STUDIES OF SYNERGISTIC NEPHROTOXICOLOGICAL ALTERATIONS INDUCED BY CIPROFLOXACIN AND GENTAMICIN IN SPRAGUE-DAWLEY RATS : Sprague-Dawley 랫트에 있어서 Gentamicin과 Ciprofloxacin에 의한 상승적인 신장 독성학적 변화 연구

손현주 Graduate School of Kon-Kuk University 1995 국내박사

Ciprofloxacin과 gentamicin은 임상에서 이용하는 광범위 항생제로 gentamicin은 신장 독성을 유발한다는 것은 이미 많이 보고되어 있으나 ciprofloxacin은 임상 사례 보고만이 보고되어 있다. 본 연구는 ciprofloxacin의 신장 독성을 알아보고 gentamicin과의 상승적인 신장독성을 유발하는지의 여부를 알아보기 위하여 먼저 ciprofloxacin을 치료 용량의 10배에서 최소 독성 용량까지 (50, 100, 250, 500mg/kg b.w.) 14일간 경구로 투여하였고, gentamicin과 ciprofloxacin의 상호작용을 알아보기 위하여 gentamicin (100mg/kg b.w.)을 10일간 근육주사후 ciprofloxacin을 14일간 투여하였으며 gentamicin과 ciprofloxacin을 같이 14일간 투여하여 랫트의 임상 증상 및 혈액 학적, 병리 조직학적 소견을 관찰하였다. Ciprofloxacin 단독 투여로 인한 독성 증상으로는 체중 증가율의 저하, 미약한 단백뇨, 혈중 요소치의 증가, 국소성 부종과 국소성 간질성 신염이 특히 500mg/kg b.w. 투여 군에서 관찰되었다. Gentamicin 투여후 ciprofloxacin투여로 인한 독성 증상으로는 체중 감소와 식욕 감퇴, 중등 도의 단백뇨, 혈중 요소치의 증가 (500mg/kg b.w.), 신장 세뇨관 상피 세포의 괴사와 재생, 국소성 간질성 신염과 그 염증으로 인한 세뇨관 상피의 위축이 관찰되었다 (250, 500mg/kg b.w.). Gentamicin과 ciprofloxacin 복합 투여로 인한 독성 중상으로는 체중 감소와 식욕 감퇴, 심한 단백뇨, 혈중요소치 및 크레아틴치의 증가, 심한 세뇨관 상피 세포의 괴사, 편평화, 상피 세포의 탈락과 중등도의 간질성 신염이 관찰되었다 (250, 500mg/kg b.w.). 부가적으로 백혈구 감소와 헤모글로빈치 저하도 관찰되었다 (500mg/kg b.w.). 이상의 결과로 볼 때 gentamicin과 ciprofloxacin 사이에 상승적인 신장 독성이 있는 것으로 사료된다. It has been reported that ciprofloxacin and gentamicin, one of broad spectrum antibiotics, were widespread acceptance to human patients and animals. The two drugs employed in this study have individually been demonstrated to be nephrotoxicity in experimental animals as well as in human patients. However most of ciprofloxacin-induced nephrotoxicity were observed from clinical cases. To investigate synergistic nephrotoxicity of ciprofloxacin and gentamicin in rats, observation of clinical signs, hematological assays, and evaluation histopathological alterations in kidneys were performed. To find renal changes to ciprofloxacin, ciprofloxacin was administered orally to male Sprague-Dawley(SD) rats from ten times of the clinical recommended dosage to minimal toxic dosage for 14 days. To find synergistic effects on renal changes to gentamicin and ciprofloxacin, after gentamicin treatment (100mg/kg b.w.; IM) for 10 days, ciprofloxacin was administered orally to male SD rats from ten times of the clinical recommended dosage to minimal toxic dosage for 14 days. Combined treatment of ciprofloxacin (oral) and gentamicin (IM) was used for male SD rats at the same dosage for 2 weeks. As a result of administration of ciprofloxacin alone daily weight gains decrease, mild proteinuria, and edema and focal interstitial nephritis with mild tubular epithelial cell degeneration were shown at 500 mg/kg/day. As a result of sequential administration of ciprofloxacin and gentamicin, decrease in body weight, moderate proteinuria, elevated BUN values, and edema and multifocal interstitial nephritis with atrophied tubular epithelial cell were shown at 250 and 500 mg/kg b.w. As a result of combined administration of ciprofloxacin and gentamicin, decrease in body weight, severe proteinuria, elevated BUN, CREA, and ALT values, edema and multifocal interstitial nephritis, and severe necrotic, flattened and desquamated tubular epithelial cell were observed at 250 and 500 mg/kg b.w. Additionally, this treatment shown leukopenia and decrease of hemoglobin(HGB) levels at 500mg/kg b.w. (p<0.05). A result of this study suggested that ciprofloxacin and gentamicin when given alone their sequential or combined treatment at 250 and 500mg/kg b.w. would induced mild synergistic nephrotoxicity.

