Nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase

Current Topics in Medicinal Chemistry

Volumn 4, Issue 9, 2004, Pages 895-921

  Sharma, Prem L ^a   Nurpeisov, Viktoria ^a   Hernandez Santiago, Brenda ^a   Beltran, Thierry ^a   Schinazi, Raymond F ^a,b,c  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c ATLANTA VA MEDICAL CENTER   (United States)

Author keywords

Combination therapy; Mitochondrial toxicity; Nucleoside analogs; Pharmacokinetics; Phosporylation; Purine analogs; Pyrimidine analogs; Resistance

Indexed keywords

ABACAVIR; ADEFOVIR; AMPRENAVIR; COTRIMOXAZOLE; DAPSONE; DELAVIRDINE; DEOXYADENOSINE DERIVATIVE; DEOXYGUANOSINE DERIVATIVE; DIDANOSINE; EFAVIRENZ; EMTRICITABINE; INDINAVIR; KETOCONAZOLE; LAMIVUDINE; MYCOPHENOLIC ACID; NELFINAVIR; NEVIRAPINE; NUCLEOSIDE ANALOG; PROTEINASE INHIBITOR; RIBAVIRIN; RITONAVIR; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; TENOFOVIR DISOPROXIL; THYMIDINE DERIVATIVE; UNINDEXED DRUG; ZALCITABINE; ZIDOVUDINE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; NUCLEOSIDE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANEMIA; ANTIVIRAL ACTIVITY; AREFLEXIA; ARTERY DISEASE; ASTHENIA; CARDIOMYOPATHY; CLINICAL TRIAL; COUGHING; DIARRHEA; DRUG BLOOD LEVEL; DRUG CLASSIFICATION; DRUG DESIGN; DRUG DISTRIBUTION; DRUG DOSE REGIMEN; DRUG ERUPTION; DRUG EXPOSURE; DRUG HALF LIFE; DRUG POTENCY; DRUG POTENTIATION; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG URINE LEVEL; DYSESTHESIA; ENZYME ACTIVATION; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; FATIGUE; FATTY LIVER; HEADACHE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HYPERPIGMENTATION; HYPERSENSITIVITY REACTION; INSOMNIA; LACTIC ACIDEMIA; LIPODYSTROPHY; LIVER DYSFUNCTION; LIVER TOXICITY; MALAISE; MITOCHONDRIAL TOXICITY; MOUTH ULCER; MUSCLE WEAKNESS; MYALGIA; MYOPATHY; NAUSEA; NEUTROPENIA; NONHUMAN; NUCLEOTIDE SEQUENCE; PAIN; PANCREATITIS; PATIENT CARE; PERIPHERAL NEUROPATHY; PHARYNGITIS; REVIEW; RHINITIS; SENSORY DYSFUNCTION; STRUCTURE ANALYSIS; VIRUS STRAIN; VOMITING; CHEMICAL STRUCTURE; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; PHYSIOLOGY; VIROLOGY; VIRUS REPLICATION;

ANTI-HIV AGENTS; HIV INFECTIONS; HIV-1; HIV-1 REVERSE TRANSCRIPTASE; HUMANS; MOLECULAR STRUCTURE; NUCLEOSIDES; REVERSE TRANSCRIPTASE INHIBITORS; VIRUS REPLICATION;

EID: 3042762534     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026043388484     Document Type: Review

References (279)

1. Skalka, A. M.; Goff, S. P. (eds) Reverse Transcriptase. Cold Spring Harbor Laboratory Press, NY, 1993.
2. Rousseau, F. S.; Kahn, J. O.; Thompson, M.; Mildvan, D.; Shepp, D.; Sommadossi, J. P.; Delehanty, J.; Simpson, J. N.; Wang, L. H.; Quinn, J. B.; Wakeford, C.; van der Horst, C. Prototype trial design for rapid dose selection of antiretroviral drugs: an example using emtricitabine (Coviracil). J. Antimicrob. Chemother. 2001, 48, 507-513.
3. Ussery, M. A.; Wood, O. L.; Kunder, S. C.; Bacho, M. A.; Broud, D. D.; Papermaker, S. F.; Hall, B. E.; Ciavarella, A.; Nielsen, C. J.; Schinazi, R. F. Anti-HIV activity in the HuPBMC SCID mouse model of six novel nucleoside analogs: (-)-FTC, (+/-)-FTC, D-DAPD, D-D4FC, CS-92, and CS-87 Antiviral Res. 1998, 37, A49.
4. Balzarini, J.; Naesens, L.; Herdewijn, P.; Rosenberg, I.; Holy, A.; Pauwels, R.; Baba, M.; Johns, D. G.; De Clercq, E. Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. Proc. Natl. Acad. Sci. 1989, 86, 332-336.
5. Barditch-Crovo, P.; Toole, J.; Hendrix, C. W.; Cundy, K. C.; Ebeling, D.; Jaffe, H. S.; Lietman, P. S. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxil (9-[2-(bis-pivaloyloxymethyl)-phosphonylmethoxyethyl]adenine) in HIV-infected patients. J. Infect. Dis. 1997, 176, 406-413.
6. FDA Approved Anti-HIV Drugs. NIAID Web Site. Available at www.niaid.nih.gov/daids/dtpdb/fdadrug.htm. Accessed Dec. 2, 2002.
7. Gumina, G.; Song, G. Y.; Chu, C. K. L-Nucleosides as chemotherapeutic agents. FEMS Microbiol. Lett. 2001, 2 02, 9-15.
8. Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.; Cannon, D.; Jeong, L. S.; Beach, J. W.; Choi, W. B.; Yeola, S.; Liotta, D. C. Activities of the four optical isomers of 2′,3′-dideoxy-3′-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes. Antimicrob. Agents Chemother. 1992, 36, 672-676.
9. Schinazi, R. F.; McMillan, A.; Cannon, D.; Mathis, R.; Lloyd, R. M.; Peck, A.; Sommadossi, J. P.; St Clair, M.; Wilson, J.; Furman, P. A.; Painter, G.; Choi, W. B.; Lioota, D. C. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine. Antimicrob. Agents Chemother. 1992, 36, 2423-2431.
10. Jarvis, B.; Faulds, D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B. Drugs. 1999, 58, 101-141.
11. Chang, C. N.; Doong, S. L.; Zhou, J. H.; Beach, J. W.; Jeong, L. S.; Chu, C. K.; Tsai, C. H.; Cheng, Y. C.; Liotta, D.; Schinazi, R. F. Deoxycytidine deaminase-resistant stereoisomer is the active form of(+/-)-2′,3′-dideoxy-3′-thiacytidine in the inhibition of hepatitis B virus replication. J. Biol. Chem. 1992, 267, 13938-13942.
12. Shewach, D. S.; Liotta, D. C.; Schinazi, R. F. Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2′-deoxycytidine kinase. Biochem. Pharmacol. 1993, 45, 1540-1543.
13. Huang, H.; Chopra, R.; Verdine, G. L.; Harrison, S. C. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 1998, 282, 1669-1675.
14. Arner, E. S. J.; Eriksson, S. Deoxycytidine and 2′,3′-dideoxycytidine metabolism in human monocytes-derived macrophages. Biochem. Biophys. Res. Comm. 1993, 197, 1499-1504.
15. Plunkett, W.; Saunders, P. P. Metabolism and action of purine nucleoside analogs. Pharmacol. Ther. 1991, 49, 239-268.
16. Waqar, M. A.; Evans, M. J.; Manly, K. R.; Hughes, R. G.; Huberman, J. A. Effects of 2′, 3′-dideoxynucleosides on mammalian cells and viruses. J. Cell Physiol. 1984, 121, 402-408.
17. Holland, J.; Spindler, K.; Horodyski, F.; Grabau, E.; Nichol, S.; VandePol, S. Rapid evolution of RNA genomes. Science 1982, 215, 1577-1585.
18. Huang, P.; Farquhar, D.; Plunket, W. Selective action of 2′,3′-didehydro-2′,3′-dideoxythymidine triphosphate on human immunodeficiency virus reverse transcriptase and human DNA polymerases. J. Biol. Chem. 1990, 265, 11914-11918.
19. Nave, J. F.; Eschbach, A.; Wolff-Kugel, D.; Halazy, S.; Balzarini, J. Enzymatic phosphorylation and pyrophosphorylation of 2′,3′-dideoxyadenosine-5′-monophosphate, a key metabolite in the pathway for activation of the anti-HIV (human immunodeficiency virus) agent 2′,3′-dideoxyinosine. Biochem. Pharmacol. 1994, 48, 1105-1112.
20. Falleto, M. B.; Miller, W. H.; Garvey, E. P.; St Clair, M. H.; Daluge, S. M.; Good, S. S. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob. Agents Chemother. 1997, 41, 1099-1107.
