Population-pharmacokinetics, safety and tolerability of sustained-release flucytosine pellets for the treatment of asymptomatic cryptococcal antigen-positive individuals: a single-arm trial

开始日期2024-06-01

申办/合作机构

Wits Health Consortium

PACTR202306577982404 / Suspended临床2期

A 10 week, open-label, randomized, controlled parallel-group trial to evaluate the comparative bioavailability, efficacy and safety of sustained-release flucytosine versus immediate-release flucytosine in adults with cryptococcal meningitis

开始日期2023-10-31

申办/合作机构

Drugs for Neglected Diseases initiative

NCT06178627 / Enrolling by invitation临床4期IIT

A Multi-center, Prospective, Randomized Trial of Amphotericin B in the Initial Antifungal Therapy for Non-HIV Cryptococcal Meningitis Patients

Cryptococcus neoformans and C. gatti are important causes of central nervous system (CNS) infections with significant mortality, remaining a great public health challenge worldwide. Commonly seen as an opportunistic infection in adults with HIV/AIDS, cryptococcal meningitis (CM) accounts for 15% of HIV-related mortality globally [1]. In addition, a growing number of non-HIV CM patients have been observed in recent years with fatality approaching 30% in some areas [2,3]. It occurs in both those with natural or iatrogenic immunosuppression, as well as the apparently immunocompetent individuals. Approximately 65-70% of non-HIV CM patients were without any predisposing factors, particularly in the East Asia [4,5]. With the increasing number of hematopoietic stem cell transplantation, solid organ transplantation recipients and administration of immunosuppressive and corticosteroids agents, this illness will assume even greater public health significance.
Current Infectious Disease Society of America (IDSA) guideline suggest the use of combination antifungal therapy: normal dose amphotericin (0.7-1mg/kg/day) combined with flucytosine for a minimum of 4 weeks, followed by fluconazole (600-800 mg/day) for a minimum of 10 weeks in total for HIV patients [6]. However, for non-HIV and immunocompetent patients, the treatment remains controversial. IDSA guideline recommended that the treatment of non-HIV patients could refer to the treatment of HIV patients. That is, amphotericin B combined with flucytosine is still administered in the induction period. However, as amphotericin B have nonspecific effect on ergosterol, it has strong side effects (hepatorenal toxicity, electrolyte disorder, anemia, ventricular fibrillation, etc.). Therefore, the dose of amphotericin B may not be appropriate for Asian patients due to the different drug metabolism and pharmacokinetic. In the prospective studies of Bennett[7] and Dismuke[8], low dose amphotericin B (0.3 mg/kg/d) combined with flucytosine achieved response rates of 66% and 85% at 6 weeks, respectively. A similar conclusion was also extracted from a large multicenter retrospective study that low dose amphotericin B (<0.7 mg/kg/d) combined with flucytosine for a minimum of 2 weeks, followed by fluconazole could achieve a response rate of 84%, indicating that the efficacy of low dose amphotericin B (< 0.7 mg/kg/d) may be equivalent with normal dose in non-HIV patients. Therefore, we plan to conduct a prospective, multicenter, open-label randomized controlled study to compare the efficacy and safety of normal dose amphotericin B (0.7 mg/kg/ d) and low dose amphotericin B (0.5 mg/kg/d) in the initial antifungal treatment for non-HIV cryptococcal meningitis patients.

开始日期2023-08-13

申办/合作机构

复旦大学附属华山医院

100 项与氟胞嘧啶相关的临床结果

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100 项与氟胞嘧啶相关的转化医学

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100 项与氟胞嘧啶相关的专利（医药）

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3,982

项与氟胞嘧啶相关的文献（医药）

2024-06-01·Biofilm

Fluoropyrimidines affect de novo pyrimidine synthesis impairing biofilm formation in Escherichia coli.

