IDEC-114 (IDEC)

IDEC is developing a PRIMATIZED-anti-B7 antibody (IDEC-114) for the treatment of autoimmune and inflammatory diseases, such as psoriasis and rheumatoid arthritis. It is currently undergoing phase II trials in patients with psoriasis [395813]. A randomized, blind, placebo-controlled, multiple-dose phase II study was initiated in January 2001 to evaluate the potential clinical activity and safety of IDEC-114 in patients with moderate-to-severe psoriasis [395813]. The antibody targets the B7 antigen on the surface of antigen-presenting cells that normally interact with T-cells to initiate an immune response. Antibodies directed at B7 may be useful in preventing unwanted immune responses in autoimmune diseases such as systemic lupus erythematosus, idiopathic thrombocytopenic purpura as well as transplant rejection [178382], [178929]. PRIMATIZED antibodies, genetically engineered from cynomolgus macaque monkey and human components, are structurally indistinguishable from human antibodies. They may, therefore, be less likely to cause adverse reactions in humans, making them potentially suited for long-term, chronic treatment [244805]. IDEC has signed an antibody humanization patent licensing agreement with Protein Design Labs [240591]. IDEC is also collaborating with Mitsubishi-Tokyo (formerly Mitsubishi Kasei) on the development of this antibody [178382].     

Linear TMC-95-based proteasome inhibitors

We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki approximately 300 nM) despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.     

114例神经系统不良反应报告分析

目的分析药品不良反应(ADR)发生的规律及特点,为临床合理用药及药物安全性评价提供依据。方法对我院2007年收集的114例神经系统ADR报告进行分析。结果114例神经系统不良反应涉及13类药物,52个品种,抗感染药居首位(18例,占15.78%),其次是眼用药物(16例,占14.04%)和消化系统药物(13例,占11.41%)。静脉用药引发神经系统ADR最多(93例,占81.58%)。ADR均较轻,无严重不良反应发生,临床主要表现为手脚麻木、头痛、精神异常。结论临床应重视ADR的报告和监测工作,指导临床合理用药,以减少或避免ADR的发生。     

Darunavir (TMC114): a new HIV-1 protease inhibitor

Effective combination therapy for HIV/AIDS is now available and has made a major impact on HIV-related mortality and morbidity. The effects of even the most active of antiretroviral drugs are hampered by drug resistance and tolerability issues. Darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/r), is a new HIV-1 protease inhibitor that has been designed to be active against both wild-type and multi-resistant virus. Darunavir/r 600/100 mg b.i.d. in a combination antiretroviral regimen in the POWER trials has provided treatment-experienced patients with substantially greater virological and immunological benefits compared with standard of care. This article reviews the presently available data on darunavir, its pharmacology, pharmacokinetics, drug-drug interactions and clinical trial results, as well as examining darunavir from a health economic perspective.     

Darunavir (TMC114): a new HIV-1 protease inhibitor

Effective combination therapy for HIV/AIDS is now available and has made a major impact on HIV-related mortality and morbidity. The effects of even the most active of antiretroviral drugs are hampered by drug resistance and tolerability issues. Darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/r), is a new HIV-1 protease inhibitor that has been designed to be active against both wild-type and multi-resistant virus. Darunavir/r 600/100 mg b.i.d. in a combination antiretroviral regimen in the POWER trials has provided treatment-experienced patients with substantially greater virological and immunological benefits compared with standard of care. This article reviews the presently available data on darunavir, its pharmacology, pharmacokinetics, drug–drug interactions and clinical trial results, as well as examining darunavir from a health economic perspective.     

关于执行“食药监安函[2004]114号文件“的反思

2004年,国家药品认证管理中心按照SFDA安全监管司的工作部署,启动了药物临床试验机构资格认定的现场检查工作。同年8月13日,安全监管司下发食药监安函【2004】114号文件(以下简称114号文件),要求在申请药物临床试验机构资格认定中的I期药物临床试验研究机构执行。管理部门做出这种决定,目的是确保I期药物临床试验研究数据真实、完整、精确。但是,由于我们向申请I期药物临床试验的医疗单位宣传力度不够,导致文件规定的执行极不通畅。1贯彻114号文件程序不明了从该文发布至今,全国已经通过资格认定现场检查的I期临床试验研究室共119家;已…     

19-Deformyl-4'-deoxydesmycosin (TMC-016): synthesis and biological properties of a unique 16-membered macrolide antibiotic

19-Deformyl-4'-deoxydesmycosin was synthesized by the following synthetic route: 19-Deformylation of desmycosin, 3,2',4'-tri-O-trimethylsilylation, 4'-O-sulfonylation, 4'-iodination, reductive deiodination and 3,2',4'-tri-O-detrimethylsilylation. Deformylation of the aldehyde group at the C-19 position was achieved by two different methods: A) A simple one-step deformylation using Wilkinson's catalyst ((Ph3P)3RhCl). B) Reductive decarboxylation of the 19-carboxyl derivative following NaClO2 oxidation of the aldehyde. 19-Deformyl-4'-deoxydesmycosin showed very strong antimicrobial activity in vitro and in vivo.     