21. Connolly, K. J.; Hammer, S. M. Antiretroviral therapy: strategies beyond single-agent reverse transcriptase inhibition. Antimicrob. Agents Chemother. 1992, 36, 509-520.
22. Kreimeyer, A., Schneider, B., Sarfati, R., Faraj, A., Sommadossi, J. P., Veron, M., Deville-Bonne, D. NDP kinase reactivity towards 3TC nucleotides. Antiviral Res. 2001 50, 147-156.
23. Ahluwalia, G. S.; Gao, W. Y.; Mitsuya, H.; Johns, D. G. 2′,3′-Didehydro-3′-deoxythymidine: regulation of its metabolic activation by modulators of thymidine-5′-triphosphate biosynthesis. Mol. Pharmacol. 1996, 50, 160-165.
24. Kewn, S.; Veal, G. J.; Hoggard, P. G.; Barry, M. G.; Back, D. J. Lamivudine (3TC) phosphorylation and drug interactions in vitro. Biochem. Pharmacol. 1997, 54, 589-595.
25. Veal, G. J.; Barry, M. G.; Back, D. J. Zalcitabine (ddC) phosphorylation and drug interactions. Antiviral Chemother. 1995, 6, 379-384.
26. Hoggard, P. G.; Veal, G. J.; Wild, M. J.; Barry, M. G.; Back, D. J. Drug interactions with zidovudine phosphorylation in vitro. Antimicrob. Agents Chemother. 1995, 39, 1376-1378.
27. Gao, W. Y.; Shirasaka, T.; Johns, D. G.; Broder, S.; Mitsuya, H. Differential phosphorylation of azidothymidine, dideoxycytidine, and dideoxyinosine in resting and activated peripheral blood mononuclear cells. J. Clin. Invest. 1993, 91, 2326-2333.
28. Gao, W. Y.; Agbaria, R.; Driscoll, J. S.; Mitsuya, H. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2′,3′-dideoxynucleoside analogs in resting and activated human cells. J. Biol. Chem. 1994, 269, 12633-12638.
29. Cammack, N.; Rouse, P.; Marr, C. L.; Reid, P. J.; Boehme, R. E.; Coates, J. A.; Penn, C. R.; Cameron J. M. Cellular metabolism of (-) enantiomeric 2′-deoxy-3′-thiacytidine. Biochem. Pharmacol. 1992, 43, 2059-2064.
30. Ho, H. T.; Hitchcock, M. J. Cellular pharmacology of 2′,3′-dideoxy-2′,3′-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. Antimicrob. Agents Chemother. 1989, 6, 844-849.
31. Stein, D. S.; Moore, K. H. Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians. Pharmacotherapy 2001, 1, 11-34.
32. Balzarini, J.; Herdewijn, P.; De Clercq, E. Differential patterns of intracellular metabolism of 2′,3′-didehydro-2′,3′-dideoxythymidine and 3′-azido-2′,3′-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. J. Biol. Chem. 1989, 264, 6127-6133.
33. Veal, G. J.; Back, D. J. Metabolism of zidovudine. Gen. Pharmacol. 1995, 26, 1469-1475.
34. Furman, P. A.; Fyfe, J. A.; St Clair, M. H.; Weinhold, K.; Rideout, J. L.; Freeman, G. A.; Lehrman, S. N.; Bolognesi, D. P.; Broder, S.; Mitsuya, H, Barry, D. W. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc. Natl. Acad. Sci. USA 1986, 83, 8333-8337.
35. Martin, J. C.; Hitchcock, M. J.; Fridland, A.; Ghazzouli, I.; Kaul, S.; Dunkle, L. M.; Sterzycki, R. Z.; Mansuri, M. M. Comparative studies of 2′,3′-didehydro-2′,3′ -dideoxythymidine (D4T) with other pyrimidine nucleoside analogues. Ann. NY Acad. Sci. 1990, 616, 22-28.
36. Avramis, V. I.; Markson, W.; Jackson, R. L.; Gomperts, E. Biochemical pharmacology of zidovudine in human T-lymphoblastoid cells (CEM). AIDS 1989, 3, 417-422.
37. Tornevik, Y.; Eriksson, S. 2′,3′-Dideoxycytidine toxicity in cultured human CEM T lymphoblasts: effects of combination with 3′-azido-3′-deoxythymidine and thymidine. Mol. Pharmacol. 1990, 38, 237-243.
38. Lavie, A.; Schlichting, I.; Vetter, I. R.; Konrad, M.; Reinstein, J.; Goody, R. S. The bottleneck in AZT activation. Nat. Med. 1997, 3, 922-924.
39. Cooney, D. A.; Dalal, M.; Mitsuya, H.; McMahon, J. B.; Nadkarni, M.; Balzarini, J.; Broder, S.; Johns, D. G. Initial studies on the cellular pharmacology of 2′,3′-dideoxycytidine, an inhibitor of HTLV-III infectivity. Biochem. Pharmacol. 1986, 35, 2065-2068.
40. Starnes, M. C.; Cheng, Y. C. Cellular metabolism of 2′,3′-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J. Biol. Chem. 1987, 262, 988-991.
41. Balzarini, J.; Pauwels, R.; Baba, M.; Herdewijn, P.; de Clercq, E.; Broder, S.; Johns, D. G. The in vitro and in vivo anti-retrovirus activity, and intracellular metabolism of 3′-azido-2′,3′-dideoxythymidine and 2′,3′ -dideoxycytidine are highly dependent on the cell species. Biochem. Pharmacol. 1988, 37, 897-903.
42. Chang, C. N.; Skalski, V.; Zhou, J. H.; Cheng, Y. C. Biochemical pharmacology of (+)- and (-)-2′,3′-dideoxy-3′-thiacytidine as anti-hepatitis B virus agents. J. Biol. Chem. 1992, 267, 22414-224120.
43. Bohman, C.; Eriksson, S. Deoxycytidine kinase from human leukemic spleen: preparation and characteristics of homogeneous enzyme. Biochemistry 1988, 27, 4258-4265.
44. Balzarini, J. Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Pharm. World Sci. 1994, 16, 113-126
45. Moore, K. H.; Barrett, J. E.; Shaw, S.; Pakes, G. E.; Churchus, R.; Kapoor, A.; Lloyd, J.; Barry, M. G.; Back D. The pharmacokinetics of lamivudine phosphorylation in peripheral blood mononuclear cells from patients infected with HIV-1. AIDS 1999, 13, 2239-2250.
46. Kewn, S.; Hoggard, P. G.; Sales, S. D.; Johnson, M. A.; Back, D. J. (3TC) and determination of 2′-deoxycytidine-5′ -triphosphate (dCTP) pools in the presence and absence of various drugs in HepG2 cells. Br. J. Clin. Pharmacol. 2000, 50, 597-604.
47. Hao, Z.; Stowe, E. E.; Ahluwalia, G.; Baker, D. C.; Hebbler, A. K.; Chisena, C.; Musser, S. M.; Kelly, J. A.; Perno, C. F.; Johns, D. G.; Conney, D. A. Characterization of 2′,3′-dideoxycytidine diphosphocholine and 2′,3′-dideoxycytidine diphosphoethanolamine. Drug Metabolism and Disposition 1993, 21, 738-744.
48. Solas, C.; Li, Y. F.; Xie, M. Y.; Sommadossi, J. P.; Zhou, X. J. Intracellular nucleotides of (-)-2′,3′-deoxy-3′ -thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus. Antimicrob. Agents and Chemother. 1998, 42, 2989-2995.
49. Schinazi, R. F.; Peck, A.; Sommadossi, J. P. Substrate specificity of Escherichia coli thymidine phosphorylase for pyrimidine nucleosides with anti-human immunodeficiency virus activity. Biochem. Pharmacol. 1992, 44, 199-204.
50. Cate, M.; Cheng, Y. C. Cellular metabolism of 2′,3′-dideoxycytidine, a compound active against human immunodeficiency virus in vitro. J. Biol. Chem. 1987, 262, 988-991.
51. Becher, F.; Pruvost, A.; Goujard, C.; Guerreiro, C.; Delfraissy, J. F.; Grassi, J.; Benech, H. Improved method for the simultaneous determination of d4T, 3TC and ddl intracellular phosphorylated anabolites in human peripheral-blood mononuclear cells using high-performance liquid chromatography/tandem mass spectrometry. Rapid Commun. Mass Spectrom. 2002, 16, 555-565.
52. Johnson, M. A.; Fridland, A. Phosphorylation of 2′,3′ dideoxyinosine by cytosolic 5′-nucleotidase of human lymphoid cells. Mol. Pharmacol. 1989, 2, 291-295.