Article

作者: Srikanth Ravishankar ; Valerio Baldelli ; Carlo Angeletti ; Nadia Raffaelli ; Paolo Landini ; Elio Rossi

Antivirulence agents are considered a promising strategy to treat bacterial infections. Fluoropyrimidines possess antivirulence and antibiofilm activity against Gram-negative bacteria; however, their mechanism of action is yet unknown. Consistent with their known antibiofilm activity, fluoropyrimidines, particularly 5-fluorocytosine (5-FC), impair curli-dependent surface adhesion by Escherichia coli MG1655 via downregulation of curli fimbriae gene transcription. Curli inhibition requires fluoropyrimidine conversion into fluoronucleotides and is not mediated by c-di-GMP or the ymg-rcs envelope stress response axis, previously suggested as the target of fluorouracil antibiofilm activity in E. coli. In contrast, 5-FC hampered the transcription of curli activators RpoS and stimulated the expression of Fis, a curli repressor affected by nucleotide availability. This last observation suggested a possible perturbation of the de novo pyrimidine biosynthesis by 5-FC: indeed, exposure to 5-FC resulted in a ca. 2-fold reduction of UMP intracellular levels while not affecting ATP. Consistently, expression of the de novo pyrimidine biosynthesis genes carB and pyrB was upregulated in the presence of 5-FC. Our results suggest that the antibiofilm activity of fluoropyrimidines is mediated, at least in part, by perturbation of the pyrimidine nucleotide pool. We screened a genome library in search of additional determinants able to counteract the effects of 5-FC. We found that a DNA fragment encoding the unknown protein D8B36_18,480 and the N-terminal domain of the penicillin-binding protein 1b (PBP1b), involved in peptidoglycan synthesis, could restore curli production in the presence of 5-FC. Deletion of the PBP1b-encoding gene mrcB, induced csgBAC transcription, while overexpression of the gene encoding the D8B36_18,480 protein obliterated its expression, possibly as part of a coordinated response in curli regulation with PBP1b. While the two proteins do not appear to be direct targets of 5-FC, their involvement in curli regulation suggests a connection between peptidoglycan biosynthesis and curli production, which might become even more relevant upon pyrimidine starvation and reduced availability of UDP-sugars needed in cell wall biosynthesis. Overall, our findings link the antibiofilm activity of fluoropyrimidines to the redirection of at least two global regulators (RpoS, Fis) by induction of pyrimidine starvation. This highlights the importance of the de novo pyrimidines biosynthesis pathway in controlling virulence mechanisms in different bacteria and makes the pathway a potential target for antivirulence strategies.

2024-02-13·Journal of fungi (Basel, Switzerland)

The Stress of Fungicides Changes the Expression of Clock Protein CmFRQ and the Morphology of Fruiting Bodies of Cordyceps militaris.

Article

作者: Jing-Mei Peng ; Dan-Dan Zhang ; Zi-Yan Huang ; Ming-Jia Fu

The physiological, biochemical, and morphological changes brought about by fungi in response to fungicides can undoubtedly bring diversity to fungi. Cordyceps militaris strains TN (mating type genes MAT1-1-1, MAT1-1-2, and MAT1-2-1) and CmFRQ-454 (mating type genes MAT1-1-1 and MAT1-1-2) were treated with non-lethal doses of fungicides amphotericin B, L-cysteine, terbinafine, and 5-fluorocytosine. The results showed that the treatment with amphotericin B, terbinafine, and 5-fluorocytosine promoted an increase in the relative content of clock protein CmFRQ (C. militaris FREQUENCY) in the mycelium of strain TN, while the high concentration of L-cysteine inhibited the expression of CmFRQ in strain TN. These four fungicides could reduce the relative contents of CmFRQ in the mycelium of strain CmFRQ454. The relative contents of CmFRQ in the mycelium of strain TN were increased after removing the four fungicides, but the relative contents of CmFRQ in the mycelium of strain CmFRQ454 were decreased after removing the four fungicides. This indicates that the effect of fungicides on CmFRQ on mycelium was still sustained after removing the stress of fungicides, and the operation of the circadian clock was changed. The fruiting bodies of C. militaris strain TN and CmFRQ-454 were still degenerated to varying degrees after removing amphotericin B, L-cysteine, and terbinafine. However, the fruiting bodies of strain TN after removing 5-fluorocytosine did not show significant degeneration; the fruiting bodies of strain CmFRQ-454 after removing 5-fluorocytosine obtained rejuvenation. These results indicate that the stress of fungicides could lead to the degeneration of fruiting bodies as well as the rejuvenation of fruiting bodies, resulting in the morphological diversity of C. militaris. The increase or decrease of the CmFRQ-454, the main component of the circadian clock, caused by the stress of fungicants, might lead to the differential degeneration of different mating-type strains of C. militaris.

