Griseofulvin

纳米技术和材料的发展给医学带来了一场深刻的革命，极大地影响了肿瘤、传染病和心血管疾病等各种重大疾病的治疗。纳米医学在过去几年中经历了爆炸性的增长。越来越多的药物已经采用纳米剂型来降低副作用，提高疗效。纳米药物递送系统（NDDSs）在过去几年中发展迅速。从2000年到2019年，关于NDDSs的研究文章增加了十倍以上。到目前为止，已有90多种NDDSs上市。针对特定疾病的不同类型纳米药物，其中肿瘤占大多数。其他疾病，如感染和心血管疾病，正在日益威胁人类健康。本文介绍了目前已上市的纳米药物及其主要特点并对已批准的处方进行了分析，并对该领域进行了展望。脂质体和脂质纳米粒（LNPs）在过去的几年里，脂质体和LNPs从概念到脂载体在NDSS中的主流地位经历了一个漫长而曲折的道路。自1985年第一批脂质体进入临床试验以来，已有20多种脂质体和LNP获准上市，脂质体药物的成功进一步刺激了对脂质相关纳米粒的广泛临床研究。它们已被用于通过疫苗和基因药物输送进行疾病治疗的临床探索。脂质体用于肿瘤治疗肿瘤是威胁世界的最严重公共卫生问题之一。近年来，随着对高效低毒NDDS的研究越来越多，纳米药物已被广泛用于抗肿瘤治疗。其中，脂质体是目前研究的热点，各种抗肿瘤脂质体相继问世。第一个上市的多柔比星脂质体是美国Sequus公司开发的Doxil®，主要用于治疗复发性卵巢癌和人类免疫缺陷病毒（HIV）诱导的卡波西肉瘤（KS）。其他上市的小分子抗肿瘤脂质体，如Marqibo®，针对急性淋巴细胞白血病（ALL）的长春新碱脂质体，Depcyte®，针对肿瘤性脑膜炎（NM）的阿糖胞苷脂质体，以及治疗晚期胰腺癌的伊立替康脂质体Onivyde™。此外，市场上还有包裹大分子药物的抗肿瘤脂质体。如Mepact®，米法莫肽（MFT）多层脂质体， 它是一种用于治疗骨肉瘤的孤儿药。脂质体用于传染病治疗除了肿瘤，传染病也威胁着人类健康和生命。利什曼病是由利什曼原虫属细胞内寄生虫引起的人畜共患疾病。两性霉素B是一种能与细胞膜中的甾醇结合的多烯大环内酯类抗生素，是目前最有效的抗利什曼药物。由于其口服吸收差，只能通过静脉注射达到给药浓度。此外，它很容易与血清蛋白结合，并在肝、肺、脾和肾中蓄积，产生毒性。脂质体的应用显著降低了药物的毒性。两性霉素B的两种脂质体AmBisome®和Amphotec®分别于1990年和1996年上市，它们有效且耐受性良好，可对抗免疫功能正常患者的内脏利什曼病和其他严重真菌感染。随后，越来越多的抗感染脂质体产品以更多的给药途径上市，而不限于静脉给药。Arikayce®的推出代表着脂质体超复合制剂的进步。它是一种脂质体吸入制剂，采用eFlow雾化系统给药，用于治疗非结核分枝杆菌（NTM）肺部疾病。目前，市场上已有10多种针对传染病的脂类产品在售。脂质体用于止痛和其他疾病治疗脂质体被用于疼痛治疗及光动力疗法（PDT），包括吗啡脂质体DepoDur™ 和布比卡因脂质体Exparel®。前者是一种包裹硫酸吗啡的脂质体，主要用于缓解术后疼痛，单次给药后镇痛作用持续48小时。Exparel®具有持久的镇痛作用，皮下注射后可达72小时的止痛效果。脂质体可以不同的方式在体内释放药物， Visudyne®是一种脂质体的PDT组合制剂，用于治疗老年性黄斑变性（AMD）和脉络膜新生血管（CNV）。脂质体用于遗传性甲状腺素淀粉样变和COVID-19治疗LNPs作为研究最多的纳米载体之一，经历了快速的技术发展并取得了重大进展。第一种siRNA药物Onpattro™ （一种新的小干扰核糖核酸（siRNA）LNP）于2018年推出，用于治疗hATTR多发性神经病，标志着LNP技术的里程碑式进步。LNPs作为信使RNA（mRNA）疫苗的重要组成成分，在保护和传递mRNA方面发挥着重要作用[87]。两种获批的信使核糖核酸疫苗mRNA-1273和BNT162b2以LNPs为载体，在预防感染方面显示出显著的效果。药物纳米晶（NCS）在过去的二十年里，超过15个NCs被批准用于临床。NCS通过多种给药途径提供疏水药物，并在许多不同领域表现出色，如高载药量、长期稳定性、增强释放、屏障穿透和易于扩展的技术。值得注意的是，由于其极高的载药量，NCS是最有希望实现长期抗病活性的纳米药物。纳米晶用于心血管疾病治疗心血管疾病是全球发病率和死亡率的主要原因之一，包括各种心脏和循环系统功能障碍。第一个被批准用于预防动脉粥样硬化和动脉内壁斑块导致中风和心脏病发作的纳米晶产品是非诺贝特纳米晶Tricor®，早在2004年11月5日批准上市。与微粉化的非诺贝特相比，它的口服生物利用度提高了9%。另一种先进的非诺贝特纳米晶产品(TriGlide®)于2005年5月7日获批，在低脂饮食条件下，160mg片剂纳米晶制剂的吸收率比200mg微粉化非诺贝特胶囊高32%。纳米晶用于抗感染治疗抗感染药物，包括抗细菌、抗真菌、抗病毒和抗寄生虫药物，已被用于治疗不同的传染病。第一个获得FDA批准用于治疗真菌感染的纳米晶产品是口服Gris PEG，该产品由Recro Gainesville LLC于1998年生产，并被批准用于口服抗真菌药物灰黄霉素治疗癣菌感染。2021年，两种商品名为Cabenuva®和Apreude®的控释/缓释注射纳米晶产品获得FDA批准，用于治疗I型艾滋病毒(HIV-1)感染。前者是一种新型长效注射制剂(每月一次)，可延长药物的释放。后者是一种暴露前预防用药，用于高危患者或体重超过35kg的青少年的艾滋病毒治疗，以降低性获得HIV-1感染的风险。Apreude®的作用机制是基于抑制HIV-1病毒复制。纳米晶用于精神病和其他疾病的治疗纳米晶产品还被用于治疗如肾移植中的器官排斥反应、厌食、精神病、慢性疼痛、恶心、呕吐等。