Liposomal itraconazole formulation for the treatment of glioblastoma using inclusion complex with HP-β-CD

윤성원,신대환,김진석 한국약제학회 2019 Journal of Pharmaceutical Investigation Vol.49 No.4

Purpose Itraconazole, which has been widely used as an antifungal-agent, is revisited as an anticancer drug but its low solubility still remains a major hurdle. Methods Inclusion complex was used to enhance the solubility of itraconazole, followed by encapsulating into liposome for glioblastoma. Results Itraconazole-inclusion complex was well formed at 1:1, 1:2 and 1:3 molar ratios of itraconazole: hydroxypropyl-β- cyclodextrin (HP-β-CD) as determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) analyses. Itraconazole-HP-β-CD inclusion complex was then encapsulated in liposome and its size was 120.5 ± 53.1 nm in diameter with 50% encapsulation efficiency. Stem cell-like property, as determined by the population ratio of CD90+/ CD133+, was decreased from 3.38 to 1.46% when the U87-MG-TL cells were treated with 100 μM itraconazole/HP-β-CD-loaded liposome. Anti-proliferative effect of itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was slightly better than that of free itraconazole ( IC50 of 17 μM vs. 26 μM). Moreover, antiproliferative effect of Itraconazole/HP-β-CD-loaded liposome on U87-MG-TL cells was higher than that of free itraconazole when the cells were co-treated with temozolomide ( IC50 of 1.58 mM vs. 2.35 mM). Conclusions Therefore, itraconazole/HP-β-CD-loaded liposomal formulation could serve as a promising strategy for targeting the glioblastoma multiforme.

호중구감소성발열 환자에서 이트라코나졸 초기 투여의 효과

최영진 부산대학교 병원 암연구소 2008 부산대병원학술지 Vol.- No.24

Background : The early diagnosis of fungal infections is difficult and persistent fever may be the only symptom. A delay in treatment, while pursuing the diagnosis, may lead to increased mortality and morbidity. The aim of this study was to evaluate defervescence and response rate of early initiation of Itraconazole in febrile neutropenic patients. Patients and methods : This was an observational study between early initiation group and historical gourp. Early initiation group defines simultaneous providing of itraconazole and broad spectrum antibiotics in neutropenic fever patients, and historical group defines providing of itraconazole in persistent fever patients in spite of 5 days of broad spectrum antibiotics. Results : A total of 88 patients were enrolled. 64 patients received itraconazole early, and 24 patients were received itraconazole conventionally. Demographic and baseline clinical characteristics were similar in both group. The defervescence rates were 85.94% vs 65.2% (p-value 0.015). The overall response rates were 67.3% vs 52.6% (p-value 0.57). Adverse events including liver dysfunction and renal dysfunction were similar both group(p-value 0.78, p-value 0.33). Conclusion : Early initiation of itraconazole has similar efficacy and toxicity to conventional treatment of itraconazole. 목적 혈액 종양 질환으로 항암 화학 요법 치료 혹은 조혈모세포이식을 시행한 환자에서 발생하는 호중구 감소성 발열의 원인이 초기에 진균 감염으로 확진 되는 비율이 2~10%로 알려져 있다. 본 연구는 혈액 종양 질환 환자에서 호중구 감소성 발열이 발생했을 때 초기 경험적 항생제와 동시에 이트라코나졸을 투여함으로써 이전의 초기 항생제 투여 후에도 5~7일 이상 발열이 지속되는 경우 이트라코나졸을 투여한 historical 군과 비교하여 효과와 안전성을 보고자 하였다. 대상과방법 부산 및 경남 지역 대학 병원에서 혈액종양질환으로 항암 치료 혹은 조혈모세포이식을 시행 받는 환자들 중 호중구<0.5 X 10^(9)/1가 최소한 7일 이상 지속될 것으로 예측되면서 호중구 감소성 발열이 있는 16세 이상의 성인 환자를 대상으로 하여 호중구성 발열 제1일에 이트라코나졸을 항생제와 같이 투여한 군과 초기 경험적 항생제를 사용하고도 호중구 감소성 발열이 5-7일 이상 지속되는 경우 1차로 이트라코나졸을 사용한 환자를 historical 군을 대상으로 하여 그 반응과 해열율을 비교하였다. 결과 Itraconazole군은 64명, historical 군은 24명이었으며 총 88명 중 남녀비율은 43명 : 45명으로 성별에 따른 차이는 없었다. 중간 나이는 itrconazole 군이 48세, historical 군이 50세 였고 두군다 기저 질환으로 AML이 가장 많았다. 해열이 된 사람은 전체 88명 중 70명 이었으며 itraconazole 군 55명 (85.94%) historical 군 15명 (62.5%) 였으며 (p=0.0152) 반응율은 itraconazole 군이 67.3 %, historical 군이 52.6 % (p-value 0.57)로 통계적 차이는 없었다. 독성으로는 간독성이 발현된 경우가 총 88명 중 31명으로 가장 많았으며 다음으로 신독성이었다. 결론 상기 연구에서 itraconazole을 호중구성 발열 환자에게 조기에 투여하는 것이 명백한 이득을 준다는 것을 밝히지는 못하였으나 혈액종양환자의 진균감염 치료에 있어 하나의 대안이 될 수 있을 것이다.