Tc-99m ciprofloxacin을 이용한 폐결핵 영상법 : Tc-99m ciprofloxacin SPECT of pulmonary tuberculosis

윤민기 가천의과학대학교 의학대학원 2007 국내석사

목적: Tc-99m ciprofloxacin이 감염을 영상화하는데 이용 가능하다. PubMed (http://www.pubmed.gov) 검색에 의하면 폐결핵을 Tc-99m ciprofloxacin을 이용해 단일광자단층촬영을 시행한 보고가 없다. 그러므로 본 연구는 활동성 폐결핵을 영상화하는데 있어 Tc-99m ciprofloxacin 단일광자단층촬영의 효능을 평가하는 것을 목적으로 하였다. 방법: 21명의 참가자들이 전향적 연구를 위하여 등록하였다. 참가자들은 임상적 및 방사선학적 평가에 따라 두 군으로 구분되었다. 1군은 5명의 정상인 자발적 참가자와 6명의 비활동성 폐결핵 환자로 구성되었고, 2군은 활동성 폐결핵이 있는 10명의 환자로 구성되었다. Tc-99m ciprofloxacin을 준비하여 555 MBq (15 mCi)을 참가자들에게 정맥주입하고 3시간 후에 흉부를 단일광자단층촬영 하였다. 한 명의 핵의학 전문의가 Tc-99m ciprofloxacin 단일광자단층촬영의 소견을 판독하였고, 그 결과는 임상적 및 방사선학적 구분을 고려하여 분석되었다. 결과: Tc-99m ciprofloxacin 단일광자단층촬영의 결과는 8명의 진양성, 10명의 진음성, 1명의 가양성, 그리고 2명의 가음성 이었다. 예민도와 특이도는 각각 80.0%와 90.9% 이고, 양성예측도와 음성예측도는 각각 88.9%와 83.3% 이다. 결론: Tc-99m ciprofloxacin 단일광자단층촬영을 이용하여 활동성 폐결핵을 영상화하는 것이 실행가능하고 유용하다. 폐결핵의 과거병력이 있는 환자들에서 활동성과 비활동성을 감별하는데 특히 유용한 핵의학 영상법이다. Background and purpose: Tc-99m ciprofloxacin is available for imaging infection. However, it was found that there was no study on single photon emission computed tomography (SPECT) using this Tc-99m ciprofloxacin related to active pulmonary tuberculosis after searching for such studies on PubMed. Therefore, it was purposed to assess the efficacy of Tc-99m ciprofloxacin SPECT for imaging active pulmonary tuberculosis. Materials and methods: Twenty-one participants were enrolled for a prospective study. They were divided into two groups by a clinical and radiological assessment. Group one (Gr. 1) consisted of five normal volunteers and six patients with inactive pulmonary tuberculosis. Group two (Gr. 2) consisted of ten patients with active pulmonary tuberculosis. SPECT was performed 3 hours after injection of 555 MBq (15 mCi) of Tc-99m ciprofloxacin (FutureChem Co., Ltd.). Findings of Tc-99m ciprofloxacin SPECT were interpreted by a nuclear medicine specialist and then the results were analyzed with the clinical and radiological classification being considered. Results: The results of Tc-99m ciprofloxacin SPECT were as follows: Eight true positive, ten true negative, one false positive, and two false negative cases. For each, sensitivity and specificity was 80.0% and 90.9%, respectively. The positive predictive value was 88.9% and the negative predictive value was 83.3%. Conclusion: Tc-99m ciprofloxacin SPECT is feasible for imaging active pulmonary tuberculosis. It is a useful nuclear-imaging method for discrimination between active and inactive states in patients with a past medical history of pulmonary tuberculosis.