例如，免疫抑制剂西罗莫司纳米晶被证明可预防≥13岁肾移植患者的器官排斥反应。抗精神病药物(帕利培酮棕榈酸酯)的三种纳米晶产品Invea Sustenna®(2009)、Invea Trinza®(2015)和InVega Hafyera®(2021)，分别延长药物释放1个月、3个月和6个月，已被批准用于治疗精神分裂症和分裂情感障碍，以及补充成年人的情绪稳定剂或抗抑郁药。聚合物纳米粒聚合物纳米药物通常是指载有活性化合物的纳米颗粒，包裹在聚合物核中或吸附在聚合物核的表面。除了基于脂质的纳米药物和纳米晶，聚合物纳米药物可以分为聚合物胶束、聚合物纳米粒和基于树枝状聚合物的纳米粒。聚合物胶束用于肿瘤治疗聚合物胶束是由两亲性嵌段共聚物在水溶液中自组装形成的，具有疏水核心和亲水外壳。疏水核心包裹了水溶性低的药物；至于亲水外壳，它保护药物并保持胶束的稳定性。常用的疏水性聚合物包括聚乳酸（PLA）、聚乳酸乙交酯酸(PLGA)和多胺酸(PAA)，而常用的亲水性聚合物是聚乙二醇、壳聚糖、透明质酸（HA）和PVP。到目前为止，市场上已经有三种聚合物胶束纳米药物：Genexol®PM、Nanoxel®M和Paclical®。Genexol®PM是2007年在韩国、菲律宾、印度和越南批准用于人类的最早的聚合物纳米药物，其适应症包括转移性乳腺癌（MBC）、非小细胞肺癌（NSCLC）和卵巢癌。Nanoxel®M是一种用于肿瘤治疗的多西他赛聚合物胶束制剂，于2012年获得批准。Paclical®于2015年在俄罗斯批准用于卵巢癌治疗。此外，许多新型的聚合物胶束的纳米药物正处于临床试验阶段。聚合物纳米粒用于肿瘤治疗聚合物纳米粒可以包裹各种活性化合物，如抗肿瘤药物、siRNA、蛋白质和造影剂[183]。到目前为止，只有一种商业化的聚合物纳米粒：白蛋白结合型紫杉醇（Abraxane®），FDA于2005年批准其用于治疗胰腺癌和MBC。临床试验中，Abraxane®不仅保持了PTX的抗肿瘤作用，还消除了Taxol®中与Cremophor®EL相关的毒性。树枝状大分子纳米粒用于抗感染治疗到目前为止，只有一种树状大分子纳米药物上市：Viva-Gel®，于2006年被批准用于预防HIV和单纯疱疹病毒（HSV）适应症。临床研究表明，含有>0.5%的SPL7013的VivaGel™可抑制70%以上的HIV-1和HSV-2，给药后活性至少维持3小时。其他纳米药物随着先进的合成或天然生物材料制备及NDDS的快速发展，各种新型纳米药物被开发成抗体-药物偶联物、细胞衍生载体、病毒载体、无机纳米颗粒、蛋白质纳米颗粒。这些纳米药物已被广泛应用于治疗或诊断各种疾病，包括肿瘤、传染病、炎症、血液疾病、免疫学疾病、心血管疾病、神经系统疾病、精神疾病、内分泌和代谢疾病等。如Ontak®是第一个通过基因构建的融合蛋白，被认为是一种结合靶向机制和细胞杀伤部分的重组分子。可用于如霍奇金病、类风湿性关节炎、银屑病、B细胞非霍奇金淋巴瘤、皮肤T细胞淋巴瘤（CTCL）和HIV感染。而Restasis®是一种环孢菌素纳米乳剂，用于干眼病的治疗。与此同时，许多用于不同适应症的新型纳米药物仍处于临床试验阶段。结论与展望自2005年以来，FDA简化了纳米药物的申报流程，以促进其开发。这一过程使数十种脂质体、纳米晶和LNPs得以上市，其中包括两种用于新冠肺炎治疗的产品，Comirnaty和mRNA-1273。鉴于90多种纳米药物已经商业化，与大量出版物相比，转化比例仍然很低。阻碍临床应用的因素较复杂，例如如对癌症患者的EPR效应不大，体内去向不明，以及毒性。尽管如此，转化的困难并不会阻碍纳米药物的快速发展，因为它在改善具有高特异性和效力的生物制药的递送方面具有相当大的好处。2018年批准的第一种siRNA药物Onpattro™，开启了生物制药临床应用的时代。之后， LNP技术使越来越多的核酸药物商业化，如mRNA疫苗，mRNA-1273和BNT162b2。可以预见，纳米技术将继续对生物制药的发展产生相当大的影响，未来与生物制剂相关的纳米药物将会越来越多地进入市场。

THURSDAY, May 11, 2023 -- The first U.S. cases of drug-resistant ringworm infection have been reported in New York City. The cases of two women with highly contagious skin infections caused by Trichophyton indotineae are reported in the May 12 issue of the U.S. Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report . The fungus causes widespread, very itchy, and very hard-to-treat tinea infections. (Tinea is also known as ringworm, which can be misleading since no actual worm is involved.) "These are the first reported cases in the United States, but the infection is now spanning the globe," said researcher Dr. Avrom Caplan , a dermatologist at NYU Langone Medical Center in New York