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I Horii

Publications and source records attributed to I Horii.

At least 19 recordsLinked to original sources
PubMed2001

Synthesis and antifungal activities of novel 1,3-beta-D-glucan synthase inhibitors. Part 1.

Highly potent 1,3-beta-D-glucan synthase inhibitors 10, 11 and 13 have been identified by the chemical modification of the fungicidal macrocyclic lipopeptidolactone, RO-09-3655 (1), isolated from the cultured broth of Deuteromycotinia spp. D-Ornithine derivative (10) showed improved antifungal activity in the systemic candidiasis model in mice and reduced hepatotoxicity in vitro, as compared with 1.

Animals↗
PubMed2000

Expression of elastin-related proteins and matrix metalloproteinases in actinic elastosis of sun-damaged skin.

Actinic elastosis is characterized by an accumulation of elastotic material in the upper dermis and is considered to be a manifestation of ultraviolet-induced skin aging. To compare the structural components of the elastotic material in actinic elastosis with those in normal skin, skin specimens were stained with antibodies raised against various elastin-related proteins. Elastotic materials exhibited a strong reaction to the antibodies for elastin, microfibril-associated glycoprotein-1 (MAGP-1), MAGP-4, matrix metalloproteinase 1 (MMP-1), MMP-2 and MMP-3, but a diminished reaction to anti-MMP-9 antibody. Fibroblast cell lines from the upper dermis of affected and unaffected skin were established, and the mRNA levels of MMPs were determined. MMP-1 and -2 mRNA levels were found to be elevated approximately twofold in the fibroblasts from actinic elastosis. Since MMP-1 and -2 are considered to be major enzymes involved in the degradation of matrix components, the accumulation of elastotic materials in actinic elastosis may be related to the degradation process.

Aged↗
PubMed2000

The design and synthesis of a new tumor-selective fluoropyrimidine carbamate, capecitabine.

To identify an orally available fluoropyrimidine having efficacy and safety profiles greatly improved over those of parenteral 5-fluorouracil (5-FU: 1), we designed a 5-FU prodrug that would pass intact through the intestinal mucisa and be sequentially converted to 5-FU by enzymes that are highly expressed in the human liver and then in tumors. Among various N4-substituted 5'-deoxy-5-fluorocytidine derivatives, a series of N4-alkoxycarbonyl derivatives were hydrolyzed to 5'-deoxy-5-fluorocytidine (5'-DFCR: 8) specifically by carboxylesterase, which exists preferentially in the liver in humans and monkeys. Particularly, derivatives having an N4-alkoxylcarbonyl moiety with a C4-C6 alkyl chain were the most susceptible to the human carboxylesterase. Those were then converted to 5'-deoxy-5-fluorouridine (5'-DFUR: 4) by cytidine deaminase highly expressed in the liver and solid tumors and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumors. When administered orally to monkeys, a derivative having the N4-alkoxylcarbonyl moiety with a C5 alkyl chain (capecitabine: 6) The highest AUC and Cmax for plasma 5'-DFUR. In tests with various human cancer xenograft models, capecitabine was more efficacious at wider dose ranges than either 5-FU or 5'-DFUR and was significantly less toxic to the intestinal tract than the others in monkeys.

Administration, Oral↗
PubMed2000

Extended activity in cynomolgus monkeys of a granulocyte colony-stimulating factor mutein conjugated with high molecular weight polyethylene glycol.

The activity of a granulocyte colony-stimulating factor (G-CSF) mutein (nartograstim; [NTG]) conjugated with an average of two polyethylene glycol (PEG) chains per protein molecule was examined in cynomolgus monkeys following a single s.c. injection. Groups of monkeys were given 10 microg/kg, 30 microg/kg, or 100 microg/kg. For comparison, one group of monkeys was given 5 microg/kg of recombinant human G-CSF (rHuG-CSF) daily for six days. In monkeys given 100 microg/kg of PEG-NTG, neutrophil levels reached a peak one day after injection approximately 20-fold higher than baseline levels. Neutrophil numbers in these animals were still significantly elevated six days after injection. In contrast, peak neutrophil levels in monkeys given six injections of rHuG-CSF reached a peak only on day 6 and were approximately the same as that in monkeys given a single dose of PEG-NTG six days before. Pharmacokinetics of PEG-NTG in these monkeys indicated that the area under the plasma concentration time curve (AUC) increased with increasing the dose from 497 ng x h/ml at 10 microg/kg, 6,140 ng x h/ml at 30 microg/kg to 27,900 ng x h/ml at 100 microg/kg. In a separate study, the effects of single doses of 100 microg/kg of PEG-NTG, rHuG-CSF, and unmodified NTG were compared. In this experiment, peak numbers of neutrophils were reached two days after injection in animals receiving PEG-NTG and one day after in animals given unmodified proteins. The pharmacokinetic parameters demonstrated increased exposure for PEG-NTG relative to the unmodified proteins with an AUC0. of 21,012 ng x h/ml compared with 5,492 ng x h/ml for rHuG-CSF and 5,153 ng x h/ml for NTG. These results demonstrate that conjugation of a G-CSF mutein with high molecular weight PEG results in a preparation that can induce prolonged elevation of neutrophils in normal nonhuman primates following a single injection.