53. Kewn, S.; Hoggard, P. G.; Henry-Mowatt, J. S.; Veal, G. J.; Sales, S. D.; Barry, M. G.; Back, D. J. Intracellular activation of 2′,3′-dideoxyinosine and drug interactions in vitro. AIDS Res. Hum. Retroviruses 1999, 15, 793-802.
54. Robbins, B. L.; Greenhaw, J.; Fridland, A. Cellular phosphorylation of 2′,3′-dideoxyadenosine-5′ -monophosphate, a key intermediate in the activation of the antiviral agent ddl, in human peripheral blood mononuclear cells. Nucleosides Nucleotides Nucleic Acids 2000, 19, 405-413.
55. Ahluwalia, G.; Cooney, D. A.; Mitsuya, H.; Fridland, A.; Flora, K. P. Initial studies on the cellular pharmacology of 2′,3′-dideoxyadenosine, an inhibitor of HIV infectivity. Biochem. Pharmacol. 1987, 36, 3797-3800.
56. Johnson, M. A.; Ahluwalia, G.; Connelly, M. C.; Cooney, D. A.; Broder, S.; Johns, D. G.; Friedland, A. Metabolic pathways for the activation of the antiretroviral agent 2′,3′-didoxyadenosine in human lymphoid cells. J. Biol. Chem. 1988, 263, 15354-15357.
57. Daluge, S. M.; Good, S. S.; Faleto, M. B.; Miller, W. H.; St. Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.; Dornsife, R. E.; Averett, D. R.; Krenitsky, T. A. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob. Agents Chemother. 1997, 41, 1082-1093.
58. Ray, A. S.; Yang, Z.; Shi, J.; Hobbs, A.; Schinazi, R. F.; Chu, C. K.; Anderson, K. S. Insights into the molecular. Mechanism of inhibition and drug resistance for HIV-1 RT with carbovir triphosphate. Biochemistry 2002, 41, 5150-5162.
59. Garvey, E. P.; Krenitsky, T. A. A novel human phosphotransferase highly specific for adenosine. Arch. Biochem. Biophys. 1992, 296, 161-169.
60. Frick, L. W.; Nelson, D. J. Effects of 3′-azido-3′-deoxythymidine on the deoxynucleoside triphosphate pools of cultured human cells. Adv. Exp. Med. Biol. 1989, 253, 389-394.
61. Fridland, A.; Connelly, M. C.; Ashmun, R. Relationship of deoxynucleotide changes to inhibition of DNA synthesis induced by the antiretroviral agent 3′-azido-3′-deoxythymidine and release of its monophosphate by human lymphoid cells (CCRF-CEM). Mol. Pharmacol. 1990, 37, 665-670.
62. Perno, C. F.; Yarchoan, R.; Cooney, D. A.; Hartman, N. R.; Gartner, S.; Popovic, M.; Hao, Z.; Gerrard, T. L.; Wilson, Y. A.; Johns D. G.; Broder, S. Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIB) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2′,3′-dideoxynucleosides. J. Exp. Med. 1988, 168, 1111-1125.
63. Bello, L. J. Regulation of thymidine kinase synthesis in human cells. Exp. Cell Res. 1974, 89, 263-274.
64. Vercammen-Grandjean, A.; Arnould, R.; Libert, A.; Ewalenko, P.; Lejeune, F. Production of the effector molecule thymidine by human lung alveolar macrophages. Eur. J. Cancer Clin. Oncol. 1984, 20, 1543-1548.
65. Jacobsson, B.; Britton, S.; He, Q.; Karlsson, A.; Eriksson, S. Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism. AIDS Res. Hum. Retroviruses 1995, 11, 805-811.
66. Toyoshima, T.; Kimura, S.; Muramatsu, S.; Takahagi, H.; Shimada, K.; Toyoshima, T.; Kimura, S.; Muramatsu, S.; Takahagi, H.; Shimada, K. A sensitive nonisotopic method for the determination of intracellular azidothymidine 5′-mono-, 5′-di-, and 5′ -triphosphate. Anal. Biochem. 1991, 96, 302-307.
67. Robbins, B. L.; Rodman, J.; McDonald, C.; Srinivas, R. V.; Flynn, P. M.; Fridland, A. Enzymatic assay for measurement of zidovudine triphosphate in peripheral blood mononuclear cells. Antimicrob. Agents Chemother. 1994, 38, 115-121.
68. Hoggard, P. G.; Kewn, S.; Barry, M. G.; Khoo, S. H.; Back, D. J. Effects of drugs on 2′,3′-dideoxy-2′,3′ -didehydrothymidine phosphorylation in vitro. Antimicrob. Agents Chemother. 1997, 41, 1231-1236.
69. Gray, N. M.; Marr, C. L.; Penn, C. R.; Cameron, J. M.; Bethell, R. C. The intracellular phosphorylation of (-)-2′-deoxy-3′-thiacytidine (3TC) and the incorporation of 3TC 5′-monophosphate into DNA by HIV-1 reverse transcriptase and human DNA polymerase gamma. Biochem. Pharmacol. 1995, 50, 1043-1051.
70. Kakuda, T. N. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin. Ther. 2000, 22, 685-708.
71. Tsai, C. C.; Emau, P.; Follis, K. E.; Beck, T. W.; Benveniste, R. E.; Bishofberger, N.; Lifson, J. D.; Morton, W. R. Effectiveness of postinoculation (R)-9-(2-phosphonylmethoxypropyl) adenine treatment for prevention of persistent simian immunodeficiency virus SIVmne infection depends critically on timing of initiation and duration of treatment. J. Virol. 1998, 72, 4265-4273.
72. Tsai, C. C.; Follis, K.; Sabo, K. A.; Beck, T. W.; Grant, R. F.; Bischofberger, N.; Benveniste, R. E.; Black, R. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl) adenine. Science 1995, 270, 1197-1199.
73. Deeks, S. G.; Barditch-Crovo, P.; Lietman, P. S.; Hwang, F.; Cundy, K. C.; Rooney, J. F.; Hellmann, N. S.; Safrin, S.; Kahn, J. O. The safety, pharmacokinetics, and antiretroviral activity of intravenous 9-[2-(R)-(phosphonomethoxy)propyl]adenine, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults. Antimicrob. Agents Chemother. 1998, 42, 2380-2384.
74. Robbins, B. L.; Srinivas, R. V.; Kim, C.; Bischofberger, N.; Fridland, A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl) PMPA. Antimicrob. Agents Chemother. 1998, 42, 612-617.
75. Harrigan, P. R.; Miller, M. D.; McKenna P.; Brumme, Z. L.; Larder, B. A. Phenotypic susceptibilities to tenofovir in a large panel of clinically derived human immunodeficiency virus type 1 isolates. Antimicrob. Agents Chemother. 2002, 46, 1067-1072.
76. Margolis, D.; Heredia, A.; Gaywee, J.; Oldach, D.; Drusano, G.; Redfield, R. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-HIV activity. J. Acquir. Immune Defic. Syndr. 1999, 21, 362-370.
77. Veal, G. J.; Barry, M. G.; Khoo, S. H.; Back, D. J. In vitro screening of nucleoside analog combinations for potential use in anti-HIV therapy. AIDS Res. Hum. Retroviruses. 1997, 13, 481-484.
78. Hoggard, P. G.; Khoo, S.; Barry, M.; Back, D. Intracellular metabolism of zidovudine and stavudine in combination. J. Infect. Dis. 1996, 174, 671-672.
79. Havlir, D. V.; Tierney, C.; Friedland, G. H.; Pollard, R. B.; Smeaton, L.; Sommadossi, J. P.; Fox, L.; Kessler, H.; Fife, K. H.; Richman, D. D. In vivo antagonism with zidovudine plus stavudine combination therapy. J. Infect. Dis. 2000, 182, 321-325.
80. Jackson, J. B.; Coombs, R. W.; Sannerud, K.; Rhame, F. S.; Balfour, H. H. Rapid and sensitive viral culture method for HIV Type-1. J. Clin. Microbiol. 1988, 26, 1416-1418.
81. Hartman, N.; Ahluwalia, G.; Cooney, D.; Mitsuya, H.; Kageyama, S.; Fridland, A.; Broder, S.; Johns, D. G. Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-HIV nucleosides 2′,3′-dideoxyadenosine and 2′,3′-didoxyinosine. Mol. Pharmacol. 1991, 40, 118-124.
82. Streeter, D.; Witkowski, J.; Khare, G. Mechanism of action of 1-[beta]-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole), a new broad spectrum antiviral agent. Proc. Natl. Acad. Sci. 1973, 70, 1174-1178.
83. Gilbert, B.; Knight, V. Biochemistry and clinical applications of ribavirin. Antimicrob. Agents Chemother. 1986, 30, 201-205.
84. Baba, M.; Pauwels, R.; Balzarini, J.; Herdewijn, P.; De Clercq, E.; Desmyter, J. Ribavirin antagonizes inhibitory effect of pyrimidine 2′,3′-dideoxynucleosides but enhanced inhibitory effects of purine 2′,3′-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob. Agents Chemother. 1987, 31, 1613-1617.