City. It has been spreading widely in India over the last decade and was termed "indotineae" in a report of two 2020 cases, he noted. "The name should not imply that it is only in India," Caplan said. "We may see more of this infection over time." The infection can be transmitted by direct contact; by contact with particles of dead skin, nails and hair shed by the host, usually animals and pets; or by contact with fungal spores. The infection is easily spread from person to person. Caplan said doctors should be aware of this infection and that topical antifungal creams aren't going to be enough to treat it. "We also know that this infection is hard to confirm with diagnostic testing," he said. "It takes analysis at specialized labs to confirm this particular infection, so clinical awareness and suspicion is very important." Treatment often requires longer courses of oral antifungals than doctors typically think about, Caplan said. It appears that one of the patients in the CDC report picked up the infection while traveling outside the United States, he said. That patient, a 47-year-old woman with no major health issues, developed a bad case of ringworm, also known as tinea, last summer in Bangladesh. She and several family members were treated there with topical antifungal and steroid creams, according to the report. After returning to the United States, the woman had continued skin eruptions and failed to respond to a common antifungal treatment called terbinafine. A four-week course of griseofulvin had better results — an 80% improvement in her symptoms — but doctors are still evaluating next steps. Her husband and son have similar symptoms and are being evaluated, the study said. The other patient in the CDC report, a 28-year-old woman, developed a rash in the summer of 2021. She had not been outside the country, suggesting potential U.S. transmission of the fungus. After treatment with itraconazole, her rash disappeared in four weeks. Doctors are continuing to monitor her, the report said. "We know this infection is spanning the globe, and we expect we will see more here," Caplan said. Outside Asia, cases have been identified in Europe and Canada, according to NBC News . "It is hard to confirm diagnostically, but suspicion can be raised clinically if patients present with widespread, itchy, inflamed scaly plaques over the face, neck, trunk or groin," Caplan said. Patients