Animals↗
PubMed2000

Aromatic retinoid Ro 40-8757 reduces immunotoxicities of cyclophosphamide as revealed by immunohistochemical staining of lymphoid tissues and general pathologic examinations.

The aromatic retinoid (arotinoid) Ro 40-8757 (4-[2-[p-(E)-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) propenyl]phenoxy]ethyl]-morpholine), a compound with antitumor activities, has been studied in a combination therapy with the cytostatic antitumor drug cyclophosphamide (CPA), and was found to protect bone marrow from the toxic effects of CPA. To evaluate its protective effects against CPA toxicities on lymphoid systems, we treated BDF1 mice with Ro 40-8757 orally for 1 to 5 weeks in combination with CPA intraperitoneally. After the combination treatment, mice were subjected to immunohistochemical analysis with antibodies against cell surface markers (Thy 1.2, Lyt-2, L3T4, Kappa chain, and Ia) and, in addition, general pathologic examinations were done. The protective effects of Ro 40-8757 on CPA toxicities were observed. The lymphocyte reductions (both in T cells and B cells) in lymphoid organs by CPA were apparently less severe. In particular, recovery of immature T cells in the thymic cortex was greater in combination treatment with Ro 40-8757 and CPA than in treatment with CPA alone. From these results, it can be concluded that Ro 40-8757 protects the lymphoid organs (thymus, spleen, and lymph node) from the immunotoxicity of CPA, and the protective effect is evident, especially in the thymic cortical lymphocytes.

Animals↗
PubMed1999

Relationship between molecular mass and duration of activity of polyethylene glycol conjugated granulocyte colony-stimulating factor mutein.

Proteins conjugated with polyethylene glycol (PEG) have increased in vivo activity compared to native proteins. We examined the activity of a variety of PEG conjugates prepared with a recombinant mutein of granulocyte colony-stimulating factor (nartograstim [NTG], KW-2228). The total PEG mass was varied by the number and size of the PEG molecules conjugated. In vitro activity, determined using a proliferation assay with G-NFS-60 cells, demonstrated an inverse relationship between PEG mass and concentration required for half-maximal proliferation. In vivo activity was examined by injecting compounds subcutaneously into normal mice and determining neutrophil counts at various times. Initial experiments in C57BL/6J mice indicated that neutrophil levels were significantly elevated 5 days after a single injection of 25 micrograms/mouse of each PEG-NTG preparation. More detailed experiments were performed with several of the preparations in C3H/HeJ mice lacking endotoxin receptors. The results demonstrated that the time after injection at which neutrophil numbers reached a maximum increased with increasing size of PEG. Similar results were obtained with purified preparations containing 1, 2, or 3 units of 20-kDa PEG per molecule of NTG, showing that increasing the extent of PEGylation also increases in vivo activity. Dose-response studies with the 20-kDa PEG-NTG demonstrated a plateau at doses > 2.7 micrograms/mouse at day 3. The plateau dose increased to 8.4 micrograms/mouse at day 5, and no plateau was evident at the highest dose tested (50 micrograms/mL) at days 7 and 10. These results demonstrate that elevated neutrophil levels can be maintained for extended periods following single administration of high-molecular-weight PEG-NTG.

Animals↗
PubMed1999

[Discovery and development of novel anticancer drug capecitabine].

