地拉韦啶原料药及其分散片的应用研究
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摘要
本课题首先测定了抗艾滋病新药地拉韦啶的pKa值及分配系数,并采用X-射线粉末衍射等技术进行了多晶型的鉴别,研究了不同条件下晶型的转变,测定了高温等影响因素对多晶型的影响,为进一步研究奠定了基础。按照国家化药3类新药的报批要求,首先对已经合成出的地拉韦啶原料进行了系统的质量研究,建立了其质量标准(草案)。对其进行了新剂型的研究,通过正交设计法进行处方的优化,制备了地拉韦啶分散片,并通过一系列的质量研究,建立了地拉韦啶分散片的质量标准(草案)。对原料药及其制剂进行了初步稳定性考察,并按照化药3类新药要求形成了申报材料,已报国家食品药品监督管理局审批。将具有免疫调节等多种药理作用的白藜芦醇分子连接到抗HIV的地拉韦啶中间体上,期望合成抗HIV-1变异性更强、具有自主知识产权的抗艾滋病新药,并进行了体外活性的初步研究。体外活性测定结果表明,地拉韦啶衍生物可抑制HIV-1逆转录酶的转录,EC50为4.54μM,对感染细胞的抑制率达95%。
原料药及其制剂的各项研究结果,为该药的临床前研究提供了可靠的理论依据。合成的新型抗HIV药物为艾滋病的治疗提供了新的研究思路,其研究结果为其进一步研究开发奠定了理论基础。
AIDS is an acquired human immunedeficiency syndrome, which is caused by retrovirus HIV. Since the first AIDS sufferer was reported in 1981, 70 million pepole have been infected with HIV in the world and 20 million of them died fom AIDS. AIDS has become one of main menaces to human health. Generally speaking, AIDS is serious infection disease which can destroy human immunity system, cause human body to lose resistent ability against all kinds of pathogeny, then result in various infections or tumours and finally lead human to death. HIV bring out different degree resistance to drugs applied in HIV treatment beause of HIV uninterrupt mutation. Though death rate of AIDS have descended after applying potent anti-AIDS drugs, the sum of global AIDS patients still rise with tendency of index number. It will provide a novel idea for AIDS treatment if a new drug with the antivirus activity and the ability to proving human immunity be developed.
At present, AIDS has been spreaded in China. The patients infected with HIV have been found in 31 provinces, autonomous region and municipality directly under the Central Government. Ministry of Public Health, the United Nations AIDS project office and World Health Organization together proclaimed that there were 700 thousand AIDS viral infection persons and AIDS patients of which 85 thousand AIDS patients inChina by the end of 2007. Relevant expert analyze that there will be one million AIDS viral infection person by the end of 2010 in China if no effective steps were taken. Though the price of imported anti-HIV drugs has been decreased recently, it’s impossible to afford for the AIDS patients who live in the region of poor economy and bad medical condition.It’s necessary that we should produce the anti-AIDS drugs with definite therapeutic effect and reasonable price. The expense of drugs will descreased from eighty thousand to 4～5 thousand after they buy the anti-AIDS drugs produced in China. We should accelerate to develope a anti-AIDS drugs possessing autonomic and intellectual property rights when we replicate the anti-AIDS drugs that won’t be about to be protected in order to cut down the drug expense.
Delavirdine mesylate would have a potent antiviral effect when it coadministrated with nucleoside reverse transcriptase such as zidovudine or with ptotein inhibitors. So far, Delavirdine mesylate haven’t been reported and produced in China. So it will bring economic and social significance if delavirdine mesylate is manufactured.
For all the above reasons, the experiment was arranged as the following: fistly, The dissociation constant and partition coefficient were determined and polymorphism was identified, which establish a base advanced study. Secondly, the quality control of dalavirdine mesylate and its preparation were investigated. The corresponding quality criteria was established according to the investigated results of quality control. Thirdly, the study of primary stability was carried out. All the data were summed up based on the request of SFDA and send to SFDA. Natural compound possessing immunomodulation effect was linked to anti-HIV drug in order to synthesize a novel anti-AIDS drug possessing potent anti-HIV-1 variability and the ability of aelevating the immunity.
The dissociation constant was determined with acid-base titration method and the partition coefficient was determined with bottle-shaking method by HPIC. The pKa and P of mesylate delavirdine in n-octyl alcohol were 4.635 and 2.907 respectively. Polymorphism of Delavirdine mesylate was identified by the techniques such as X-ray power diffraction. Polymorphism transition and the factors affecting the polymorphism stability were investigated. All the above results provide certain foundation of advanced study.
Delavirdine mesylate was identified indluding the methods such as physical and chemical property, infrared spectra and HPLC. The content and relative substance was determined by HPLC. The organic solvent from delvirdine mesylate was investigated by GC. Moreover, loss of drying, arsenicum and heavy metals were investigated. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate.
The stability to the three batches of delavirdine mesylate was carried out on the basis of its quality criteria. The results indicated that characters, discriminations, contents, relative substances and the hygiology index of delavirdine mesylate had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of raw drug meet the new medicine requirement under the condition of indoor temperature.
The orthogonal design was applied to optimize formulation with disintegrated time and dissolution rates in vitro as consideration index. The dissolution rates in vitro, disintegration time and dispersion uniformity were determined. The content and relative substance was determined by HPLC. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate dispersible tablets. Its quality reached the standard of Chp.2000 and the dissolution rate in vitro was faster than marketed tablet.
The stability to the three batches of delavirdine mesylatediset dispersible tablets was carried on the basis of its quality criteria. The results indicated that characters, discriminations, water content, disintegrated time, dissolution rates, contents, relative substances and the hygiology index in delavirdine mesylate dispersible tablets had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of dispersible tablets meet the new medicine requirement. under the condition of indoor temperature.
According to principle of hybridization, a natural immunocompetent compound resveratrol (trans -3, 4, 5’-trihydrolystilbene) and analogue delavirdine(1-[3-[(1-methylethyl)amino]-2-pyridinyl]-4[(5-amino-1H-indol-2-yl)-carbonyl]-piperazine) were linked wtih different cyclic anhydrides as conjugated agent. The structur of main intermediates and target compound were confirmed by means of 1H NMR, 13C NMR, IR, MS and elemental analysis. For the quantification of the inhibitory effect in vitro of reverse transcriptase inhibitors, all steps of the HIV-1 Reverse Transcriptase(RT) Assay including the RT reaction, can be performed directly in the MP modules by supplied with the kit. EC50 of Resdelasu (the concentration of an inhibitor that is required for 50% inhibition) was 4.54μm and its inhibitory activity was concentration dependent(r = 0.941). The inhibition activity of delavirdine derivate was 95% .
The results of delavirdine mesylate and its disperble tablets can provide a reliable theory accordance for the advanced clinical investigation. Mesnwhile, a novel anti-HIV compound has been successfully synthesized according to principle of hybridization. It will provide a new direction to the research of new type of anti-HIV drugs.
原料药及其制剂的各项研究结果,为该药的临床前研究提供了可靠的理论依据。合成的新型抗HIV药物为艾滋病的治疗提供了新的研究思路,其研究结果为其进一步研究开发奠定了理论基础。
AIDS is an acquired human immunedeficiency syndrome, which is caused by retrovirus HIV. Since the first AIDS sufferer was reported in 1981, 70 million pepole have been infected with HIV in the world and 20 million of them died fom AIDS. AIDS has become one of main menaces to human health. Generally speaking, AIDS is serious infection disease which can destroy human immunity system, cause human body to lose resistent ability against all kinds of pathogeny, then result in various infections or tumours and finally lead human to death. HIV bring out different degree resistance to drugs applied in HIV treatment beause of HIV uninterrupt mutation. Though death rate of AIDS have descended after applying potent anti-AIDS drugs, the sum of global AIDS patients still rise with tendency of index number. It will provide a novel idea for AIDS treatment if a new drug with the antivirus activity and the ability to proving human immunity be developed.
