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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Biomolecules & Therapeutics
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Journal DOI :
The Korean Society of Applied Pharmacology
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Volume & Issues
Volume 2, Issue 4 - Dec 1994
Volume 2, Issue 3 - Nov 1994
Volume 2, Issue 2 - Aug 1994
Volume 2, Issue 1 - Apr 1994
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Acute and Subacute Toxicity of DWP305 (Ursodeoxycholic acid : Silymarin : Fursulthiamine : Riboflavin tetrabutyrate) in Rats
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 213~222
The acute tonicity of DWP305 (Ursodeoxycholic acid : Silymarin : Fursulthiamine : Riboflavin tetrabutyrate=1: 1 : 0.1 : 0.05) was evaluated in both sexes of Sprague-Dawley rats, 6weeks old by the oral route of administration. DWP305 was not considered to induce any toxic effect on the rats in mortalities, clinical findings, body weights and gross findings. It is suggested that LD
value in rats would be above 5 g/kg in the oral administration. Subacute toxicity of DWP305 was examined in Sprague-Dawley rats. Four groups of rats were administered orally at doses of 0, 0.32, 0.8, and 2.0 g/kg/day of DWP305 for one month. Any significant toxic clinical symptom was not observed in the treated rats during the experimental period. Macroscopic examination on the organs of tested animals showed no abnormal findings. On autopsy, no significant changes were found in organs examined. Maximum tolerated dose of DWP305 for the rat was estimated to be above 2 g/kg in this study.y.
Changes of Gangliosides Metabolism in Streptozotocin-Induced Diabetic Rats and Effect of Deer Antler
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 223~228
In this study, we examined gangliosides from streptozotocin-induced diabetic rat brain. To obtain the diabetic rat brain, we sacrified the rat three days after injecting the streptozotocin into venus in tail. We measured blood glucose level according to Somogy-Nelson method and measured insulin level using
I-insulin RIA kit. The gangliosides were extracted according to Folch-Suzuki method from the rat brain. We also examined the effect of major lipid components extracted from deer antler on diabetic rat brain. The results showed that the major lipids components lowered both blood glucose and insulin level in normal rat. However only the blood glucose level in diabetic rat was lowered with major lipid components. In diabetic rat brain, gangliosides metabolism were changed. The amount of GMla was increased while GDla, GDlb, and GTlb were not synthesized. Furthermore, undefined ganglioside was found. In major lipid component-treated diabetic rat brain, the ganglioside metabolism proceeded as same as the normal rat. On the contrary, in bovine brain gangliosides-treated diabetic rat brain, the gangliosides metabolism was not recovered to normal one.
Effect of Renal Denervation on Renal Action of Methoxyverapamil in Dogs
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 229~235
In dogs, renal denervation did not affect the diuretic action accompanied with renal hemodynamic chanties and inhibition of electrolytes reabsorption rates in renal tubules by methoxyverapamil infused into the vein or into a renal artery, while renal denervation blocked the antidiuretic action due to the decreased free water and osmolar clearances along with the reduced sodium amounts excreted in urine by methoxyverpamil infused into the carotid artery. These experimental results suggest that methoxyverapamil may cause diuresis by direct action in kidney but the antidiuretic action through central function mediated by renal nerves.
A Development of Methods for detecting Immunosuppression induced by Cyclophosphamide in vitro
;Michael P. Holsapple;;;;;
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 236~243
A splenocyte culture system supplemented with liver microsomes was developed to detect immunotoxic chemicals which require metabolic activation using cyclophosphamide as a positive standard. When liver microsomes were added to splenocyte cultures isolated from female B6C3Fl mice, the proliferation of splenocytes by lipopolysaccharide (LPS) was increased and the proliferation by concanavalin A (Con A) was decreased. However, when compared with each corresponding control, cyclophophamide was successfully activated to metabolites capable of suppressing Iymphoproliferative responses. This suppression was clearly dependent upon the amounts of microsomes added and/or the concentration of cyclophosphamide exposed. In these cultures, the proliferation of splenocytes was suppressed when the cells were exposed to cyclophosphamide on the day of culture initiation. On the other hand, microsome was responsible for the increase in LPS mitogenicity and NADPH was responsible for the decrease in Con A mitogenicity. Finally, our present culture system was compared with the hepatocyte-splenocyte coculture system which we had developed earlier. We found that the hepatocyte-splenocyte coculture was better able to activate cyclophosphamide to metabolites capable of suppressing the antibody response to sheep erythrocytes. Although our present culture system was relatively poor to activate cyclophosphamide in cultures for antibody response, it will be useful as a simple screening method to detect suppression of certain in vitro immunotoxic parameters like LPS mitogenicity by chemicals which require metabolism.
