HIV蛋白酶抑制剂的药代动力学相互作用

艾滋病的治疗是一个长期的过程,HIV蛋白酶抑制剂是此类病人最常选用的抗病毒药物。在治疗过程中,病人很可能患其它疾病,艾滋病自身也常伴随众多并发症,使得临床上不可避免的需要联用其它药物。由于HIV蛋白酶抑制剂对药物代谢酶和转运体有广泛的作用,因此探索HIV蛋白酶抑制剂的药物相互作用问题显得十分必要。本文重点从药代相互作用机制的角度综述了HIV蛋白酶抑制剂在临床上可能出现的药物相互作用方面的研究文献,包括HIV蛋白酶抑制剂与其它药物的相互作用以及蛋白酶抑制剂之间的相互作用及机制等,期望对于临床给药方案的设计和提高临床用药的安全性和有效性提供有价值的参考和借鉴。     

HIV化学治疗的最新进展

分两部分介绍了抗HIV的化学治疗药物的新进展,一是作用于现有病毒靶位的属于逆转录酶抑制剂和蛋白酶抑制剂的新化合物,另一部分是作用于病毒新靶位的化合物如HIV整合酶抑制剂、核糖核酸酶-H抑制剂以及病毒进入抑制剂。主要从化学结构、对耐药性病毒的抑制作用、作用机制和临床效果等几个方面介绍了解决HIV耐药性问题的新化合物。     

新的抗人类获得性免疫缺陷病毒药

由于耐药性破坏了应用的抗逆转录病毒药的有效性 ,艾滋病临床医师希望实验中的抗逆转录病毒药可以扩展治疗选择。目前 ,研究的最前沿是融合抑制剂 ,其通过阻止人类获得性免疫缺陷病毒 (HIV)与宿主细胞的结合和进入宿主细胞而发挥作用。由于融合和其它进入抑制剂针对的作用靶与现在使用的抗逆转录病毒药处于不同的 HIV生命周期 ,研究人员预计这些实验性药物可能对标准疗法耐药性菌株感染患者具有部分价值。在一项实验性融合抑制剂 T- 12 4 9的 期和 期临床研究中 ,6 3名 HIV感染患者接受每日 1或 2次不同剂量的 T- 12 4 9注射 ,疗程 1…     

抗HIV新药raltegravir*

整合酶(integrase)是HIV病毒复制的必需酶,因而成为抗HIV药物设计的一个合理靶点。目前尚无整合酶抑制剂类药物上市,raltegravir是第一个进入Ⅲ期临床的此类药物。与上市的抗HIV药物相比,具有更高或相近的抗逆转录病毒的活性,无交叉耐药性,毒副作用小,有可能成为第一个上市的整合酶抑制剂。现对其作用机制、临床前研究、药动学、临床应用及安全性等做一综述。     

抗HIV感染治疗的现状

<正> 抗HIV感染治疗从核苷类逆转录酶抑制剂到蛋白酶抑制剂,现已进入了规范有效的治疗时期——HAART治疗。即是联合多种抗逆转录病毒药物的高活性抗逆转录病毒方法。此法除能增强抑制HIV的复制作用外,还可延缓或阻断病毒因变异而产生的耐药性。其治疗原则为:(1)及早治疗,最好争取免疫功能尚未破坏之前;(2)联合治疗药物至少     

新型HIV蛋白酶抑制剂阿扎那韦

阿扎那韦是一日给药1次的新型氮杂多肽蛋白酶抑制剂。可与其它抗逆转录病毒药物联用,发挥抗HIV作用,值得临床关注。[编者按]     

FDA批准扩展HIV药物Prezista的适应证

强生制药公司于2008-10-22宣布，美国FDA已经批准扩展其HIV治疗药物——Prezista的适应证，即与其他药物联用治疗从未接受过治疗的HIV感染者。Prezista（darunavir）已经获得FDA批准与其他HIV药物联用治疗那些已经接受蛋白酶抑制剂治疗但出现耐药性的患者。     

欧委会批准抗HIV药物Prezista 800mg片剂上市

<正>2013年1月16日,欧委会批准Prezista(da-runavir)800 mg片剂上市,与其他抗逆转录病毒药物联合用于已接受或未接受过治疗且无darunavir耐药突变的HIV患者的治疗。Prezista是一种新型HIV-1蛋白酶抑制剂,对耐其他蛋白酶抑制剂的HIV病毒具有抑制活性,早期获批与利托那韦联用     