85. Ahluwalia, G.; Cooney, D.; Bondoc, L.; Currens, M. J.; Ford, H.; Johns, D. G.; Mitsuya, H.; Fridland, A. Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2′,3′-dideoxyguanosine. Biochem. Biophys. Res. Commun. 1990, 171, 1297-1303.
86. Balzarini, J.; Naesens, L.; De Clercq, E. Potentiating effect of ribavirin on the in vitro and in-vivo antiretrovirus activities of 2′,3′-dideoxyinosine and 2′,3′-dideoxy-2′ ,6′-diaminopurine riboside. J. Acquir. Immune Defic. Syndr. 1990, 3, 1140-1147.
87. Johns, D. G.; Ahluwalia, G. S.; Counet, D. A.; Mitsuya, H.; Driscoll, J. S. Enhanced stimulation by ribavirin of the 5′ phosphorylation and anti-human immunodeficiency virus activity of purine 2′-[beta]-fluoro-2′,3′-dideoxynucleosides. Mol. Pharmacol. 1993, 44, 517-523.
88. Balzarini, J.; Lee, C. K.; Herdewijn, P.; De Clercq, E. Mechanism of the potentiating effect of ribavirin on the activity of 2′,3′-dideoxyinosine against human immunodeficiency virus. J. Biol. Chem. 1991, 266, 21509-12154.
89. Japour, A. J.; Lertora, J. J.; Meehan, P. M.; Erice, A.; Connor, J. D.; Griffith, B. P.; Clax, P. A.; Holden-Wiltse, J.; Hussey, S.; Walesky, M.; Cooney, E.; Pollard, R.; Timpone, J.; McLaren, C.; Johanneson, N.; Wood, K.; Booth, D.; Bassiakos, Y.; Crumpacker, C.S. A Phase-I study of the safety, pharmacokinetics, and antiviral activity of combination of didanosine and ribavirin in patients with HIV-1 disease. AIDS Clinical Trials Group 231 Protocol Team. J. Acquir. Immune Defic. Syndr. 1996, 13, 235-246.
90. Veal, G. J.; Wild, M. J.; Barry, M. G.; Back, D. J. Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells. Br. J. Clin. Pharmacol. 1994, 38, 323-328.
91. Project Inform Incorporation. Information, Inspiration, and Advocacy for People Living with HIV/AIDS. Available at: www.thebody.com. Accessed Feb. 28, 2003.
92. Larder, B. A.; Darby, G.; Richman, D. D. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989, 243, 1731-1734.
93. Land, S.; Terloar, G.; McPhee, D.; Birch, C.; Doherty, R.; Cooper, D.; Gust, I. Decreased in vitro susceptibility to zidovudine of HIV isolates obtained from patients with AIDS. J. Infect. Dis. 1990, 161, 326-329.
94. Boucher, C. A.; Tersmette, M.; Lange, J. M.; Kellam, P.; de Goede, R. E.; Mulder, J. W.; Darby, G.; Goudsmit, J.; Larder, B. A. Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy. Lancet. 1990, 336, 585-590.
95. Broadhurst, K.; Lowdell, M.; Ball, A. Virological identification of three subgroups of patients during extended treatment with zidovudine. Antiv. Res. 1992, 167, 132.
96. Schuetz, J. D.; Connelly, M. C.; Sun, D.; Paibir, S. G.; Flynn, P. M.; Srinivas, R. V.; Kumar, A.; Fridland, A. MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat. Med. 1999, 5, 1048-1051.
97. Gupta, S.; Gollapudi, S. P-glycoprotein (MDR 1 gene product) in cells of the immune system: its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. J. Clin. Immunol. 1993, 13, 289-301.
98. Gollapudi, S.; Gupta, S. Human immunodeficiency virus induced expression of P-glycoprotein. Biochem Biophys. Res. Commun. 1990, 171, 1002-1007.
99. Antonelli, G.; Turriziani, O.; Cianfriglia, M.; Riva, E.; Dong, G.; Fattorossi, A.; Dianzani, F. Resistance of HIV-1 to AZT might also involve the cellular expression of multidrug resistance P-glycoprotein. AIDS Res. Hum. Retroviruses. 1992, 8, 1839-1844.
100. Peter, K.; Gambertoglio, J. G. Intracellular phosphorylation of zidovudine (ZDV) and other nucleoside reverse transcriptase inhibitors (RTI) used for human immunodeficiency virus (HIV) infection. Pharm. Res. 1998, 15, 819-825.
101. Blum, M. R.; Liao, S. H.; Good, S. S.; de Miranda, P. Pharmacokinetics and bioavailability of zidovudine in humans. Am. J. Med. 1988, 85, 189-194.
102. Collins, J. M.; Unadkat, J. D. Clinical pharmacokinetics of zidovudine. An overview of current data. Clin. Pharmacokinet. 1989, 17, 1-9.
103. Singlas, E.; Pioger, J. C.; Taburet, A. M.; Colaneri, S.; Fillastre, J. P. Comparative pharmacokinetics of zidovudine (AZT) and its metabolite (GAZT) in healthy subjects and HIV seropositive patients. Eur. J. Clin. Pharmacol. 1989, 36, 639-640.
104. Dudley, M. N. Clinical pharmacokinetics of nucleoside antiretroviral agents. J. Infect. Dis. 1995, 171, S99-S112.
105. Zhu, Z.; Hitchcock, M. J.; Sommadossi, J. P. Metabolism and DNA interaction of 2′,3′-didehydro-2′,3′ -dideoxythymidine in human bone marrow cells. Mol. Pharmacol. 1991, 40, 838-845.
106. Klecker, R. W. Jr.; Collins, J. M.; Yarchoan, R. C.; Thomas, R.; McAtee, N.; Broder, S.; Myers, C. E. Pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS and related disorders. J. Clin. Pharmacol. 1988, 28, 837-842.
107. Gustavson, L. E.; Fukuda, E. K.; Rubio, F. A.; Dunton, A. W. A pilot study of the bioavailability and pharmacokinetics of 2′,3′-dideoxycytidine in patients with AIDS or AIDS-related complex. J. Acquir. Immune Defic. Syndr. 1990, 3, 28-31.
108. Yarchoan, R.; Perno, C. F.; Thomas, R. V.; Klecker, R. W.; Allain, J. P.; Wills, R. J.; McAtee, N.; Fischl, M. A.; Dubinsky, R.; McNeely, M. C.; Mitsuya, H.; Pluda, J. M.; Lowely, T. J.; Leuther, M.; Safai, B.; Collins, J. M.; Myers, C. E.; Broder, S. Phase I studies of 2′,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988, 1, 76-81.
109. Yuen, G. J.; Morris, D. M.; Mydlow, P. K.; Haidar, S.; Hall, S. T.; Hussey, E. K. Pharmacokinetics, absolute bioavailability, and absorption characteristics of lamivudine. J. Clin. Pharmacol. 1995, 35, 1174-1180.
110. Moore, K. H.; Yuen, G. J.; Raasch, R. H.; Eron, J. J.; Martin, D.; Mydlow, P. K.; Hussey, E. K. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin. Pharmacol. Ther. 1996, 59, 550-558.
111. Hartman, N. R.; Yarchoan, R.; Pluda, J. M.; Thomas, R. V.; Wyvill, K. M.; Flora, K. P.; Broder, S.; Johns, D. G. Pharmacokinetics of 2′,3′-dideoxyinosine in patients with severe human immunodeficiency infection. The effects of different oral formulations and the presence of other medications. Clin. Pharmacol. Ther. 1991, 50, 278-285.
112. Knupp, C. A.; Shyu, W. C.; Dolin, R.; Valentine, F. T.; McLaren, C.; Martin, R. R.; Pittman, K. A.; Barbhaiya, R. H. Pharmacokinetics of didanosine in patients with acquired immunodeficiency syndrome or acquired immunodeficiency syndrome-related complex. Clin. Pharmacol. Ther. 1991, 49, 523-535.
113. Kumar, P. N.; Sweet, D. E.; McDowell, J. A.; Symonds, W.; Lou, Y.; Hetherington, S.; LaFon, S. Safety and pharmacokinetics of abacavir (1592U89) following oral administration of escalating single doses in human immunodeficiency virus type 1-infected adults. Antimicrob. Agents Chemother. 1999, 43, 603-608.
114. Stretcher, B. N.; Pesce, A. J.; Frame, P. T.; Greenberg, K. A.; Stein, D. S. Correlates of zidovudine phosphorylation with markers of HIV disease progression and drug toxicity. AIDS 1994, 8, 763-769.
