신규 피리미딘 구조를 함유한 항바이러스성 화합물 CPD의 수용약중 가용화

송석길(Sukgil Song),권호석(Ho Seok Kweon),정연복(Youn Bok Chung) 대한약학회 2006 약학회지 Vol.50 No.1

The purpose of the present study was to formulate the aqueous solution of 1-cyclopent-3-enylmethyl-6(3,5-dimethyl-benzoyl)-5-ethyl-1H-pyrimidine-2,4-dione (CPD), a novel antivirus compound containing pirimidine structure. For this purpose, the effects of various solubilization agents such as cosolvents [ethanol, propylene glycol (PG), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), glycerin], surfactants (Tween 80, Cremophor?? RH40, Cremophor?? EL, Poloxamer 407, Poloxamer 188) and complexation agent [hydroxypropyl-β-cyclodextrin (HPBCD)], on the solubility of CPD in aqueous solution were evaluated. The solubility of CPD in water was under 1 ㎍/㎖ at 20℃. Cosolvents such as ethanol, PG, PEG 300, PEG 400 and glycerin did not enhance the solubility of CPD at the 0~40% concentration range. The solubility of CPD was significantly elevated by the addition of cosolvents over the 80% concentration range. On the other hand, tween 80, Cremophor?? L, Cremophor?? RH40, and HPBCD showed enhanced effects on the solubility of CPD. The enhanced effects of Poloxamer 407 or Poloxamer 188 on the CPD solubility were less pronounced compared with tween 80, Cremophor?? L or Cremophor?? RH40. As a results, tween 80 aqueous solution was selected as an optimum solvent system. The aqueous solutions containing 20% tween 80 were formulated as a dosing solution containing CPD for its intraperitoneal and intrahypodermic administration, respectively. The formular showed physical stability after stored for 7 days at 4℃. Keywords : CPD, solubility, stability, cosolvent, surfactant

신규 항암성 화합물 아크리플라빈과 구아노신 복합체를 흰쥐에 근육주사시 아크리플라빈의 체내분포

송석길(Sukgil Song),정연복(Youn Bok Chung) 대한약학회 2006 약학회지 Vol.50 No.1

A 1:1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is currently being evaluated as a possible antitumor agent in preclinical studies. Guanosine is known to potentiate the anticancer activity of some compounds. However, the distributions of trypaflavine (TRF) or proflavine (PRF) have not been investigated in mammals. We, therefore, investigated the distribution of TRF and PRF after i.m. administration of the combination mixture (ACF and guanosine) at a does of 30 ㎎/㎏ ACF in rats. To analyze TRF and PRF levels in biological samples, we used an HPLC-based method. The calibration curves for TRF and PRF in the sample were linear over the concenration range of 0.05~200 ㎍/㎖. The intra- and inter-day assay accuracies of this method were within ±15% of norminal values and the precision did not exceed 15% of relative standard diviation. The lower limits of quantitation were 50 ng/㎖ for both TRF and PRF. The distribution of TRF or PRF was determined by 48h after i.m. administraion of the combination mixture at a dose of 30㎎/㎏ ACF. TRF and PRF were distributed as the followeing order; kidney>lung>liver>small intestine>muscle. Of the various tissues, TRF and PRF were mainly distributed to the kidney and lung. The concentrations of TRF or PRF in the tissues 24 h after i.m. administration decreased to undetectable levels. The concentrations of TRF or PRF in the blood cells were comparable to those for the plasma. However, the concentrations of TRF or PRF in the both plasma and blood cells 12h after i.m. administration were not detected. The number of the platelets in the 1㎖ of the blood was calculated to be 0.183×108/㎖ of blood. The PRF concentration in platelets was higher than that of TRF at initial times after i.m. administration of the combination mixture. However, both the TRF and PRF concentrations in the plateles 24h after i.m. administraion of the combination mixture were below the quantifiable limit. In conclusion, the concentrations of TRF or PRF in the various tissues, plasma, blood cells, and plateles decreased to undetectable levels 24h after i.m. administration of the combination mixture at a dose of 30 ㎎/㎏ ACF.