HIV蛋白酶抑制剂帕利那韦在大鼠体内的药代动力学

目前,尚无合适的动物模型用于HIV蛋白酶抑制剂的药效学评价,因而药代动力学参数成为筛选药物的重要依据。帕利那韦(pali-navir)在体外具有抑制HIV-1和HIV-2蛋白酶的活性,是一个有前途的治疗艾滋病候选药,因而对其药代动力学进行了研究。实验用雄性Sprague-Dawley大鼠,给药途径和剂量分别为口服:2,3,5,10和20mg.kg-1;静注:1,2,3和5mg.kg-1;十二指肠内给药:2,3和5mg.kg-1。最后将实验的结果与其他HIV蛋白酶抑制剂的动力学参数进行比较并推测帕利那韦在胃中降解的可能性。实验结果显示,静脉给药的AUC与给药剂量不成比例,平均生物半衰期…     

人类免疫缺陷病毒蛋白酶抑制剂的研究开发与展望

人类免疫缺陷病毒(HIV)是艾滋病的主要致病因,针对艾滋病的化学药物治疗中HIV蛋白酶抑制剂发挥的重要作用,此文综述了HIV蛋白酶抑制剂的研究现状、研究进展以及研究开发策略等。     

The Bowman-Birk inhibitor. Trypsin- and chymotrypsin-inhibitor from soybeans

Four decades of studies on the isolation, characterization, properties, structure, function and possible uses of the Bowman-Birk trypsin- and chymotrypsin-inhibitor from soybeans are reviewed. Starting from Bowman's Acetone Insoluble factor, designated Ai, AA and SBTIAA, the Bowman-Birk inhibitor (BBI) was found to be a protein molecule consisting of a chain of 71 amino acids cross linked by 7 disulfide bonds, with a tendency to self-associate. BBI possesses two independent sites of inhibition, one at Lys 16-Ser 17 against trypsin and the other at Leu 43-Ser 44 against chymotrypsin. It forms a 1:1 complex with either trypsin or chymotrypsin and a ternary complex with both enzymes. Ingestion of BBI by rats, chicks or quails affects the size and protein biosynthesis of the pancreas. Establishment of the full covalent structure of BBI revealed a high homology in the sequences around the two inhibitory sites, suggesting evolutionary gene duplication from a single-headed ancestral inhibitor. Scission of BBI by CNBr followed by pepsin results in two active fragments, one that inhibits trypsin and the other, chymotrypsin. Replacements and substitutions in the reactive sites result in changes in inhibitory activity and in specificity of inhibition. Conformation studies, labeling of BBI with a photoreactive reagent, chemical synthesis of cyclic peptides that include inhibitory sites, in vitro synthesis of BBI, and species specificity regarding the inhibited enzymes are described. The significance of BBI as a prototype of a family of inhibitors present in all legume seeds is discussed.     

Partial characterization of a subtilisin inhibitor from black bean seeds

The subtilisin inhibitor (SI), isolated from black beans (Phaseolus vagaris) has a molecular weight of 8918 and it contains four half cystine residues. The N-terminal residue is arginine and the C-terminal is lysine. The subtilisin inhibiting site is composed of an Ala-Leu or Ile bond. This site interacts in addition to subtilisin (S) with elastase from human leukocytes (HLE), both of which compete for the inhibitor. Also, HLE-cleaved SI (SI_HLE) is inactive against HLE as well as against S. It was shown that the inhibition of S by SI resembles a temporary inhibition, involving a very slow release of enzyme activity. The trypsin reactive site is a Lys-Val bond, and its interaction with bovine trypsin is very weak. No complexes of SI or trypsin-cleaved SI (SI_T) with trypsin could be detected on cellulose-acetate membrane electrophoresis, while SI_T forms a clearly visible complex with S.     

抗艾滋病药物研究进展

艾滋病是由人免疫缺陷病毒感染导致人体防御机能缺陷，而易于发生机会性感染和肿瘤的临床综合征。本文按照人免疫缺陷病毒复制周期中的不同环节，分别介绍融合抑制剂，逆转录酶抑制剂，蛋白酶抑制剂和整合酶抑制剂的最新研究进展。     

Novel investigational drugs active as single agents in multiple myeloma

Introduction: Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of malignant plasma cells. patient outcome has improved markedly over the last decades due to the introduction of novel therapeutic agents such as bortezomib, thalidomide and lenalidomide. However, MM still remains largely incurable and patients eventually become refractory to available treatments. To address this unmet medical need, a variety of new molecules are currently being developed in preclinical models and/or are being investigated in clinical studies.

Areas covered: We summarized available data on new investigational drugs showing anti-myeloma single-agent activity and that might have a role in the future therapeutic armamentarium against MM. Besides their single-agent activity, the synergic potential of these new agents with the currently approved drugs will be pivotal in their integration into consolidated MM backbone therapies. The drugs discussed include alkylators, new proteasome inhibitors, novel anti-CD38 monoclonal antibodies, Bcl-2 inhibitors, Cyclin-Dependent-Kinase inhibitor, Kinesin-spindle protein inhibitors, MEK1/2 inhibitors, AKT inhibitors and PIM-Kinase inhibitors.