At present, AIDS has been spreaded in China. The patients infected with HIV have been found in 31 provinces, autonomous region and municipality directly under the Central Government. Ministry of Public Health, the United Nations AIDS project office and World Health Organization together proclaimed that there were 700 thousand AIDS viral infection persons and AIDS patients of which 85 thousand AIDS patients inChina by the end of 2007. Relevant expert analyze that there will be one million AIDS viral infection person by the end of 2010 in China if no effective steps were taken. Though the price of imported anti-HIV drugs has been decreased recently, it’s impossible to afford for the AIDS patients who live in the region of poor economy and bad medical condition.It’s necessary that we should produce the anti-AIDS drugs with definite therapeutic effect and reasonable price. The expense of drugs will descreased from eighty thousand to 4～5 thousand after they buy the anti-AIDS drugs produced in China. We should accelerate to develope a anti-AIDS drugs possessing autonomic and intellectual property rights when we replicate the anti-AIDS drugs that won’t be about to be protected in order to cut down the drug expense.
Delavirdine mesylate would have a potent antiviral effect when it coadministrated with nucleoside reverse transcriptase such as zidovudine or with ptotein inhibitors. So far, Delavirdine mesylate haven’t been reported and produced in China. So it will bring economic and social significance if delavirdine mesylate is manufactured.
For all the above reasons, the experiment was arranged as the following: fistly, The dissociation constant and partition coefficient were determined and polymorphism was identified, which establish a base advanced study. Secondly, the quality control of dalavirdine mesylate and its preparation were investigated. The corresponding quality criteria was established according to the investigated results of quality control. Thirdly, the study of primary stability was carried out. All the data were summed up based on the request of SFDA and send to SFDA. Natural compound possessing immunomodulation effect was linked to anti-HIV drug in order to synthesize a novel anti-AIDS drug possessing potent anti-HIV-1 variability and the ability of aelevating the immunity.
The dissociation constant was determined with acid-base titration method and the partition coefficient was determined with bottle-shaking method by HPIC. The pKa and P of mesylate delavirdine in n-octyl alcohol were 4.635 and 2.907 respectively. Polymorphism of Delavirdine mesylate was identified by the techniques such as X-ray power diffraction. Polymorphism transition and the factors affecting the polymorphism stability were investigated. All the above results provide certain foundation of advanced study.
Delavirdine mesylate was identified indluding the methods such as physical and chemical property, infrared spectra and HPLC. The content and relative substance was determined by HPLC. The organic solvent from delvirdine mesylate was investigated by GC. Moreover, loss of drying, arsenicum and heavy metals were investigated. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate.
The stability to the three batches of delavirdine mesylate was carried out on the basis of its quality criteria. The results indicated that characters, discriminations, contents, relative substances and the hygiology index of delavirdine mesylate had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of raw drug meet the new medicine requirement under the condition of indoor temperature.
The orthogonal design was applied to optimize formulation with disintegrated time and dissolution rates in vitro as consideration index. The dissolution rates in vitro, disintegration time and dispersion uniformity were determined. The content and relative substance was determined by HPLC. Quality criteria was formulated on the basis of the above results and it is suitable to control delavirdine mesylate dispersible tablets. Its quality reached the standard of Chp.2000 and the dissolution rate in vitro was faster than marketed tablet.
The stability to the three batches of delavirdine mesylatediset dispersible tablets was carried on the basis of its quality criteria. The results indicated that characters, discriminations, water content, disintegrated time, dissolution rates, contents, relative substances and the hygiology index in delavirdine mesylate dispersible tablets had no obvious variety and can meet various regulation of the standard drafted plan of quantity, which prove that the stability of dispersible tablets meet the new medicine requirement. under the condition of indoor temperature.
According to principle of hybridization, a natural immunocompetent compound resveratrol (trans -3, 4, 5’-trihydrolystilbene) and analogue delavirdine(1-[3-[(1-methylethyl)amino]-2-pyridinyl]-4[(5-amino-1H-indol-2-yl)-carbonyl]-piperazine) were linked wtih different cyclic anhydrides as conjugated agent. The structur of main intermediates and target compound were confirmed by means of 1H NMR, 13C NMR, IR, MS and elemental analysis. For the quantification of the inhibitory effect in vitro of reverse transcriptase inhibitors, all steps of the HIV-1 Reverse Transcriptase(RT) Assay including the RT reaction, can be performed directly in the MP modules by supplied with the kit. EC50 of Resdelasu (the concentration of an inhibitor that is required for 50% inhibition) was 4.54μm and its inhibitory activity was concentration dependent(r = 0.941). The inhibition activity of delavirdine derivate was 95% .
The results of delavirdine mesylate and its disperble tablets can provide a reliable theory accordance for the advanced clinical investigation. Mesnwhile, a novel anti-HIV compound has been successfully synthesized according to principle of hybridization. It will provide a new direction to the research of new type of anti-HIV drugs.
引文
[1] 汪华等著.艾滋病防治实用手册[M].上海:科学技术文献出版社,2004:5.
[2] Gottlieb MS, Schroff R, Scanker HM, et al. Pneumocystis Carinii Pneumonia and Mucosal Candidiasis in Previously Helthy Homosexual Men[J]. N Engl J Med, 1981, 305: 1425-1431.
[3] Fauci AS. The human immunodeficiency virus infectivity and mechanisms of pathogenesis[J]. Science, 1988, 239(4840): 617-622.
[4] Barré-Sinoussi F, Chermann JC, Rey M, et al.Isolation of a T-Lymph- -otropic Retrovirus from a Patient at Risk for Acquired Immunodeficiency Syndrom(AIDS)[J]. Science, 1983, 220: 868-871.
[5] Gallo RC, Salahuddin SZ, Popovic M, et al.Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients With AIDS and at Risk for AIDS[J]. Science, 1984, 224: 500-503.
[6] Levy JA, Hoffman AD, Kramer SM, et al . Isolation of Lymphocytopathic Retroviruses from San Francisco Patients with AIDS[J]. Science, 1984, 225: 840-842.
[7] Brun Vezinet F, Rouzioux C, Barre Sinoussi F, et al. Detection of IgG Antibodies to Lymphadenopathy Associated Virus in Patients with AIDS or Lymphadenopathy Syndrome[J]. Lancet, 1984, 1: 1253-1256.
[8] Clavel F, Guétard D, Brun-Vézinet F, et al. Isolation of a New Human Retrovirus from West African Patients With AIDS[J]. Science, 1986, 233: 343-346.
[9] 傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007,31(5):211-216.
[10] http://blog.163.com/ufo541873374@126/blog/static/4374277820071 11113845504/
[11] 张淑玲,罗端德.艾滋病抗病毒药物的研究进展[J]. 国际流行病学传染病学杂志. 2006,33(1):45-47.
[12] Shuzo Matsushita. Current status and future issues in the treatment of HIV-1 infection[J]. Int J Hematol, 2000, 72: 20-27.
[13] Erik DC. Review: New developments in anti-HIV chemotherapy[J]. Biochemica et Biophysica Acta(BBA), 2002, 1587(2-3): 258-275.
[14] 貌盼勇,洪世雯.HIV的感染[M].周先志,赵敏.艾滋病诊疗新技术.北京:人民军医出版社,2005:21-23.