115. Fletcher, C. V.; Acosta, E. P.; Henry, K.; Page, L. M.; Gross, C. R.; Kawle, S. P.; Remmel, R. P.; Erice, A.; Balfour, H. H. Jr. Concentration-controlled zidovudine therapy. Clin. Pharmacol. Ther. 1998, 64, 331-338.
116. Rodman, J. H.; Robbins, B.; Flynn, P. M.; Fridland, A. A systemic and cellular model for zidovudine plasma concentrations and intracellular phosphorylation in patients. J. Infect. Dis. 1996, 174, 490-499.
117. Stretcher, B. N.; Pesce, A. J.; Frame, P. T.; Stein, D. S. Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 1994, 38, 1541-1547.
118. Drusano, G. L.; Yuen, G. J.; Lambert, J. S.; Seidlin, M.; Dolin, R.; Valentine, F. T. Relationship between dideoxyinosine exposure, CD4 counts, and p24 antigen levels in human immunodeficiency virus infection. A Phase I trial. Ann. Intern. Med. 1992, 16, 562-566.
119. Flexner, C.; van der Horst, C.; Jacobson, M. A.; Powderly, W.; Duncanson, F.; Ganes, D.; Barditch-Crovo, P. A.; Petty, B. G.; Baron, P. A.; Armstrong, D.; Bricmont, P.; Kuye, O.; Yacobi, A.; DesJardins, R.; Polsky, B. Relationship between plasma concentrations of 3′-deoxy-3′-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. J. Infect. Dis. 1994, 170, 1394-1403.
120. Weller, S.; Radomski, K. M.; Lou, Y.; Stein, D. S. Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects. Antimicrob. Agents Chemother. 2000, 44, 2052-2060.
121. Lange, J. A. rational approach to the selection and sequencing of nucleoside/nucleotide analogues: a new paradigm. Antivir. Ther. 2001, 3, 45-54.
122. Tebas, P.; Patick, A. K.; Kane, E. M.; Klebert. M. K.; Simpson, J. H.; Erice, A.; Powderly, W. G.; Henry, K. Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999, 13, F23-F28.
123. Katlama, C.; Schneider, L.; Agher, R.; Delaugerre, C.; Calvez, V.; Legrand, M.; Tubiana, R. Ritonavir (RTV)/Amprenavir (APV) combination therapy in HIV infected patients who failed several protease inhibitor containing regimen. AIDS 2000, 14,S28.
124. Zaccarelli, M.; Cingolani, A.; Forbici, F.; Rizzo, M. G.; Trotta, M. P.; Bertoli, A.; Di Giambendetto, S.; D' Arrigo, R.; Baldini, F.; Liuzzi, G.; Ciancio, B.; Bellocchi, M. C.; Murri, R.; Girardi, F.; Ammassari, A.; Ippolito, G.; De Luca, A.; Antinori, A.; Perno, C. F. Cross-resistance among NNRTIs: evaluation of the option of recycling efavirnez after nevirapine failure. Antivir. Ther. 2001, 6, S26.
125. Moore, J. D.; Valette, G.; Darque, A.; Zhou, X. J.; Sommadossi, J. P. Simultaneous quantitation of the 5′-triphosphate metabolites of zidovudine, lamivudine, and stavudine in peripheral mononuclear blood cells of HIV infected patients by high-performance liquid chromatography tandem mass spectrometry. J. Am. Soc. Mass Spectrom. 2000, 11, 1134-1143.
126. Hammer, S. M.; Katzenstein, D. A.; Hughes, M. D.; Gundacker, H.; Schooley, R. T.; Haubrich, R. H.; Henry, W. K.; Lederman, M. M.; Phair, J. P.; Niu, M.; Hirsch, M. S.; Merigan, T. C. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. N. Engl. J. Med. 1996, 335, 1081-1090.
127. Saravolatz, L. D.; Winslow, D. L.; Collins, G.; Hodges, J. S.; Pettinelli, C.; Stein, D. S.; Markowitz, N.; Reves, R.; Loveless, M. O.; Crane, L.; Thompson, M.; Abrams, D. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. Investigators for the Terry Beirn Community Programs for Clinical Research on AIDS. N. Engl. J. Med. 1996, 15, 1099-1106.
128. Delta Coordinating Committee. Evidence for prolonged clinical benefit from initial combination antiretroviral therapy: Delta extended follow up. HIV Med. 2001, 2, 181-188.
129. Mayers, D. L.; Japour, A. J.; Arduino, J. M.; Hammer, S. M.; Reichman, R.; Wagner, K. F.; Chung, R.; Lane, J.; Crumpacker, C. S.; McLeod, G. X.; Beckett, L. A.; Roberts, C. R.; Winslow, D.; Burke, D.; RV43 Study Group. Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. The RV43 Study Group. Antimicrob. Agents Chemother. 1994, 38, 307-314.
130. Collins, J. M.; Klecker, R. W. Jr.; Kelley, J. A.; Roth, J. S.; McCully, C. L.; Balis, F. M.; Poplack, D. G. Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid. J. Pharmacol. Exp. Ther. 1988, 245, 466-470.
131. Morse, G. D.; Shelton, M. J.; O'Donnell, A. M. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin. Pharmacokinet. 1993, 24, 101-123.
132. Perry, C. M.; Balfour, J. A. Didanosine: An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy
133. Singlas, E.; Taburet, A. M.; Bursa Lebas, F.; Parent de Curzon, O.; Sobel, A.; Chauveau, P.; Viron, B.; al Khayat, R.; Poignet, J. L.; Mignon, F.; Humbert, G.; Fillastre, J.P. Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis. Antimicrob. Agents Chemother. 1992, 36, 1519-1524.
134. Burger, D. M.; Meenhorst, P. L.; Kroon, F. P.; ten Napel, C. H.; Mulder, J. W.; Neef, C.; Koks, C. H.; Bult, A.; Beijnen, J. H. Pharmacokinetic interaction study of zidovudine and didanosine. J. Drug Dev. 1994, 187-194.
135. Heylen, R.; Miller, R. Interactions with antiretroviral drugs. Pharm. J. 1993, 250, 214-216.
136. Dudley, M. N.; Graham, K.K.; Kaul, S.; Geletko, S.; Dunkle, L.; Browne, M.; Mayer, K. Pharmacokinetics of stavudine in patients with AIDS or AIDS-related complex. J. Infect. Dis. 1992, 166, 480-485.
137. Klecker, R. W. Jr.; Collins, J. M., Yarchoan, R.; Thomas, R.; Jenkins, J. F.; Broder, S.; Myers, C. E. Plasma and cerebrospinal fluid pharmacokinetics of 3′-azido-3′-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases. Clin. Pharmacol. Ther. 1987, 41, 407-412.
138. Lea, A. P.; Faulds, D. Stavudine: a review of its pharmacodynamic and pharmacokinetic properties and clinical potential in HIV infection. Drugs 1996, 51, 846-864.
139. Seifert, R. D.; Stewart, M. B.; Sramek, J. J.; Conrad, J.; Kaul, S.; Cutler N. R. Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients. Br. J. Clin. Pharmacol. 1994, 38, 405-410.
140. Moore, K. H.; Shaw, S.; Laurent, A. L.; Lloyd, P.; Duncan, B.; Morris, D. M.; O'Mara, M. J.; Pakes, G. E. Lamivudine/zidovudine as a combined formulation tablet: bioequivalence compared with lamivudine and zidovudine administered concurrently and the effect of food on absorption. J. Clin. Pharmacol. 1999, 3, 593-605.
141. McDowell, J. A.; Chittick, G. E.; Pilati, S. C.; Edwards, K. D.; Stein, D. S. Pharmacokinetic interaction of abacavir (1592U89) and ethanol in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother. 2000, 44, 1686-1690.
142. Hervey, P. S.; Perry, C. M. Abacavir: a review of its clinical potential in patients with HIV infection. Drugs 2000, 60, 447-479.
143. Wang, L. H.; Chittick, G. E.; McDowell, J. A. Single -dose and steady state pharmacokinetics and safety of abacavir (1592U89), zidovudine, and lamivudine administered alone and in combination in adults with human immunodeficiency virus infection. Antimicrob. Agents Chemother. 1999, 43, 1708-1715.
144. Symonds, W. T.; McDowell, J.; Chittick, G.; Moss, J.; Bye, A. The safety and pharmacokinetics of GW1592U89, zidovudine, and lamivudine administered alone and in combination after single-dose administration in HIV-infected patients. AIDS 1996, 2, 23, 523.
145. Carlisle, R.; Belleau, B.; Nguyen-Ba, N.; Stern, D.; Sommadossi, J. P. Cellular pharmacology of the anti-HIV agent BCH-189 (2′-deoxy-3′-thiacytidine) in human peripheral blood mononuclear cells (PBMC). Proc. Am. Assoc. Cancer Res. 1990, 31, 2435.