퀴놀론 내성 Escherichia coli가 원인균인 여성의 급성 단순 신우신염에 대한 초기 경험적 치료로서 ciprofloxacin의 치료효과 : 전향적 관찰 연구

전재현 경북대학교 대학원 2010 국내석사

Backgrounds: Urinary tract infection (UTI) including acute pyelonephritis (APN) is one of the common infectious diseases in women. Escherichia coli (E. coli) is the most common pathogen. ciprofloxacin is recommended as the first line antibiotic regimen where trimethoprim-sulfomethoxazole (TMP-SMX) resistance rate of urinary pathogens is exceeding 10 to 20%. But there is little information about the efficacy of ciprofloxacin trreatment where ciprofloxacin resistance rate of urinary pathogens is high. Purposes: This study was designed to reveal the clinical efficacy of empirical treatment of ciprofloxcin is different between quinolone sensitive E. coli infected women and quinolone resistant E. coli infected women who have uncomplicated APN. Methods: All patients who has been diagnosed clinically and microbiologically as APN were enrolled. Of total 367 patients, 112 patients were excluded because of complication of APN ( abscess, urinary tract obstruction, severe sepsis), ciprofloxacin allergy, pregnancy, and breast feeding. Intravenous ciprofloxacin (400mg) was administered at first and followed by oral ciprofloxacin (500mg q 12 hours). All patient was followed up in 4 to 7 days and 22 to 42 days from first treatment day. In each follow-up day, all patients were evaluated about not only improvement of symptoms and signs but also microbiologic irradication . Results : Finally 255 patients were included. Patients were divided to ciprofloxacin resistant group (QNR-EC) (n= 39) and ciprofloxacin sensitive group (QNS-EC) (n=216). In the first follow up, clinical cure rate of QNR-EC and QNS-EC was 76.9 (30/216)% and 87.0 (188/216)%, (p=0.135) and microbiologic cure rate was 33.3 (12/206)% and 95.1 (194/206)%, (p=0.000) respectively. In the second follow up day, the clinical cure rate was 94.9 (37/243)% in QNR-EC and 98.6 (206/243)% in QNS-EC (p=0.177). Conclusions: Even in case of the quinolone resistant E. coli related APN, ciprofloxacin can be used empirically.

응급실로 내원한 지역사회 획득 급성 신우신염 환자의 원인균 및 Ciprofloxacin 내성의 변화와 이에 영향을 미치는 인자

전대홍 경상대학교 대학원 2011 국내석사

Purpose: Over the 10 years, ciprofloxacin has been used as one of antibiotics of choice for the empirical treatment of community-acquired acute pyelonephritis (APN), of which Escherichia coli (E. coli) is the main causative bacterium. Recently, however, some studies show that ciprofloxacin-resistant E. coli is increasing in APN. This study aimed to re-evaluate ciprofloxacin as one of initial antibiotics for APN according to the survey of the patients' clinical and microbiologic characteristics, and consider adequate antibiotics therapy according to change in resistance of bacterium to ciprofloxacin and other antibiotics. Patients & methods: The records of 356 patients who visited Gyeongsang National University Hospital emergency room from Jan 01, 2000 to Dec 31, 2009 and diagnosed as APN were reviewed retrospectively. This study investigated the clinical characteristics of patients, causative organisms and annual change of antibiotics susceptibility to each antibiotics, associated factors that influence the ciprofloxacin resistance, and appropriate choice of initial antibiotics afterward. Results: The proportion of males to females was 1 : 6.3, and the average age was 54.9±18.1 years old. Complicated APNs were 150 out of 356 patients, and diabetes ranked highest as 26.7% (95/356). According to the urine or blood cultures, the patients with isolated microorganism reached up to 60.4% (215/356) and E. coli occupied 84.2% (181/215) out of the isolates. Among the antibiotics chosen initially, ciprofloxacin was most common (75.0%, 267/356) and the third generation cephalosporin was next (23.0%, 82/356). The analysis of antibiotics sensitivity among 181 E. coli isolates, demonstrated that ciprofloxacin susceptibility was 81.8%, 94.5% in the third generation cephalosporin, 39.2% in ampicillin and 69.4% in trimethoprim-sulfamethoxazole (TMP-SMX). And in the recent 3 years, from 2007 to 2009, ciprofloxacin susceptibility was 87.7% and this was higher than the years before 2007 (77.8%). When the ciprofloxacin-resistant bacterium was isolated, the patients tended to have a higher proportion of complicated APNs (especially, complicated by diabetes mellitus and urinary anatomical abnormalities) Conclusion: For the community acquired APNs, among the E. coli isolates, there were no significant change in ciprofloxacin resistance by years. However, when APNs were complicated by diabetes mellitus, ciprofloxacin resistance was meaningfully higher than others. Therefore, ciprofloxacin should be carefully used as initial antibiotics especially in case of the patients having diabetes mellitus and urinary anatomical abnormalities.

