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4．卡泊芬净
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卡泊芬净（caspofungin）是棘白菌素类中首个被美国FDA批准上市的抗真菌药物，系葡聚糖合成酶抑制剂，通过抑制对于维持包括曲霉菌和念珠菌属的细胞壁完整性至关重要的β-(1, 3)-D-葡聚糖合成，而破坏真菌细胞壁，使其通透性改变，渗透压消失，细胞溶解。由于人类细胞中无β-(1, 3)-D-葡聚糖合成，因此卡泊芬净的作用机制使其发生毒性作用的可能性很低。为现有抗真菌药物中最安全的品种。
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卡泊芬净抗菌谱广，对所有念珠菌属（包括非白念），对耐氟康唑、两性霉素B或氟胞嘧啶的念珠菌均具有体外抗菌活性。对于曲霉菌、卡氏肺孢子菌均有效。并且与氮唑类或多烯类无交叉耐药，对念珠菌分离株未发现天然耐药现象。但对隐球菌无效。
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5．米卡芬净
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米卡芬净（micafungin）其抗菌谱与卡泊芬净相似，但药物的最佳剂量尚有待于进一步研究。研究显示与米卡芬净AmB联合使用无药物拮抗作用；两者联合使用对曲霉菌和镰刀霉菌具有附加或协同作用。
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（三）抗真菌药物的联合应用
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联合应用抗真菌药物具备以下优点：增强抗菌活性、尽快控制感染、拓宽抗菌谱、防止耐药产生、组织分布更理想及减少药物毒性。但在联合应用中必须注意可能存在的缺陷：药物之间可能出现拮抗，毒性增加，治疗费用昂贵等。因此抗真菌药物的联合应用需慎重。两性霉素B和5-FC的联合使用已得到公认，动物试验和体外药敏试验均证实两者合用具有协同作用，并作为临床常规治疗用药。现将有关联合抗真菌治疗临床试验结果归纳如下（表2-5）。
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表2-5 联合抗真菌治疗临床试验结果
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侵袭性肺真菌病的诊断与治疗是近年呼吸内科及相关学科研究发展迅速的一个领域，但仍有许多令人感到困惑的方面，如真菌病早期床边诊断方法，既安全又价廉的药物，抗真菌治疗的疗程如何判断等等，有待于进一步的研究来揭示。
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【思考题】
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1．试述真菌的分类，并各举一例子。
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2．抗真菌药物可分为哪几类？并各举一例子。
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参考文献
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[1] Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis, 2002, 34:7-14.
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[2] Annie WB, Jane K. Systemic antifungal therapy: new options, new challenges. Pharmcotherapy, 2003, 23:1441-1462.
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[3] Thomas J. Walsh, Elias J. Anaissie, David W. Denning, et al. Treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of America. Clin Infect Dis, 2008, 46:327-360.
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（沈毅弘）
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内科学新进展 [:1700626999]
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内科学新进展 第三章 消化系统疾病
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内科学新进展 [:1700627000]
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第一节 胃癌基础研究的若干进展
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摘 要 正常细胞发展为癌细胞是多基因突变累积和细胞内外分子环境发生重大改变的结果，其过程极为复杂。在上述情况下，正常细胞可能失去控制而形成肿瘤。恶性肿瘤不仅在原发部位生长，浸润累及邻近组织，而且能通过毛细血管、淋巴管等多种途径扩散到其他部位，生成同样类型的肿瘤，这个过程称为肿瘤的转移。它是恶性肿瘤的特征之一，也是导致肿瘤患者死亡的主要原因。转移是一个多阶段复杂的过程，肿瘤细胞需经过脱离原发瘤群体、黏附、降解、运动迁移、血管生成等一系列过程。总之，肿瘤的发生、发展及转移是一个多因素、多步骤、复杂的渐进过程，涉及一系列分子生物学变化，包括原癌基因的激活、抑癌基因的失活、细胞周期调节因子、基因的多态性、微卫星不稳定、端粒酶、细胞凋亡相关基因、细胞因子及其受体、细胞黏附分子、细胞外基质降解酶、运动因子及转移相关基因等。各个因素在不同的阶段或同一阶段的不同方面发挥其作用，同时相互之间存在复杂的协调、促进或制约的关系。胃癌亦是如此，其发生与遗传因素、免疫因素、社会经济状况、理化因素、感染因素尤其是幽门螺杆菌（helicobacter pylori, Hp）等多种因素有关。值得注意的是，自从Hp发现以来，其在胃癌中的作用越来越受到重视。按照组织学差异，胃癌可分为肠型（或分化良好型，即腺管型）和弥漫型（或分化不良型，即无腺管形成的腺癌、印戒细胞癌及硬癌），两种类型的病因、好发部位、发生率及生物学行为和分子改变明显不同。因此，研究胃癌不同发展阶段的分子和基因表达变化不仅有助于阐明其发病机制，而且对于其预防、早期诊断、治疗及预后判断具有重要的意义。随着分子生物学尤其是基因芯片等技术在胃癌基础研究中的应用，目前已发现多种与其发生、发展及转移相关的分子和基因。本文重点回顾近年来有关胃癌发生、发展和转移相关的因子及其作用机制，以及Hp相关性胃癌的分子机制。
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Abstract The process of normal cells turning into cancer cells is intricate, as is the result of accumulation of multiple gene mutations and great changes of molecular environment inside or outside cells. Under the conditions above-mentioned, normal cells may be out of control and result in tumorigenesis. Malignant tumors not only grow in the primary site and invade ambient tissues, but also can extend to distant places and develop into new tumors of the same kind via blood capillary, lymph vessel, etc, which is called metastasis. It is one of the features of malignant tumors, as well as the main cause of tumor suffers’ death. Metastasis is a complex multistep process that includes tumor cells abscission, adhesion, degradation, migration and angiogenesis, etc. In a word, the process of tumorigenesis, progression and metastasis is gradually, multifactorial, multi-phases and complicated, various molecular events and signal transduction pathways involved, including activation of oncogenes, inactivation of anti-oncogenes, regulation factors of cell cycle, polymorphism of genes, microsatellite instability, telomerase, apoptosis-associated genes, cytokines and their receptors, cell adhesion molecules, extracellular matrix degradation enzymes, motility factors and tumor metastasis-associated genes, etc. All the factors play a part in different stages or different aspects of the same stage of tumorigenesis, progression and metastasis. Meanwhile, they promote, restrict or cooperate with each other in the procedure. So is gastric cancer. Many agents such as genetic factors, immune agents, socioeconomic status, physical and chemical agents, infect agents especially helicobacter pylori, etc, are related to development of gastric cancer. It’s notable that since helicobacter pylori was discovered, more and more attention has been paid to its role in gastric cancer. According to histological difference, Gastric cancer can be divided into intestinal type（well-differentiated type, i.e. cryptae type）and diffuse type（mal-differentiated type, i.e. adenocarcinoma with no cryptae, signet-ring cell carcinoma and scirrhous carcinoma), whose etiopathogenisis, predilection site, incidence rate, biological behavior and molecular changes are quite different. Therefore, to study the genetic and molecular changes of gastric cancer not only conduces to elucidating its pathogenesis, but also is very important to its prevention, early diagnosis, treatment and prognosis judgement. As the application of cell molecular biology technique especially gene chip in researches of gastric cancer, many related molecular factors and genes have been found. In this text, recent advances in associated factors of gastric cancer and their mechanisms of action were summarized, as well as the molecular mechanism of helicobacter pylori-associated gastric cancer.