146. Painter, G.R.; Rimsky, L.T.; Furman, P.A.; Liotta, D.C.; Schinazi, R.F.; Quinn, J.B. Preclinical and clinical development of the anti-HIV, anti-HBV oxathiolane nucleoside analog emtricitabine. In: Frontiers in viral hepatitis Eds.; Schinazi, R.F.; Sommadossi, J.P.; Rice, C. 2003, 521-555.
147. Viread (Tenofovir DF) Prescribing Information. Gilead Sciences, Inc., October 2001.
148. Naesens, L.; Bischofberger, N.; Augustijns, P.; Annaert, P.; Van den Mooter, G.; Arimilli, M. N.; Kim, C. U.; De Clercq, E. Antiretroviral efficacy and pharmacokinetics of oral bis (isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl) adenine in mice. Antimicrob. Agents Chemother. 1998, 42, 1568-1573.
149. Cundy, K. C.; Sueoka, C.; Lynch, G. R.; Griffin, L.; Lee, W. A.; Shaw, J. P. Pharmacokinetics and bioavailability of the anti-human immunodeficiency virus nucleotide analog 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in dogs. Antimicrob. Agents Chemother. 1998, 42, 687-690.
150. Barditch-Crovo, P.; Deeks, S. G.; Collier, A.; Safrin, S.; Coakley, D. F.; Miller, M.; Kearney, B. P.; Coleman, R. L.; Lamy, P. D.; Kahn, J. O.; McGowan, I.; Lietman, P. S. Phase I/II trial of the pharmacokinetics, safety, and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency virus-infected adults. Antimicrob. Agents Chemother. 2001, 45, 2733-2739.
151. Robbins, B. L.; Srinivas, R. V.; Kim, C.; Bischofberger, N.; Fridland, A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob. Agents Chemother. 1998, 42, 612-617.
152. Reichard, P. Interactions between deoxyribonucleotide and DNA synthesis. Annu. Rev. Biochem. 1988, 57, 349-374.
153. Sherley, J. L.; Kelly, T. J. Regulation of human thymidine kinase during the cell cycle. J. Biol. Chem. 1988, 263, 8350-8358.
154. 0) cells. Oncogene 1991, 6, 1427-1435.
155. Kit, S.; Leung, W. C. Submitochondrial localization and characteristics of thymidine kinase molecular forms in parental and kinase-deficient HeLa cells. Biochem. Genet. 1974, 11, 231-247.
156. Munch-Petersen, B.; Cloos, L.; Tyrsted, G.; Eriksson, S. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. J. Biol. Chem. 1991, 266, 9032-9038.
157. Wang, L.; Munch-Petersen, B.; Herrstrom Sjoberg, A.; Hellman, U.; Bergman, T.; Jornvall, H.; Eriksson, S. Human thymidine kinase 2: molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates. FEBS Lett. 1999, 443, 170-174.
158. Kramer, R..; Palmieri, F. Molecular aspects of isolated and reconstituted carrier proteins from animal mitochondria. Biochim. Biophys. Acta 1989, 974, 1-23.
159. LaNoue, K. F.; Schoolwerth, A. C. Metabolite transport in mitochondria. Annu. Rev. Biochem. 1979, 48, 871-922.
160. Klingenberg, M. J. Dialectics in carrier research: the ADP/ATP carrier and the uncoupling protein. Bioenerg. Biomembr. 1993, 25, 447-457.
161. Bridges E. G.; Jiang, Z.; Cheng Y. C. Characterization of a dCTP transport activity reconstituted from human mitochondria. J. Biol. Chem. 1999, 274, 4620-4625.
162. Dolce, V.; Fiermonte, G.; Runswick, M. J.; Palmieri, F.; Walker, J. E. The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals. Proc. Natl. Acad. Sci. 2001, 98, 2-3.
163. Lewis, W.; Dalakas, M. C. Mitochondrial toxicity of antiviral drugs. Nat. Med. 1995, 1, 417-422.
164. Brinkman, K.; Smeitink, J. A.; Romijn, J. A.; Reiss, P. Mitochondrial toxicity induced by nucleoside-analogue reverse transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy Lancet 1999, 354, 1112-1115.
165. Carr, A.; Samaras, K.; Thorisdottir, A.; Kaufmann, G. R.; Chisholm, D. J.; Cooper, D. A. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor- associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: A cohort study. Lancet 1999, 353, 2093-2099.
166. Moyle, G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin. Ther. 2000, 22, 911-936.
167. Arnaudo, E.; Dalakas, M.; Shanske, S.; Moraes, C. T.; DiMauro, S.; Schon, E. A. Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy. Lancet 1991, 337, 508-510.
168. Lewis, W.; Gonzalez, B.; Chomyn, A.; Papoian, T. Zidovudine induces molecular, biochemical, and ultrastructural changes in rat skeletal muscle mitochondria. J. Clin. Invest. 1992, 89, 1354-1360.
169. Parker, W. B.; Cheng, Y. C. Mitochondrial toxicity of NRTI analogs. J. NIH Res. 1994, 6, 57-61.
170. Wright, G. E.; Brown, N. C. Deoxyribonucleotide analogs as inhibitors and substrates of DNA polymerases. Pharmacol. Ther. 1990, 47, 447-497.
171. Lim, S. E.; Longley, M. J.; Copeland, W. C. The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethylmaleimide resistance. J. Biol. Chem. 1999, 274, 38197-38203.
172. Martin, J. L.; Brown, C. E.; Matthews-Davis, N.; Reardon, J. E. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis. Antimicrob. Agents Chemother. 1994, 38, 2743-2749.
173. Cui, L.; Yoon, S.; Schinazi, R. F.; Somadossi, J. P. Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells. J. Clin. Invest. 1995, 95, 555-563.
174. Dalakas, M. C.; Illa, I.; Pezeshkpour, G. H.; Laukaitis, J. P.; Cohen, B.; Griffin, J. L. Mitochondrial myopathy caused by long-term zidovudine therapy. N. Engl. J. Med. 1990, 322, 1098-1105.
175. Dalakas, M. C.; Leon-Monzon, M. E.; Bernardini, I.; Gahl, W. A.; Jay, C. A. Zidovudine-induced mitochondrial myopathy is associated with muscle creatine deficiency and lipid storage. Ann. Neurol. 1994, 35, 482-487.
176. Peters, B. S.; Winer, J.; Landon, D. N.; Stotter, A.; Pinching, A. J. Mitochondrial myopathy associated with chronic zidovudine therapy in AIDS. Q. J. Med. 1993, 86, 5-15.
177. Herskowitz, A.; Willoughby, S. B.; Baughman, K. L.; Schulman, S. P.; Bartlett, J. D. Cardiomyopathy associated with antiretroviral therapy in patients with HIV infection: A report of six cases. Ann. Intern. Med. 1992, 116, 311-313.
178. Chattha, G.; Arieff, A. I.; Cummings, C.; Tierney, L. M. Jr. Lactic acidosis complicating the acquired immunodeficiency syndrome. Ann. Intern. Med. 1993, 118, 37-39.
179. Freiman, J. P.; Helfert, K. E.; Hamrell, M. R.; Stein, D. S. Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS 1993, 7, 379-385.
180. Jolliet, P.; Widmann, J. J. Reye's syndrome in adult with AIDS. Lancet 1990, 335, 1457.
181. Moore, R.; Keruly, J.; Chaisson, R. Incidence of pancreatitis in HIV-infected patients receiving nucleoside reverse transcriptase inhibitor drugs. AIDS 2001, 15, 617-620.
182. Boubaker, K.; Sudre, P.; Flepp, M.; Furrer, H. J.; Haensel, A.; Hirschel, B.; Boggian, K.; Chave, J. P.; Bernasconi, E.; Opravil, M.; Rickenbach, M.; Telenti, A. Hyperlactatemia and antiretroviral therapy: the Swiss HIV Cohort Study. Clin. Infect. Dis. 2001, 33, 1931-1937.
183. Lonergan, J. T.; Havlir, D.; Behling, C.; Pfander, H.; Hassanein, T.; Mathews, W.C. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin. Infect. Dis. 2000, 31, 162-166.
184. Ter Hofstede, H.; De Marie, S.; Foudraine, N.; Danner, S.; Brinkman, K. Clinical features and risk factors of lactic acidosis following long-term antiretroviral therapy: 4 fatal cases. Int. J. STD AIDS 2000 11, 611-616.
185. Church, J.; Mitchell, W.; Gonzalez-Gomez, I.; Christensen, J.; Vu, T. H.; Dimauro, S.; Boles, R. Mitochondrial DNA depletion, near-fatal metabolic acidosis, and liver failure in an HIV-infected child treated with combination antiretroviral therapy. J. Pediatr. 2001, 138, 748-751.