[15] 张淑玲,罗端德.艾滋病的发病机制和病理改变[J].新医学,2006,37(1):11-13.
[16] Blower SM, Gershengorn HB, Gramt RM. A tale of two future: HIV and antiretroviral therapy in San Francisco[J]. Science, 2000, 287 (5453): 650-654.
[17] Blundell T, Pearl L. A second front against AIDS[J]. Nature, 1989, 337(6027/6029): 596-598.
[18] 韩 冰,杨峻山.淫羊藿药理作用研究概况[J].中草药,2000,31(11):873-875.
[19] 琦祖和,蒋效松,杨显荣,等.天花粉蛋白质与苦瓜子蛋白质改变DNA构型的活性[J].中草药,l999,30(11):807-810.
[20] 刘因华,曹志红.抗艾滋病药物的发展近况[J].云南中医中药杂志,2004,25(6):44-45.
[21] Shirataki Y, Motohashi N, Tani S, et a1. In vitro biological activity of Prenyl flavanones[J].Anticancer Res, 2001, 21: 275-280.
[22] 魏文青,卢洁.王明霞.抗艾滋病药物的研究进展[J].国外医学药学分册,2001,28(5):294-297.
[23] 吕维柏.中医药治疗艾滋病的最新进展和对策[J].河南中医学院学报,2004,19(2):l11-115.
[24] 李春凤.抗艾滋病药物研究进展[J].中国药师,2006,9(7):661-663.
[25] Schaeffer DJ, Krylov VS. Anti-HIV activity of extracts and compounds from algae and cyanobacterial[J]. Ecotoxicol Environ Saf, 2000, 45(3): 208-227.
[26] 刘学铭,梁世华.小球藻的保健和药理作用[J].中草药,1999,30(5):383-384.
[27] 杨文雄,康来仪,潘孝彰,等.XQ-9302中药制剂对艾滋病疗效的初步研究[J].上海中医药杂志,1999,1:4-8.
[28] 江明性.新编实用药物学[M].北京:科学出版社,2000:601- 610.
[29] Harris M, Montaner JSG. Clinical uses of non-nucleoside reverse transcriptase inhibitors[J]. Rev Med Virol, 2000, 10: 217-229.
[30] Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non- nucleoside reverse transcriptase inhibitors[J]. Clin Pharmacokinet, 2001, 40(12): 893-905.
[31] De Clercq E. Antiviral drugs: current state of art[J]. J Clin Virol, 2001, 22(1): 73-89.
[32] Aggarwal SK, Gogu SR, Rangan SR, et al. Synthsis and biological evalution of prodrug of zidovudine[J]. J Med Chem, 1990, 33(5): 1505-1510.
[33] 蒋为民,等著.艾滋病的抗病毒治疗进展[J].国外医学微生物分册,2000,23(1):215-219.
[34] Hrisch MS, Brun Vezinet F, D’Aquila RT, et, al. Antiretroviral drug resistance testing in adult HIV -1 infection: recommendations of an international AIDS Society-USA Panel[J]. J Am Med Assoc, 2000, 282(18): 2417-2426.
[35] Shellon MJ, O’Donnell AM, Morse GD. Didanosine[J]. Ann Pharmacother, 1992, 26(5): 660-670.
[36] Shellon MJ, O’Donnell AM, Morse GD. Zalcitabine[J]. Ann Pharmacother, 1993, 27(4): 480-489.
[37] Venkatachalam TK, Samuel P, Kourinov IV, et, al. Synthsis and anti-HIV activity of carbmates of antiviral agent stavudine[J]. Antivir Chem Chemother, 2002, 13(5): 289-297.
[38] Ohta Y, Shinka I. New drugs-reports of new drugs recently approved by the FDA, Lamivudine [J]. Bioorg Med Chem, 1997, 5(4): 639-640.
[39] 赵云利,宋礼华.抗病毒药物治疗艾滋病研究的探讨[J].河南中医学院学报,2006, 21(2):8-10.
[40] Henry K, Erice A, Tiemey C, et, al. A randomized, controlled, doublely-blined study comparing the survival benefit of four different reverse transcripatase inhibitors therapies(three-drug, two-drug and alternating drug) for the treatment of advanced AIDS Clinical Trial Group 193A Study Team[J]. J Acquit Immune Defic Syndr Hum Retrovivor, 1998, 19(4:) 339-349.
[41] Yarchoan R, Mitsuya H, Myers CE, et. al. Clinical pharmacology of 3’-azido-2’,3’–dideoxythymidine(zidovudine) and related dideoxy- -nucleosides[J]. N Engl J Med, 1989, 321: 726-738.
[42] Lambert JS, Seidlin RC, Reichman CS, et. al. 2’,3’–dideoxythymi- -dine(ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial[J]. N Engl J Med, 1990, 322: 1333-1340.
[43] Kellam, Boucher CAB, and Larder BA. Fifth mutation in a huaman immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine[J]. Proc Natl Acad Sci USA, 1992, 89: 1934-1938.
[44] Clair MHSt, Martin JL, Tudor-Willians D, et. al. Resistance to ddI and sensitivity to ZAT induced by a mutation in HIV-1 reverse transcriptase[J]. Science, 1991, 253: 1557-1559.
[45] 张宏梁,肖 宏.临床试验阶段的抗人免疫缺陷病毒化学药物研究进展[J].中国新药与临床杂志,2006,25(5):388-392.
[46] Sluis-Cremer N, Temiz NA, Bahar I. Conformational changes in HIV-l reverse transcriptase induced by nonucleoside reverse transcriptase inhibitor binding[J]. Curr HIV Res, 2004, 2(4): 323-332.
[47] Dueweke TJ, Kezdy, FJ, Waszak GA, et al. The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase[J]. J Biol Chem, 1992, 267: 27-30.
[48] Goldman ME, Numberg JH, O’Brein JA, et al. Pyridine derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity[J]. Proc Natl Acad Sci USA, 1991, 88: 6863-6867.
[49] Vasudevachari MB, Battista BC, Lane HC, et al. Prevention of the spread HIV-1 infection with nonnucleeoside everse transcriptase inhibitors acts through a nonsubstrate binding sites[J]. Biochemistry, 1991, 30: 2022-2026.
[50] Gadi B, Dominique A, Marka W, el a1. The thicarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of (AZT)againt AZT-resistant human immunodeficiency virus type 1[J]. Antimicrob Agent Chemother, 1999, 43(2): 259-263.
[51] Bryant M, German D, Smidt M, et. At. SC-52151, a novel inhibitor of huma n immunodeficiency virus protease[J]. J Antimicrob Agents Chemother, 1995, 39(10): 2229-2236.
[52] 刘新泳.抗艾滋病药物研究[M]. 北京:人民卫生出版社,2006:12.
[53] http://www.fda.gov/oashi/aids/virals.html
[54] Moyle GJ, Boosted. PIs: competition hots up[J]. AIDs, 2003, 13(9): 425-429.
[55] Walrmley S, Christian MD. The role of lopinavir/ritonavir(Kaletra)in the management of HIVinfected adults[J]. Exp Rev Anti Infect Ther, 2003, 1(3): 389-401.
[56] Skowron G, Leoung G, Hall DB, et. a1. Pharmacokinetic evaluation and short-term activity of stavudine, nevirapine, and nelfinavir therapy in HIV-l-infected adults[J]. J Acquir Immune Defic Syndr, 2004, 35(4): 351-358.
