26 results on '"Irimura K"'
Search Results
2. Ethanol Administration Delays Recovery From Acute Pancreatitis Induced by Exocrine Hyperstimulation
- Author
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Chie, Y., Irimura, K., and Oka, T.
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- 1998
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3. Beneficial effects of suplatast tosilate (IPD-1151T) in a rat cystitis model induced by intravesical hydrochloric acid.
- Author
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Kirimoto T, Nakano K, Irimura K, Hayashi Y, Matsuura N, Kiniwa M, Oka T, and Yoshimura N
- Subjects
- Animals, Cystitis, Interstitial pathology, Disease Models, Animal, Female, Rats, Rats, Sprague-Dawley, T-Lymphocytes pathology, Treatment Outcome, Anti-Allergic Agents therapeutic use, Arylsulfonates therapeutic use, Cystitis, Interstitial drug therapy, Sulfonium Compounds therapeutic use
- Abstract
Objective: To examine the effects of suplatast tosilate (IPD-1151T), a Th2 cytokine inhibitor recently recognized to improve the symptoms in patients with interstitial cystitis (IC), in a rat model of HCl-induced chronic cystitis, to elucidate the possible mechanisms by which the drug improves the symptoms of IC., Materials and Methods: Chronic cystitis was induced by intravesical instillation of 0.2 mL of 0.4 m HCl in female adult rats. After a once-daily oral administration of IPD-1151T (0.1-100 mg/kg) or prednisolone (5 mg/kg) for 7 days, cystometry was performed under urethane anaesthesia. The bladder from HCl-induced cystitis rats was also assessed histopathologically., Results: On cystometrography there was frequent voiding in cystitis rats. Administration of IPD-1151T for 7 days after intravesical HCl instillation dose-dependently increased the micturition volume and intercontraction intervals. Treatment with prednisolone had similar therapeutic effects. Histological analyses in the bladder from cystitis rats revealed oedema and infiltration of inflammatory cells such as mast cells and eosinophils in the lamina propria and the transitional epithelial thickening. These histological changes and the number of mast cells and eosinophils were reduced by administration of IPD-1151T or prednisolone., Conclusion: The present results indicate that IPD-1151T improves bladder function and pathological changes in HCl-induced cystitis rats, as previously observed in patients with IC. The rat cystitis model induced by HCl could provide useful information for studying proposed therapies for IC which might involve T cell-dependent inflammatory responses as one of its potential pathophysiologies.
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- 2007
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4. Accelerated blood clearance of PEGylated liposomes following preceding liposome injection: effects of lipid dose and PEG surface-density and chain length of the first-dose liposomes.
- Author
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Ishida T, Harada M, Wang XY, Ichihara M, Irimura K, and Kiwada H
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- ATP-Binding Cassette Transporters biosynthesis, Animals, Biological Availability, Blood Cell Count, Excipients, Injections, Intravenous, Liposomes chemistry, Liver drug effects, Liver metabolism, Male, Microscopy, Electron, Transmission, Polyethylene Glycols chemistry, Radiopharmaceuticals administration & dosage, Radiopharmaceuticals pharmacokinetics, Rats, Rats, Wistar, Structure-Activity Relationship, Surface Properties, Tissue Distribution, Liposomes pharmacokinetics, Polyethylene Glycols pharmacokinetics
- Abstract
We recently reported that a second dose of polyethylene glycol (PEG) (M.W. 2000)-modified liposomes (mPEG2000-liposomes) is rapidly cleared from the blood and accumulates in the liver when injected twice in the same rat or mouse at several-day intervals (referred to as the "accelerated blood clearance (ABC) phenomenon"). In the present study we observed that a high dose (5 micromol/kg) of conventional liposomes (CL: without a PEG-coating) can induce the same phenomenon, while a low lipid dose (0.001 micromol/kg) did not. The induction of the phenomenon by mPEG2000-liposomes decreased with increasing first dose (0.001-5 micromol/kg). We observed a strong inverse relationship between the dose of initially injected PEG2000-liposomes and the extent to which the ABC phenomenon was induced: the higher the dose the smaller the phenomenon. Increasing the PEG density at the liposome surface beyond 5 mol% attenuated rather than induced the induction of the phenomenon, but elongation of the PEG chain length up to M.W. 5000, had no effect. In a series of hematological, serum-biochemical and histopathological safety evaluations we observed neither acute toxicity nor any signs of hepatic damage during the induction of the ABC phenomenon. Morphological examination of the liver by transmission electron microscopy (TEM) showed extensive accumulation of the second dose of mPEG2000-liposomes in the Kupffer cells, even already after 15 min, suggesting that the PEG liposomes had somehow lost the protective effect of the surface-grafted PEG against rapid clearance. The observations reported in this paper may have a considerable impact on the design and engineering of PEGylated liposomal formulations for use in multiple drug therapy.
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- 2005
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5. Accelerated clearance of a second injection of PEGylated liposomes in mice.
- Author
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Ishida T, Masuda K, Ichikawa T, Ichihara M, Irimura K, and Kiwada H
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- Animals, Area Under Curve, Chemistry, Pharmaceutical, Cholesterol administration & dosage, Cholesterol toxicity, Dose-Response Relationship, Drug, Injections, Intravenous, Liposomes, Liver drug effects, Liver metabolism, Liver pathology, Male, Metabolic Clearance Rate, Mice, Phosphatidylethanolamines administration & dosage, Phosphatidylethanolamines toxicity, Phosphatidylglycerols administration & dosage, Phosphatidylglycerols toxicity, Polyethylene Glycols administration & dosage, Polyethylene Glycols toxicity, Spleen drug effects, Spleen metabolism, Tissue Distribution, Cholesterol pharmacokinetics, Phosphatidylethanolamines pharmacokinetics, Phosphatidylglycerols pharmacokinetics, Polyethylene Glycols pharmacokinetics
- Abstract
We recently reported that the firstly injected PEGylated liposomes dramatically affected the rate of blood clearance of secondly injected PEGylated liposomes in rats in a time interval of injection dependent manner [J. Control. Release (2003)]. Mice are frequently used in evaluations of the therapeutic efficacy of PEGylated liposomal formulations, but the pharmacokinetics of repeatedly injected PEGylated liposomes in mice is not fully understood. In this study, therefore, we examined in mice the effect of the repeated injection of PEGylated liposomes on their pharmacokinetics. An intravenous pretreatment with PEGylated liposomes produced a striking change in the biodistribution of the second dose which was given several days after the first injection. The first dose resulted in a reduction in the circulation half-life of the second dose. The degree of alteration was dependent on the time interval between the injections. The rapid clearance of the second dose was strongly related to hepatic clearance (CLh). This finding suggests that a considerable increase in hepatic accumulation accounts for this phenomenon. But, no liver injury or an increase in the number of Kupffer cells were detected in histopathological evaluations. Collectively, although the multiple injections of the PEGylated liposomes had no obvious physical effects, such as inflammation, their pharmacokinetic behavior was clearly altered in mice. The results obtained here have important implications not only with respect to the design and engineering of liposomes for human use, but for evaluating the therapeutic efficacy of liposomal formulations in experimental animal models as well.