생분해성 Poly [(amino acid ester) phosphazenes]의 합성과 Ciprofloxacin 이식제의 제조 및 평가

박주애 梨花女子大學校 1999 국내박사

An implant is a dosage form that increasess bioavailability, reduces the dose frequency by extending the duration of drug in blood and maintains the concentration in the body through controlled-release of drug. Using the biodegradable polymer as the matrix of implant attains lots of benefits that it has no need to get rid of the remnant matrix after the completion of drug release and controls release mechanism through the degradation of matrix. Polyphosphazene satisfied biocompatibility and can be synthesized as polymers of various physical characteristics through the induction of many kinds of substituents. In this paper, physicochemical characteristics such as Tg, degradability, hydrophilicity and solubility could be changed by substitution of various hydrophilic and hydrophobic amino acids. Ciprofloxacin loaded implants with synthesized polyphosphazenes as matrices were prepared and in vitro degradation test revealed that the degradation profiles were different according to the matrices. Serine and hydrophobic phenylalanine or leucine substituted polymers were degraded rapidly within 24 hours. It was occured by the rapid degradation of serine-rich portion of polymers and the initial burst release of CFX from PPSP and PLSP matrices was also due to it. On the other hand, it was not occured in glycine substituted polymers instead of serine. Degradations of PGGP and PTGP showed that acceleration of degradation by hydroxyl group as well as catalytic action of carboxylic acid played an important role. Surface morphologies were varied according to the substituted amino acids. Surfaces of hydrophobic PLGP and PPGP were porous but the tyrosine substituted polymers had fine surfaces. The release of drug from PPGP and PLGP with low degradability was based on the porous surfaces. In vitro release experiment showed that the drug was released at zero-order from the implants. Compared with degradation ratio, the main mechanism of drug release was drug diffusion through the polymer matrix. The hydrophilicity and degradation profiles of polymer were contributed to the zero order release. The result of pharmacokinetic assessment of the implantation into rabbit showed good applicability as sustained release formulation with the fact that the implant of antibiotics CFX, using biodegradable poly[(amino acid ester)phosphazenes] as the matrix, satisfied the appropriate pharmaceutical condition such as bioavailibility, biodegradability and biocompatibility, and that the effective drug concentration in plasma was maintained for more than 600 hours. The implants made by PTGP or PGGP showed the