[57] Holland DT, DiFrancesco R, Stone J, et a1. Adult and pediatric AIDS clinical trials group pharmacology laboratory committees, pediatricAIDs clinical trials group. quality assurance program for clinical measurement of antiretrovirals: AIDS clinical trials group proficiency testing program for pediatric and adult pharmacology laboratories[J]. Antimicrob Agents Chemother , 2004, 48(3): 824-831.
[58] Musial BL, Chojnacki JK, Colemalrl CI. Atazanavir: a new protease inhibitor to treat HIV infection[J]. Am J Health Syst Pharm, 2004, 61(13): 1365-1374.
[59] Surleraux DL, Tahri A, Verschueren WG, et a1. Discovery and selection of TMCl14. a next generation HIV-l protease inhibitor[J]. J Med Chem, 2005, 48(6): l8l3-l822.
[60] 丁晓明,刘新泳.I型人免疫缺陷病毒蛋白酶抑制剂临床应用新进展[J].中国新药与临床杂志,2007,26(8):623-627.
[61] Molla A, Granneman GR, Sun E, et. al. Recent developments in HIV protease inhibitor therapy[J]. Antivir Res,1998, 39(1): 1-23.
[62] Yates PJ, Hazen R, st Clair M, et a1. In vitro development of resistance to human immunodeficiency virus protease inhibitor GW640385[J]. Antimierob Agents Chemother, 2006, 50(3): 1092-1095.
[63] Di Bello C, Pasquato A, Dettin M. Synthetic peptides for AIDs research[J]. Curr Protein Pept Sci, 2004, 5(4): 225-234.
[64] 张 鸽,范 明.抗HIV药物Maraviroc[J].药学进展,2006,30(7):333-334.
[65] 姜晓华,龙亚秋.结构多样的HIV-1整合酶抑制剂:过去、现在和未来[J].有机化学,2004,24(11):1380-1388.
[66] Reinke R, Lee DJ, Robinson WE Jr. Inhibition of hunmanimmunodeficiency virus type l isolates by the integrase inhibitor L-731 988, a diketo Acid[J]. Antimicrob Agents Chemother, 2002, 46(10): 3301-3303.
[67] Hazucla DJ, Felock P, Witmer M, et a1. Inhibitor of strand transfer that prevent integration and inhibit HIV-1 replication in cells[J]. Science, 2000, 287(5453): 646-650.
[68] Goebel FD, Hemmer R, Schmtt JC, et a1. Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretmviral therapy[J]. AIDS, 200l, 15(1): 33-45.
[69] Ahlers JD, Belyakov IM. Cytokine, chemokine and costimulatory molecule modulation to enhance efficacy of HIV vaccines [J]. Curr Mol Med, 2003, 3(3): 285-30l.
[70] Bachmann MF, Dyer MR. Therapeutic vaccination for chronic disease: a new class of drugs in sight[J]. Nat Rev Drug Discov, 2004, 3(1): 81-88.
[71] Rescriptor Product Information. Pharmacia & Upjohn Company, Kalamazoo, Mich, 1997.
[72] Dueweke TJ, Poppe SM, Romero DL, et al. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication[J]. Antimicro Agents Chemother, 1993, 37: 1127-1131.
[73] Davey RTJr., Chaitt DG., Reed GF., et al. Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in immunodeficiency virus type 1-infected patients[J]. Antimicrob Agents Chemother, 1996, 40(7):1657-1664.
[74] Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor[J]. Adv Exp Med Biol, 1996, 394: 279-3289.
[75] Cheng CL, Smith DE, Carver PL, et al.Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test[J]. Clin Pharmacol Ther. 1997, 61(5): 531-543.
[76] Morse GD, Fischl MA, Shelton MJ, et al. Effect of food on the steady-state pharmacokinetics of delavirdine in patients with HIV infection[J]. Clin Drug Invest, 2003, 23(4): 255-261.
[77] Tran JQ, Gerber JG., Kerr BM. Delavirdine: clinical pharmacokineti- -cs and drug interactions[J]. Clin-Pharmacokinet. 2001, 40(3): 207-226.
[78] Scott LJ, Perry CM. Delavirdine: a review of its use in HIV infection[J]. Drugs, 2000, 60(6): 1411-44.
[79] Morse GD, Fischl MA, Shelton MJ, et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection[J]. Antimicrob Agents Chemother, 1997, 41(1) : 169-174.
[80] Chang M, Sood VK, Wilson GJ, et al. Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats[J]. Drug Metab Dispos. 1997 , 25(2): 228-242.
[81] Voorman RL, Payne NA, Wienkers LC, et al. Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6[J]. Drug MetabDispos, 2001, 29(1): 41-47.
[82] Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-l reverse transcriptase inhibitor[M]. In: Mills J, VolberdingPA, Corey L, eds. Antiviral Chemotherapy. Vo1 4. New York: Plenum Press; 1996: 279-289.
[83] Tran JQ, Petersen C, Garrett M, et al. Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir[J]. Clin Pharmacol Ther, 2002, 72(6): 615-626.
[84] Demer LM, Shafer RW, Para M, et al. Delaviedine (DLV) susceptibility of HIV-1 isolates obtained from patients (PTS) receiving DLV monotherapy (ACTG 260)[E]. The 4th International Workshop on HIV Drug-Resitance. Sardinia, Italy, 6-9 July, 1995: Abstract 23.
[85] Chong KT , Pagano PJ, Hinshaw RR. Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3'-azido-3'-deoxythy- -midine or 2', 3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro [J]. Antimicrob Agents Chemother, 1994, 38(2): 288-293.
[86] Romero DL, Morge RA, Genin MJ, et al. Bis(heteroaryl) piperazines(BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indol analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl) carbonyl]-4-[3-[(1-methylethyl)amino)]-2-pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidates[J]. J Med Chem, 1993, 36: 1505-1508.
[87] Romero DL., Morge RA., Biles C., et al. Discovery, Synthesis and Bioactivity of Bis(heteroaryl) piperazines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors[J]. J Med Chem, 1994, 37: 999-1014.
[88] Romero DL, Olmstd RA, Poel TJ, et al. Targeting Delavirdine /Alavirdine Resistant HIV-1: Idetification of (Alkylamino) Piperidine-Containing Bis (heteroaryl) Piperazines as Broad Spectum HIV-1 Reverse Transcriptase Inhibitors[J]. J Med Chem, 1996, 39: 3769-3789.
[89] Pinna GA, Loriga G., Murineddu G., et al. Synthesis and Anti-HIV-1 Activity of New Delavirdine Analogues Carrying Arylpyrrole Moieties[J]. Chem Pharm Bull,2001, 49(11): 1406-1411.
[90] Romero DL. Delavirdine Mesylate[J]. Drugs Future, 1994, 19(3): 238-242.
[91] Perrauh WR, Shephard KP, Lapean LA, et a1. Production Scale Synthesis of the Non-nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate(U-87201E)[J]. Organic Process Research & Development, 1997, 1(2): 106-l16.
[92] 宁兆伦,燕方龙,贺丽鹏,王恩思,等.新型抗艾滋病药物地拉韦啶的合成[J].吉林大学学报(理学版),2006,44(1):118-122.
[93] Bi YX, Sunada H, Yonezawa Y, et al. Prepartion and evalution of a compressed tablets rapidly disintegrating in the oral cavity [J]. Chem Pharm Bull, 1996, 44(11): 2121-2128.
[94] Li QC, Kenneth AC, Zhuang G. A Capillary gas chromatographyic proceduce for the analysis of nine common residual solvents in water insoluble bulk pharmaceuticals [J ]. J Chromatogr Sci , 1998, 36 (5)∶119-124.
[95] 丁野,雷玉萍. 毛细管气相色谱法测定头孢米诺钠中几种有机溶剂残留量[J]. 中国新药杂志,2005,14(9):1169-1171.