- Published
- 2003
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6. Accelerated clearance of PEGylated liposomes in rats after repeated injections.
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Ishida T, Maeda R, Ichihara M, Irimura K, and Kiwada H
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- Animals, Cell Count, Injections, Intravenous, Kupffer Cells drug effects, Liposomes administration & dosage, Liver cytology, Liver drug effects, Liver pathology, Male, Phosphatidylcholines, Polyethylene Glycols administration & dosage, Rats, Rats, Wistar, Spleen cytology, Spleen drug effects, Spleen metabolism, Tissue Distribution, Liposomes pharmacokinetics, Polyethylene Glycols pharmacokinetics
- Abstract
Polyethylene glycol-modified liposomes (PEGylated liposomes) represent promising carrier systems for therapeutic agents. Herein, we report on a study of the effect of repeated injection of PEGylated liposomes on their pharmacokinetics in rats. The first dose resulted in a reduction in the circulation time and an increase in hepatic accumulation of the second dose in a time-interval of injection-dependent manner. No significant increases in the number of Kupffer cells were detectable, although the liver most likely played an important role in the accelerated clearance. Interestingly, the acceleration in clearance became less pronounced, when the third dose was injected at 4, 7 or 14 days after the second injection (the second dose was given 5 weeks after the first injection). An accelerated clearance was evoked in normal rats by the transfusion of serum from rats that had received PEGylated liposomes 5 days earlier, indicating that humoral serum factor(s) are also involved in causing the accelerated clearance. A complement consumption assay indicated that the complement system is not the factor. In summary, multiple injections of PEGylated liposomes clearly altered their pharmacokinetic behavior in rats. It is likely that cellular immunity (Kupffer cells) and humoral immunity are required to cause the phenomenon. The results reported here have a considerable impact in and important implications on the clinical application, design and engineering of PEGylated liposomes for use in repeated intravenous administration.
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- 2003
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7. Potential usage of liposomal 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53) for cancer chemotherapy.
- Author
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Shimizu K, Takada M, Asai T, Irimura K, Baba K, and Oku N
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- 1,2-Dipalmitoylphosphatidylcholine, Animals, Antineoplastic Agents adverse effects, Blood Vessels pathology, Body Weight drug effects, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors therapeutic use, Etoposide adverse effects, Liposomes, Mice, Neoplasm Transplantation, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Survival Analysis, Topoisomerase II Inhibitors, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Etoposide administration & dosage, Etoposide analogs & derivatives, Etoposide therapeutic use
- Abstract
To enhance the therapeutic efficacy as well as to reduce the side effect, we attempted to liposomalize 4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin (TOP-53), a novel and effective topoisomerase II inhibitor. More than 90% of TOP-53 was efficiently incorporated into the liposomes composed of dipalmitoylphosphatidylcholine and cholesterol by remote-loading method. Anti-tumor activity of liposomal TOP-53 against solid tumor was examined in vivo using colon26 NL-17 carcinoma model mice. Three doses of liposomal TOP-53 (12 mg/kg/dose) showed significant tumor growth suppression (97.5% reduction determined at day 25) and the increase in life span (33%) of tumor-bearing mice. Furthermore, one mouse out of 5 was completely cured after treatment. Since similar efficacy was observed in the free TOP-53 treated group, liposomalization does not contribute much to the enhancement of therapeutic efficacy. However, a slight but measurable damage at the injection site was observed when free TOP-53 was injected, and the damage was diminished by the liposomalization. Taken together, liposomalization reduces the side effect rather than enhancing the therapeutic efficacy when TOP-53 is used.
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- 2002
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8. The accelerated clearance on repeated injection of pegylated liposomes in rats: laboratory and histopathological study.
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Ishida T, Maeda R, Ichihara M, Mukai Y, Motoki Y, Manabe Y, Irimura K, and Kiwada H
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- Animals, Drug Carriers, Humans, Injections, Intravenous, Liposomes, Liver metabolism, Metabolic Clearance Rate, Models, Animal, Rats, Spleen metabolism, Polyethylene Glycols pharmacokinetics