most excellent properties in the comparison of AUC, MRT and Tmax. PPGP and PLGP had strong point of low initial burst effect having similar sustained effect. It was also verified that POT concept can be the proper standard of evaluation in addition to in vivo quality evaluation of the implants by AUC and MRT, and Css used in POT was applied as the standard of initial burst effect that mostly matters for a matrix material. The applicability of biodegradable poly[(amino acid ester) phosphazenes] as a matrix of sustained-release long-term drug delivery system was verified from above results. Keywords : Poly[(amino acid ester)phosphazenes], Controlled release implant, Ciprofloxacin, Degradation, Pharmacokinetic parameter, Bioavailability, POT 이식제는 약의 생체 내 효능을 높이고 혈중 약물의 지속시간을 연장시켜 투여 횟수를 줄일 수 있으며 약물의 조절방출로 체내 농도를 일정하게 유지시키는 장점이 있는 제형이다. 특히 생분해성 고분자를 이식제에 사용한 경우 약물의 용출이 끝난 후 남아있는 기제를 제거할 필요가 없고 매트릭스의 분해에 의해 약물의 방출 기전이 조절되는 등 많은 장점이 있다. Poly- phosphazene도 생체적합성이 확립된 고분자로 여러 가지 치환기의 도입으로 다양한 물성의 고분자로 합성할 수 있다. 본 논문에서는 polyphosphazene에 aromatic hydrocarbon, aliphatic hydrocarbon, carboxylic aicd, hydroxyl기 등 각각 다른 기능기를 갖는 아미노산을 치환시킴으로 Tg, 분해성, hydrophilicity, 용해도 등의 고분자의 물리화학적 성질을 변화시킬 수 있었다. 또한 합성한 생분해성 poly[(amino acid ester)phosphazenes]가 매트릭스이고 항생제인 ciprofloxacin이 봉입된 이식제를 제조하고 이에 대한 in vitro 분해 시험에서, 매트릭스의 종류에 따른 분해양상의 차이가 있었다. Hydrophobic한 phenylalanine과 leucine과 함께 serine이 치환된 고분자 매트릭스에서 초기 분해가 매우 크게 나타났는데 이는 수용성 serine이 주로 치환된 부분이 먼저 빨리 분해되기 때문이었다. 반면에 phenylalanine과 leucine이 glycine과 함께 치환된 고분자 매트릭스는 초기의 빠른 분해가 나타나지 않았다. 이러한 초기 분해의 차이에 의해 in vitro 용출시험에서 PPSP와 PLSP 이식제에서 initial burst release가 나타났다. 표면 형태도 다양하였는데 leucine과 phenylalanine이 치환된 고분자는 다공성 표면이었으나 tyrocine이 함유된 고분자의 표면에는 pore가 없었다. 분해율이 낮은 PPGP와 PLGP에서도 용출량에 차이가 없었던 것은 pore에 의해 표면적이 증가되었기 때문으로 생각되었다. 또한 PGGP보다 PTGP가 더 많이 분해되는 것으로 보아 carboxylic aicd에 의한 분해의 촉매작용도 중요하지만 hydroxyl기에 의한 분해 촉진 작용이 크게 작용함을 알 수 있었다. 이식제로부터 CFX의 in vitro 용출은 0차 속도로 일어나며 주된 용출 기전은 고분자내 약물의 확산이며 고분자의 hydrophilicity와 고분자 분해 등이 보완적 작용을 하여 0차 용출 속도로 나타나는 것으로 확인하였다. 제조된 이식제를 토끼에 이식하여 약물속도론적 평가를 행한 결과 생분해성 poly[(amino acid ester)phosphazenes]을 매트릭스로 한 항생제 CFX의 이식제는 생체내이용율, 생분해성, 생체적합성 등의 면에서 제제학적 조건을 충족시켰으며 혈중 유효 약물농도가 600시간 이상까지 유지되는 등 지속성 제제로서의 사용 가능성을 시사하였다. 특히 PTGP, PGGP로 제조한 이식제가 AUC, MRT 등으로 종합적으로 평가하였을 때 가장 우수하였으며 PPGP, PLGP로 제조한 이식제도 지속효과에서는 유의적인 차이가 없었으나 initial burst effect가 낮다는 면에서 장점을 찾을 수 있었다. 또한 AUC, MRT에 의한 제제의 in vivo 품질 평가 외에 POT 개념을 사용한 결과 적절한 평가 기준이 됨을 확인하였고 매트릭스 제제에서 가장 문제시 되는 initial burst effect의 기준으로 POT에서 사용되는 Css를 적용하여 평가할 수 있었다. 이상의 결과로부터 생체분해성 poly[(amino acid ester)phosphazene]을 매트릭스로하는 이식제의 지속방출형 장기 투여 제제로 사용 가능성을 확인하였다. 주요어 : poly[(amino acid ester)phosphazene], 이식제, ciprofloxacin, 분해, 용출, 약물동력학적 파라미터, 생체내이용율, POT