2024-02-01·Acta crystallographica. Section C, Structural chemistry

Hydrogen-bonding interactions in 5-fluorocytosine-urea (2/1), 5-fluorocytosine-5-fluorocytosinium 3,5-dinitrosalicylate-water (2/1/1) and 2-amino-4-chloro-6-methylpyrimidine-6-chloronicotinic acid (1/1).

Article

作者: Marimuthu Sangavi ; Narayanasamy Kumaraguru ; Ray J Butcher ; Colin D McMillen

Three new compounds, namely, 5-fluorocytosine-urea (2/1), 2C₄H₄FN₃O·CH₄N₂O, (I), 5-fluorocytosine-5-fluorocytosinium 3,5-dinitrosalicylate-water (2/1/1), 2C₄H₄FN₃O·C₄H₅FN₃O⁺·C₇H₂N₂O₇^-·H₂O, (II), and 2-amino-4-chloro-6-methylpyrimidine-6-chloronicotinic acid (1/1), C₆H₄ClNO₂·C₅H₆ClN₃, (III), have been synthesized and characterized by single-crystal X-ray diffraction. In compound (I), 5-fluorocytosine (5FC) molecules A and B form two different homosynthons [R₂²(8) ring motif], one formed via N-H...O hydrogen bonds and the second via N-H...N hydrogen bonds. In addition to this interaction, a sequence of fused-ring motifs [R₂¹(6), R₃³(8), R₂²(8), R₄³(10) and R₂²(8)] are formed, generating a supramolecular ladder-like hydrogen-bonded pattern. In compound (II), 5FC and 5-fluorocytosinium are linked by triple hydrogen bonds, generating two fused-ring motifs [R₂²(8)]. The neutral 5FC and protonated 5-fluorocytosinum cation form a dimeric synthon [R₂²(8) ring motif] via N-H...O and N-H...N hydrogen bonds. On either side of the dimeric synthon, the neutral 5FC, 5-fluorocytosinium cation, 3,5-dinitrosalicylate anion and water molecule are hydrogen bonded through N-H...O, N-H...N, N-H...OW and OW-HW...O hydrogen bonds, forming a large ring motif [R₁₀¹⁰(56)], leading to a three-dimensional supramolecular network. In compound (III), 2-amino-4-chloro-6-methylpyrimidine (ACP) interacts with the carboxylic acid group of 6-chloronicotinic acid via N-H...O and O-H...O hydrogen bonds, generating an R₂²(8) primary ring motif. Furthermore, the ACP molecules form a base pair via N-H...N hydrogen bonds. The primary motif and base pair combine to form tetrameric units, which are further connected by Cl...Cl interactions. In addition to this hydrogen-bonding interaction, compounds (I) and (III) are further enriched by π-π stacking interactions.