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M

The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.     

环肽类蛋白酶体抑制剂TMC-95的研究进展

环肽类化合物TMC-95是以蛋白酶体为靶点的新型抗肿瘤先导化合物,目前受到越来越多药物化学家的关注.本文通过收集近年来国内外的相关文献对环肽类蛋白酶体抑制剂TMC-95的作用机制、构效关系等方面研究进行综述,为进一步研究此类化合物提供参考.     

TMC-171A,B,C and TMC-154, novel polyketide antibiotics produced by Gliocladium sp. TC 1304 and TC 1282

Four new antibiotics, TMC-171A (2), B (3), C (4) and TMC-154 (5) have been isolated from the fermentation of fungal strains Gliocladium sp. TC 1304 and TC 1282, respectively. Spectroscopic and degradation studies have shown that TMC-171s and TMC-154 were new members of the TMC-151 class of antibiotics, unique polyketides modified with a D-mannose and a D-mannitol or a D-arabitol. These compounds showed moderate cytotoxicity to various tumor cell lines.     

Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers

BACKGROUND AND OBJECTIVE: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIV-negative, healthy volunteers. METHODS: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout. RESULTS: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens. CONCLUSION: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.     

A phase II study of Irofulven (MGI 114) in patients with stage IV melanoma

Sixteen patients with stage IV melanoma,who were heavily pretreated, received11 mg/m²/day of intravenous Irofulvenfor five consecutive days every 28 days.There were no objective tumor responses,although one patient exhibited stabledisease after 4 cycles. The most commontoxicities were grade 1/2 nausea, vomiting,fatigue, anemia, and thrombocytopenia. Onepatient required a dose reduction for anelevated creatinine while another patientrequired cessation of treatment because ofacute ataxia that may have been related toIrofulven. Based upon these data, Irofulvendoes not demonstrate significant antitumoractivity to warrant further investigationin advanced melanoma.     

Enhancement of antitumor activity of OK-432 (picibanil) by Triton X-114 phase partitioning

OK-432 (Picibanil), a Streptococcal immunotherapeutic agent, has been used for immunotherapy of various cancers as a biological response modifier (BRM). However, OK-432 contains multiple components consisting of immunotherapeutic ones and contaminants which may weaken the effects or exert side-effects. In this study, we investigated extraction of contaminants from OK-432 using Triton X-114 (TX-114)-water phase partitioning and examined an antitumor effect of the resulting preparation. OK-432 was subjected to TX-114 partitioning to give residual precipitate designated as OK-TX-ppt. OK-TX-ppt exerted no TLR2-mediated activity, but induced interleukin (IL)-6 in human PBMC. OK-TX-ppt also induced tumor necrosis factor (TNF)-alpha, IL-10, IL-12, and interferon (IFN)-gamma in PBMC. Moreover, IFN-gamma-inducing activity of OK-TX-ppt was significantly higher and IL-10 production was lower than that of OK-432. In tumor-bearing mice model, administration of OK-TX-ppt i.p. extended the survival time of Meth-A-bearing mice compared to OK-432. OK-TX-ppt also increased the levels of IL-12 and IFN-gamma in mouse spleen cells in vitro. These results indicated that TX-114 partitioning removed some contaminants, which attenuates the antitumor effect, from OK-432 and increase the immunotherapeutic effects of OK-432.     

抗肺结核的ATP合成酶抑制剂TMC-207

肺结核（TB）为严重威胁人类健康的主要传染性疾病之一,由于耐药结核分枝杆菌的不断出现,合并HIV感染造成的治疗障碍以及目前治疗方案实施的繁杂等,该病尚未得到有效控制,亟待研发出新的、作用迅速且有效的药物,以缩短治疗TB的疗程并简化其治疗方案。强生公司的子公司Tibotec公司开发了一种具有独特作用机制的新型二芳基喹啉化合物TMC-207（R-207910）,     

Efficacy of MGI 114 (HMAF) against the MRP+ metastatic MV522 lung carcinoma xenograft

This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agents. MGI 114 is a novel semisynthetic anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human MDR1/gp170+ solid tumor xenografts. Recent evidence suggests overexpression of the MRP protein may also be clinically relevant to development of drug resistance in solid tumors. We evaluated the efficacy of MGI 114 against a human MRP+ lung carcinoma xenograft. Parent MV522 lung carcinoma cells were transfected with a MRP cDNA expression vector and resistant cells selected by exposure to vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP mRNA and MRP protein. Administration of MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x/week for 3 weeks) to MRP tumor-bearing mice demonstrated this novel agent was active against MRP+ tumors and significantly extended their lifespan (p<0.001). In contrast, other cytotoxic agents had minimal activity against this MRP+ xenograft. These results indicate MGI 114 should retain activity in vivo against MRP+ tumor types. The development of this MRP+ xenograft model, in conjunction with the parent MV522 and MDR1/gp170+ xenograft models, will be useful for screening new classes of agents for activity against multidrug-resistant tumors.