조갑진균증 치료의 순응도와 장기적 추적 관찰

김지은,박현정,이준영,조백기 대한의진균학회 2003 대한의진균학회지 Vol.8 No.3

Development of Novel Itraconazole-loaded Solid Dispersion without Crystalline Change with Improved Bioavailability

Park, Young-Joon,Xuan, Jing-Ji,Oh, Dong-Hoon,Balakrishnan, Prabagar,Yang, Ho-Joon,Yeo, Woo-Hyun,Lee, Mi-Kyung,Choi, Han-Gon,Yong, Chul-Soon 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.8

To develop a novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability, various itraconazole-loaded solid dispersions were prepared with water, polyvinylpyrroline, poloxamer and citric acid. The effect of carriers on aqueous solubility of itraconazole was investigated. Their physicochemical properties were investigated using SEM, DSC, and powder X-ray diffraction. The dissolution, bioavailability in rats and stability of solid dispersions were evaluated. Unlike conventional solid dispersion system, the itraconazole-loaded solid dispersion with relatively rough surface did not change crystalline form of drug. Our DSC and powder X-ray diffraction results suggested that this solid dispersion was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in conversion of the hydrophobic drug to hydrophilic form. The itraconazole-loaded solid dispersion at the weight ratio of itraconazole/polyvinylpyrroline/poloxamer of 10/2/0.5 gave maximum drug solubility of about 20 ${\mu}g/mL$. It did not change the crystalline form of drug for at least 6 months, indicating that it was physically stable. It gave higher AUC, $C_{max}$ and $T_{max}$ compared to itraconazole powder and similar values to the commercial product, suggesting that it was bioequivalent to commercial product in rats. Thus, it would be useful to deliver a poorly water-soluble itraconazole without crystalline change with improved bioavailability.

Intravenous Itraconazole vs. Amphotericin B Deoxycholate for Empirical Antifungal Therapy in Patients with Persistent Neutropenic Fever

( Sun Hee Park ),( Su Mi Choi ),( Dong Gun Lee ),( Jung Hyun Choi ),( Jin Hong Yoo ),( Woo Sung Min ),( Wan Shik Shin ) 대한내과학회 2006 The Korean Journal of Internal Medicine Vol.21 No.3

