• 대한골관절종양학회지
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• 제9권2호
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• pp.190-199
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• 2003

목적: Holmium-166은 류마티스성 관절염 및 간암 치료에서 이미 임상적으로 사용이 보고된 방사성 동위원소이다. 본 연구는 holmium-166-chitosan 복합체를 외과적으로 생체에 투입하여 임상에 적용 가능한 방법을 연구하고, 투여량과 기간, 투여 부위에 따른 조직학적 반응 정도를 정성 및 정량 분석하여 임상적용의 기초로 활용하는 것이다. 재료 및 방법: Absorbable gelatin sponge에 액체상태의 holmium-166-chitosan 복합체를 50 ${\mu}l}$ 도포하여 고형제로 만들었다. 최종 삽입전에 caliberator로 측정한 방사선량은 약 1.5 mCi였다. Wistar종 흰쥐에 외과적 시술을 통하여 대퇴근육 내부와, 그리고 대퇴골에 접하게 holmium-166-chitosan 복합체가 부착된 gelatin sponge를 삽입 후 봉합하였다. 대퇴 근육내와 대퇴골에 투여한 후 2주, 4주, 6주에 육안 및 현미경 소견하에서 조직 괴사의 깊이, 조직 변화의 양상, 삽입된 gelatin sponge의 변화 등을 관찰하였다. 결과: 2주후의 현미경 소견상 holmium-166과의 접촉면에서는 정상 근육세포의 모양을 찾아 볼 수 없을 만큼 심한 괴사 소견을 보였고 근육세포의 퇴화 및 재생, 근육간 부종, 염증세포의 침윤 소견을 보였으며 유발된 괴사의 깊이는 평균 3.3 mm 였다. 대퇴골에서는 holmium-166과의 접촉면에 있는 골피질은 골소강내 골세포의 소실이 관찰되었고 골수강내의 골수 세포도 파괴되고 섬유화 또는 염증성 반응을 보였다. 괴사의 깊이는 평균 2.9 mm 였다. 4주 때 근육에서는 석회화와 보다 심해진 섬유화 소견이 추가 되었고 괴사의 깊이는 평균 3.3 mm 였다. 골조직에서도 골수강의 섬유화가 더 증가되었고 괴사의 깊이는 평균 3.3 mm였다. 경과 관찰 6주 군에는 연부 조직의 위축과 섬유화의 증가, 육아조직의 형성, 염증 소견의 소실 등이 관찰되었다. 결론: Holmium-166-chitosan 복합체를 생체 흡수 가능한 gelatin sponge에 부착시킨 후 실험동물에 삽입한 결과, 실험동물의 사망을 유발하지도 않았으며 상처의 괴사, 염증, 감염 등의 부작용이 전혀 없어, 생체에 외과적 적용이 가능하였다. 유발된 조직 괴사의 범위는 약 3 mm로 미리 예측한 정도에 근접하는 것으로 악성종양 치료에 임상적 적용이 가능할 것으로 생각한다.

• Journal of Korean Neurosurgical Society
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• 제29권10호
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• pp.1309-1315
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• 2000

Objectives : We performed an in vivo experiment to investigate the effect of $^{166}Holmium$ and $^{166}Holmium$-chitosan complex($^{166}Ho$-CHICO) on the normal brain of rats and to determine the sublethal dose of $^{166}Ho$-CHICO. Materials and Methods : $^{166}Ho$ is a beta and gamma ray emitter. $^{166}Ho$-CHICO is a novel radio-pharmaceutical complex with chitosan to facilitate the transport of $^{166}Ho$ obtained from Korea Atomic Energy Research Center(Taejon, Korea). It is in acidic form and becomes gel state at alkaline pH. One hundred and seventy consecutive rats were divided into four groups : $^{166}Ho$ treated(n＝50), $^{166}Ho$-CHICO treated(n＝57), saline treated(n＝5) and chitosan treated(n＝5) groups. $^{166}Ho$ and $^{166}Ho$-CHICO were injected into the rat brain stereotactically with various doses of 0.1mCi/$20{\mu}l$, 0.2mCi/$20{\mu}l$, 0.3mCi/$20{\mu}l$, and 0.4mCi/$20{\mu}l$ using an automated microinjector. Nuclear imaging, histopathological and hematological studies were performed in 10 rats in each group at 1 day, 3days, 7 days, 1 month and 3 months after the injections. Results : An infiltration of inflammatory cells and necrotic changes were noted in $^{166}Ho$ treated group at 1 week after the injection. A wedge-shaped tissue defect due to necrosis, lined with infiltrated glial cells in $^{166}Ho$ treated group and a cystic defect lined with reactive astroglial cells in $^{166}Holmium$-CHICO treated group at 3 months after the injection were observed. $^{166}Ho$ alone without chitosan leaked out and caused necrotic lesion on the cerebral surface but $^{166}Holmium$-CHICO treated group did not show this feature. As the dose of $^{166}Ho$ increased, the mortality rates were also increased. The mortality rate of the $^{166}Holmium$-CHICO group was higher than the $^{166}Ho$ treated group at a dose of 0.4mCi/$20{\mu}l$/300g. There was no detectable radioactivity due to the leakage or extravasation from the injected site of the brain on the scintigraphy performed at 1 hour, 24 hours and 48 hours after the injection. There was also no detectable activity of $^{166}Holmium$-CHICO in other organs including spleen, liver and kidney. Conclusions : $^{166}Ho$-CHICO did not leak out to the critical cortical surface of the brain from the injection site and induced radiation changes of the parenchyma around the injection site without cortical damage. The sublethal dose of $^{166}Ho$-CHICO for the normal brain in rats was determined to be 0.2mCi/$20{\mu}l$/300g.