- Published
- 2002
9. Suppression of gingival inflammation induced by Porphyromonas gingivalis in rats by leupeptin.
- Author
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Kitano S, Irimura K, Sasaki T, Abe N, Baba A, Miyake Y, Katunuma N, and Yamamoto K
- Subjects
- Adhesins, Bacterial metabolism, Animals, Bacteroidaceae Infections drug therapy, Cysteine Endopeptidases metabolism, Cysteine Proteinase Inhibitors therapeutic use, Disease Models, Animal, Disease Progression, Gingipain Cysteine Endopeptidases, Gingivitis drug therapy, Gingivitis pathology, Hemagglutinins metabolism, Leupeptins therapeutic use, Male, Maxilla pathology, Porphyromonas gingivalis enzymology, Rats, Rats, Wistar, Virulence, Adhesins, Bacterial drug effects, Bacteroidaceae Infections microbiology, Cysteine Endopeptidases drug effects, Cysteine Proteinase Inhibitors pharmacology, Gingivitis microbiology, Hemagglutinins drug effects, Leupeptins pharmacology, Porphyromonas gingivalis pathogenicity
- Abstract
In this study, we developed a procedure to produce gingivitis in rats by inoculation of Porphyromonas gingivalis and studied the contribution of the bacterial cysteine proteinases, Arg-gingipain (Rgp) and Lys-gingipain (Kgp), to the pathology in the gingiva. To adhere the bacterium to periodontal tissues, a cotton thread was inserted between the first and second molar of right maxillary sites of rats. Rats in group A were administered with vehicle alone after bacterial (strain W83) inoculation. In group B, the bacteria were inoculated in combination with leupeptin, a potent inhibitor of Rgp and Kgp, and then leupeptin alone was administered the week after. Rats in group C were administered leupeptin for 6 weeks after bacteria inoculation. All left maxillary gingiva in three groups showed no inflammatory changes. Right maxillary gingiva of group A showed most of the clinical landmarks of gingivitis. Leupeptin exhibited only a little inhibitory effect on this gingivitis in group B, whereas it had a strong inhibitory effect on the inflammation in group C. These results suggest that P. gingivalis-induced gingivitis is attributable to Rgp and Kgp and that leupeptin is more effective in the late phase than the early stage of gingivitis.
- Published
- 2001
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10. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 26). Detection of 1,3-dinitrobenzene-induced histopathological changes in testes and epididymides of rats with 2-week daily repeated dosing.
- Author
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Irimura K, Yamaguchi M, Morinaga H, Sugimoto S, Kondou Y, and Koida M
- Subjects
- Administration, Oral, Animals, Atrophy chemically induced, Atrophy pathology, Body Weight drug effects, Dinitrobenzenes administration & dosage, Dose-Response Relationship, Drug, Epididymis drug effects, Epididymis pathology, Male, Organ Size drug effects, Rats, Rats, Sprague-Dawley, Seminiferous Epithelium drug effects, Seminiferous Epithelium pathology, Specific Pathogen-Free Organisms, Sperm Count, Testis pathology, Time Factors, Toxicity Tests, Dinitrobenzenes toxicity, Testis drug effects
- Abstract
As part of a collaborative work, male rats were administered 1,3-dinitrobenzene (1,3-DNB) daily at 0, 25 and 50 mg/kg/day from the age of 6 weeks for 4 weeks (4-week exp.), or at 25, 50 and 75 mg/kg/day from the age of 8 weeks for 2 weeks (2-week exp.). After the end of each administration period, all survivors were sacrificed, and their testes and epididymides were removed, weighed and examined histopathologically. The following results were obtained. In the 4-week exp.: At 50 mg/kg/day, the weights of testes and epididymides showed decrease with macroscopic atrophy. The testicular spermatogenic epithelium showed decrease in the number of sperm-spermatocytes, degeneration/necrosis, giant cell formation and vacuolation, reduction in sperm counts also being evident in the ducts of the epididymides. In the 2-week exp.: At 50 and 75 mg/kg/day, the weights of testes and/or epididymides showed decrease with macroscopic atrophy. Several histopathological changes in the testes and epididymides were essentially the same changes as in the group given 50 mg/kg/day in the 4-week exp., with a clear relation. These results indicate that a 2-week administration period is sufficient to detect testicular and epididymal histopathological changes induced by 1,3-dinitrobenzene in male rats.
- Published
- 2000
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11. Oral administration of sepimostat mesilate prevents acute alcohol pancreatic injury in rats.
- Author
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Yuasa C, Irimura K, Oda M, Fukui K, and Oka T
- Subjects
- Acute Disease, Administration, Oral, Amylases blood, Amylases drug effects, Animals, Ceruletide adverse effects, Esters, Guanidines pharmacology, Lipase blood, Lipase drug effects, Male, Pancreas pathology, Pancreatitis chemically induced, Rats, Rats, Wistar, Ethanol adverse effects, Gabexate analogs & derivatives, Imidazoles pharmacology, Pancreas drug effects, Pancreatitis prevention & control, Protease Inhibitors pharmacology
- Abstract
The preventive effect of a novel synthetic serine protease inhibitor, sepimostat mesilate (sepimostat), on acute alcohol pancreatic injury, induced by exocrine hyperstimulation and ethanol administration, was assessed and compared with that of a similar protease inhibitor, camostat mesilate (camostat). Conscious rats were infused with 1 microg mL(-1) h(-1) caerulein intravenously for 6 h and with 0.1 g mL(-1) h(-1) ethanol for 9 h, with the latter infusion beginning 3 h after the start of the caerulein infusion. Sepimostat or camostat was administered orally 1 h before the caerulein infusion. Rats infused with caerulein plus ethanol showed increased plasma amylase and lipase activities, and aggravated pancreatic interstitial oedema when compared with rats given caerulein alone. Sepimostat at 10 and 30 mg kg(-1) prevented the increase in plasma amylase and lipase activities caused by caerulein plus ethanol infusion. Sepimostat at 30 mg kg(-1) suppressed the histological change. Camostat did not show any preventive effects at the equivalent dose. When conscious rats were infused with 1 microg mL(-1) h(-1) caerulein alone intravenously for 6 h, plasma amylase and lipase activities were increased compared with rats given saline. Neither drug prevented the increase in these activities at 30mg kg(-1). Our results suggest that sepimostat has superior preventive effects on alcohol-induced acute pancreatic injury compared with camostat. Sepimostat may thus be a useful drug in the therapy of alcohol-induced pancreatitis.
- Published
- 1999
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12. Ethanol administration delays recovery from acute pancreatitis induced by exocrine hyperstimulation.