项与氟胞嘧啶相关的新闻（医药）

2024-03-30

·医药地理

【好文推荐】氢氯噻嗪-氟胞嘧啶共晶的制备、表征及溶解性考察

未经授权，不得转载氢氯噻嗪-氟胞嘧啶共晶的制备、表征及溶解性考察Preparation, Characterization and Solubility Investigation ofHydrochlorothiazide-flucytosine Cocrystal邓雪珍，陈乐乐，谭雨梦，钱坤*，杨婕(江西中医药大学药学院，江西南昌 330004)摘要：为提高氢氯噻嗪(1) 的水溶性和改善氟胞嘧啶(2) 的引湿性，该文制备了1-2 共晶。应用单晶X 射线衍射、粉末X 射线衍射、傅里叶变换红外光谱、热重和差示扫描量热等方法对其进行了表征，并研究了1-2 共晶的溶解性和引湿性。结果表明，与1 相比，1-2 共晶中的1 在盐酸(pH 1.2)、磷酸盐缓冲液(pH 6.8) 和纯水(pH 7.0) 中的平衡溶解度和特性溶出速率均得到提高。并且，1-2 共晶在25 ℃和相对湿度95％的条件下未发生增重。研究结果表明所制备的1-2 共晶增加了1 的溶解性，并减轻了2 的引湿性，为提高难溶性药物溶解性的研究提供了参考。关键词：氢氯噻嗪；氟胞嘧啶；共晶；溶解性；引湿性以下为文章节选药物共晶是由API 与其他一种或一种以上的共晶形成物(cocrystal former，CCF) 或药物以一定比例通过非共价键结合于一个晶格内并堆积而成的物质状态[1]。自首个用于治疗心脑血管疾病的共晶药物“沙库巴曲+ 缬沙坦”获FDA 批准上市以来，药物共晶受到了广泛关注[2—3]。随着对药物共晶及API 理化性质的深入研究，共晶技术被广泛用于改善API 因其原有结构而导致的生物利用度低、渗透性差、溶解性差、稳定性低等的研究之中[4—5]。氢氯噻嗪(hydrochlorothiazide，1，图1A) 是一种利尿性抗高血压药，被广泛用于治疗浮肿和高血压，属于低溶解性和低渗透性的BCS Ⅳ类药物，体内生物利用度低[6—7]。氟胞嘧啶(flucytosine，2，图1B) 是一种常用的抗真菌药，可用于治疗念珠菌和隐球菌感染，但其稳定性较差，易因水合作用导致晶型改变，不利于生产和贮存[8—9]。本研究采用溶剂挥发法制备1-2 共晶，并通过平衡溶解度、特性溶出速率(intrinsic dissolution rate，IDR) 和引湿性试验考察共晶是否改善了1 的溶解性和2 的引湿性，以期为提高难溶性药物1 的溶解性和增加2 的片剂成药性研究提供数据参考。↑长按二维码阅读全文基金项目：国家自然科学基金资助项目(22165014)、江西省2022年度研究生创新专项资金项目(YC2022-s856)、中药炮制技术的传承与创新项目(CXTD22003)作者简介：邓雪珍(1998—)，女，硕士研究生，专业方向：药物化学。通信作者：钱坤(1979—)，男，副教授，博士，从事药物共晶的研究。E-mail：qiankun@jxutcm.edu.cn文章详情欢迎登录《中国医药工业杂志》官网查看。END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