• Investigative Magnetic Resonance Imaging
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• 제5권1호
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• pp.43-48
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• 2001

목적: 방사성 등위원소인 Holmium-166을 가토 간 실질 내에 경피적 주입한 후 나타나는 변화에 대한 조직학적 소견과 MR영상 소견을 알아보고자 하였다. 대상 및 방법: 12예의 가토의 간 실질 내에 Holmium-166 방사성 등위원소 10∼25 mCi를 초음파 유도하에 경피적 주입 후, MR 영상을 시행하기 전에 사망하지 않은 8예의 가토 중 4예는 급성기 (1-2주)에, 나머지 4예는 아급성기 (3-4주)에 MR 영상을 시행한 후 희생시켜, 조직표본을 얻었으며 , MR 영상을 시행하기 전에 사망한 4예 중 1예는 급성기에, 3예는 아급성기에 조직표본만을 검사하였다. 결과 괴사부위는 중심부의 액화괴사와 주변부의 응괴 괴사(coagulative necrosis). 과립성 입자의 침착, 출혈 등의 변화를 보였으며, 테두리에는 육아조직의 형성과 섬유화가 관찰되었는데, 섬유화는 급성기보다 아급성기에서 현저하였다. Holmium-166 주입양과 간 실질의 괴사 면적과는 비례하는 경향을 보였다. MR영상에서 괴사의 중앙부는 T1 강조영상에서는 저신호, T2 강조영상에서는 고신호를 나타냈으며, 조영후 역동적 영상에서는 조영증강이 되지 않았다 주변부는 T1 강조영상에서는 동등 신호 또는 약간 저신호, T2 강조영상에서는 저신호를 보였으며, 조명후 역동적 영상에서는 지 연기에서 약한 조영 증강이 말초부에서 관찰되었다. 테두리는 T1 강조영상에서는 저신호, T2 강조영상에서는 저신호, 조명후 역동적 영상에서는 초기에 약간 조영 증강하고, 후기에는 좀더 조영증강이 강해지는 소견을 보였다. 결론: 정상 간조직에 경피적으로 Holmium-166을 주입하였을 때, 조직학적으로 중앙부는 액화괴사, 주변부는 응고괴사, 테두리에는 육아 조직, 섬유화, 출혈과 과립성 입자의 침착이 관찰되었으며, MR 영상은 조직변화를 평가하는 데 유용할 것으로 생각한다.

• Journal of Korean Neurosurgical Society
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• 제54권3호
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• pp.175-182
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• 2013

Objective : Intracavitary injection of beta-emitting radiation source for control of cystic tumors has been tried with a benefit of localized internal radiation. The authors treated cystic brain tumor patients with Holmium-166-chitosan complex (Ho-166-chico), composed of a beta-emitting radionuclide Holmium-166 and biodegradable chit polymer, and evaluated the safety and effective measurement for response. Methods : Twenty-two patients with recurrent cystic brain tumor and/or located in a deep or eloquent area were enrolled in this pilot study. The cyst volume and wall thickness were determined on CT or MRI to assess radiological response. The activity of Ho-166-chico injected via Ommaya reservoir was prescribed to be 10-25 Gy to the cyst wall in a depth of 4 mm. Results : There was neither complications related to systemic absorption nor leakage of Ho-166-chico in all 22 patients. But, two cases of oculomotor paresis were observed in patients with recurrent craniopharyngioma. Radiological response was seen in 14 of 20 available follow-up images (70%). Seven patients of 'evident' radiological response experienced more than 25% decrease of both cyst volume and wall thickness. Another 7 patients with 'suggestive' response showed decrease of cyst volume without definitive change of the wall thickness or vice versa. All patients with benign tumors or low grade gliomas experienced symptomatic improvement. Conclusion : Ho-166-chico intracavitary radiation therapy for cystic tumor is a safe method of palliation without serious complications. The determination of both minimal effective dosage and time interval of repeated injection through phase 1 trial could improve the results in the future.