Capecitabine (N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) is a novel oral fluoropyrimidine carbamate, which was designed to be sequentially converted to 5-fluorouracil (5-FU) by three enzymes located in the liver and in tumors. N4-alkoxycarbonyl-5'-deoxy-5-fluorocytidine derivatives including capecitabine pass intact through the intestinal tract and are sequentially converted to 5-FU by a cascade of the three enzymes. The first step is the conversion to 5'-deoxy-5-fluorocytidine (5'-DFCR) by carboxylesterase located in the liver, then to 5'-deoxy-5-fluorouridine (5'-DFUR) by cytidine deaminase highly expressed in the liver and various solid tumors, and finally to 5-FU by thymidine phosphorylase (dThdPase) preferentially located in tumor tissues. Among large numbers of the derivatives, capecitabine was selected based on its susceptibility to hepatic carboxylesterase, oral bioavailability in monkeys and efficacy in a human cancer xenograft. Capecitabine given orally yielded substantially higher concentrations of 5-FU within tumors than in plasma or normal tissue (muscle). The tumor 5-FU levels were also much higher than those achieved by intraperitoneal administration of 5-FU at equi-toxic doses. This tumor selective delivery of 5-FU ensured greater efficacy and a more favourable safety profile than with other fluoropyrimidines. In 24 human cancer xenograft models studied, capecitabine was more effective at a wider dose range and had a broader spectrum of antitumor activity than 5-FU, UFT or its intermediate metabolite 5'-DFUR. The susceptibility of the xenografts to capecitabine correlated with tumor dThdPase levels. Moreover, the conversion of 5'-DFUR to 5-FU by dThdPase in tumor was insufficient in a xenograft model refractory to capecitabine. In addition, the efficacy of capecitabine was enhanced by dThdPase up-regulators, such as by taxanes and cyclophosphamide and by X-ray irradiation. The efficacy of capecitabine may, therefore, be optimized by selecting the most appropriate patient population based on dThdPase status and/or by combining it with dThdPase up-regulators. Capecitabine has additional characteristics not found with 5-FU, such as potent antimetastatic and anticachectic actions in mouse tumor models. With these profiles, capecitabine may have substantial potential in cancer treatment.

Animals↗
PubMed1998

Advantages of toxicokinetics in new drug development.

Toxicokinetic (TK) study is generally required for toxicological evaluation and safety assessment, particularly in the pivotal toxicological studies which are requested on the basis of drug registration. The estimation points of TK data are: (1) determination of TK profile in toxicity study, (2) selection of dose, dosing form, alternative dosing route, (3) help for the evaluation of toxicity (non-effect/toxic dose, toxicological mechanism), (4) comparative evaluation between animal and human cases, (5) recommendation of the starting dose in the first human clinical trial. On the other hand, as a very recent trend, TK data are practically used for the purpose of drug discovery such as lead-optimization and candidate-selection. This paper presents practical examples of TK data in terms of their usefulness, and discusses how to evaluate the toxicity of a drug with the aid of a variety of TK studies.

Animals↗
PubMed1998

Flow cytometric analysis for sperm viability and counts in rats treated with trimethylphosphate or pyridoxine.

Six-week old SD-Slc male rats were treated for 4 weeks with compounds known to induce toxicological changes in male reproductive organs (pyridoxine in saline, 500 mg/kg/day, i.p.) or sperm (trimethylphosphate in distilled water, 100 mg/kg/day, p.o.). Each sperm sample taken from the cauda epididymis was analyzed with flow cytometry for the evaluation of sperm viability and counts. Sperm motility and morphology by microscopical observation, and histopathological examination of reproductive organs were also performed for estimating the adverse effects of each compound on spermatogenesis and sperm. While a decrease in sperm motility was noted for the trimethylphosphate group, the low motile sperm was evaluated as being viable sperm, not moribund, with flow cytometry. In the pyridoxine group, microscopical observation revealed morphological changes of sperm and a decrease of motility. The present sperm analysis with flow cytometry also suggested morphological changes reflected by dot plot as well as decrease of sperm viability and counts. These results indicated that this procedure led to profound findings in the compound-treated animals, with evaluation as viable sperm, not moribund, in a low motile sperm sample, and suggesting morphological changes in the dot plot of flow cytometry.

Animals↗
PubMed1996

Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors.

SUMMARY: Mice lacking p27(Kip1) have been created by gene targeting in embryonic stem cells. These mice are larger than the control animals, with thymus, pituitary, and adrenal glands and gonadal organs exhibiting striking enlargement. CDK2 activity is elevated about 10-fold in p27(-/-) thymocytes. Development of ovarian follicles seems to be impaired, resulting in female sterility. Similar to mice with the Rb mutation, the p27(-/-) mice often develop pituitary tumors spontaneously. The retinas of the mutant mice show a disturbed organization of the normal cellular layer pattern. These findings indicate that p27(Kip1) acts to regulate the growth of a variety of cells. Unexpectedly, the cell cycle arrest mediated by TGFbeta, rapamycin, or contact inhibition remained intact in p27(-/-) cells, suggesting that p27(Kip1) is not required in these pathways.