[96] Watanabe, Y, Koizumi, K, Zama, Y, et al. New compressed tablet rapidly disintegrating in saliva in the mouth using crystalline cellulose and a disintegrant[J]. Biol. Pharm. Bull. 1995, 18: 1308–1310.
[97] Chang RK, Guo X, Burnside BA, et al. Fast-dissolving tablets[J]. Pharm. Technol. Eur, 2000, 12 (6): 52–58.
[98] Dobetti L. Fast-melting tablets: developments and technologies[J]. Pharm Technol Eur, 2000, 12 (9): 32–42.
[99] Bi Y, Sunada H, Yonezawa Y, et. al. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity[J]. Chem Pharm Bull, 1996, 44: 2121–2127.
[100] Bi Y, Sunada H, Yonezawa Y, et al. Evaluation of rapidly disintegrating tablets prepared by a direct compression method[J]. Drug Dev Ind Pharm, 1999, 25: 571–581.
[101] Kremzar L, Mohar M, Fercej-Temeljotov D, et al. Formulation of dispersible nabumetone tablets[J]. Acta Pharm Zagreb, 1998, 48 (3): 187–192.
[102] Martin TP, Hayes P, Collins DM. Tablet dispersion as an alternative to formulation of oral liquid dosage forms[J]. Aust J Hosp Pharm 1993, 23: 378–381.
[103] 黄胜炎.分散片进展[J].中国药学杂志,1992,27(4):226-228.
[104] 王玉玲.分散片中的崩解剂[J]. 食品与药品,2005,7(3):51-52.
[105] 沈岚,林晓,冯怡,等.分散片的研究进展[J].中成药,2004,26(2):145-158.
[106] 彭礼明.分散片处方、工艺特点及其进展[J].药品评价,2005,2(3):230-233.
[107] Bi YX, Sunada H, Yonezawa Y, et al. Prepartion and evalution of a compressed tablets rapidly disintegrating in the oral cavity [J]. Chem Pharm Bull, 1996, 44(11): 2121-2127.
[108] Watanabe Y, Koizumi K, Zama Y, et a1. New Compressed tablet disintegrating in saliva in the mouth using Crystalline cellulose and a disintegrant[J]. Biol Pharm Bull 1995, 18(9): 1308-1314.
[109] 上海医药工业研究院制剂研究室.药用辅料应用技术[M].北京:中国医药科技出版社,l991.
[110] 方小玲,杨敏,穆尼拉,等.几种新型辅料在速释片剂中的应用[J].中国医药工业杂志,2000,31(6):257-259.
[111] Bolhuis GK, Zurman K, Wierik GHP. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant 2. The choice of super disintegrants and effect of granulation[J]. Eur J Pharm Sci, 1997, 5(2): 63-69.
[112] 陈燕军,臧琛,赵小妹等. 几种常用填充剂与崩解剂在中药分散片应用中的性能比较[J]. 中国中药杂志,2002,27(8):580-583.
[113] Shimizu T, NakanoY, Morimoto S, et a1. Formulation study for lansoprazole fast disintegrating tablet.Effect of compression on dissolution behavior[J]. Chem Pharm Bull, 2003, 51(8): 942-947.
[114] 崔福德.药剂学[M].北京:人民卫生出版社,2003:330-332.
[115] Clercq ED. Antiviral drugs: current state of the art[J]. Journal of Clinical Virology. 2001, 22 : 73–89.
[116] 索绪斌,邓英杰,郝爱军等.月桂酰吲达帕胺的解离常数及分配 系数的测定[J].沈阳药科大学学报,2005,22(5):335-337.
[117] Benet LZ, Goyan JE. Nonlogarithmic titration curves for the determination of dissociation constants and purity[J]. J Pharm Sci, 1965, 54(8): 1179-1182.
[118] 倪维骅.药物多晶型的研究方法[J].医药工业,1981,9(1):33-39.
[119] Bergren M S,Chao R S,Meulman P A,et a1.Solid Phase of Delavirdine Mesylate[J].J Pharm Sci,1996,85(8):834-841.
[120] Sarver R W,Meulman P A,Bowerman D K,et a1.Factor Analysis of Infrared Spectra for Solid-state Forms of Delavirdine Mesylate [J].International Journal of Pharmaceutics. 1998,167:105-120.
[121] 常俊标.艾滋病的分子生物学及治疗[M].北京:科学出版社,22001: 44-45.
[122] 仇缀百.药物设计学[M].北京:高等教育出版社,1999:88.
[123] 白杨,潘隽丽,苏薇薇.白藜芦醇与白藜芦醇苷的研究进展[J].中药材,2004,27(1):55-59.
[124] 王世盛,赵伟杰,刘志广.天然多羟基芪化合物的生物活性[J].国外医药·植物药分册,2001,16(1):9-11.
[125] 高路,袁育康,吕卓人,等.白藜芦醇的免疫调节作用[J].西安交通大学学报(医学版),2003,24(2):121-123.
[126] 于良,吴胜利,张梅,等.白藜芦醇及环保菌素A联用对人体周血T细胞免疫功能的影响[J].细胞与分子免疫学杂志,2003,19(6):549-551.
[127] 贺丽鹏.吉林大学硕士学位论文.
[128] Kimpton J﹠Emerman M. Detection of replicatoion-competent and pseudotype human immunodeficiency virus with a sensitive cell line on the basis of activitation of an integrated beta-galactosidase gene[J]. J. Virl,1992, 66:2232-2239.
[129] Deibel MR, McQuade TJ, Brunner DP, et al. Denaturation/refolding of purified recombinant HIV reverse transcriptase yields monomeric enzyme with high enzymatic activity[J]. AIDS Res Hum Retroviruses, 1990, 6: 329-340.
[130] Romero DL, Busso M, Tan CK, et al. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication[J]. Proc. Natl Acad Sci USA, 1991, 88: 8806-8810.
[2] Gottlieb MS, Schroff R, Scanker HM, et al. Pneumocystis Carinii Pneumonia and Mucosal Candidiasis in Previously Helthy Homosexual Men[J]. N Engl J Med, 1981, 305: 1425-1431.
[3] Fauci AS. The human immunodeficiency virus infectivity and mechanisms of pathogenesis[J]. Science, 1988, 239(4840): 617-622.
[4] Barré-Sinoussi F, Chermann JC, Rey M, et al.Isolation of a T-Lymph- -otropic Retrovirus from a Patient at Risk for Acquired Immunodeficiency Syndrom(AIDS)[J]. Science, 1983, 220: 868-871.
[5] Gallo RC, Salahuddin SZ, Popovic M, et al.Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients With AIDS and at Risk for AIDS[J]. Science, 1984, 224: 500-503.
[6] Levy JA, Hoffman AD, Kramer SM, et al . Isolation of Lymphocytopathic Retroviruses from San Francisco Patients with AIDS[J]. Science, 1984, 225: 840-842.
[7] Brun Vezinet F, Rouzioux C, Barre Sinoussi F, et al. Detection of IgG Antibodies to Lymphadenopathy Associated Virus in Patients with AIDS or Lymphadenopathy Syndrome[J]. Lancet, 1984, 1: 1253-1256.
[8] Clavel F, Guétard D, Brun-Vézinet F, et al. Isolation of a New Human Retrovirus from West African Patients With AIDS[J]. Science, 1986, 233: 343-346.
[9] 傅婷婷,倪孟祥.核苷类抗艾滋病药物研发近况[J].药学进展,2007,31(5):211-216.