• 대한방사성의약품학회지
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• 제7권2호
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• pp.69-77
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• 2021

No-carrier-added holmium-166 (n.c.a ¹⁶⁶Ho) separation is performed based on the results of separation conditions using stable isotopes dysprosium (Dy) and holmium (Ho) to minimize radioactive waste from separation optimization procedures. Successful separation of two adjacent lanthanides was achieved by cation-exchange chromatography using a sulfonated resin in the H+ form (BP-800) and α-hydroxyisobutyric acid (α-HIBA) as eluent. For the identification process after separation of stable isotopes, the use of chromogenic reagents alternatively enables on-line detection because the lanthanides are hardly absorb light in the UV-vis region or exhibit radioactivity. Four different chromogenic reagents were pre-tested to evaluate suitable coloring reagents, of which 4-(2-Pyridylazo)resorcinol is the most recommendable considering the sensitivity and specificity for lanthanides. Lanthanide radioisotopes (RI) were monitored for separation with an RI detector using a lab-made separation LC system. Under the proper separation conditions, the n.c.a ¹⁶⁶Ho was effectively obtained from a large amount of 100 mg dysprosium target within 2 hrs.

• 대한핵의학회:학술대회논문집
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• 대한핵의학회 1997년도 제36차 춘계학술대회 초록집
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• pp.123-123
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• 1997

• 한국원자력학회:학술대회논문집
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• 한국원자력학회 2001년도 춘계학술발표회요약집
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• pp.441-441
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• 2001

• Biomolecules & Therapeutics
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• 제5권1호
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• pp.100-105
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• 1997

DW-166HC ($^{166}$Holmium-chitosan) is a complex of $^{166}$Ho, $\beta$- and $\gamma$-ray emitter, and chitosan, a polymer of glucosamine, with radiotherapeutic potential. The current study was performed to determine the acute toxicities of $^{165}$Ho-chitosan in mice by two different routes of administration. The both sex mice were given a single intravenous bolus injection of $^{165}$Ho-chitosan complex at doses of 12, 10, 6, 5 and 4 mg/kg or subcutaneous administration at doses of 600, 500, 400 and 300 mg/kg. Chitosan was dosed to control animals as 16 and 800 mg/kg, intravenously and subcutaneously, respectively. The doses of $_{165}$Ho-chitosan complex were expressed as $_{165}$holmium nitrate pentahydrate and the ratio of $^{165}$Ho$(NO_3)_3$).$5H_2O$ to chitosan was 3/4 Severe convulsion and respiratory failure were followed by death within 10 min after intravenous dosing. Transient unilateral hindlimb hypokinesias were found in two mice of 5 mg/kg dosing group during the study period. No abnormalities were observed during the necropsy of survived animals in intravenous dosing group. Only one male animal was found dead in 500 mg/kg subcutaneously dosed group. Alopecia with or without cutaneous ulcer were found in most mice including control animals. During necropsy, omental adhesion was observed in all dose ranges and enlarged spleen was found in several animals including control group. It is suggested that the acute intravenous >).$LD_{50}s$ for male and female mice were 4.90 and 6.03 mg/kg, respectively. The lowest lethal dose in male was 500 mg/kg by subcutaneous administration.

• 대한핵의학회:학술대회논문집
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• 대한핵의학회 1999년도 제38차 춘계학술대회
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• pp.200-204
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• 1999

Rheumatoid arthritis (RA) is o chronic inflammatory disease of joints with proliferation of synovial epithelial tissue. Therapeutic approach of the RA consists of pharmacological and surgical interventions. Synovectomy is indicated in patients with progressive inflammatory signs and symptoms intractable to medical treatment including local intracavitary steroid injection. Recently, local injection of radionuclides which emit high energy beta rays are labeled with chemical compounds such as $^{90}Y,\;^{165}Dy-ferric$ hydroxide macroaggregate and have been introduced as an alternative therapeutic modality to surgical synovectomy. Holmium-166 is one of beta emitter and Ho-166-chitosan complex was developed for radiation synovectomy. Preclinical trial is on-going at our hospital using Ho-166-chitosan. The procedure and methods of preclinical trial are discussed.

• 대한핵의학회:학술대회논문집
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• 대한핵의학회 1995년도 제34차 춘계학술대회 초록집
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• pp.201-201
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• 1995