- Author
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Yuasa C, Irimura K, and Oka T
- Subjects
- Acute Disease, Amylases urine, Animals, Calcium metabolism, Central Nervous System Depressants blood, Ceruletide blood, Ceruletide pharmacology, Disease Progression, Ethanol blood, Lipase blood, Male, Pancreas drug effects, Pancreas metabolism, Pancreatitis, Alcoholic blood, Pancreatitis, Alcoholic pathology, Prognosis, Rats, Rats, Wistar, Stimulation, Chemical, Central Nervous System Depressants toxicity, Ethanol toxicity, Pancreas physiopathology, Pancreatitis, Alcoholic therapy
- Abstract
Alcohol consumption causes acute alcohol pancreatitis and worsens the prognosis; however, there is no useful model for elucidation of the mechanism underlying this worsening. The aim of our study was to establish a new prognostic model of acute alcohol pancreatitis in rats. To ascertain the effect of continuous infusion of ethanol on each phase, i.e., progression and recovery, in caerulein-induced pancreatic injury in rats, we infused a physiological or supramaximal dose of caerulein intravenously to conscious Wistar rats for up to 6 h (time: 0-6 h) with or without ethanol infusion for 9 h (time: 3-12 h). Ethanol did not induce the pancreatic injury alone or when combined with a physiological dose of caerulein. In the progression phase, ethanol infusion for 3 h (time: 6 h) did not aggravate the pancreatic injury induced by a supramaximal dose of caerulein in terms of plasma amylase and lipase activities but did increase the pancreatic calcium level. In the recovery phase, however, ethanol infusion for 9 h (time: 12 h) significantly restrained the recovery from pancreatic injury as monitored in terms of these activities. Further, ethanol infusion for 9 h significantly increased the cumulative urinary excretion of amylase from 12 to 27 h but did not do the same from 0 to 12 h. In the histological evaluation at 27 h, the induction of acinar cell vacuolization and dilation of the glandular lumina and ducts were significant in the caerulein plus ethanol-treated group. Our findings suggest that ethanol administration delays the recovery rather than worsens the progression in acute pancreatic injury induced by exocrine hyperstimulation, and we consider our experimental model to be a useful tool for studying the pathogenesis of worsening prognosis in acute alcohol pancreatitis.
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- 1998
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13. [Oral single-dose toxicity study of a new antineoplastic agent S-1, and its components, CDHP, and Oxo].
- Author
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Hayashi T, Tanaka G, Irimura K, Hirota T, and Ohmae S
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- Administration, Oral, Alopecia chemically induced, Animals, Antimetabolites, Antineoplastic administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Body Weight drug effects, Diarrhea chemically induced, Dogs, Drug Combinations, Female, Lethal Dose 50, Lymph Nodes drug effects, Lymph Nodes pathology, Male, Mice, Motor Activity drug effects, Oxonic Acid administration & dosage, Oxonic Acid chemistry, Pyridines administration & dosage, Pyridines chemistry, Rats, Salivation drug effects, Spleen drug effects, Spleen pathology, Survival Rate, Tegafur administration & dosage, Tegafur chemistry, Thymus Gland drug effects, Thymus Gland pathology, Antimetabolites, Antineoplastic toxicity, Antineoplastic Combined Chemotherapy Protocols toxicity, Oxonic Acid toxicity, Pyridines toxicity, Tegafur toxicity
- Abstract
S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.
- Published
- 1996
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14. [A 52-week chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187) in dogs].
- Author
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Nakano S, Yada H, Irimura K, Asanoma H, Hirota T, and Terazawa K
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- Administration, Oral, Animals, Body Weight drug effects, Dogs, Drug Administration Schedule, Eating drug effects, Electrocardiography drug effects, Female, Hematologic Tests, Imidazoles pharmacokinetics, Kidney Function Tests, Liver Function Tests, Male, Organ Size drug effects, Time Factors, Tissue Distribution, Urinalysis, Imidazoles administration & dosage, Imidazoles toxicity
- Abstract
A chronic oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1992
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15. [A fifty-two week oral chronic toxicity study of suplatast tosilate (IPD-1151T) in rats].
- Author
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Kuwata M, Irimura K, Kurokawa K, Kashihara A, and Yamashita K
- Subjects
- Administration, Oral, Animals, Arylsulfonates administration & dosage, Drug Administration Schedule, Drug Evaluation, Preclinical, Female, Histamine Antagonists administration & dosage, Male, Rats, Rats, Inbred Strains, Sulfonium Compounds administration & dosage, Arylsulfonates toxicity, Histamine Antagonists toxicity, Sulfonium Compounds toxicity
- Abstract
A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 300 and 1800 mg/kg/day using male and female rats. The results were as follows: 1. In general conditions, transient salivation after each administration and excretions with peculiar smells were noted in both sexes given 1800 mg/kg/day. Since one male and six female rats given 1800 mg/kg/day showed bradypnea, clonic/tonic convulsions, lying on the belly and/or side, subnormal temperature, abnormal gait, paralysis of extremities, they were sacrificed in moribund. 2. The body weight was lowered from the early stage of administration period in both sexes given 1800 mg/kg/day. 3. There were no remarkable changes in food consumption, urinalysis, fecal examination, hematology and ophthalmology. 4. Biochemical examination revealed a decrease in triglyceride in males given 300 mg/kg/day or more. 5. In pathological examination, the animals sacrificed in moribund showed necrosis and degeneration of neurons and/or sponge-like change of neuropile in nucleus caudatus of the cerebrum, necrosis and partial disappearance of granular cells and Purkinje's cells, and swelling of Bergmann's cells in the cerebellum. In survived animals, the relative organ weight in the liver increased in males given 300 mg/kg/day or more and females given 1800 mg/kg/day, and histopathological examination revealed slight vacuolization, hypertrophy of centrilobular hepatocytes in males given 1800 mg/kg/day. Furthermore, in some females, similar changes of the cerebrum and the cerebellum, as mentioned above, were slightly observed. In electron microscopic examination, slight proliferation of smooth endoplasmic reticulum in hepatocytic cytoplasm was observed in males given 1800 mg/kg/day. The necrobiotic changes, such as condensation of nuclear chromatin, increased electron density of cytoplasm and nuclei, mitochondrial accumulation and vacuolization, in the cells possibly derived from small granular cells in the cerebellum were observed in females given 1800 mg/kg/day. The mitochondrial swelling, decreased and dilated rough endoplasmic reticulum, and increased electron density of cytoplasm and nuclei with formation of cytoplasmic vacuole and membranous degenerated structure in neurons of cerebral temporal lobe cortex were observed in females given 1800 mg/kg/day. 6. In a recovery study, electron microscopic examination revealed a slight degeneration of myelinated nerve fibers in the cerebellum in males given 1800 mg/kg/day. On the contrary, there were no remarkable changes in general condition, body weight and various clinical parameters. It was noted that these changes induced by IPD-1151T seemed to be reversible changes.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1992
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16. [A thirteen-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in dogs].
