macrophages readily explains the increased susceptibility to tuberculosis found amoung patients receiving glucocorticosteroids. In the BCG lesions, the local decrease in the number and function of leukocytes probably explains the decreased tissue necrosis. Such antiinflammatory effects of corticosteroids may offset, in selected antimicrobial-treated cases, the hormone's detrimental effect on host resistance to infectious agents.

Animals↗
PubMed1977

Enhancement of phytohemagglutinin-induced DNA synthesis of mouse thymocytes and T-lymphocytes by a neutral protease of polymorphonuclear leukocytes.

Mouse thymocytes were poorly triggered in vitro with phytohemagglutinin (PHA) to induce DNA synthesis and the response was markedly enhanced by culture supernatant (SUP) of polymorphonuclear leukocytes (PMN). The PMN factor was nondialysable, heat-labile and precipitated with 65% ammonium sulphate. Its molecular weight was approximately 19,000 on sephadex G-75. The sephadex fraction had a proteolytic activity on 3H-acetyl hemoglobin at neutral pH. The protease seemed to be a chymotrypsin-like enzyme on the basis of inhibition profile using various protease inhibitors. The thymocyte-helping activity in the protease fraction was absorbed by affinity columns of protease inhibitors. The PMN-protease also enhanced the DNA synthesis by antigen-stimulated lymph node cells and by PHA-stimulated T-lymphocytes, but not by LPS-stimulated B-lymphocytes. Only the lymphocytes already been stimulated with antigen or mitogen received preferentially the helping action by PMN-protease. The helping activity was effectively absorbed by PHA-stimulated thymocytes but not by nonstimulated thymocytes. These evidences seems to suggest that acceptor sites for the protease, newly developed on lymphocyte surface after stimulation, may play an important role in the enhanced DNA synthetic response.

Animals↗