上市批准

2024-02-28

·CPHI制药在线

研发 | 白念珠菌感染常用抗真菌药物及其耐药机制研究进展

关注并星标CPHI制药在线念珠菌病主要是由白念珠菌引起的急性、亚急性或慢性感染，临床症状错综复杂、急缓不一，严重威胁人类健康。目前临床上常用的抗真菌药物种类有限，抗菌谱窄、耐药性高，是导致临床治疗失败和念珠菌血症死亡率高的重要原因之一。常用的系统抗真菌药物主要包括三唑类、多烯类和棘白菌素类等。常用抗白念珠菌药物现况 1、多烯类药物多烯类化合物是大环内酯类的有机分子，该类药物有很强的抗真菌活性和较宽的抗菌谱，其中制霉菌素（nystation）和两性霉素 B（amphotericin B，AmB）是临床上常用的代表药物。制霉菌素对念珠菌有显著的杀灭作用，但吸收差、不良反应大，所以临床上使用较少。AmB 是深部真菌感染的抗菌谱最广的有效药物，但肾毒性及明显的输液不良反应限制了其临床应用。另外白念珠菌生物被膜形成后，对 AmB、制霉菌素的敏感性也明显降低。近年来，AmB 含脂制剂的开发减轻了AmB 的肾毒性，我国应用的含脂制剂主要是L-AmB，其抗菌谱、抗菌活性、临床疗效与AmB相仿，肾毒性降低，但价格偏高，所以 AmB 含脂制剂目前仅批准用于不能耐受AmB 毒性反应，或出现与静脉用药相关的严重毒性反应，或AmB治疗无效的患者。 2、三唑类药物三唑类抗真菌药物是目前使用最为广泛的一类抗真菌药，其中氟康唑（FCA）是临床早期经验治疗念珠菌感染尤其作为高危人群预防念珠菌感染的首选药物，使其在人体内长期处于亚治疗水平，引起耐药性增加。伏立康唑（VRC）作为新一代三唑类抗真菌药物，具有抗菌活性更高、抗菌谱更广、生物利用度更高等优点，对包括耐氟康唑菌株等均有较强的活性。CHIF-NET 2010-2014年中国多中心侵袭性酵母菌的研究报道，94%的白念珠菌对伏立康唑最敏感，氟康唑次之。随着长时间的药物滥用和不必要的药物接触，白念珠菌对唑类药物的耐药性正在增加，使得对唑类耐药念珠菌患者的治疗选择受限，是全球范围内临床医生和患者面临的日益严峻的挑战。 3、棘白菌素类药物目前，已上市的棘白菌素类药物包括卡泊芬净（caspofungin）、米卡芬净（mycamine）、阿尼芬净（anidulafunngin）。卡泊芬净对耐氟康唑、伊曲康唑的念珠菌有较好活性。米卡芬净对念珠菌属、耐唑类和耐两性霉素 B 菌株有较好的抑制活性，且在治疗严重念珠菌感染时毒性较小。阿尼芬净具有更大的分布容积和更广的抗菌谱，对白念珠菌的抗菌活性大大高于两性霉素 B、伊曲康唑和氟康唑，对念珠菌属最低抑菌浓度低于氟康唑和卡泊芬净。随着临床上的广泛应用，白念珠菌对此类药物已出现不同程度的耐药性，不过由于棘白菌素类与唑类药物无明显的交叉耐药性，故临床上常用棘白菌素类与三唑类或多烯类药物联合使用治疗侵袭性念珠菌感染。白念珠菌耐药机制研究进展目前发现的白念珠菌的耐药机制主要包括药物靶点的改变、药物外排泵的过表达、代谢途径的改变及适应性应激反应的启动等方面。 1、对唑类药物的耐药机制 ①药物靶点的改变。白念珠菌中唑类药物靶酶基因ERG11的突变或过表达可使靶酶维持活性而产生耐药。研究显示，ERG11基因突变已发现有140个错义突变，并证实Y123F、K143R、F449V和G464S等多个突变位点与白念珠菌对氟康唑耐药有关。ERG11的点突变，特别是发生在105-165、266-287、405-488氨基酸之间的3个"热点"区域，可以降低念珠菌对唑类药物的敏感性。白念珠菌耐药菌株中ERG11的过表达主要是由Upc2p的功能获得性突变如 G648D、G648S、A643T、A643V、Y642F、G304R、A646V、W478C等导致。研究报道，ERG3是ERG11的上游基因，ERG3功能失活可导致白念珠菌对唑类药物的耐药。 ②药物外排泵的过表达。白念珠菌中药物外排泵有2类：ABC转运蛋白（CaCdr1和CaCdr2）和MFS转运蛋白（CaMdr1）。调控CaCdr1和CaCdr2表达的CaTAC1以及调控CaMDR1表达的CaMRR1发生突变使得药物外排泵过表达从而导致白念珠菌对唑类药物耐药。ABC转运体借助核苷酸结合结构域与ATP结合获取能量完成外排，其中CaCdr1是唑类耐药的主要决定因素，临床分离物中Cdr1的缺失可使唑类耐药降低4～8倍。最近的研究发现，转运蛋白CaCdr6/Roa1的缺失使得TOR信号通路过度激活抑制了药物的摄入，从而导致白念珠菌对唑类药物的耐药。