- Author
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Yamashita K, Yada H, Hayashi T, Irimura K, Hirota T, and Morita K
- Subjects
- Administration, Oral, Animals, Arylsulfonates administration & dosage, Dogs, Drug Administration Schedule, Drug Evaluation, Preclinical, Female, Histamine Antagonists administration & dosage, Male, Sulfonium Compounds administration & dosage, Arylsulfonates toxicity, Histamine Antagonists toxicity, Sulfonium Compounds toxicity
- Abstract
A 13-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 50, 150, 450 and 1350 mg/kg/day using male and female beagle dogs. The results were as follows: 1. In general conditions, soft feces and diarrhea with specific smell were dose-dependently observed in males and females given 450 mg/kg/day or more. Both sexes given 1350 mg/kg/day, revealed reeling with dropped head, abnormal gait, dysstasia, lying at lateral or prone position, sedation, and tremor, and one male and one female in this group died after showing respiratory depression, collapse and cyanosis. 2. There were no significant or remarkable changes in body weight, food consumption, water consumption, ophthalmology, electrocardiogram, urinalysis, hematology, biochemistry, fecal occult blood test, and absolute and relative organ weights. 3. Pathological examination in dead animals revealed hemorrhagic change in the heart and slight vacuolar changes in hepatocytes. In survived animals, there were no pathological changes attributable to the IPD-1151T. 4. In electron microscopic examination, there were no abnormalities in the liver and kidney attributable to the IPD-1151T. 5. After 5-week recovery period, above-mentioned changes disappeared. 6. From the above results, the non-effective dose level and the toxic dose level were estimated to be 150 mg/kg/day and 1350 mg/kg/day, respectively, and no sex differences were found.
- Published
- 1992
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17. [A thirteen-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in rats].
- Author
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Nakano S, Hayashi T, Irimura K, Maruden A, Nakagawa K, and Morita K
- Subjects
- Administration, Oral, Animals, Arylsulfonates administration & dosage, Drug Administration Schedule, Drug Evaluation, Preclinical, Female, Histamine Antagonists administration & dosage, Male, Rats, Rats, Inbred Strains, Sulfonium Compounds administration & dosage, Arylsulfonates toxicity, Histamine Antagonists toxicity, Sulfonium Compounds toxicity
- Abstract
A 13-week oral repeated dose toxicity study of Suplatast tosilate (IPD-1151T), a new anti-allergic agent, as well as a 5-week recovery study were carried out at dose levels of 0 (control), 200, 600, 1800 and 5400 mg/kg/day using male and female rats. The results were as follows: 1. In general conditions, salivation were observed in some rats of both sexes given 1800 mg/kg/day. Both sexes given 5400 mg/kg/day disclosed salivation and soft stool and then died after showing ataxic gait, hyperesthesia and convulsion of legs. 2. Inhibition of body weight gain in both sexes given 5400 mg/kg/day were observed from the early stage of the treatment period. 3. The food consumption was decreased from about 3-week and the water consumption was increased from the initiation of study to about 3-week in both sexes given 5400 mg/kg/day. However, both of them were remarkably decreased prior to death. 4. Fecal examination for occult blood showed an increasing tendency in the incidence of positive findings in both sexes given 1800 mg/kg/day. 5. Hematological examination showed slight decreases in erythrocytic parameters in both sexes given 1800 mg/kg/day. In both sexes given 5400 mg/kg/day hemoconcentration was observed, some animals showing decreases in leucocyte and lymphocyte counts and lymphocyte percentage. 6. Biochemical examination showed increases in total and free cholesterol levels in males given 600 mg/kg/day or more, an increased cholinesterase and decreased levels of triglyceride and cholesterol ester ratio in males given 1800 mg/kg/day. An increase in LDH was observed in both sexes given 5400 mg/kg/day and half of these animals also showed increases in GOT and Urea N. 7. The absolute weights of the pituitary, brain, thymus, heart, lungs and kidneys were increased. However, no histopathological lesion was observed in these organs. As treatment-related histological changes, atrophy in the thymus and spleen, dilation in digestive tracts, neuronal necrosis and necrotic foci in the central nervous system, necrosis of lymphocytes in the lymphoid organs and a decrease in bone marrow cell were observed in both sexes given 5400 mg/kg/day. 8. After a 5-week recovery period, above-mentioned changes had disappeared. 9. From the above results, the non-effective dose level was estimated to be 200 mg/kg/day in males and 600 mg/kg/day in females, and toxic dose level 1800-5400 mg/kg/day in both sexes.
- Published
- 1992
- Full Text
- View/download PDF
18. [Single dose toxicity studies of suplatast tosilate (IPD-1151T)].