Development of Ciprofloxacin Loaded Liposomes Using Hydrophobic Ion Pairing for Dry Powder Inhalation

Jeon, Yu Im 연세대학교 일반대학원 2025 국내석사

The present study describes the development of a dry powder inhalation (DPI) formulation of ciprofloxacin for pulmonary delivery, employing hydrophobic ion pairing (HIP) to enhance lipophilicity and encapsulation efficiency within PEGylated liposomes. Ciprofloxacin was ion paired with disodium pamoate to form ciprofloxacin pamoate (CIP-PAM), which was encapsulated in liposomes composed of hydrogenated soy phosphatidylcholine (HSPC), cholesterol, and DSPE PEG2000. A drug-to-lipid weight ratio of 1:15 yielded nanosized liposomes (<200 nm) with a polydispersity index of <0.26 and encapsulation efficiency >95%. Lactose was selected as a cryoprotectant following screening, and the liposomes were freeze-dried and co-jet milled with varying concentrations of magnesium stearate (MS; 0–0.5% w/w). The resulting powders exhibited respirable particle sizes (<5 μm) and maintained liposomal morphology after reconstitution. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) confirmed partial amorphization induced by HIP and formulation processing. Aerodynamic performance, assessed using a Next Generation Impactor (NGI), demonstrated fine particle fractions (FPF) of 46.70 49.62%, emitted doses (ED) of 83.20–93.27%, and mass median aerodynamic diameters (MMAD) of 3.20–3.88 μm. In vitro release studies revealed sustained release from both TH15_FB (before freeze-drying) and TH15_FA (after freeze-drying) liposomal formulations over 72 h, in contrast to the burst release from CIP HCl. Antibacterial activity and biofilm inhibition against Pseudomonas aeruginosa strains ATCC® 9027 and ATCC® 14207 were retained in both liposomal formulations, with comparable MIC values and inhibition zones. Overall, the developed CIP-PAM-loaded PEGylated liposomal DPI system exhibited favorable physicochemical stability, pulmonary delivery characteristics, and preserved antimicrobial efficacy, supporting its potential as an inhalable therapeutic for respiratory infections.

임균의 항균제 내성 및 분자 역학적 연구

김태숙 연세대학교 대학원 2003 국내박사

임균은 전 세계적으로 흔한 성인성 질환인 임질, 요도염 및 난관염 등의 원인균이다. 1990년대 초반까지 WHO와 CDC는 임균 감염증의 치료제로 fluoroquinolone 등의 항균제를 권장하였으나, 최근이 약제에 고도내성인 임균이 보고되고 있다. 임균의 fluoroquinolone 내성은 이 약제의 표적인 DNA gyrase 와 topoisomerase IV를 지배하는 유전자인 gyrA와 parC의 변이에 의한 것으로 알려져 있으나, 국내 분리 균주에서 gyrA와 parC 유전자 변이 및 분자 역학적 연구를 수행한 예는 매우 드물다. 본 연구에서는 1999-2001년에 우리나라의 특수직업 여성 및 본원 내원 환자에서 분리된 임균을 대상으로, 1) β-lactamase 생성시험, NCCLS 디스크 확산법 및 한천 희석법으로 항균제 내성 양상을 규명하고, 2) gyrA와 parC 유전자의 quinolone resistance-determining region(QRDR)의 염기서열을 분석하여 내성기전을 규명하고, 3) pulsed-field gel electrophoresis(PFGE)를 통한 국내분리 임균과 외국 분리주의 분자 역학적 성상을 규명하고자 하였다. 디스크 확산법으로 penicillin G에 감수성인 균주는 없었고, tetracycline에는 모든 균주가 내성이었다. 반면에 ceftriaxone과 spectinomycin에 내성인 균주는 없었으며, 소수의 균주가 spectinomycin에 중간이었다. Ciprofloxacin에는 대부분의 균주가 비감수성이었는데, 내성인 균주의 비율은 점차 증가하여 1999년 분리주 중에는 16%이었고, 2001년에는 40%이었다. 한천희석법으로 시험한 ceftriaxone의 MIC 범위는 ≤0.008-0.12μg/ml로 가장 낮았다. Ciprofloxacin의 MIC 범위는 non-PPNG에 대해서는 ≤0.008-32 μg/ml이었으나, PPNG에 대해서는 ≤0.008-0.5 μg/ml이었다. 