Background: Amphotericin B dexoycholate is currently the standard empirical antifungal therapy for neutropenic patients with hematologic malignancies and who also have persistent fever that does not respond to antibacterial therapy. The antifungal triazoles offer a potentially safer and effective treatment alternative to Amphotericin B dexoycholate. Methods: We assessed the efficacy and safety of intravenous itraconazole, as compared with the efficacy and safety of amphotericin B deoxycholate, as an empirical antifungal therapeutic agent in a matched case-control clinical trial from June 2004 to August 2005. Results: Efficacy was evaluated in 96 patients (48 received itraconazole and 48 received amphotericin B deoxycholate) and all the patients who received the study drugs were evaluated for safety. The baseline demographic characteristics were well matched. The overall success rates were 47.9% for itraconazole and 43.8% for amphotericin B deoxycholate (% difference: 4.1 % [95% confidence interval for the difference: -15.8 to 24]), which fulfilled the statistical criteria for the non-inferiority of itraconazole. The proportions of patients who survived for at least seven days after discontinuation of therapy or who were prematurely discontinued from the study were not significantly different between the two groups. The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in both groups. More patients who received amphotericin B deoxycholate developed nephrotoxicity, hypokalemia or infusion-related events than did those patients who received itraconazole (nephrotoxicity: 16.7% vs. 1.8%, hypokalemia: 66.7% vs. 24.6%, and infusion-related events: 41.7% vs. 3.5%, respectively). Conclusions: Intravenous itraconazole is as effective as amphotericin B deoxycholate and it is generally better tolerated than amphotericin B deoxycholate when it is given as empirical antifungal therapy for Korean patients with persistent neutropenic fever.

Posaconazole versus Itraconazole as Prophylactic Antifungal Agents during Induction Chemotherapy for Acute Myeloid Leukemia: A Real-World Single Center Comparison

Changgon Kim,Seug Yun Yoon,Min-Young Lee,Kyoung Ha Kim,Namsu Lee,Jong-Ho Won 순천향대학교 순천향의학연구소 2019 Journal of Soonchunhyang Medical Science Vol.25 No.2

Objective: To prevent invasive fungal disease (IFD) in acute myeloid leukemia (AML) patients, the use of posaconazole as a prophylactic antifungal agent has become standard in patients undergoing induction chemotherapy. However, there are few data comparing itraconazole and posaconazole as prophylactic antifungal agents in the real world. Methods: Patients at the Soonchunhyang University Seoul Hospital, who were treated with itraconazole or posaconazole for preventing IFD during induction chemotherapy for AML from January 2009 to April 2018, were included in the study. The collected clinical data were reviewed, and IFD was diagnosed using the revised definition of IFD from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group. Results: A total of 53 patients were recruited to receive either posaconazole (n=29) or itraconazole (n=24). IFD occurred in seven patients (29.1%) who used posaconazole and in six patients (20.6%) who used itraconazole for antifungal prophylaxis (P=0.475). The 100-day mortality rate was 4 (13.8%) in the posaconazole group and 2 (8.3%) in the itraconazole group (P=0.535). Conclusion: There was no significant difference in the incidence of IFD and 100-day mortality between the patients with induction chemotherapy for newly diagnosed AML who received posaconazole and itraconazole as prophylactic antifungal agents. These results suggest that it would be worthwhile to ascertain whether posaconazole is widely known as a better approach than itraconazole as prophylactic antifungal agents in the real-world.

폐이식 환자에서 tacrolimus와 itraconazole 혹은 voriconazole 병용 시 tacrolimus의 혈중 농도 변화에 미치는 영향

정유진,이영숙,안지현,손은선,박민수,이장익,장민정 한국임상약학회 2016 한국임상약학회지 Vol.26 No.4

Objective: This study was performed to compare the changes in the blood concentrations of tacrolimus when either itraconazole or voriconazole is together with tacrolimus to prevent or treat invasive aspergillus pneumonia (IAP) in patients with lung transplants. Therefore we can compare the degree of drug-drug interactions between tacrolimus and itraconazole against tacrolimus and voriconazole. Methods: Patients who were admitted and had lung transplants in a territory referral hospital from September 2012 to May 2015 were analyzed retrospectively. The effects of itraconazole and voriconazole on the plasma concentrations of tacrolimus were analyzed. Results: Mean tacrolimus concentrations was 10.49±2.35 ng/mL vs. 10.95±2.98 ng/mL (p=0.722), and mean concentration of tacrolimus over the dose of tacrolimus per day was 8.510±5.890 (ng/mL)/(mg/d) vs. 15.45±28.47 (ng/mL)/(mg/d) (p=0.947) in itraconazole vs. voriconazole group each. The ratio of the number of the results out of target tacrolimus concentrations to the total number of tacrolimus concentration results was 18.0±13.3% vs. 24.4±18.5% (p=0.185). Conclusion: There were no significant differences between itraconzaole and voriconazole to have influences on mean concentrations of tacrolimus over tacrolimus dose per weight per day. However voriconazole tended to raise tacrolimus plasma concentrations more than itraconazole. Safer and more effective drug management to prevent and treat fungal infections should be done by therapeutic drug monitoring not only of tacrolimus but of itraconazole and voriconazole in lung transplant patients.