Animals↗
PubMed1996

Epidermal cell proliferative activity assessed by proliferating cell nuclear antigen (PCNA) decreases following immobilization-induced stress in male Syrian hamsters.

The effects of immobilization-induced stress on epidermal cell proliferative activity, assessed by the proliferating cell nuclear antigen (PCNA) positive ratio, were examined in male Syrian hamsters. In non-stressed animals, PCNA-positive cells were identified frequently in the epidermis in pinna, abdomen, dorsum and scrotum. However, in animals stressed for 4 consecutive days (6 h/day) PCNA-positive cells were significantly reduced in all areas. In stressed animals, the plasma levels of cortisol, corticosterone, epinephrine, and norepinephrine, which are inhibitory to epidermal cells, increased, but plasma testosterone, which is stimulatory to epidermal cells, decreased. The present findings suggest that psychological or physiological stress influences proliferative activity, a fundamental cutaneous function, by inducing changes in the neuroendocrine system.

Animals↗
PubMed1996

Comparative immunotoxicity assessment of N4-Trimethoxybenzoyl-5'-deoxy-5- fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) in BDF1 mice.

N4-Trimethoxybenzoyl-5'-deoxy-5-fluorocytidine (Ro 09-1390) and 5'-deoxy-5-fluorouridine (5'-DFUR) are 5-fluorouracil (5-FU) derivatives developed as anti-tumor pharmaceuticals. To evaluate immunotoxicities of these compounds, BDF1 mice were administered vehicle, 300-2700 mg (0.68-6.14 mmol)/kg/day of Ro 09-1390, or 100-900 mg (0.41-3.66 mmol)/kg/day of 5'-DFUR for 1 to 7 days, and effects on cellularity in lymphoid organs were assessed by immunohistochemistry as well as general toxicologic parameters. To distinguish compound-specific direct action from nonspecific indirect action caused by dietary reduction, dietary restriction groups were also included as control groups. Final body weight, thymus weight, bone marrow cell number (BMC), and leukocyte number were reduced with high dose of both compounds. Reduction of BMC in groups administered with Ro 09-1390 or 5'-DFUR was more severe than in dietary restriction groups given comparative amount of diet with compound-administered groups. Diffuse thymic cortical hypoplasia was observed in the highest dose of both compounds and more apparent in the Ro 09-1390 than in the 5'-DFUR. Focal nodular thymocyte hyperplasia was observed especially in the lower dose of 5'-DFUR. The results indicate that immunotoxic profiles of Ro 09-1390 and 5'-DFUR are very similar and characterized primarily by myelotoxicity and Ro 09-1390 is approximately two-times less toxic than 5'-DFUR on a molar basis in BDF1 mice.

Animals↗
PubMed1996

The role of two endogenous proteases of the stratum corneum in degradation of desmoglein-1 and their reduced activity in the skin of ichthyotic patients.

We investigated the role of stratum corneum (SC) trypsin-like and chymotrypsin-like serine proteases in the degradation of desmoglein-1 (DSG-1) in the SC sheet. DSG-1, whose presence in the SC sheet was confirmed by Western blot analysis, was degraded completely during incubation of the SC sheet in Tris buffer. The degradation of DSG-1 was inhibited by the addition of protease inhibitors, such as aprotinin or a mixture of leupeptin and chymostatin. Either leupeptin or chymostatin alone did not inhibit its degradation. These results indicated that both trypsin-like and chymotrypsin-like serine proteases are involved in the degradation of DSG-1. We further examined the activities of the two proteases in the SC obtained from patients with ichthyosis vulgaris, in whom SC desquamation is abnormal. The enzymatic activities measured using synthetic substrates were significantly decreased in these ichthyotic SC samples. This result supports the idea that these proteases play an important role in normal SC desquamation.

Adolescent↗
PubMed1995

Different effects of acute and chronic immobilization stress on plasma testosterone levels in male Syrian hamsters.

Time-course variations in plasma testosterone levels after various periods of immobilization stress (10 min, 30 min, 2 h, 6 h) were examined in male Syrian hamsters. The immobilization stress consisted of placing the animals in a prone position and wrapping them with flexible steel wire gauze. This was done at room temperature. Testosterone levels were determined in blood samples taken after the hamsters were decapitated. Chronic (2 h, 6 h) immobilization stress produced a drastic and enduring fall in plasma testosterone levels. Reduction of plasma testosterone following the 6-h immobilization stress was observed even 18 h after the stress had been relieved. However, acute (10 min, 30 min) immobilization stress did not influence plasma testosterone. These findings indicated that the effect of immobilization stress on plasma testosterone in hamsters was not biphasic, which it is in rats. Further, these results suggest that immobilization stress in hamsters would be a valuable technique with which to investigate the effects of physiological ranges of testosterone on physiological and psychological functions.