2000년 분리주의 ciprofloxacin의 MIC_(50)는 0.5μg/ml이었는데, 1993년과 1996년 분리주에 대한 MIC50 보다 각각 32배와 4배가 상승하였다. Ciprofloxacin 고도내성 균주 중 GyrA에서는 91번째 serine이 phenylalanine으로, 95번째 aspartic acid가 glycine으로, ParC에서는 87번째 serine이 arginine으로 주로 치환되었다. 우리나라와 국외 분리 ciprofloxacin 내성 임균의 PFGE형 분석 에서 같은 아형을 관찰할 수 없었다. 또한 A형인 균주가 ciprofloxacin 고도 내성 국내 분리주 중 1주 관찰되었고, 감수성 혹은 중간인 국내외 분리주에서도 관찰되었다. 우리나라 특수직업여성 및 환자에서 분리된 임균 중 spectinomycin, ceftriaxone에 내성인 균주는 없었고, PPNG의 비율은 크게 저하되었다. 임질의 경구 치료제인 ciprofloxacin에 고도 내성인 균주가 현저히 증가하고 있어서, 이 약제를 임균 치료에 경험적으로 사용하기 어려울 것으로 판단되었다. 국내 ciprofloxacin고도 내성 임균은 역학적 양상이 외국 분리 균주와 상이하였기 때문에, 국외로부터 유입되었기 보다는 유전자 변이에 의한 선택으로 출현된 것으로 판단된다. Neisser a gonorrhoeae is a frequent cause of sexually transmitted disease worldwide, and there is a high prevalence of penicillin- or tetracycline-resistant strains. Recently, a high-level of resistance to fluoroquinolone in N. gonorrhoeae has been reported. The fluoroquinolone-resistant mechanisms of N. gonorrhoeae were reported to be point mutations of gyrA and parC, which encode quinolone resistance-determining region (QRDR), fluoroquinolone target. However, as far as the author is aware, there are only a few reports on the resistance mechanisms and molecular epidemiological studies of Korean isolates. The aims of this study were 1) to determine the antimicrobial susceptibilities by using the NCCLS disk diffusion and agar dilution method, 2) to determine the sequences of the QRDR of gyrA and parC, and 3) to conduct a molecular epidemiological analysis on the strains isolated from Korea and other countries. None of the isolates were susceptible to penicillin G, and all strains were resistant to tetracycline. However, there were no ceftriaxone- or spectinomycin-resistant strains. A marked increase in ciprofloxacin-resistant isolates was noted, from 16% in 1999 to 40% in 2001. The MIC range of ceftriaxone was ≤0.008-0.12 μg/ml, and the MIC ranges of ciprofloxacin were ≤0.008-32 μg/ml for the non-PPNG strains, but were ≤0.008-0.5 μg/ml for the PPNG strains. The MIC_(50) of ciprofloxacin was 0.5 μg/ml in this study, which had increased 32- and 4-fold in compared with those isolates in 1993 and 1996, respectively. The strains with a high-level ciprofloxacin-resistance carried mainly a double substitution in gyrA and a single substitution in parC. The level of fluoroquinolone resistance appeared to correlate with the location and number of mutations in gyrA and parC. Analysis of the PFGE profiles showed different genotypic profiles among the ciprofloxacin-resistant strains isolated from Korea and other countries. In conclusion, no spectinomycin- or ceftriaxone-resistant N gonorrhoeae strains isolated in Korea were detected. Because of the high prevalence of ciprofloxacin-resistant N. gonorrhoeae, fluoroquinolones are no longer recommended for the empiric treatment of gonorrhea in Korea. Because the results of PFGE analysis patterns showed differences between the isolates in Korea and those in other countries, the increase in the number of fluoroquinolone-resistant strains was more likely to be due to the domestic clonal spread rather than importation from abroad.