研究还发现ABC转运蛋白CaMlt1通过液泡摄取机制来调控白念珠菌对唑类药物的耐药。另外，介体复合物在Tac1介导的唑类耐药中起着重要作用，Tac1功能获得突变体中介体尾模块的缺失减少了CDR1的转录，从而增加了对氟康唑的敏感性。MFS 转运体依靠电化学梯度扩散完成外排，在白念珠菌95个MFS转运蛋白中，仅Mdr1参与了白念珠菌对唑类药物的耐药。白念珠菌Swi/Snf染色质重塑复合物被认为是Mrr1的主要共激活因子，在功能菌株的Mrr1获得中，Swi/Snf复合物的催化亚基SNF2的缺失导致Mdr1激活和对氟康唑耐药的急剧降低。 ③应激反应的调节。热休克蛋白（Hsps）能够通过calcium-calcineurin、MAPK以及 Ras1-Camp-PKA信号通路来调控白念珠菌对唑类药物的耐药。研究发现，Hsp90的底物蛋白和 Hsp90翻译后修饰过程可以作为上游调控因子缓解耐药性，甾醇C-22 脱氢酶EGR5和磷脂酰肌醇-4激酶（PI4K）STT4能够参与调控Hsp90。此外，金属离子应激能够影响白念珠菌对唑类药物的敏感性。有研究报道，铁离子的缺乏能够导致CaERG11表达下调和ERG3上调，从而提高菌株对唑类药物的敏感性，铁离子转运蛋白Ftr1、Ftr2和Ftr11参与铁离子介导的药物敏感性。有研究还发现，CaUpc2和热休克因子1（Hsf 1）参与铁离子介导的药物敏感性。白念珠菌对唑类药物的耐药还与生物膜的生成有关。另有研究显示，白念珠菌生物膜产生过程中，CaERG25和CaERG11的表达水平增高，从而导致其对唑类药物的耐药。 2、对多烯类药物的耐药机制念珠菌对多烯类药物耐药性的产生是通过降低药物对膜的结合亲和力或从膜中消耗麦角甾醇的酶的改变介导的。研究显示，白念珠菌ERG2、ERG3、ERG5或ERG11发生突变能够导致菌株对AmB耐药。AmB 耐药念珠菌分离株的适应性和存活率严重依赖于Hsp90的表达和功能。因此，在白念珠菌耐药菌株中抑制Hsp90 的药理学作用可以消除AmB抵抗。白念珠菌在接触AmB 后具有补偿性抗氧化反应，与AmB耐药念珠菌的研究表明，活性氧（ROS）积累显著减少，蛋白质碳酸化减少，线粒体基础呼吸减少，过氧化氢酶的产量也有显著的增加。另外，Rlm和Smil等转录调节因子可调控念珠菌生物膜基质主要成β-葡聚糖的产生量，导致念珠菌对药物耐药。 3、对棘白菌素类药物的耐药机制葡聚糖合酶既是棘白菌素药物的靶标也是耐药位点。1，3-β-葡聚糖合成酶编码基因FKS1的突变能够导致白念珠菌对棘白素类药物耐药，与此相关的突变主要为S645P和S645F，且在易感菌株该区域突变情况下，对应菌株耐压性升高，导致棘白菌素类药物的抗菌效果显著降低。白念珠菌除FKS1基因与棘白菌素耐药相关外，还表达了FKS2和 FKS3，最近研究发现，FKS2和 FKS3作为FKS1表达的负调控子，当白念珠菌中缺失FKS2和 FKS3后， FKS1表达明显上调进而影响其对棘白素类药物的敏感性。同时，对临床分离得到的白念珠菌耐药株的检测发现，Ser645发生突变的频率最高，目前已发现 3种突变，即S645P、S645F和S645Y，当易感菌株中该区域发生突变，菌株会产生耐药性。白念珠菌转录因子Cas5是影响真菌对棘白菌素耐受性的细胞因子，Cas5的纯合缺失可降低FKS1介导的棘白细胞的耐药性。此外，镁离子的缺乏造成白念珠菌中组氨酸激酶基因NIK1的突变，进而抑制Hog1的激活提高菌株对卡泊芬净的敏感性。 4、对氟胞嘧啶的耐药机制对白念珠菌的基因组学研究证实，5-氟胞嘧啶（5-FC）的耐药性是由特殊菌株的隐性基因决定的，其中以FUR1基因突变最为常见。编码UPRTase的FUR1基因在301位点突变，降低了5-FC转化为具有细胞毒性代谢产物的能力，以及编码胞嘧啶脱氨酶的FCA1基因发生突变可能导致药物摄入减少，均可影响有毒化合物的代谢和在胞内的聚集而导致耐药等。此外，胞嘧啶渗透酶、胞嘧啶脱氨酶功能缺陷或胸苷酸合酶活性改变也可能产生耐药。参考资料 [1]张欠欠,罗传玉,陈嘉琪等.白念珠菌感染现状及抗真菌药物研究进展[J].中国真菌学杂志,2021,16(05):356-360. [2]张欠欠,封小川,张凯玄等.白念珠菌对临床常用抗真菌药物耐药机制研究进展[J].中国真菌学杂志,2022,17(03):251-254. 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