[10] http://blog.163.com/ufo541873374@126/blog/static/4374277820071 11113845504/
[11] 张淑玲,罗端德.艾滋病抗病毒药物的研究进展[J]. 国际流行病学传染病学杂志. 2006,33(1):45-47.
[12] Shuzo Matsushita. Current status and future issues in the treatment of HIV-1 infection[J]. Int J Hematol, 2000, 72: 20-27.
[13] Erik DC. Review: New developments in anti-HIV chemotherapy[J]. Biochemica et Biophysica Acta(BBA), 2002, 1587(2-3): 258-275.
[14] 貌盼勇,洪世雯.HIV的感染[M].周先志,赵敏.艾滋病诊疗新技术.北京:人民军医出版社,2005:21-23.
[15] 张淑玲,罗端德.艾滋病的发病机制和病理改变[J].新医学,2006,37(1):11-13.
[16] Blower SM, Gershengorn HB, Gramt RM. A tale of two future: HIV and antiretroviral therapy in San Francisco[J]. Science, 2000, 287 (5453): 650-654.
[17] Blundell T, Pearl L. A second front against AIDS[J]. Nature, 1989, 337(6027/6029): 596-598.
[18] 韩 冰,杨峻山.淫羊藿药理作用研究概况[J].中草药,2000,31(11):873-875.
[19] 琦祖和,蒋效松,杨显荣,等.天花粉蛋白质与苦瓜子蛋白质改变DNA构型的活性[J].中草药,l999,30(11):807-810.
[20] 刘因华,曹志红.抗艾滋病药物的发展近况[J].云南中医中药杂志,2004,25(6):44-45.
[21] Shirataki Y, Motohashi N, Tani S, et a1. In vitro biological activity of Prenyl flavanones[J].Anticancer Res, 2001, 21: 275-280.
[22] 魏文青,卢洁.王明霞.抗艾滋病药物的研究进展[J].国外医学药学分册,2001,28(5):294-297.
[23] 吕维柏.中医药治疗艾滋病的最新进展和对策[J].河南中医学院学报,2004,19(2):l11-115.
[24] 李春凤.抗艾滋病药物研究进展[J].中国药师,2006,9(7):661-663.
[25] Schaeffer DJ, Krylov VS. Anti-HIV activity of extracts and compounds from algae and cyanobacterial[J]. Ecotoxicol Environ Saf, 2000, 45(3): 208-227.
[26] 刘学铭,梁世华.小球藻的保健和药理作用[J].中草药,1999,30(5):383-384.
[27] 杨文雄,康来仪,潘孝彰,等.XQ-9302中药制剂对艾滋病疗效的初步研究[J].上海中医药杂志,1999,1:4-8.
[28] 江明性.新编实用药物学[M].北京:科学出版社,2000:601- 610.
[29] Harris M, Montaner JSG. Clinical uses of non-nucleoside reverse transcriptase inhibitors[J]. Rev Med Virol, 2000, 10: 217-229.
[30] Smith PF, DiCenzo R, Morse GD. Clinical pharmacokinetics of non- nucleoside reverse transcriptase inhibitors[J]. Clin Pharmacokinet, 2001, 40(12): 893-905.
[31] De Clercq E. Antiviral drugs: current state of art[J]. J Clin Virol, 2001, 22(1): 73-89.
[32] Aggarwal SK, Gogu SR, Rangan SR, et al. Synthsis and biological evalution of prodrug of zidovudine[J]. J Med Chem, 1990, 33(5): 1505-1510.
[33] 蒋为民,等著.艾滋病的抗病毒治疗进展[J].国外医学微生物分册,2000,23(1):215-219.
[34] Hrisch MS, Brun Vezinet F, D’Aquila RT, et, al. Antiretroviral drug resistance testing in adult HIV -1 infection: recommendations of an international AIDS Society-USA Panel[J]. J Am Med Assoc, 2000, 282(18): 2417-2426.
[35] Shellon MJ, O’Donnell AM, Morse GD. Didanosine[J]. Ann Pharmacother, 1992, 26(5): 660-670.
[36] Shellon MJ, O’Donnell AM, Morse GD. Zalcitabine[J]. Ann Pharmacother, 1993, 27(4): 480-489.
[37] Venkatachalam TK, Samuel P, Kourinov IV, et, al. Synthsis and anti-HIV activity of carbmates of antiviral agent stavudine[J]. Antivir Chem Chemother, 2002, 13(5): 289-297.
[38] Ohta Y, Shinka I. New drugs-reports of new drugs recently approved by the FDA, Lamivudine [J]. Bioorg Med Chem, 1997, 5(4): 639-640.
[39] 赵云利,宋礼华.抗病毒药物治疗艾滋病研究的探讨[J].河南中医学院学报,2006, 21(2):8-10.
[40] Henry K, Erice A, Tiemey C, et, al. A randomized, controlled, doublely-blined study comparing the survival benefit of four different reverse transcripatase inhibitors therapies(three-drug, two-drug and alternating drug) for the treatment of advanced AIDS Clinical Trial Group 193A Study Team[J]. J Acquit Immune Defic Syndr Hum Retrovivor, 1998, 19(4:) 339-349.
[41] Yarchoan R, Mitsuya H, Myers CE, et. al. Clinical pharmacology of 3’-azido-2’,3’–dideoxythymidine(zidovudine) and related dideoxy- -nucleosides[J]. N Engl J Med, 1989, 321: 726-738.
[42] Lambert JS, Seidlin RC, Reichman CS, et. al. 2’,3’–dideoxythymi- -dine(ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial[J]. N Engl J Med, 1990, 322: 1333-1340.
[43] Kellam, Boucher CAB, and Larder BA. Fifth mutation in a huaman immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine[J]. Proc Natl Acad Sci USA, 1992, 89: 1934-1938.
[44] Clair MHSt, Martin JL, Tudor-Willians D, et. al. Resistance to ddI and sensitivity to ZAT induced by a mutation in HIV-1 reverse transcriptase[J]. Science, 1991, 253: 1557-1559.
[45] 张宏梁,肖 宏.临床试验阶段的抗人免疫缺陷病毒化学药物研究进展[J].中国新药与临床杂志,2006,25(5):388-392.
[46] Sluis-Cremer N, Temiz NA, Bahar I. Conformational changes in HIV-l reverse transcriptase induced by nonucleoside reverse transcriptase inhibitor binding[J]. Curr HIV Res, 2004, 2(4): 323-332.
[47] Dueweke TJ, Kezdy, FJ, Waszak GA, et al. The binding of a novel bisheteroarylpiperazine mediates inhibition of human immunodeficiency virus type 1 reverse transcriptase[J]. J Biol Chem, 1992, 267: 27-30.
[48] Goldman ME, Numberg JH, O’Brein JA, et al. Pyridine derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity[J]. Proc Natl Acad Sci USA, 1991, 88: 6863-6867.
[49] Vasudevachari MB, Battista BC, Lane HC, et al. Prevention of the spread HIV-1 infection with nonnucleeoside everse transcriptase inhibitors acts through a nonsubstrate binding sites[J]. Biochemistry, 1991, 30: 2022-2026.
[50] Gadi B, Dominique A, Marka W, el a1. The thicarboxanilide nonnucleoside inhibitor UC781 restores antiviral activity of (AZT)againt AZT-resistant human immunodeficiency virus type 1[J]. Antimicrob Agent Chemother, 1999, 43(2): 259-263.
[51] Bryant M, German D, Smidt M, et. At. SC-52151, a novel inhibitor of huma n immunodeficiency virus protease[J]. J Antimicrob Agents Chemother, 1995, 39(10): 2229-2236.