Physicochemical Properties of G009
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 244~246
G009, isolated from the mycelia of Ganoderma lucidum, has been reported as a potent liver-protecting compound. To characterize this compound, its physicochemical properties were studied. The average molecular weight of the most abundant constituent of G009 was 9.4 kD. The contents of carbohydrate and protein in G009 were 70% and 12.4% respectively. The main carbohydrate constituents were glucose, xylose, mannose and galactose. Seventeen kinds of amino acid were detected. The contents of carbon, hydrogen, and nitrogen were 40, 5.7, and 1.8%, respectively. Ca, Mg, Zn were also determined.
Studies on Local Irritation of DA-3030, a new granulocyte colony stimulating factor
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 247~255
As a series of safety studies of DA-3030, a new rhO-CSF, its local irritancy was examined in the rabbits after the following treatment; application into the conjunctival sac of the eye(single), subcutaneous injection(single), intramuscular injection(single), and intravenous injection(8-day repeated). In addition, paravenous irritation of DA-3030 was investigated in mice. The results obtained were as follows. 1. In the result of ocular irritation test, 0.03% solution of DA-3030 could be considered as a non-irritating material. 2. The local irritation of DA-3030 by an injection of 0.5mι of its solution subcutaneously or intramuscularly was negligible and not so much different from that of saline. 3. In the vascular irritancy test, macro- and microscopic observations revealed that the irritating activity of DA-3030 in blood vessels was not different from that of saline when they were injected once a day into vein retroauricularis of rabbits for 8 days.4. The paravenous administration of DA-3030 did not induce any abnormal changes at injection sites except mild swelling in 1 mouse at 3 hours after injection which was thought to be due to slow absorption. The above-mentioned results suggest that DA-3030 has no irritating activity when injected through intravenous or subcutaneous route for clinical practice as 0.03% solution.
Acute toxicity of DA-3030(G-CSF) in rats and mice
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 256~259
This study was performed to evaluate the acute toxicity of DA-3030(granulocyte-colony stimulating factor, G-CSF) in mice and rats via intragastrical and intravenous routes. DA-3030(G-CSF) in the acute toxicity study did not induce any toxic signs in the mice and rats in mortalities, clinical findings, body weights and gross findings. It is suggested that LD
values in mice and rats would be >13, 800
/kg in the oral route and >6, 900
/kg in the intravenous route.e.
Four-Week Intravenous Toxicity of DA-3030 (G-CSF) in Beagle Dogs
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 260~269
This study was performed to determine the toxic effect of DA-3030(granulocyte-colony stimulating factor, G-CSF) in beagle dogs. DA-3030(G-CSF) was injected intravenously at doses of 115
/kg/day and 1.15
/kg/day seven days per week for 28 days. After completion of the treatments, the dog were necropsied. The number of dead animal was zero in all groups. No specific clinical sign was found, either. In hematological results, WBC was significantly increased dose-dependently in treated groups. In histopathological findings, megakaryocyte and rubricyte were found in the liver and spleen at the dose of 115
/kg/day. Therefore, we could find the extramedullary hematopoiesis was increased. Megaka yocyte and rubricyte were increased in bone marrow, too. In conclusion, those signs were estimated the pharmacological effect of DA-3030(G-CSF). According to the results, non toxic dose of DA-3030(G-CSF) was higher than 115
Four-week Intravenous Toxicity Study of DA-3030, a Recombinant Human G-CSF, in Rats
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 270~280
This study was conducted to evaluate the repeated dose toxicity of DA-3030, a recombinant human granulocyte colony stimulating factor(rhG-CSF), in rats. DA-3030 was administered intravenously once a day for 4 weeks to 20 males and 20 females per group at doses of 0(control), 115 and 1150
/kg, and to 15 males and 15 females per group at doses of 1.15 and 11.5
/kg. After the administration period, 5 males and 5 females per group in the 0,115 and 1150
/kg groups were placed on withdrawal for 2 weeks. Through-out the study, all the rats survived. The administration of DA-3030 induced, a marked increase in the number of peripheral neutrophils, elevation of serum alkaline phosphatase activity, and splenomegaly in the rats of both sexes receiving 115 or 1150
/kg. Histopathologic examination revealed extramedullary granulopoiesis in spleen and liver, and increase in the number of activated macrophages in spleen in rats of both sexes in 115 and 115
/kg groups, and increased M/E ratio in 11.5, 115 and 1150
/kg groups. Most of the changes produced by DA-3030 were thought to be attributable to exaggerated pharmacological effect of the drug, and subsided or disappeared after the recovery period. Under the present condition, no effect dose of DA-3030 is estimated at 1.15
General Pharmacology of Recombinant Human Granulocyte-colony Stimulating Factor DA-3030 Expressed in E. coli
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 281~285
Neutropenia is a major dose-limiting factor in cancer chemotherapy diminishing its usefulness and increase patient's susceptibility to infectious disease. Some recombinant human granulocyte colony stimulating factors(rhG-CSFs) are in use to reduce the risk of this serious side effect. In this study, we examined the pharmacological properties of DA-3030, a rhG-CSF expressed in E. coli. DA-3030 100 and
/kg, i. v., had no significant effect on the central nervous, gastrointestinal system in mice and cardiovascular system in rabbits, but it slightly inhibited the spontaneous motility of isolated nonpregnant uterus in rats. It also had no influence on excretion of urinary electrolytes. DA-3030 administered for successive 3 days increased the blood WBC count in zymosan air pouch inflammed rats and in normal rats. These results indicate that DA-3030 has little side effects in animals.