Preparation and characterization of lipid-coated PLGA nanoparticles containing hydrophobic ion pairs of ciprofloxacin and pamoate

Choi, Jihyeon 연세대학교 일반대학원 2025 국내석사

Cu-Free “Click" Chemistry를 이용한 펩타이드 F-18 표지방법 및 PET연구를 위한 F-18 표지된 Ciprofloxacin의 합성 : Chapter I. Synthesis and Evaluation of 18F-Labeled N-Substituted Ciprofloxacin Derivative for the Imaging of Bacterial Infection with PET. Chapter II. Simple and R

카름사킨우마칸트 Chonbuk National University, Medical School 2013 국내박사

Chapter I. Synthesis and Evaluation of 18F-Labeled N-Substituted Ciprofloxacin Derivative for the Imaging of Bacterial Infection with PET. A series of new N-substituted ciprofloxacin derivatives were synthesized connected at N-1 position of ciprofloxacin by various linkers according to their structure activity relationship studies. Preliminary results indicated that most compounds tested in this study demonstrated comparable or better in vitro antibacterial activity against Gram-negative microorganism. Among these analogues, N4′-3-fluoropropylciprofloxacin (16) showed the significant antibacterial activity against E. coli strains (DH5R and TOP10) and a high binding affinity for DNA gyrase of bacteria. To develop bacteria-specific infection imaging agents for positron emission tomography (PET), no-carrier-added N4′-3-[18F]fluoropropylciprofloxacin ([18F]16) was prepared in two steps approach by radiofluorination of N4′-3-methanesufonyloxypropylciprofloxacin and followed by the hydrolysis using LiOH reagents, resulting in a 40% radiochemical yield (decay corrected for 100 min) via the tert-alcohol media radiofluorination protocol with high radiochemical purity (>99%) as well as high specific activity (149 ± 75 GBq/µmol). The agent was stable (>90%), as shown by an in vitro human serum stability assay. A bacterial uptake and blocking study of [18F]16 using authentic compound 16 in TOP10 cells demonstrated its high specific bacterial uptake. The results suggest that this radiotracer holds promise as a useful bacterial infection radiopharmaceutical for PET imaging. Keywords: Fluoroquinolones; Ciprofloxacin derivatives; In vitro antibacterial activity; Fluorine-18; Positron emission tomography. Chapter II. Simple and Rapid Radiosynthesis of F-18 labeled Peptides by Strain-Promoted Catalyst-Free Click Chemistry for PET Imaging. As an effort in the development of more flexible 18F-labeled peptides, I introduce a facile efficient 18F-labeling protocol based on chemo-orthogonal strain-promoted cycloaddition using aza-dibenzocyclootyne-substituted peptides as precursors with 18F-azide synthon for high-throughput synthesis of various 18F-labeled peptide tracers under physiologically friendly reaction condition. 18F-PEG-azide [18F]2 was prepared by nucleophilic substitution of the corresponding PEG-azide mesylate precursor in 63% decay-corrected radiochemical yield with high radiochemical purity (> 99%) with total reaction time 75 min including HPLC purification. The SPAAC reaction and subsequent chemo-orthogonal purification reaction with azide resin proceeded quickly and selectively under physiologically friendly reaction condition (i.e., toxic chemical reagents-free, aqueous medium, room temperature, pH≈7), and provided four 18F-labelled tumor targetable bioactive peptides such as cyclic Arg-Gly-Asp (cRGD) peptide cRGD-ADIBOT-18F (specific activity, 51 GBq/µmol), bombesin (BBN) BBN-ADIBOT-18F (specific activity, 49.0 GBq/µmol), c-Met binding peptide (cMBP) cMBP-ADIBOT-18F (specific activity, 40.1 GBq/µmol) and apoptosis targeting peptide (ApoPep) ApoPep-ADIBOT-18F (specific activity, 55.0 GBq/µmol) in high radiochemical yield as direct injectable solutions without any HPLC purification and formulation process. In vitro binding assay and in vivo PET molecular imaging study using the 18F-labelled cRGD peptide also demonstrated successful application of our 18F-labeling protocol. Keywords: Catalyst-free click chemistry; Fluorine-18; Peptide labeling; RGD; BBN; cMBP; positron emission tomography (PET) imaging. Chapter III. Synthesis of F-18 labeled mono-, di- and tertameric cRGD Peptides via Copper-free "Click" Chemistry and microPET Imaging Study. A series of 18F-labeled cRGD peptide have been developed based on chemo-orthogonal strain-promoted cycloaddition using aza-dibenzocyclootyne-substituted cRGD mono-, di- and tertameric peptides as precursors with 18F-azide synthon for positron emission tomography (PET) imaging of tumor αvβ3 integrin expression. In this study, the SPAAC reaction and subsequent chemo-orthogonal purification reaction with azide resin proceeded quickly and selectively under physiologically friendly reaction condition (i.e., toxic chemical reagents-free, aqueous medium, room temperature, pH≈7), provided mono-, di- and tertameric 18F-labelled tumor targetable bioactive peptides such as cRGD1-ADIBOT-18F, cRGD1-PEG4-ADIBOT-18F, cRGD2-ADIBOT-18F, cRGD2-PEG4-ADIBOT-18F, and cRGD4-PEG4-ADIBOT-18F in high radiochemical yield and high specific activity. In vitro binding assay and in vivo PET molecular imaging study using the 18F-labelled mono-, di- and tertameric cRGD peptides also demonstrated successful application of our 18F-labeling protocol. Keywords: integrin αvβ3; RGD multimer; tumor angiogenesis; Catalyst-free click chemistry; Fluorine-18; RGD Peptide labeling; PET imaging.

Hydrophobic ion pairing strategy for development of sustained release ciprofloxacin dry powder inhalation

Lee, Jong-Ju 연세대학교 일반대학원 2025 국내박사