96-well microplate를 이용한 Trichophyton Rubrum의 항진균제 감수성검사

이무웅,김종철,최종수,김기홍 영남대학교 의과대학 1992 Yeungnam University Journal of Medicine Vol.9 No.2

저자들은 Granade와 Artis의 방법에 따라 96-well microplate와 24-well macroplate를 이용하여 T. rubrum 9주를 대상으로 경구용 항진균제인 ketoconazole과 itraconazole에 대한 MIC를 측정하여 실제 임상사용 가능성을 알아보고 배양온도, 배양용기의 크기, 배지의 종류를 달리하여 MIC에 영향을 줄 수 있는 요소를 점검하여 다음과 같은 결론을 얻었다. 1. 96-well microplate를 사용하여 25℃에서 배양시 균농도에 따른 판독시기의 차이는 높은 균농도(흡광도 2.0, 1.0)에서는 4일만에, 낮은 균농도(흡광도 0.5, 0.25)에서는 6-8일만에 판독할 수 있었고, MIC는 높은 균농도에서 높았으나 시간이 경과시 점차 차이가 줄어들었다. 2. 37℃와 25℃에서 각각 배양시 배양온도에 따른 MIC의 차이는 96-well microplate를 사용하여 37℃에서 배양시 ketoconazole에 대한 MIC는 0.006이하-0.04㎍/ml, itraconazole에 대한 MIC는 0.006이하-0.04㎍/ml였으며 25℃에서의 ketoconazole에 대한 MIC는 0.08-5.68㎍/ml, itraconazole에 대한 MIC는 0.06-0.71㎍/ml로 37℃에서의 MIC는 25℃에서의 MIC에 비해 현저히 낮았다. 3. 24-well microplate와 96-well microplate에서 각각 배양시 배양용기의 크기에 따른 판독시기는 96-well microplate액체배지에서는 4-6일로 24-well macroplate액체배지에서의 8-12일에 비해 판독 시기가 빨랐으나, MIC의 차이는 없었다. 4. 액체배지와 고체배지에서 배양시 배지종류에 따른 MIC의 차이는 액체배지를 함유한 24-well macroplate를 이용한 경우 ketoconazole에 대한 MIC는 0.006이하-5.68㎍/ml, itraconazole에 대한 MIC는 0.006이하-5.68㎍/ml로 고체배지에서의 MIC가 다소 높게 측정되었다. 5. 이상의 결과를 종합하여 볼때 96-well microplate를 사용하여, 흡광도 1.0의 균농도로 접종하여, 25℃에서 배양 후 5-6일째 육안으로 판독하는 것이 항진균제 감수성 검사를 빠르고 간편하게 실시 할 수 있는 방법이다. Various susceptibility tests have been used to determine minimal inhibition concentration(MIC) of dermatophytes. They have limitations to apply practically because they need long time to determine MIC. Authors examined MIC of T. rubrum to ketoconazole and itraconazole using 96-well microplate and 24-well macroplate by method of Granade and Artis and tried to check the possiblity of this method on clinical application. Nine strains of T. rubrum from patients with dermatophytosis were used. Evaluations of the factors affecting MIC were also tried. The results were as follows. 1. Effect of inoculation density on determination time and MIC: Determination of MIC were possible in 4th days after inoculation at higher inoculation density (aborbance 2.0, 1.0) compared to 6th days at lower inoculation density (absorbance 0.5, 0.25). 2. Effect of incubation temperature on MIC: When incubating at 37℃, MIC were below 0.006-0.04㎍/ml to ketokckonazole and below 0.006 -0.04㎍/ml to itraconazole while at 25℃ 0.08-5.68㎍/ml to ketoconazole and 0.006-0.71㎍/ml to itraconazole. Significant reduction of MIC was observed at 37℃ compared to 25℃. 3. Effect of container size on determination time and MIC : When incubating in 96-well microplate and 24-well macroplate, determination of MIC was possible in 4th to 6th days after inoculation in broth-containig 96-well microplate compared to 8th to 12th days in broth-containing 24-well macroplate. But no difference in MIC was observed between different container size. 4. Effect of media on MIC : When using broth as media. MIC were below 0.006- 5.68㎍/ml to ketoconazole, below 0.006-0.36㎍/ml to intraconzole in broth-containg 24-well macroplate. When using agar as media, MIC were below 0.006 - 5.68㎍/ml to ketoconzole, below 0.006-5.68㎍/ml to intraconzole in agar-containing 24-well macroplate. There was slight increase of MIC with agar media compared to broth media. 5. These findings confirm that determination of MIC of dermatophtes by method of Granade and Artis is fast and simple technique for antifungal susceptibility test.