[52] 刘新泳.抗艾滋病药物研究[M]. 北京:人民卫生出版社,2006:12.
[53] http://www.fda.gov/oashi/aids/virals.html
[54] Moyle GJ, Boosted. PIs: competition hots up[J]. AIDs, 2003, 13(9): 425-429.
[55] Walrmley S, Christian MD. The role of lopinavir/ritonavir(Kaletra)in the management of HIVinfected adults[J]. Exp Rev Anti Infect Ther, 2003, 1(3): 389-401.
[56] Skowron G, Leoung G, Hall DB, et. a1. Pharmacokinetic evaluation and short-term activity of stavudine, nevirapine, and nelfinavir therapy in HIV-l-infected adults[J]. J Acquir Immune Defic Syndr, 2004, 35(4): 351-358.
[57] Holland DT, DiFrancesco R, Stone J, et a1. Adult and pediatric AIDS clinical trials group pharmacology laboratory committees, pediatricAIDs clinical trials group. quality assurance program for clinical measurement of antiretrovirals: AIDS clinical trials group proficiency testing program for pediatric and adult pharmacology laboratories[J]. Antimicrob Agents Chemother , 2004, 48(3): 824-831.
[58] Musial BL, Chojnacki JK, Colemalrl CI. Atazanavir: a new protease inhibitor to treat HIV infection[J]. Am J Health Syst Pharm, 2004, 61(13): 1365-1374.
[59] Surleraux DL, Tahri A, Verschueren WG, et a1. Discovery and selection of TMCl14. a next generation HIV-l protease inhibitor[J]. J Med Chem, 2005, 48(6): l8l3-l822.
[60] 丁晓明,刘新泳.I型人免疫缺陷病毒蛋白酶抑制剂临床应用新进展[J].中国新药与临床杂志,2007,26(8):623-627.
[61] Molla A, Granneman GR, Sun E, et. al. Recent developments in HIV protease inhibitor therapy[J]. Antivir Res,1998, 39(1): 1-23.
[62] Yates PJ, Hazen R, st Clair M, et a1. In vitro development of resistance to human immunodeficiency virus protease inhibitor GW640385[J]. Antimierob Agents Chemother, 2006, 50(3): 1092-1095.
[63] Di Bello C, Pasquato A, Dettin M. Synthetic peptides for AIDs research[J]. Curr Protein Pept Sci, 2004, 5(4): 225-234.
[64] 张 鸽,范 明.抗HIV药物Maraviroc[J].药学进展,2006,30(7):333-334.
[65] 姜晓华,龙亚秋.结构多样的HIV-1整合酶抑制剂:过去、现在和未来[J].有机化学,2004,24(11):1380-1388.
[66] Reinke R, Lee DJ, Robinson WE Jr. Inhibition of hunmanimmunodeficiency virus type l isolates by the integrase inhibitor L-731 988, a diketo Acid[J]. Antimicrob Agents Chemother, 2002, 46(10): 3301-3303.
[67] Hazucla DJ, Felock P, Witmer M, et a1. Inhibitor of strand transfer that prevent integration and inhibit HIV-1 replication in cells[J]. Science, 2000, 287(5453): 646-650.
[68] Goebel FD, Hemmer R, Schmtt JC, et a1. Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretmviral therapy[J]. AIDS, 200l, 15(1): 33-45.
[69] Ahlers JD, Belyakov IM. Cytokine, chemokine and costimulatory molecule modulation to enhance efficacy of HIV vaccines [J]. Curr Mol Med, 2003, 3(3): 285-30l.
[70] Bachmann MF, Dyer MR. Therapeutic vaccination for chronic disease: a new class of drugs in sight[J]. Nat Rev Drug Discov, 2004, 3(1): 81-88.
[71] Rescriptor Product Information. Pharmacia & Upjohn Company, Kalamazoo, Mich, 1997.
[72] Dueweke TJ, Poppe SM, Romero DL, et al. U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication[J]. Antimicro Agents Chemother, 1993, 37: 1127-1131.
[73] Davey RTJr., Chaitt DG., Reed GF., et al. Randomized, controlled phase I/II, trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in immunodeficiency virus type 1-infected patients[J]. Antimicrob Agents Chemother, 1996, 40(7):1657-1664.
[74] Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor[J]. Adv Exp Med Biol, 1996, 394: 279-3289.
[75] Cheng CL, Smith DE, Carver PL, et al.Steady-state pharmacokinetics of delavirdine in HIV-positive patients: effect on erythromycin breath test[J]. Clin Pharmacol Ther. 1997, 61(5): 531-543.
[76] Morse GD, Fischl MA, Shelton MJ, et al. Effect of food on the steady-state pharmacokinetics of delavirdine in patients with HIV infection[J]. Clin Drug Invest, 2003, 23(4): 255-261.
[77] Tran JQ, Gerber JG., Kerr BM. Delavirdine: clinical pharmacokineti- -cs and drug interactions[J]. Clin-Pharmacokinet. 2001, 40(3): 207-226.
[78] Scott LJ, Perry CM. Delavirdine: a review of its use in HIV infection[J]. Drugs, 2000, 60(6): 1411-44.
[79] Morse GD, Fischl MA, Shelton MJ, et al. Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection[J]. Antimicrob Agents Chemother, 1997, 41(1) : 169-174.
[80] Chang M, Sood VK, Wilson GJ, et al. Metabolism of the human immunodeficiency virus type 1 reverse transcriptase inhibitor delavirdine in rats[J]. Drug Metab Dispos. 1997 , 25(2): 228-242.
[81] Voorman RL, Payne NA, Wienkers LC, et al. Interaction of delavirdine with human liver microsomal cytochrome P450: inhibition of CYP2C9, CYP2C19, and CYP2D6[J]. Drug MetabDispos, 2001, 29(1): 41-47.
[82] Freimuth WW. Delavirdine mesylate, a potent non-nucleoside HIV-l reverse transcriptase inhibitor[M]. In: Mills J, VolberdingPA, Corey L, eds. Antiviral Chemotherapy. Vo1 4. New York: Plenum Press; 1996: 279-289.
[83] Tran JQ, Petersen C, Garrett M, et al. Pharmacokinetic interaction between amprenavir and delavirdine: evidence of induced clearance by amprenavir[J]. Clin Pharmacol Ther, 2002, 72(6): 615-626.
[84] Demer LM, Shafer RW, Para M, et al. Delaviedine (DLV) susceptibility of HIV-1 isolates obtained from patients (PTS) receiving DLV monotherapy (ACTG 260)[E]. The 4th International Workshop on HIV Drug-Resitance. Sardinia, Italy, 6-9 July, 1995: Abstract 23.
[85] Chong KT , Pagano PJ, Hinshaw RR. Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3'-azido-3'-deoxythy- -midine or 2', 3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro [J]. Antimicrob Agents Chemother, 1994, 38(2): 288-293.
[86] Romero DL, Morge RA, Genin MJ, et al. Bis(heteroaryl) piperazines(BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indol analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl) carbonyl]-4-[3-[(1-methylethyl)amino)]-2-pyridinyl]piperazine monomethanesulfonate (U-90152S), a second-generation clinical candidates[J]. J Med Chem, 1993, 36: 1505-1508.
[87] Romero DL., Morge RA., Biles C., et al. Discovery, Synthesis and Bioactivity of Bis(heteroaryl) piperazines. 1. A Novel Class of Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors[J]. J Med Chem, 1994, 37: 999-1014.