186. Saint-Marc, T.; Partisani, M.; Poizot-Martin, I.; Bruno, F.; Rouviere, O.; Lang, J. M.; Gastaut, J. A.; Touraine, J. L. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999, 13, 1659-1667.
187. Harrison, D. G. Cellular and molecular mechanisms of endothelial cell dysfunction. J. Clin. Invest. 1997, 100, 2153-2157.
188. Sutliff, R. L.; Paul, R. J.; Lewis, W. Aortas from NL4-3 gag/pol AIDS mice have impaired endothelium-dependent relaxation. Presented at FASEB: Experimental Biology, San Diego, CA, 2000.
189. Cohen, P.; Sande, M.; Volberding, P. The AIDS knowledge Base. Little Brown and Company, Boston, 1994, 5, 61-62.
190. Berger, A. R.; Arezzo, J. C.; Schaumburg, H. H.; Skowron, G.; Merigan, T.; Bozzette, S.; Richman, D.; Soo, W. 2′,3′ -dideoxycytidine (ddC) toxic neuropathy: A study of 52 patients. Neurology 1993, 43, 358-362.
191. Dubinsky, R. M.; Yarchoan, R.; Dalakas, M.; Broder, S. Reversible axonal neuropathy from the treatment of AIDS and related disorders with 2′,3′-dideoxycytidine (ddC). Muscle Nerve 1989, 12, 856-860.
192. Merigan, T. C.; Skowron, G.; Bozzette, S. A.; Richman, D.; Uttamchandani, R.; Fischl, M.; Schooley, R.; Hirsch, M.; Soo, W.; Pettinelli, C. Circulating p24 antigen levels and responses to dideoxycytidine in human immunodeficiency virus (HIV) infections. A phase I and II study. Ann. Intern. Med. 1989, 110, 189-194.
193. Yarchoan, R.; Pluda, J. M.; Thomas, R. V.; Mitsuya, H.; Brouwers, P.; Wyvill, K. M.; Hartman, N.; Johns, D. G.; Broder, S. Long-term toxicity/activity profile of 2′,3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet 1990, 336, 526-529.
194. Cooley, T. P.; Kunches, L. M.; Saunders, C. A.; Ritter, J. K.; Perkins, C. J.; McLaren, C.; McCaffrey, R. P.; Liebman, H. A. Once-daily administration of 2′,3′-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Results of a Phase I trial. N. Engl. J. Med. 1990, 322, 1340-1345.
195. Lambert, J. S.; Seidlin, M.; Reichman, R. C.; Plank, C. S.; Laverty, M.; Morse, G. D.; Knupp, C.; McLaren, C.; Pettinelli, C.; Valentine, F. T. 2′,3′-dideoxyinosine (ddI) in patients with the acquired immunodeficiency syndrome or AIDS-related complex. A phase I trial. N. Engl. J. Med. 1990, 322, 1333-1340.
196. Rana, K. Z.; Dudley, M. N. Clinical pharmacokinetics of stavudine. Clin. Pharmacokinet. 1997, 33, 276-284.
197. Anderson, T. D.; Davidovich, A.; Feldman, D.; Sprinkle, T. J.; Arezzo, J.; Brosnan, C.; Calderon, R. O.; Fossom, L. H.; DeVries, J. T.; DeVries, G. H. Mitochondrial schwannopathy and peripheral myelinopathy in a rabbit model of dideoxycytidine neurotoxicity. Lab. Invest. 1994, 70, 724-739.
198. Cupler, E. J.; Dalakas, M. C. Exacerbation of peripheral neuropathy by lamivudine. Lancet 1995, 345, 460-461.
199. Wain-Hobson, S. The fastest genome evolution ever described: HIV variation in situ. Curr. Opin. Genet. Dev. 1993, 3, 878-883.
200. Vandamme, A. M.; Van Laethem, K.; De Clercq, E. Managing resistance to anti-HIV drugs: an important consideration for effective disease management. Drugs 1999, 57, 337-361.
201. Isel, C.; Ehresmann, C.; Walter, P.; Ehresmann, B.; Marquet, R. The emergence of different resistance mechanisms toward nucleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase. J. Biol. Chem. 2001, 276, 48725-48732.
202. Roberts, J. D.; Bebenek, K.; Kunkel, T. A. The accuracy of reverse transcriptase from HIV-1. Science 1988, 242, 1171-1173.
203. Arion, D.; Kaushik, N.; McCormick, S.; Borkow, G.; Parniak, M. A. Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry 1998, 37, 15908-15917.
204. Arion, D.; Sluis-Cremer, N.; Parniak, M. A. Mechanism by which phosphonoformic acid resistance mutations restore 3′-azido-3′-deoxythymidine (AZT) sensitivity to AZT-resistant HIV-1 reverse transcriptase. J. Biol. Chem. 2000, 275, 9251-9255.
205. Götte, M.; Arion, D., Parniak, M. A.; Wainberg, M. A. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. J. Virol. 2000, 74, 3579-3585.
206. Carroll, S. S.; Geib, J.; Olsen, D. B.; Stahlhut, M.; Shafer, J. A.; Kuo, L. C. Sensitivity of HIV-1 reverse transcriptase and its mutants to inhibition by azidothymidine triphosphate. Biochemistry 1994, 33, 2113-2120.
207. Meyer, P. R.; Matsuura, S. E.; Mian, A. M.; So, A. G.; Scott, W. A. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol. Cell 1999, 4, 35-43.
208. Meyer, P. R.; Matsuura, S. E.; Schinazi, R. F.; So, A. G.; Scott, W. A. Differential removal of thymidine nucleotide analogues from blocked DNA chains by human immunodeficiency virus reverse transcriptase in the presence of physiological concentrations of 2′ -deoxynucleoside triphosphates. Antimicrob. Agents Chemother. 2000, 44, 3465-3472.
209. Meyer, P. R.; Matsuura, S. E.; So, A. G.; Scott, W. A. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc. Natl. Acad. Sci. USA 1998, 95, 13471-13476.
210. Canard, B.; Sarfati, S. R.; Richardson, C. C. Enhanced binding of azidothymidine-resistant human immunodeficiency virus 1 reverse transcriptase to the 3′-azido-3′-deoxythymidine 5′-monophosphate-terminated primer. J. Biol. Chem. 1998, 273, 14596-14604.
211. Feng, J. Y.; Anderson, K. S. Mechanistic studies comparing the incorporation of (+) and (-) isomers of 3TCTP by HIV-1 reverse transcriptase. Biochemistry 1999, 38, 55-63.
212. Wilson, J. E.; Aulabaugh, A.; Caligan, B.; McPherson, S.; Wakefield, J. K.; Jablonski, S.; Morrow, C. D.; Reardon, J. E.; Furman, P. A. Human immunodeficiency virus type-1 reverse transcriptase. Contribution of Met-184 to binding of nucleoside 5′-triphosphate. J. Biol. Chem. 1996, 271, 13656-13662.
213. Krebs, R.; Immendorfer, U.; Thrall, S. H.; Wohrl, B. M.; Goody, R. S. Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3TC. Biochemistry 1997, 36, 10292-10300.
214. Gao, H. Q.; Boyer, P. L.; Sarafianos, S. G.; Arnold, E.; Hughes, S. H. The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase. J. Mol. Biol. 2000, 300, 403-418.
215. Gu, Z.; Arts, E. J.; Parniak, M. A.; Wainberg, M. A. Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2′,3′-dideoxycytidine 5′-triphosphate and other drugs. Proc. Natl. Acad. Sci. 1995, 92, 2760-2764.
216. Martin, J. L.; Wilson, J. E.; Haynes, R. L.; Furman, P. A. Mechanism of resistance of human immunodeficiency virus type 1 to 2′,3′-dideoxyinosine. Proc. Natl. Acad. Sci. 1993, 90, 6135-6139.
217. Selmi, B.; Boretto, J.; Navarro, J. M.; Sire, J.; Longhi, S.; Guerreiro, C.; Mulard, L.; Sarfati, S.; Canard, B. The valine-to-threonine 75 substitution in human immunodeficiency virus type 1 reverse transcriptase and its relation with stavudine resistance. J. Biol. Chem. 2001, 276, 13965-13974.
218. Schinazi, R. F.; Larder, B. A.; Mellors, J. W. Mutations in retroviral genes associated with drug resistance: 2000-2001 update. International Antiviral News 2001, 8, 65-91.
219. Boucher, C. A.; O'Sullivan, E.; Mulder, J. W.; Ramautarsing, C.; Kellam, P.; Darby, G.; Lange. J. M.; Goudsmit, J.; Larder, B. A. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. J. Infect. Dis. 1992, 165, 105-110.