음이온계 약물의 간수송과정에 있어서 대향수송의 약물동력학적 모델링 및 시뮬레이션

송석길(Sukgil Song),이준섭(Jun Seup Lee),정연복(Youn Bok Chung) 대한약학회 2005 약학회지 Vol.49 No.4

The purpose of the present study was to kinetically investigate the carrier-mediated uptake in the hepatic transport of organic anions, and to simulate the "in vivo counter-transport" phenomena, using kinetic model which was developed in this study. The condition that the mobility of carrier-ligand complex is greater than that of free carrier is not essential for the occurrence of "counter-transport" phenomenon. To examine the inhibitory effects on the initial uptake of organic anions by the liver, it is necessary to judge whether the true counter-transport mechanism (trans-stimulation) is working or not. Effects of bromophenol blue (BPB) or bromosulfophthalein (BSP) on the plasma disappearance curves of a 1-anilino-8-naphthalene sulfonate (ANS) were then kinetically analyzed based on a flow model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). Moreover "in vivo counter-transport" phenomena were simulated based on the perfusion model which incorporated the carrier-mediated transport and the saturable intracellular binding. The "in vivo counter-transport" phenomena in the hepatic transport of a organic anions were well demonstrated by incorporating the carrier-mediated process. However, the "in vivo counter-transport" phenomena may be also explained by the enhancement of back diffusion due to the displacement of intracellular binding. In conclusion, one should be more cautious in interpreting data obtained from so-called "in vivo counter-transport" experiments.

결장암에 대한 활성 자연살해세포의 항암효능

성혜란(Hyeran Sung),김지연(Jee Youn Kim),박민경(Min Gyeong Park),김일회(Il-Hoi Kim),이동욱(Dong Wook Lee),한상배(Sang-Bae Han),이종길(Chong-Kil Lee),송석길(Sukgil Song) 대한약학회 2010 약학회지 Vol.54 No.3

Colorectal cancer is one of the most common alimentary malignancies. In this study, the antitumor activity of activated human natural killer (NK) cells against human colorectal cancer was evaluated in vivo. Human NK cells are the key contributors of innate immune response and the effective functions of these cells are enhanced by cytokines. Human peripheral blood mononuclear cells (PBMC) were cultured with interleukin-2 (IL-2)-containing medium for 14 days and resulted in enriched NK cell population. The resulting populations of the cells comprised 7% CD3+CD4+ cells, 25% CD3+CD8+ cells, 13% CD3-CD8+ cells, 4% CD3+CD16/CD56+ cells, 39% CD3+CD16/CD56- cells, and 52% CD3-CD16/CD56+ cells. Tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), IL-2, IL-4, and IL-5 transcripts of the activated NK cells were confirmed by RT-PCR. In addition, activated NK cells at doses of 2.5, 5 and 10 million cells per mouse inhibited 10%, 34% and 47% of SW620-induced tumor growth in nude mouse xenograft assays, respectively. This study suggests that NK cell-based immunotherapy may be used as an adoptive immunotherapy for colorectal cancer patients.

비소세포성폐암에 대한 자연살해세포의 항암효능

박민경(Min Gyeong Park),한상배(Sang-Bae Han),김지연(Jee Youn Kim),박지성(Ji-sung Park),성혜란(Hyeran Sung),윤병규(Byung Kui Yun),송석길(Sukgil Song),이종길(Chong-Kil Lee) 大韓藥學會 2011 약학회지 Vol.55 No.3

Human NK cells, identified 30 years ago based on their ability to spontaneously kill tumor cells, constitute a subset of lymphocytes, which play an important role in the first line of immune defense and the effective function of these cells are enhanced by cytokines. Lung carcinoma has been one of the most commonly diagonosed cancer as well as the leading cause of cancer death in male. Here we provide the evidence that human natural killer cells has inhibitory effects on tumor growth of human lung cancer cell NCI-H460 (non-small cell lung cancer). Enriched NK cell population was obtained by 2 weeks cultivation in interleukin-2(IL-2)-containing medium. The resulting population comprised 26% CD3+ cells, 9% CD3+CD4+ cells, 16% CD3+CD8+ cells, 76% CD56+ cells, 6% CD3+CD56+ cells and 70% CD3-CD56+ cells. Activated NK cells at doese of 2.5, 5, and 10 million cells per mouse inhibited 2%, 12% and 45% of NCI-H460-induced tumor growth in nude mouse xenograft assays, repectively. This result suggests that NK cell-based immunotherapy may be used as an adoptive immunotherapy for lung cancer patients.