[88] Romero DL, Olmstd RA, Poel TJ, et al. Targeting Delavirdine /Alavirdine Resistant HIV-1: Idetification of (Alkylamino) Piperidine-Containing Bis (heteroaryl) Piperazines as Broad Spectum HIV-1 Reverse Transcriptase Inhibitors[J]. J Med Chem, 1996, 39: 3769-3789.
[89] Pinna GA, Loriga G., Murineddu G., et al. Synthesis and Anti-HIV-1 Activity of New Delavirdine Analogues Carrying Arylpyrrole Moieties[J]. Chem Pharm Bull,2001, 49(11): 1406-1411.
[90] Romero DL. Delavirdine Mesylate[J]. Drugs Future, 1994, 19(3): 238-242.
[91] Perrauh WR, Shephard KP, Lapean LA, et a1. Production Scale Synthesis of the Non-nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate(U-87201E)[J]. Organic Process Research & Development, 1997, 1(2): 106-l16.
[92] 宁兆伦,燕方龙,贺丽鹏,王恩思,等.新型抗艾滋病药物地拉韦啶的合成[J].吉林大学学报(理学版),2006,44(1):118-122.
[93] Bi YX, Sunada H, Yonezawa Y, et al. Prepartion and evalution of a compressed tablets rapidly disintegrating in the oral cavity [J]. Chem Pharm Bull, 1996, 44(11): 2121-2128.
[94] Li QC, Kenneth AC, Zhuang G. A Capillary gas chromatographyic proceduce for the analysis of nine common residual solvents in water insoluble bulk pharmaceuticals [J ]. J Chromatogr Sci , 1998, 36 (5)∶119-124.
[95] 丁野,雷玉萍. 毛细管气相色谱法测定头孢米诺钠中几种有机溶剂残留量[J]. 中国新药杂志,2005,14(9):1169-1171.
[96] Watanabe, Y, Koizumi, K, Zama, Y, et al. New compressed tablet rapidly disintegrating in saliva in the mouth using crystalline cellulose and a disintegrant[J]. Biol. Pharm. Bull. 1995, 18: 1308–1310.
[97] Chang RK, Guo X, Burnside BA, et al. Fast-dissolving tablets[J]. Pharm. Technol. Eur, 2000, 12 (6): 52–58.
[98] Dobetti L. Fast-melting tablets: developments and technologies[J]. Pharm Technol Eur, 2000, 12 (9): 32–42.
[99] Bi Y, Sunada H, Yonezawa Y, et. al. Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity[J]. Chem Pharm Bull, 1996, 44: 2121–2127.
[100] Bi Y, Sunada H, Yonezawa Y, et al. Evaluation of rapidly disintegrating tablets prepared by a direct compression method[J]. Drug Dev Ind Pharm, 1999, 25: 571–581.
[101] Kremzar L, Mohar M, Fercej-Temeljotov D, et al. Formulation of dispersible nabumetone tablets[J]. Acta Pharm Zagreb, 1998, 48 (3): 187–192.
[102] Martin TP, Hayes P, Collins DM. Tablet dispersion as an alternative to formulation of oral liquid dosage forms[J]. Aust J Hosp Pharm 1993, 23: 378–381.
[103] 黄胜炎.分散片进展[J].中国药学杂志,1992,27(4):226-228.
[104] 王玉玲.分散片中的崩解剂[J]. 食品与药品,2005,7(3):51-52.
[105] 沈岚,林晓,冯怡,等.分散片的研究进展[J].中成药,2004,26(2):145-158.
[106] 彭礼明.分散片处方、工艺特点及其进展[J].药品评价,2005,2(3):230-233.
[107] Bi YX, Sunada H, Yonezawa Y, et al. Prepartion and evalution of a compressed tablets rapidly disintegrating in the oral cavity [J]. Chem Pharm Bull, 1996, 44(11): 2121-2127.
[108] Watanabe Y, Koizumi K, Zama Y, et a1. New Compressed tablet disintegrating in saliva in the mouth using Crystalline cellulose and a disintegrant[J]. Biol Pharm Bull 1995, 18(9): 1308-1314.
[109] 上海医药工业研究院制剂研究室.药用辅料应用技术[M].北京:中国医药科技出版社,l991.
[110] 方小玲,杨敏,穆尼拉,等.几种新型辅料在速释片剂中的应用[J].中国医药工业杂志,2000,31(6):257-259.
[111] Bolhuis GK, Zurman K, Wierik GHP. Improvement of dissolution of poorly soluble drugs by solid deposition on a super disintegrant 2. The choice of super disintegrants and effect of granulation[J]. Eur J Pharm Sci, 1997, 5(2): 63-69.
[112] 陈燕军,臧琛,赵小妹等. 几种常用填充剂与崩解剂在中药分散片应用中的性能比较[J]. 中国中药杂志,2002,27(8):580-583.
[113] Shimizu T, NakanoY, Morimoto S, et a1. Formulation study for lansoprazole fast disintegrating tablet.Effect of compression on dissolution behavior[J]. Chem Pharm Bull, 2003, 51(8): 942-947.
[114] 崔福德.药剂学[M].北京:人民卫生出版社,2003:330-332.
[115] Clercq ED. Antiviral drugs: current state of the art[J]. Journal of Clinical Virology. 2001, 22 : 73–89.
[116] 索绪斌,邓英杰,郝爱军等.月桂酰吲达帕胺的解离常数及分配 系数的测定[J].沈阳药科大学学报,2005,22(5):335-337.
[117] Benet LZ, Goyan JE. Nonlogarithmic titration curves for the determination of dissociation constants and purity[J]. J Pharm Sci, 1965, 54(8): 1179-1182.
[118] 倪维骅.药物多晶型的研究方法[J].医药工业,1981,9(1):33-39.
[119] Bergren M S,Chao R S,Meulman P A,et a1.Solid Phase of Delavirdine Mesylate[J].J Pharm Sci,1996,85(8):834-841.
[120] Sarver R W,Meulman P A,Bowerman D K,et a1.Factor Analysis of Infrared Spectra for Solid-state Forms of Delavirdine Mesylate [J].International Journal of Pharmaceutics. 1998,167:105-120.
[121] 常俊标.艾滋病的分子生物学及治疗[M].北京:科学出版社,22001: 44-45.
[122] 仇缀百.药物设计学[M].北京:高等教育出版社,1999:88.
[123] 白杨,潘隽丽,苏薇薇.白藜芦醇与白藜芦醇苷的研究进展[J].中药材,2004,27(1):55-59.
[124] 王世盛,赵伟杰,刘志广.天然多羟基芪化合物的生物活性[J].国外医药·植物药分册,2001,16(1):9-11.
[125] 高路,袁育康,吕卓人,等.白藜芦醇的免疫调节作用[J].西安交通大学学报(医学版),2003,24(2):121-123.
[126] 于良,吴胜利,张梅,等.白藜芦醇及环保菌素A联用对人体周血T细胞免疫功能的影响[J].细胞与分子免疫学杂志,2003,19(6):549-551.
[127] 贺丽鹏.吉林大学硕士学位论文.
[128] Kimpton J﹠Emerman M. Detection of replicatoion-competent and pseudotype human immunodeficiency virus with a sensitive cell line on the basis of activitation of an integrated beta-galactosidase gene[J]. J. Virl,1992, 66:2232-2239.
[129] Deibel MR, McQuade TJ, Brunner DP, et al. Denaturation/refolding of purified recombinant HIV reverse transcriptase yields monomeric enzyme with high enzymatic activity[J]. AIDS Res Hum Retroviruses, 1990, 6: 329-340.
[130] Romero DL, Busso M, Tan CK, et al. Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication[J]. Proc. Natl Acad Sci USA, 1991, 88: 8806-8810.