微生物疗法临床研究

2023-08-22

·Science Daily

New antifungal therapy for fungal meningitis

A team of researchers successfully tested a new antifungal therapy to treat fungal meningitis. A team of University of Minnesota Medical School researchers successfully tested a new antifungal therapy to treat fungal meningitis. The trial results were published today in the peer-reviewed journal Clinical Infectious Diseases. The research team tested a new oral formulation of the antifungal medication amphotericin among people who had HIV and cryptococcal meningitis -- a common fungal infection around the brain. Cryptococcal meningitis is the most common cause of central nervous system infection in people living with HIV worldwide. Conventional amphotericin B can only be administered directly into veins and is highly toxic. The new lipid nanocrystal formulation -- which was tested in the EnACT trial -- can be taken orally and is non-toxic. "An orally administered amphotericin that is effective against nearly all fungus and non-toxic sounds like the holy grail of antifungal medicines. While further clinical trials are needed in other fungal conditions, the EnACT trial establishes proof of concept for the safe and effective treatment of invasive fungal infections," said David Boulware, MD, MPH, an infectious disease physician and professor at the University of Minnesota Medical School and M Health Fairview. Dr. Boulware is also the senior investigator of the EnACT trial. In this randomized trial, 141 HIV-positive people with cryptococcal meningitis received the oral amphotericin combined with oral flucytosine. This combination was found to be promising for cryptococcal meningitis in regard to antifungal activity, similar survival and less toxicity in comparison to intravenous amphotericin B. Statistically fewer lab abnormalities occurred with the six weeks of LNC-enabled oral amphotericin B compared to one week of intravenous amphotericin B. In the group given two IV loading doses then the experimental oral amphotericin formulation, 90% of participants survived >4 months compared to 85% who received one week of standard intravenous amphotericin. "With the rising incidence of life-threatening fungal infections, our currently available conventional methods are limited by rising rates of drug resistance and toxicities," said Mahsa Abassi, DO, assistant professor at the U of M Medical School and co-investigator on the trial. "The development of new antifungal regimens that are orally available, less toxic, and can treat highly resistant fungal infections is crucial." The trial was conducted in partnership with researchers from the U of M's Medical School, School of Public Health, the Infectious Diseases Institute of Makerere University in Uganda and Matinas BioPharma, a clinical-stage biopharmaceutical company. "We are very pleased that the important EnACT data are being shared with the clinical and scientific community at large through publication in this peer-reviewed journal," said Theresa Matkovits, PhD, and Chief Development Officer of Matinas. "The results from EnACT in cryptococcal meningitis and our experience with patients enrolled in our ongoing Compassionate/Expanded Use Access Program support our belief that MAT2203 has the potential to become an important part of the regimen for treatment of invasive fungal infections, including in the highest-need patients who require longer-term treatment and have limited or no treatment options. The publication of the EnACT data in Clinical Infectious Diseases is yet another milestone for our development program. We would like to thank all the EnACT participants, our dedicated investigators, and the entire clinical study team in Uganda for their commitment to this important clinical trial." Funding for the EnACT trial was provided by the National Institutes of Health's National Institute of Neurological Disorders and Stroke.

临床结果临床研究合格传染病产品

100 项与氟胞嘧啶相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00323	氟胞嘧啶	J02AX01 D01AE21	DB01099

研发状态

适应症	最高研发状态	国家/地区	公司
真菌血症	批准上市	日本更多	Kyowa Pharmaceutical Industry Co., Ltd. 更多
念珠菌病	批准上市	美国更多	Bausch Health US LLC 更多
真菌病	批准上市	日本更多	Kyowa Pharmaceutical Industry Co., Ltd. 更多
真菌性脑膜炎	批准上市	日本更多	Kyowa Pharmaceutical Industry Co., Ltd. 更多
呼吸道感染	批准上市	日本更多	Kyowa Pharmaceutical Industry Co., Ltd. 更多