Expert opinion: Isatuximab, oprozomib, melflufen, venetoclax and filanesib seem to be the most promising agents with single agent activity. Nevertheless, lack of clinical activity as single agent does not imply clinical inefficacy in combination treatments.     

Clinical outcome of treatment with serine-threonine kinase inhibitors in recurrent epithelial ovarian cancer: a systematic review of literature

Introduction: While serine-threonine kinases (STK) are attractive therapeutic targets in epithelial ovarian cancer, clinical outcomes of STK inhibitors in the management of recurrent disease have not been completely described.

Areas covered: A systematic literature review of published clinical studies on STK inhibitors targeting mTOR, MAPK, and aurora kinase pathways in recurrent epithelial ovarian cancer was conducted, revealing 18 clinical trials (497 patients). Pooled analyses were performed to assess treatment response, survival time, and adverse events. Median progression-free survival was 3.4 months in STK inhibitor-based therapy, and the average response rate and clinical benefit rate were 13% and 67%, respectively. Among regimens comprised of only STK inhibitors (11 trials, 299 patients), median progression-free time was 2.7 months, response rate was 10%, and clinical benefit rate was 64%. Compared to single STK inhibitor monotherapy (52.5%), clinical benefit rates significantly improved when STK inhibitors were combined with a cytotoxic agent (71.4%), other class biological agent (74.2%), or an additional STK inhibitor (95.0%) (all, P ≤ 0.002).

Expert opinion: STK inhibitor-based therapy showed modest activity for recurrent epithelial ovarian cancer with reasonable clinical benefit rates, suggesting its potential utility for maintaining disease stability if supported by future studies. Efficacy appears greatly improved in appropriately selected patient populations, especially those with low-grade serous ovarian carcinoma, platinum-sensitive disease, cancers with somatic RAS or BRAF mutations, and when used in a combination regimen with a cytotoxic or biological agent.     

Recent developments of cathepsin inhibitors and their selectivity

Cathepsins play an important role in the degradation of host connective tissues, the generation of bioactive proteins and antigen processing. They have been implicated in osteoporosis, muscular dystrophy, rheumatoid arthritis, bronchitis, emphysema, viral infection, cancer metastasis and neurodegenerative diseases, such as Alzheimer’s disease and Huntington’s disease. Recently, increased interest in cathepsin inhibitors has been generated with potential therapeutic targets, such as cathepsin K or cathepsin L for osteoporosis and cathepsin S for immune modulation. Of the 53 patents assessed in this review, granted between March 1998 and February 2001, there were 40 patents related to cysteine proteinase inhibitors, 7 related to aspartic proteinase inhibitors and 6 related to serine proteinase inhibitors. Of the 40 patents, 14 disclosed the novel compounds that were more selective against cathepsin K or cathepsin S than cathepsin B and cathepsin L. The compounds, showing experimental evidences, were evaluated and their biological activities in animal models determined. However, only 4 patents presented significant results in vivo. These patents may be a basis for promoting further evaluation and developing second generation cathepsin inhibitors.     

Difluorotetrahydropyridothiazinone: a selective β-galactosidase inhibitor

Selective difluorination, introducing a lactame moiety (instead of an amine) and a double bond in a trihydroxy-2-thiaquinolizidine derivative reverses the selectivity of the glycosidase inhibitor - a selective inhibitor for an α-glucosidase is altered into an excellent, competitive inhibitor for a β-galactosidase.     

Respivert’s multikinase inhibitors,an evaluation of WO2014033446 to WO2014033449

These four patent applications all claim that N-aryl-N′-pyrazol-5-yl urea derivatives , related to RV-568, which are inhibitors of p38, Syk and Src kinases. All four applications claim their use in the treatment of inflammatory diseases, notably asthma and chronic obstructive pulmonary disease. The four applications are primarily differentiated by the claimed substitution of the pyrazole ring. This is accompanied by differential kinase specificity profiles. Many of the exemplified compounds show reduced potency as p38 inhibitors but high potency as inhibitors of Syk and/or Src kinases.     

糖尿病并发症的药物治疗

糖尿病并发症对人类健康造成极大危害，针对各种糖尿病并发症的病因开发其治疗药物已成为人们关注的热点，并取得可喜进展。本文分类概述糖尿病并发症治疗药物的作用机制、临床应用及疗效研究，其药物包括醛糖还原酶抑制剂、糖基化终产物抑制剂、抗氧剂以及血管紧张素转换酶抑制剂。