- Author
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Yamashita K, Nakano S, Kuwata M, Yada H, Irimura K, Morinaga H, and Morita K
- Subjects
- Animals, Dogs, Drug Evaluation, Preclinical, Female, Lethal Dose 50, Male, Mice, Rats, Arylsulfonates toxicity, Histamine Antagonists toxicity, Sulfonium Compounds toxicity
- Abstract
Single dose toxicity studies of suplatast tosilate (IPD-1151T) were carried out in mice, rats and dogs of both sexes. The results were as follows: 1. The LD50 values of IPD-1151T were as follows: Mice, 12,500 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Mice 81 (male) and 96 (female) mg/kg in intravenous route; Rats, 10,000 (both sexes) mg/kg or more in oral route (maximum dose for technical manner); Rats, 96 (male) and 93 (female) mg/kg in intravenous route; Dogs, 2,124 (male) and 2,660 (female) mg/kg in oral route. On the LD50 values, no sexual difference was apparent in all species, but the species difference was noted between the rodent and dog. LD50 values of dog were lower level than those of rodent. 2. As toxic signs, mucous diarrhea with specific smell was noted in orally administered rodent. In addition, rats showed soiled fur in the perianal. In intravenous route, the rodent showed dyspnea, tonic convulsion and lateral position and deaths occurred within 10 min in mice and within 30 min in rats after administration. Dog showed toxic signs similar to those in rodents and deaths occurred within 3 hours. 3. In pathological examinations, dead mice and dogs administered orally showed lung congestion, liver fading or slight hemorrhage in the endo-and/or exocardium. Dead rodent administered intravenously showed only slight hemorrhage and congestion in the lung. Alive mice, rats and dogs showed no remarkable changes. 4. The main cause of deaths seemed to be respiratory disturbance in all species.
- Published
- 1992
- Full Text
- View/download PDF
19. [Fifty-two-week oral chronic toxicity study of propiverine hydrochloride in rats].
- Author
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Yamashita K, Kuwata M, Irimura K, Morinaga N, Kurokawa K, and Ashizawa M
- Subjects
- Administration, Oral, Animals, Female, Kidney drug effects, Kidney pathology, Kidney ultrastructure, Liver drug effects, Liver pathology, Liver ultrastructure, Male, Rats, Rats, Inbred Strains, Urination Disorders drug therapy, Benzilates toxicity, Parasympatholytics toxicity
- Abstract
An oral chronic toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose levels of 0 (control), 0.5, 5 and 50 mg/kg/day using male and female rats. They were treated for 52 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. There were no deaths related to P-4. Mydriasis, transitory salivation were observed in both sexes receiving 50 mg/kg/day, and soil of the abdomen was also noted in females receiving 50 mg/kg/day. 2. Body weight gain was suppressed from initiation of administration in both sexes receiving 50 mg/kg/day. 3. There were no significant or remarkable changes in food consumption, hematology and ophthalmology. 4. Urinary findings in animals receiving 50 mg/kg/day showed increases of urine and potassium excretion volumes and decrease of urine osmotic pressure in both sexes, negativity of urine protein and decrease of urobilinogen value in females. 5. Biochemical findings in animals receiving 50 mg/kg/day showed increase of urea-nitrogen (Urea N) in both sexes and decrease of triglyceride (TG), total cholesterol (T. cho), free cholesterol (F. cho), non-esterified fatty acids (NEFA) and phospholipid (PL) in males. 6. The absolute and/or relative weights of the liver increased in animals receiving 50 mg/kg/day. Histopathological examination in animals receiving 50 mg/kg/day revealed intranuclear eosinophilic inclusions and cytoplasmic eosinophilic substance in renal proximal tubular epithelium and midzonal lipid droplets in liver. Histochemical examination in animals receiving 50 mg/kg/day revealed the slight increase of gamma-GTP positive area in peripheral zone of liver. Electron-microscopic examination in animals receiving 50 mg/kg/day revealed intranuclear and intracellular large and homogeneous spherical-like structure with low electron density in renal proximal tubular epithelium, and slight hyperplasia of smooth endoplasmic reticulum with dilatation of cisternae and deposition of large lipid droplets in hepatocytes, but there was no difference of VLDL and its distributions in hepatocytes among groups.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
20. [Thirteen-week oral toxicity study of propiverine hydrochloride in rats].
- Author
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Nakano S, Kuwata M, Hasegawa H, Irimura K, Maruden A, and Morita K
- Subjects
- Administration, Oral, Animals, Body Weight drug effects, Eating drug effects, Female, Kidney drug effects, Kidney ultrastructure, Liver drug effects, Liver ultrastructure, Male, Organ Size drug effects, Rats, Rats, Inbred Strains, Urination Disorders drug therapy, Benzilates toxicity, Parasympatholytics toxicity
- Abstract
A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in gamma-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.
- Published
- 1989
- Full Text
- View/download PDF
21. [Five-week subacute intravenous toxicity study of cefodizime sodium in dogs].
- Author
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Nakano S, Yada H, Irimura K, Kurokawa K, Hirota T, and Morita K
- Subjects
- Animals, Cefotaxime administration & dosage, Cefotaxime toxicity, Cefotetan administration & dosage, Cefotetan toxicity, Dogs, Female, Fibrosis, Granulation Tissue drug effects, Granulation Tissue pathology, Injections, Intravenous, Male, Salivation drug effects, Serum Albumin metabolism, Serum Globulins metabolism, Veins drug effects, Veins pathology, Vomiting chemically induced, Cefotaxime analogs & derivatives
- Abstract
A subacute toxicity study of cefodizime sodium (THR-221), a new cephem antibiotics, was carried out using male and female beagle dogs. THR-221 was intravenously administered to the dog at dose levels of 500, 1000 and 2000 mg/kg/day for 5 weeks, followed by 4 weeks recovery period. Cefotetan (CTT) as a reference drug was administered in the same manner at a dose level of 2000 mg/kg/day. The summarized results obtained are as follows: 1. Vomiting and salivation were observed in dogs given 1000 and 2000 mg/kg/day of THR-221. However, it caused no deaths or significant effects on body weight and food consumption in all groups treated with THR-221. 2. No toxicological changes associated with the administration of THR-221 were found in urinary and hematological examinations. 3. In serum biochemical examinations, increase or tendencies of increase of albumin and A/G ratio, probably due to the antibacterial action of THR-221, were detected at all dose levels of THR-221. 4. There were no dose-related changes in hepatic and renal function, fecal occult blood, ophthalmological, electrocardiographic and auditory examinations, absolute and relative organ weights. 5. Histopathological examinations revealed fibrosis or granulation in perivascular area of injection sites, particularly in males given 2000 mg/kg/day of THR-221. 6. After 4 weeks of recovery period, above-mentioned changes were generally disappeared and it was suggested that these were reversible ones. 7. In groups treated with CTT (2000 mg/kg/day), damages were recognized mainly in erythron values, liver and kidney, as compared with the same dose of THR-221. Therefore the toxicity of THR-221 was less than that of CTT. 8. From these results, the non toxic effective dose level and the toxic dose level of THR-221 were estimated to be 500 mg/kg/day and more than 2000 mg/kg/day respectively, for male and female dogs.