may report the use of topical corticosteroids or combination creams with topical antibiotics. They may or may not report traveling, Caplan said. "Given the ease of transmission between people though, it's highly likely that we will see at least family spread if not other local spread," he said. This infection is hard to treat, Caplan stressed. Oral antifungals for eight to 12 weeks or more are usually required. Typically, the treatment of choice is itraconazole, which in the past was not usually a first-line oral antifungal. Even afterward, patients may relapse. Caplan urged doctors to be on watch for patients with widespread, very itchy, scaly and red plaques that look like tinea. They should be asked about travel history, exposures to anyone with similar rashes, and about their use of topical creams, especially corticosteroids, he said. So far the fungus doesn't seem to be a widespread problem in the United States, he added. "Public health officials are monitoring the situation closely, and we want to catch cases early to prevent spread," Caplan said. "And we want to emphasize the importance that people should seek a diagnosis from a health care provider if they are concerned about widespread tinea infections." Dr. Marc Siegel , a clinical professor of medicine at NYU Langone Medical Center, who was not involved in the study, said that these cases, though isolated, have alerted the CDC to a growing problem with fungi that are resistant to common remedies. Part of the problem comes from misuse and overuse of antifungals, he said. "This is a growing problem not just with tinea but with other fungi as well including Candida auris ," Siegel said. A second expert, Dr. Raman Madan , a dermatologist at Northwell Health in Huntington, N.Y., said he isn't too worried about this infection. "A few isolated cases that they found in New York isn't very concerning to me," he said. "I think it becomes more of a problem if a year from now we start seeing more and more of these. It's something that should be on dermatologists' radar but I wouldn't be too concerned as a patient right now." Sources Avrom Caplan, MD, dermatologist, NYU Langone Medical Center, New York City Marc Siegel, MD, clinical professor, medicine, NYU Langone Medical Center, New York City Raman Madan, MD, dermatologist, Northwell Health, Huntington, N.Y. Morbidity and Mortality Weekly Report , May 12, 2023 Posted May 2023