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02414165 (Pubmed \| Sci Transl Med) 人工标引	临床1期	复发性恶性胶质瘤	45	5-fluorocytosine+vocimagene amiretrorepvec	(膚淵鏇艱窪築鹽顧餘積) = 鑰糧鹽簾簾夢顧壓醖廠積積憲築襯簾範築觸選 (鏇網窪鏇夢憲襯憲鏇蓋, 10.8 ~ 20.0)	积极	2016-06-01
NCT02414165 (Pubmed \| Sci Transl Med) 人工标引	临床1期	复发性恶性胶质瘤	45	5-fluorocytosine+subgroup from an external control	-	积极	2016-06-01
EUCTR2018-000039-28-BE (ESMO2022) 人工标引	临床1/2期	恶性上皮肿瘤	30	5-FC+TG6002	(築鑰醖獵鹹顧選夢積艱) = a single dose-limiting toxicity was observed among these 30 pts consisting of a disseminated pustular rash in one pt treated at the dose of 3x109 pfu 廠壓獵憲顧鹽繭網醖鏇 (廠製襯願襯遞鑰範構醖 )	积极	2022-09-10
ACTA (Pubmed \| Clin Infect Dis)	N/A	隐球菌脑膜炎	-	2 weeks of oral 5FC and FLU	鹹鑰淵衊糧窪膚憲鹽鹹(觸築獵餘製衊艱觸範窪) = 簾範積淵衊願簾顧顧醖鑰獵憲鏇襯範鹹蓋鬱糧 (積網鹽齋廠願鏇簾蓋夢 )	-	2019-08-01
ACTA (Pubmed \| Clin Infect Dis)	N/A	隐球菌脑膜炎	-	1 week of AmB and FLU	鹹鑰淵衊糧窪膚憲鹽鹹(觸築獵餘製衊艱觸範窪) = 醖範壓艱窪鹽醖獵餘蓋鑰獵憲鏇襯範鹹蓋鬱糧 (積網鹽齋廠願鏇簾蓋夢 )	-	2019-08-01
NCT00978107 (Pubmed \| Ann Oncol) 人工标引	临床1期	肝癌	16	TG4023+flucytosine	(淵願繭顧繭蓋衊鑰餘糧) = 4 × 108 p.f.u. 蓋衊遞窪憲膚網夢窪夢 (壓選憲壓獵醖鬱蓋鏇膚 ) 更多	积极	2017-01-01
NCT04194034 (TG6002.03, AACR2023) 人工标引	临床1期	转移性结直肠癌	15	TG6002+5-fluorocytosine	(醖鬱淵鑰構繭築淵鏇積) = 窪憲遞廠築襯簾膚襯繭襯艱壓顧鹹網範鹽鑰鏇 (衊築壓繭衊憲選顧蓋壓 ) 更多	积极	2023-04-14
NCT03281382 (Pubmed \| Mol Ther Oncolytics) 人工标引	临床1期	胰腺继发性恶性肿瘤	12	Flucytosine+Ad5-yCD/mutTKSR39 rep-hIL-12	(築淵艱夢齋簾餘範鹹簾) = ~94% of the 121 events were grade 1/2 requiring no medical intervention 築鬱壓繭鬱遞願築範淵 (鏇醖鑰蓋鏇網繭選壓窪 )	积极	2020-12-03
AACR2023 人工标引	临床1期	复发性前列腺癌	15	Ad5-yCD/mutTKSR39rep-hIL-12+5-fluorocytosine+Valganciclovir	(遞襯齋獵齋築衊鹹觸壓) = 醖積壓鏇選遞鏇夢製願願蓋淵艱廠願觸憲淵蓋 (顧鑰廠製膚餘淵艱鹽製 ) 更多	积极	2023-04-14
NCT01470794 (Pubmed \| Neuro Oncol) 人工标引	临床1期	复发性恶性胶质瘤	56	5-fluorocytosine+Vocimagene amiretrorepvec (IDH1 mutant and wild-type tumors)	(顧鹹壓醖糧鹹遞壓膚鑰) = 鏇蓋夢壓鹹衊獵窪製積觸齋糧選膚網襯襯憲壓 (積網夢鏇齋網範獵網獵 ) 更多	积极	2018-09-03
NCT04031833 (EnACT, Corporate Publications) 人工标引	临床2期	隐球菌脑膜炎	80	Flucytosine+Fluconazole+MAT2203 (Cohort 4)	窪願繭積繭壓憲獵醖獵(積選願簾遞鹹繭鏇簾齋) = 蓋齋遞積構鏇選願襯製網鏇鹽蓋獵積繭艱淵積 (壓觸顧窪壓簾願製範獵, 0.22 ~ 0.38) 更多	积极	2022-10-21
NCT04031833 (EnACT, Corporate Publications) 人工标引	临床2期	隐球菌脑膜炎	80	Standard of Care	(構醖醖艱鏇鏇糧窪鹹膚) = 積壓獵蓋齋鏇鹹齋繭構願築憲構衊膚繭觸襯齋 (簾網夢鏇蓋簾遞鹽鹹鬱 ) 更多	积极	2022-10-21
NCT02894944 (Pubmed \| Gastrointest Endosc) 人工标引	临床1期	胰腺癌	9	gemcitabine+5-fluorocytosine+valganciclovir+Ad5-DS	(遞積鏇鬱齋選遞鬱膚淵) = 鹹遞齋膚積鏇簾獵淵鹽襯網襯網繭廠廠膚築壓 (願遞壓鬱構廠繭積觸顧 ) 更多	积极	2020-11-01