• Title/Summary/Keyword: rhG-CSF

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Pharmacokinetics and Tissue Distribution of DA-3030 (recombinant human granulocyte colony-stimulating factor) after Intravenous, Intramuscular or Subcutaneous Administrations to the Laboratory Animals. (DA-3030(recombinant human granulocyte colony-stimulating factor)의 정맥, 근육 또는 피하주사시 실험동물에서의 약물동력 학 및 조직 분포)

  • 이응두;심현주;이종진;이상득;강수형;김원배;양중익
    • Biomolecules & Therapeutics
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    • v.2 no.4
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    • pp.310-315
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    • 1994
  • The pharmacokinetics and tissue distribution of DA-3030 (recombinant human granulocyte colony-stimulating factor, rhG-CSF, recently manufactured by Dong-A research laboratory of Dong-A Pharmaceutical Company) were compared with reported data in the literature. After intravenous(i.v.) administration of DA-3030, at dose of 5, 10 and 100 $\mu\textrm{g}$/kg to rats, some pharmacokinetic parameters, such as terminal half-lives(1.05, 1.19 and 1.83 hr, respectively) and clearance (84.0, 54.8 and 45.5 mι/hr/kg, repectively), were dose-dependent. This could be due to the saturable metabolism of DA-3030 in rats. Similar results were also reported. After subcutaneous(s.c.) and intramuscular(i.m.) administrations of DA-3030, 10 $\mu\textrm{g}$/kg to rats, the extent of bioavailability(absolute bioavailability) were incomplete; the values were 23.3 and 18.2% after s.c. and i.m. injections, respectively, due to the degradation of DA-3030 by protease. After 7-consecutive day i.v. administrations of DA-3030, 10 $\mu\textrm{g}$/kg/day, to rats, the plasma concentrations and pharmacokinetic parameters of DA-3030 were not significantly different from those in single administration. In mice and dogs at DA-3030 dose of 10 $\mu\textrm{g}$/kg, the plasma concentrations of DA-3030 were also declined rapidly with terminal half-lives of 1.31 and 1.15 hr, respectively. DA-3030 was highly concentrated in the kidney after i.v. administration of DA-3030, 10 $\mu\textrm{g}$/kg, to rats, and the results were similar to those obtained using radiolabelled rhG-CSF in the literature. Above data indicate that DA-3030 has similar properties to rhG-CSF manufactured by other companies in view of pharmacokinetics.

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Studies on Local Irritation of DA-3030, a new granulocyte colony stimulating factor (새로운 과립구 콜로니 자극인자(rhG-CSF) DA-3030의 국소자극성에 관한 연구)

  • 김옥진;안병옥;이순복;김원배;양중익
    • Biomolecules & Therapeutics
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    • v.2 no.3
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    • pp.247-255
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    • 1994
  • 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.

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Four-week Intravenous Toxicity Study of DA-3030, a Recombinant Human G-CSF, in Rats (재조합 인 과립구 콜로니 자극인자 DA-3030의 랫드에 대한 4주 정맥내 반복투여 독성연구)

  • 강경구;김옥진;안병옥;백남기;이순복;김원배;양중익
    • Biomolecules & Therapeutics
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    • v.2 no.3
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    • pp.270-280
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    • 1994
  • 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 $\mu\textrm{g}$/kg, and to 15 males and 15 females per group at doses of 1.15 and 11.5$\mu\textrm{g}$/kg. After the administration period, 5 males and 5 females per group in the 0,115 and 1150 $\mu\textrm{g}$/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 $\mu\textrm{g}$/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 $\mu\textrm{g}$/kg groups, and increased M/E ratio in 11.5, 115 and 1150$\mu\textrm{g}$/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 $\mu\textrm{g}$/kg/day.

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Expression and Production of Human Granulocyte Colony Stimulating Factor (G-CSF) in Silkworm Cell Line (누에세포를 이용한 인간 G-CSF의 발현 및 생산)

  • Park, Jeong-Hae;Jang, Ho-Jung;Kang, Seok-Woo;Goo, Tae-Won;Chung, Kyung-Tae
    • Journal of Life Science
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    • v.20 no.11
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    • pp.1577-1581
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    • 2010
  • Granulocyte colony stimulating factor (G-CSF) is a hematopoietic cytokine that stimulates bone marrow cells to proliferate and differentiate into granulocytes. G-CSF is approved and used for therapeutic purposes. The endoplasmic reticulum (ER) signal peptide of hG-CSF was replaced with silkworm-specific signal peptides to express and efficiently secrete recombinant hG-CSF by silkworm cells. Plasmids that contain cDNAs for hG-CSF and hG-CSF fused with silkworm- specific signal peptides of prophenoloxidase activating enzyme (PPAE), protein disulfide isomerase (PDI), and bombyxin (BX) were constructed. The G-CSF protein was expressed in insect cell line BM5 and was detected by western blot analysis. The cells transfected with plasmids containing rhG-CSF genes with silkworm-specific signal sequences released mature rhG-CSF protein more efficiently than the cells transfected with pG-CSF, the plasmid containing human G-CSF gene, including its own signal sequence. The production of hG-CSF reached maximal level at four days post-transfection and remained at a high level until 7 days post-transfection. These data demonstrate that the modification of the human G-CSF mimic to insect proteins synthesized in ER greatly improves the production of the protein.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