- Published
- 1988
- Full Text
- View/download PDF
22. [Nephrotoxicity of cefodizime sodium in rats--single and 14-day repeated intravenous administration].
- Author
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Hayashi T, Maruden A, Irimura K, Kuwata M, and Morita K
- Subjects
- Animals, Cefazolin toxicity, Cefmetazole toxicity, Cefotaxime administration & dosage, Cefotaxime toxicity, Cephaloridine toxicity, Drug Administration Schedule, Drug Therapy, Combination toxicity, Epithelium drug effects, Epithelium pathology, Furosemide administration & dosage, Gentamicins administration & dosage, Glycosuria chemically induced, Glycosuria urine, Injections, Intravenous, Kidney pathology, Kidney Tubules drug effects, Kidney Tubules pathology, Male, Necrosis, Organ Size drug effects, Proteinuria chemically induced, Proteinuria urine, Rats, Rats, Inbred Strains, Cefotaxime analogs & derivatives, Kidney drug effects
- Abstract
Nephrotoxicity of cefodizime sodium (THR-221), a new cephem antibiotic, was studied in rats by comparing its toxic effect with those of other cephem antibiotics including cephaloridine (CER), cefazolin (CEZ) and cefmetazol (CMZ). Each drug was administered single and consecutive 14-day dosage with its alone or in combination with either furosemide or gentamicin. The results are summarized as follows: 1. In the single dosage study, the rats treated with THR-221 at dose levels of 1200 mg/kg and more showed slight changes in urinary protein and glucose. In rats treated with CER at a dose of 1200 mg/kg, creatinine level in plasma and weights of kidneys were increased, and degeneration and/or necrosis of the renal proximal tubular epithelia were observed. Furthermore, by the consecutive dosage of CER at a dose of 1000 mg/kg, remarkable renal responses including increase in urinary protein and glucose, and weights of kidneys, were observed. In addition, histopathological examinations showed degeneration and/or regeneration of the renal proximal tubular epithelia. 2. No enhanced effect of nephrotoxicity by combination with furosemide or gentamicin was observed except in case of combination of CER with furosemide. 3. The above results indicate that the nephrotoxic potency among these four antibiotics on the single and consecutive dosage studies is CER much greater than THR-221 greater than or equal to CEZ = CMZ and CER much greater than THR-221 = CEZ = CMZ, in the decreasing order.
- Published
- 1988
- Full Text
- View/download PDF
23. [Local irritation studies of cefodizime sodium].
- Author
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Yamakita O, Koida M, Shinomiya M, Imamura K, Nakagawa M, Kashihara A, Irimura K, Tanaka G, and Yoshida R
- Subjects
- Animals, Cefotaxime administration & dosage, Cefotaxime toxicity, Cefotetan toxicity, Cephalothin toxicity, Edema chemically induced, Edema pathology, Eye drug effects, Eye pathology, Hemorrhage chemically induced, Hemorrhage pathology, Injections, Intramuscular, Injections, Intravenous, Male, Mucous Membrane drug effects, Mucous Membrane pathology, Muscles drug effects, Muscles pathology, Muscular Diseases chemically induced, Muscular Diseases pathology, Necrosis, Rabbits, Thrombophlebitis chemically induced, Veins drug effects, Veins pathology, Cefotaxime analogs & derivatives, Irritants
- Abstract
Four local irritation studies of cefodizime sodium (THR-221), a new developed cephem-type antibiotics, were carried out with NZW rabbits. 1. In eye irritation test, 25% THR-221 water solution had no irritancy on eye mucosa in rabbits. 2. In single injective intramuscular irritation study, regardless of solvents (water or 0.5% lidocaine), 25% THR-221 solution had irritancy equal to 0.75% acetic acid. But recovery process of the muscle injured with THR-221 was faster and better than with 0.75% acetic acid. 3. In five days injective muscular irritation study, the irritancy of 25% THR-221 water solution on the muscle was milder than that of CTT or CET. Histopathological damage with THR-221, necrosis/degeneration of muscle fibers and edema/hemorrhage in interstitium etc., were well recovered. 4. In vessel irritation study, 10% or more THR-221 water solution had irritancy on ear vessel. THR-221, as same as CTT, caused organized thrombi and inflammation at the surrounding area. The degree of irritation of 20% THR-221 solution was slightly stronger than that of 20% CET, but weaker than that of 20% CTT. 5. In a clinical phase, it is to be desired that THR-221 like as CTT or CET shall be avoided repeated intramuscular or intravenous injections at the same site.
- Published
- 1988
- Full Text
- View/download PDF
24. [Thirteen-week oral toxicity study of propiverine hydrochloride in dogs].