Mutagenicity Study of DA-3030, A New Recombinant Human G-CSF(rhG-CSF)
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 286~291
The mutagenicity of DA-3030(rhG-CSF)was studied by reverse mutation test, chromosome aberration test and micronucleus test. The reverse mutatuon test in bacteria was performed using salmonella typhimurium strain TA100, TA98, TA1535 and TA1537 with rhG-CSF in any of the concentrations(150, 75, 37.5, 18.75, 9.375 and 4,6875
/plate), no increase in the number of revertant colonies in each strain was observed, irrespective of treatment with the metabolic activation system(S-9 mix) The chromosome aberration test was carried out using CHL cells, cell line from chinese hamster lung. With 4 doses(75, 37.5, 18.75 and 9.375
/ml) of rhG-/CSF the cells were treated for 24 or 48 hours in the direct method or for 6 hours followed by 18 hour-expression time in the metabolic activation method. Results of the study showed, by the direct method or metabolic activation method, no trend toward increase in the number of aberrant metaphase. The micronucleus test was carried out using ICR mice at the age of 8 weeks. Three doses(862.5, 1725 and 3450
/kg) of DA-3030 were admintstered intraperitoneally with single shot and bone marrow cells were sampled at 24 hours after administration. Neither the number of polychromatic erythrocytes with micronuclei nor the ratio of normochromatic erythrocytes to polychromatic erythrocytes increased singinficantly in each dose, compared with a vehicle control. These results indicate that rhG-CSF has not mutagenic potential under the condiions.
Antigenicity of DA-3030, a Recombinant Human Granulocyte-colony Stimulating Factor, in Guinea Pigs and Mice
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 292~297
This study was conducted to investigate antigenic potential of DA-3030, a recombinant human granulocyte-colony stimulating factor, in guinea pigs and mice. In the active systemic anaphylaxis test, the guinea pigs sensitized with 1.25 or 12.5
/head of DA-3030 alone did not show any anaphylactic reaction. In the homologous passive cutaneous anaphylaxis reaction, anti-DA-3030 antibody was not detected in guinea pigs sensitized with 1.25 or 12.5
/head of DA-3030 alone. On the other hand, the guinea pigs sensitized with 12.5
/heed of DA-3030 incorporated in Freund's complete adjuvant(FCA) or 1 mg/head of ovalbumin incorporated in FCA showed anaphylactic reaction. Anti-DA-3030 antibody was also detected in those guinea pigs. In immunodiffusion test using the sera sensitized with DA-3030 incorporated in FCA, precipitating antibodies were detected only in the sera sensitized with DA-3030 or DA-3030 incorporated in FCA showed. In 24-hour heterologous PCA reaction with sera of C57BL/6 mice immunized with 1.25 or 12.5
/head of DA-3030 alone, none of the sera showed positive reaction. But sera of the animals immunized with 12.5
/head of DA-3030 incorporated in aluminum hydroxide gel(Alum) or 5
/head of ovalbumin incorporated in alum showed positive PCA reaction. DA-3030 did not cause anaphylactic shock or passive cutaneous anaphylaxis in guinea pigs and mice when given alone although DA-3030 incorporated in FCA or Alum induced anaphylactic shock and passive cutaneous anaphylaxis. From these results, it may be concluded the DA-3030 does not induce systemic allergic reaction when administered alone in its clinical use.
Effects of Mercuric Chloride on the Lipid Peroxidation and Oxygen Free Radical scavenging Enzymes Activities in the Liver of Rats
Biomolecules & Therapeutics, volume 2, issue 3, 1994, Pages 298~302
Wistar albino rats were injected subcutaneously with mercuric chloride (5 mg/kg) to define the early biochemical determinants that participate in the pathogenesis of mercuric chloride-induced hepatotoxicity, especially focusing on oxygen free radicals, we studied malondialdehyde(MDA) level and the activities of catalase and superoxide dismutase in the liver of rats at 24, 48 and 72 hr after the injection of mercuric chloride. MDA levels at 24, 48 and 72 hr after the injection of mercuric chloride increased as compared with that of control group. The activities of catalase and superoxide dismutase at 24, 48 and 72hr after the injection of mercuric chloride decreased as compared with that of control group. These results suggest that the depression of the activities of catalase and superoxide dismutase resulting from excessive oxygen free radicals is an important determinant in pathogenesis of mercuric chloride-induced hepatotoxicity.