  • Lee, JooBuom;Lee, Kyungsun;Choe, Keunbum;Jung, Hyunseob;Cho, Hyunseok;Choi, Kiseok;Kim, Taegon;Kim, Seojin;Lee, Hyeong-Seok;Cha, Mi-Jin;Song, Si-Whan;Lee, Chul Kyu;Chun, Gie-Taek
    • Toxicological Research
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    • v.31 no.4
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    • pp.371-392
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    • 2015
  • TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of $1000{\mu}g/kg/day$. Rats received TS-DP2 intravenously at doses of 250, 500, and $1000{\mu}g/kg/day$ once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 $500{\mu}g/kg/day$ and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was $250{\mu}g/kg/day$, and no observed adverse effect level (NOAEL) in females was $250{\mu}g/kg/day$ in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures ($AUC_{0-24h}$ and $C_0$) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

Pharmacokinetics of CJ-50001i Recombinant Human Granulocyte-Colony Stimulating Factor, in Rats and Dogs (CJ-50001 (recombinant human granulocyte-colony stimulating factor)의 흰쥐와 개에서의 약물동태학적 연구)

  • 김성남;신재규;이수정;정용환;하석훈;김기완;고형곤;김제학
    • Biomolecules & Therapeutics
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    • v.6 no.4
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    • pp.400-405
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    • 1998
  • The pharmacokinetics of CJ-50001 (recombinant human granulocyte-colony stimulating factor, developed by R&D center of Cheil Jedang Corp.) were investigated in rats and dogs. The serum concentrations of CJ-50001 were measured by a sandwich enzyme immunoassay. After single intravenous (iv) administration of Cf-50001 to rats at a dose of 5 $\mu$g/kg, the mean terminal half-life and area under the concentration-time curve (AUC) were 0.96 h and 124.497g . h/ml, respectively. After single subcutaneous (sc) administration at the same dose, maximum serum concentration was observed at about 2 hours after administration, and the mean terminal half-life, AUC and the bioavailability were 1.11 h,63.58$\mu$g . h/ml and 51.07%, respectively. In repeated dosing studies, CJ-50001 was administered iv and sc to rats at a daily dose of 5$\mu$g/kg for 7 days. The pharmacokinetic parameters, such as mean AUC and terminal half-life, were no significantly different from those of single administration. Following single iv and sc administration of CJ-50001 to dogs at a dose of 5 $\mu$g/kg, mean AUCs were much higher than those of rats, due to the decreased clearence (CL). After sc administration to dogs, maximum serum concentration was observed at 2~4 hours after administration and the bioavailability was 54.60%.

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Genotoxicity Study of HM10411, Recombinant Human Granulocyte Colony Stimulating Factor (재조합 인과립구 콜로니 자극인자 HM10411의 유전독성 연구)

  • 권정;이미가엘;홍미영;조지희;정문구;권세창;이관순
    • Biomolecules & Therapeutics
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    • v.10 no.4
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    • pp.268-273
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    • 2002
  • Mutagenic potential of HM10411 (recombinant human granulocyte colony stimulating factor) was evaluated by bacterial reverse mutation test, in vitro chromosome aberration test and in vivo micronucleus test. The bacterial reverse mutation test was performed using the histidine auxotroph strains of Salmonella typhimurium TA100, TA1535, TA98, TA1537 and tryptophan auxotroph strain of Escherichia coli WP2 uvrA. The negative results of the bacterial reverse mutation test suggest that HM10411 does not induce mutation, in the genome of Salmonella typhimurium and E. coli under the conditions used. In addition, it has little clastogenicity either in vitro chromosome aberration test or in vivo micronucleus test. For in vitro chromosomal aberration test, Chinese hamster lung(CHL) cells were exposed to HM10411 of 23, 46 or 92 $\mu\textrm{g}$/ml for 6 or 24 hours in the absence and for 6 hours in the presence of metabolic activation system. There was no significant increase in the number of aberrant metaphase in HM 10411-treated groups at any dose levels both in the presence and absence of metabolic activation system. The micronucleus test was carried out using specific pathogen free(SPF) 7-week old male ICR mice, The test item, HM10411 was intraperitoneally administered at 1150, 2300 or 4600 $\mu\textrm{g}$/kg once a day for 2 consecutive days. There was no significant increase in the frequencies of micronucleated polychromatic erythrocytes(PCEs) at any treated groups compared with negative control group. Therefore, these results demonstrate that the test item, HM10411, was not mutagenic under the condition of these studies.