Real-world Adverse Events Associated with Fluconazole and Itraconazole: Analysis of Nationwide Data Using a Spontaneous Reporting System Database

이유경,이정민,천부순,Lee, Yu gyeong,Lee, Jungmin,Chun, Pusoon Korean College Of Clinical Pharmacy 2022 한국임상약학회지 Vol.32 No.3

Objective: This study aimed to investigate the occurrence and types of the adverse events (AEs) associated with oral fluconazole and itraconazole and factors associated with specific types of AEs. Methods: We analyzed AEs reported by community pharmacies nationwide over 10 years using the Korea Adverse Event Reporting System database. Various AE terms were categorized into 18 types, and concomitant medications were classified by drug-drug interaction (DDI) severity. The relationship between the specific type of AE and age, sex, and number of concomitant medications was investigated using multiple logistic regression analysis. Results: A total of 879 AE reports of fluconazole and 401 reports of itraconazole were analyzed; of these reports, 321 and 83 reports of fluconazole and itraconazole, respectively, described concomitant drug administration categorized as DDI severity of contraindicated or major. Women had a higher risk of psychiatric AEs associated with fluconazole use (OR, 1.587; p=0.042). Polypharmacy increased the risk for psychiatric AEs (OR, 3.598; p<0.001 for fluconazole and OR, 2.308; p=0.046 for itraconazole). In dermatologic AEs, the mean age of patients who received itraconazole was lower than that of patients who received fluconazole (46.3±16.8 vs. 54.9±15.4; p<0.001). Co-administration of fluconazole with 1-3 drugs increased the risk of neurological AEs (OR, 1.764; p=0.028). Conclusion: When using fluconazole and itraconazole, psychiatric AEs should be noted, particularly in women and in case of polypharmacy; moreover, when fluconazole is co-administered with other drugs, attention should be paid to the occurrence of neurological AEs.

Itraconazole/HP-β-CD 포접복합체 제조를 위한 ASES 공정에 관한 연구

유종훈 수원대학교 산업기술연구소 2005 산업기술연구소논문집 Vol.20 No.-

In this work, solid-state inclusion complex powders of itraconazole and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) were produced by an aerosol solvent extraction system (ASES) process. In order to evaluate the properties of complexes, differential scanning calorimetry (DSC), x-ray diffraction (XRD) and solubility test in a buffer solution of pH 1.2 were carried out. The particle size of the ASES-processed inclusion complexes was dramatically reduced ( < 0.l~0.5㎛) compared with untreated itraconazole (30~50㎛) and HP-β-CD (50~100㎛). The aqueous solubility of the itraconazole complexed with HP-β-CD was significantly increased. At a constant temperature the aqueous solubility was increased with pressure and enhanced up to ca. 758.6 ㎍/mL in an aqueous medium of pH 1.2.