Animals↗
PubMed1995

Immobilization-induced stress decreases lipogenesis in sebaceous glands as well as plasma testosterone levels in male Syrian hamsters.

The effects of immobilization-induced stress on plasma testosterone levels and lipogenesis in the sebaceous gland were examined in male Syrian hamsters. To induce immobilization stress, the animals were placed in the prone position and wrapped with flexible steel wire gauze at room temperature. Plasma testosterone levels were determined by radioimmunoassay (RIA) of blood samples and sebaceous lipogenesis was determined by measurement of the incorporation of a lipid precursor, 14C-acetate, in ear skin biopsy samples. Both specimens were obtained immediately after the hamsters were decapitated. Immobilization stress for 4 consecutive days produced a marked fall in plasma testosterone levels and sebaceous lipogenesis. These reductions were reversible, the decreased plasma testosterone levels and decreased sebaceous lipogenesis recovering to the nonstressed or prestimulus levels after approximately 1 week. In 4-day stressed animals in occurrence with a decrease in plasma testosterone, sebaceous lipogenesis in ear with topical application of a small dose of testosterone, which have no effect on plasma testosterone level, was equivalent to that in nonstressed animals. These findings indicated that immobilization-induced stress lowered testosterone secretion, and consequently the testosterone levels in the skin, resulting in decreased lipogenesis in the skin. These results thus suggest that psychological or physiological stress can influence cutaneous function by inducing changes in the neuroendocrine system.

Animals↗
PubMed1995

The dithiane Ro 44-5912 enhances vinblastine sensitivity of drug resistant and parental KB lines in vivo.

The multidrug resistance modifying activity of a dithiane analogue of tiapamil, Ro 44-5912, was examined in vivo. Results of acute toxicity studies in mice indicated that lethal toxicity occurred with doses greater than 1 mmol/kg of body weight. In a preliminary pharmacokinetic investigation, Ro 44-5912 appeared to have a longer half-life in mice than did its (R) enantiomer Ro 44-5911 (3.15 +/- 0.02 h versus 2.15 +/- 0.14 h) as measured by total radiolabel in plasma. In non-tumour bearing mice, Ro 44-5912 enhanced the toxicity of vinblastine in a manner that was dependent on the dose of both drugs. Vinblastine did not have a significant effect on tumour growth when given to nude mice bearing the parental cell line KB-3-1 at a dose of 1.5 mg/kg once per week for 3 weeks. Combination treatment with Ro 44-5912 markedly enhanced the antitumour activity of vinblastine. Similar results were seen when KB-3-1 tumours were treated with the combination of vinblastine plus cyclosporin A. Another tiapamil analogue, Ro 11-2933, had no enhancing activity with this tumour when used at an equitoxic combination dose. Ro 44-5912 also significantly enhanced vinblastine activity with P-glycoprotein-expressing KB-8-5 tumours. In three independent experiments, Ro 44-5912 enhanced the growth inhibiting activity of vinblastine by a mean of approximately 40%. Neither Ro-11-2933 nor cyclosporin A, at the maximal tolerated doses in combination with vinblastine, led to significant inhibition of KB-8-5 tumour growth compared to treatment with the two vehicles alone. These results show that Ro 44-5912 is an active modulator of drug resistance in vivo.

Animals↗
PubMed1995

Male fertility in rats treated with etretinate for 4 weeks.

The toxicity of Etretinate, a retinoid compound, on the male reproductive system was studied in male rats. The drug was administered for four weeks at the dose levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were then allowed to mate, and their male reproductive functions and organs were examined in detail. No significant changes due to toxicity were observed in male reproductive functions and organs in the 5 mg/kg/day group after the 4-week treatment. In contrast, males in the 25 mg/kg/day group showed drug-related changes in their reproductive performance (decrease of mating ability and fertility rate), testosterone blood level, sperm head counts, sperm viability and number in the caudal epididymis, organ weight and in the histopathology of their reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even though Etretinate belong to the retinoid group of compounds, the changes seen in the 25 mg/kg/day group were almost the same as those observed in Vitamin A-deficient animals. In conclusion, there is a correlation between changes due to toxicity observed for parameters of male fertility and for histopathological evaluation of the testis of rats that receiving high dose, treatment with Etretinate for 4 weeks.

Animals↗