- Author
-
Yamashita K, Yada H, Irimura K, Maruden A, and Morita K
- Subjects
- Animals, Body Weight drug effects, Dogs, Eating drug effects, Female, Kidney drug effects, Kidney ultrastructure, Liver drug effects, Liver ultrastructure, Male, Organ Size drug effects, Urination Disorders drug therapy, Benzilates toxicity, Parasympatholytics toxicity
- Abstract
A subacute oral toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out at dose-levels of 0, 1, 3, 9, and 27 mg/kg/day using male and female beagle dogs. They were treated for 13 weeks, followed by 5 weeks recovery period. The results obtained from the present study were as follows. 1. In the observation of general symptoms, mydriasis was observed in females receiving 3 mg/kg/day or more and in males receiving 9 mg/kg/day or more, every day, intermittently or sporadically. The incidence of mydriasis varied greatly in individuals. However, this sign disappeared within administration period. 2. Body weight gain was slightly suppressed in males and females receiving 27 mg/kg/day. 3. There were no significant changes in food consumption, water consumption, hematology, urinalysis and fecal occult blood, and no remarkable changes in ophthalmology, electrocardiogram. 4. Serum biochemical findings showed a decrease in Total cholesterol (T. cho), Free cholesterol (F. cho), Triglyceride (TG), Phospholipid (PL), Total protein (TP), Albumin (ALB), alpha 1-Globulin (alpha 1-GLO) and Calcium (Ca), and an increase in Alkaline phosphatase (Al P), gamma-Glutamyltranspeptidase (gamma-GTP) activities and Choresterol ester ratio (EST/T) in males and females receiving 27 mg/kg/day. Further, a decrease in lipoprotein-T. cho, -TG and -PL were noted, on the other hand, lipoprotein-T. cho, -TG and -PL in the liver tissue increased. Similar slight changes were observed in males and females receiving 9 mg/kg/day. 5. Pathological examination revealed an enlargement of hepatocytes in a few animals receiving 3 mg/kg/day. In males and females receiving 9 mg/kg/day or more, yellowish liver, a increase in liver weights, an enlargement of hepatocytes with fatty degeneration and the appearance of eosinophilic inclusions in the hepatocytes were observed. Furthermore, some males and females receiving 27 mg/kg/day showed a slight cellular infiltration in glisson's sheaths, proliferation of the bile ducts and deposition of lipid droplets. Histochemical examination of liver tissue showed an increase in Al P and gamma-GTP activities in addition. Electronmicroscopically, the proliferation of smooth endoplasmic reticulum, increases in myelin-like inclusions and small lipid droplets in the hepatocytes were noted and these changes suggested the induction of drug-metabolizing enzyme in the liver. 6. After 5 weeks recovery period, above-mentioned changes were disappeared and it was suggested that these were reversible ones. 7. From the above results, the non-effective dose and the toxic one were estimated to be 1 mg/kg/day and 9 mg/kg/day for males and females, respectively.
- Published
- 1989
- Full Text
- View/download PDF
25. A fifty-two-week chronic toxicity study of halopredone acetate (THS-201) in dogs.
- Author
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Yamashita K, Yada H, Irimura K, Hayashi T, Morinaga H, and Morita K
- Subjects
- Animals, Anti-Inflammatory Agents administration & dosage, Body Weight drug effects, Dogs, Eating drug effects, Female, Fluprednisolone administration & dosage, Fluprednisolone toxicity, Hematologic Tests, Injections, Intra-Articular, Knee Joint drug effects, Knee Joint ultrastructure, Male, Microscopy, Electron, Organ Size drug effects, Time Factors, Anti-Inflammatory Agents toxicity, Fluprednisolone analogs & derivatives
- Abstract
In order to evaluate the long-term-safety of halopredone acetate (THS-201: 17 alpha, 21-diacetoxy-2-bromo-6 beta, 9 alpha-difluoro-11 beta-hydroxy-1, 4-pregnadiene-3, 20-dione), a 52-week chronic toxicity study was performed on the basis of its local accumulation in dogs. In doses of 0.1, 0.5 and 2.5 mg/kg, THS-201 was injected into the right knee joint in both sexes of dogs every 2 weeks for 39 weeks and withdrawn for 13 weeks. In this study, the below slight local changes were observed in both sexes of dogs treated with 2.5 mg/kg/2 weeks of THS-201: focal loss of hair of the injection site, lesser stain in cartilage matrix of articular cartilage and meniscus in light microscopic examinations, and irregular thickness and elongation of collagen fibers, roughness of fibrous density and decrement of proteoglycans in electron microscopic examinations. In conclusion, systemic adverse effects were not observed in any dogs treated with THS-201.
- Published
- 1986
- Full Text
- View/download PDF
26. [Acute toxicity studies of propiverine hydrochloride].
- Author
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Yamashita K, Nakano S, Kuwata M, Yada H, Irimura K, Morinaga H, and Morita K
- Subjects
- Animals, Body Weight drug effects, Dogs, Lethal Dose 50, Mice, Mice, Inbred ICR, Rats, Rats, Inbred Strains, Urination Disorders drug therapy, Benzilates toxicity, Parasympatholytics toxicity
- Abstract
Acute toxicity studies of propiverine hydrochloride (P-4) were carried out in mice, rats and dogs of both sexes. 1. The LD50 values of P-4 were as follows: Mice; 410 (male) and 323 (female) mg/kg in oral route, 223 (male) and 283 (female) mg/kg in subcutaneous route and 36 (male and female) mg/kg in intravenous route, Rats; 1000 (male) and 1092 (female) mg/kg in oral route, 1632 (male) and 1411 (female) mg/kg in subcutaneous route, and 22 (male) and 25 (female) mg/kg in intravenous route. On the LD50 values, no sexual difference was apparent but the species difference between mice and rats observed to be present in oral and subcutaneous routes. The approximate lethal doses of P-4 in dogs were 987-1137 mg/kg for male and 865-894 mg/kg for female in oral route, and the values were almost same as those in rats of oral route. 2. Major toxic signs such as clonic convulsion, bradypnoea, dyspnoea, decreased spontaneous activity and hematuria were observed in mice and rats. Furthermore mydriasis in rats, and transitory salivation and/or vocalization in mice and rats were observed. In some rats, sedation, salivation, soil at hypogastrium, rale and emaciation were detected from the next day of oral administration. In dogs, toxic signs such as vomiting, tremor, tonic and/or clonic convulsion, mydriasis and gasping were observed. 3. Pathological changes observed in dead animals were congestion of lungs, liver and kidneys in all routes, congestion and hemorrhage in digestive tracts in oral route, inflammatory changes at the injection site in subcutaneous route. In addition, retention of hematuria in urinary bladder in rats of oral and subcutaneous routes, the hemorrhagic changes of heart, atonia of urinary bladder and retention of urine in dogs were observed. 4. The main cause of death seemed to be respiratory disturbance in all species and the weakness in a few rats of oral route.
- Published
- 1989
- Full Text
- View/download PDF
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