220. Zakharova, O. D.; Suturina, O. A.; Timofeeva, O. A.; Gudima, S. O.; Yamkovoi, V. I.; Kochetkov, S. N.; Fournier, M.; Tarrago-Litvak, L.; Litvak, S.; Nevinsky, G. A. Interaction of tRNA-derivatives and oligonucleotide primers with AZT-resistant mutants of HIV-1 reverse transcriptase. Bioorg. Med. Chem. 1998, 6, 2041-2049.
221. Boyer, P.; Sarafianos, E.; Arnold, E.; Hughes, S. H. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J. Virol. 2001, 75, 4832-4842.
222. Fitzgibbon, J. E.; Farnham, A. E.; Sperber, S. J.; Kim, H.; Dubin, D. T. Human immunodeficiency virus type 1 pol gene mutations in an AIDS patient treated with multiple antiretroviral drugs. J. Virol. 1993, 67, 7271-7275.
223. Boyer, P. L.; Tantillo, C.; Jacobo-Molina, A.; Nanni, R. G.; Ding, J.; Arnold, E.; Hughes, S. H. Sensitivity of wild-type human immunodeficiency virus type 1 reverse transcriptase to dideoxynucleotides depends on template length; the sensitivity of drug-resistant mutants does not. Proc. Natl. Acad. Sci. 1994, 91, 4882-4886.
224. Arion, D.; Borkow, G.; Gu, Z.; Wainberg, M. A.; Parniak, M. A. The K65R mutation confers increased DNA polymerase processivity to HIV-1 reverse transcriptase. J. Biol. Chem. 1996, 271, 19860-19864.
225. St Clair, M. H.; Martin, J. L.; Tudor-Williams, G.; Bach, M. C.; Vavro, C. L.; King, D. M.; Kellam, P.; Kemp, S. D.; Larder, B. A. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 1991, 253, 1557-1559.
226. Larder, B. Mechanisms of HIV-1 drug resistance. AIDS 2001, 15, Suppl. 5, S27-S34.
227. Larder, B. A.; Wang, D. Use of neural networks to define the genetic basis of HIV-1 resistance to d4T. AIDS 2000, 14, S12-S13.
228. Romano, L.; Venturi, G.; Bloor, S.; Harrigan, R.; Larder, B. A.; Major, J. C.; Zazzi, M. Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse-transcriptase mutations at codons 44 and 118. J. Infect. Dis. 2002, 185, 898-904.
229. Tisdale, M.; Kemp, S. D.; Parry, N. R.; Larder, B. A. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc. Natl. Acad Sci. 1993, 90, 5653-5656.
230. Schinazi, R. F.; Lloyd, R. M. Jr.; Nguyen, M. H.; Cannon, D. L.; McMillan, A.; Ilksoy, N.; Chu, C. K.; Liotta, D. C.; Bazmi, H. Z.; Mellors, J. W. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob. Agents Chemother. 1993, 37, 875-881.
231. Tisdale, M.; Alnadaf, T.; Cousens, D. Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89. Antimicrob. Agents Chemother. 1997, 41, 1094-1098.
232. Wainberg, M. A.; Miller, M. D.; Quan, Y.; Salomon, H.; Mulato, A. S.; Lamy, P. D.; Margot, N. A.; Anton, K. E.; Cherrington, J. M. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antiviral. Ther. 1999, 4, 87-94.
233. Srinivas, R. V.; Fridland, A. Antiviral activities of 9-R-2-phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl) PMPA against various drug-resistant human immunodeficiency virus strains. Antimicrob. Agents Chemother. 1998, 42, 1484-1487.
234. Miller, M. D.; Margot, N. A.; Hertogs, K.; Larder, B.; Miller, V. Antiviral activity of tenofovir (PMPA) against nucleoside-resistant clinical HIV samples. Nucleosides Nucleotides Nucleic Acids 2001, 20, 1025-1028.
235. Masquelier, B.; Descamps, D.; Carriere, I.; Ferchal, F.; Collin, G.; Denayrolles, M.; Ruffault, A.; Chanzy, B.; Izopet, J.; Buffet-Janvresse, C.; Schmitt, M.P.; Race, E.; Fleury, H. J.; Aboulker, J. P.; Yeni, P.; Brun-Vezinet, F. Zidovudine resensitization and dual HIV-1 resistance to zidovudine and lamivudine in the delta lamivudine roll-over study. Antivir. Ther. 1999, 4, 69-77.
236. Larder, B. A.; Kemp, S. D.; Harrigan, P. R. Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science. 1995, 269, 696-699.
237. Katlama, C.; Ingrand, D.; Loveday, C.; Clumeck, N.; Mallolas, J.; Staszewski, S.; Johnson, M.; Hill, A. M.; Pearce, G.; McDade, H.; Lamivudine European HIV Working Group. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. 1996, 276, 118-125.
238. Ingrand, D.; Weber, J.; Boucher, C. A.; Loveday, C.; Robert, C.; Hill, A.; Cammack, N.; The Lamivudine European HIV Working Group. Phase I/II study of 3TC (lamivudine) in HIV-positive, asymptomatic or mild AIDS-related complex patients: sustained reduction in viral markers. AIDS. 1995, 9, 1323-1329.
239. Phillips, A. N.; Eron, J.; Bartlett, J.; Kuritzkes, D. R.; Johnson, V. A.; Gilbert, C.; Johnson, J.; Keller, A.; Hill, A. M.; North American Lamivudine HIV Working Group. Correspondence between the effect of zidovudine plus lamivudine on plasma HIV level/CD4 lymphocyte count and the incidence of clinical disease in infected individuals. AIDS 1997, 11, 169-175.
240. CAESAR Coordinating Committee. Randomized trial of addition of lamivudine or lamivudine plus loviridine to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997, 349, 1413-1421.
241. Skowron, G.; Kuritzkes, D. R.; Thompson, M. A.; Squires, K. E.; Goodwin, S. D.; Dusak, B. A.; Tolson, J. M.; Stevens, M.; Yuen, G. J.; Rooney, J. F. Once-daily quadruple-drug therapy with adefovir dipivoxil, lamivudine, didanosine, and efavirenz in treatment-naive human immunodeficiency virus type 1-infected patients. J. Infect. Dis. 2002, 186, 1028-1033.
242. Winters, M. M.; Bosch, R. J.; Albrecht, M. A.; Katzensteinfor, D. A. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside-experienced patients. Antiviral Therapy 2002, 7, S101.
243. Eron, J.; Bosch, R. J.; Petch, L.; Fiscus, S.; Frank, I. Antiretroviral activity of didanosine in lamivudine-experienced patients in comparison to activity in subjects who were lamivudine-naïve. Antivir. Ther. 2002, 7, S102.
244. Loutfy, M. R.; Walmsley, S. L. Salvage antiretroviral therapy in HIV infection. Expert Opin. Pharmacother. 2002, 3, 81-90.
245. Physicians' Desk Reference. 2003. 57th ed., p. 1104-1107. Medical Economics Company, Inc., Montvale, NJ.
246. Mulato, A.; Cherrington, J. M. Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. Antiviral Res. 1997, 36, 91-97.
247. Richman, D. D. Antiretroviral activity of emtricitabine, a potent nucleoside reverse transcriptase inhibitor. Antivir. Ther. 2001, 6, 83-88.
248. Skowron, G. ddC (zalcitabine). Adv. Exp. Med. Biol. 1996, 394, 257-269.
249. Perry, C. M.; Fauld, D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1997, 53, 657-680.
250. Devineni, D.; Gallo, J. M. Zalcitabine. Clinical pharmacokinetics and efficacy. Clin. Pharmacokinet. 1995, 28, 351-360.
251. Chu, C. K.; Schinazi, R. F.; Arnold, B. H.; Cannon, D. L.; Doboszewski, B.; Bhadti, V. B.; Gu, Z. Comparative activity of 2′,3′-saturated and unsaturated pyrimidine and purine nucleosides against HIV-1 in peripheral blood mononuclear cells. Biochem Pharmacol. 1988, 37, 19, 3543-3548.
252. Balzarini, J.; Van Aeschot, A.; Herdewijn, P.; De Clercq, E. 5-Chloro-substituted derivatives of 2′, 3′-didehydro-2′,3′-dideoxyuridine, 3′-fluoro-2′,3′-dideoxyuridine and 3′-azido-2′,3′-dideoxyuridine as anti-HIV agents. Biochem. Pharmacol. 1989, 38, 869-874.
253. Coates, J. A. V.; Cammack, N.; Jenkinson, H. J.; Mutton, I. M.; Pearson, B. A.; Storer, R.; Cameron, J. M.; Penn, C. R. The separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob. Agents Chemother. 1992, 36, 202-205.
254. Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric synthesis and biological evaluation of beta-L-(2R,5S)- and alpha-L-(2R, 5R)-1,3-oxathiolane-pyrimidine and purine nucleosides as potential anti-HIV agents. J. Med. Chem. 1993, 36, 181-195.
255. Arimilli, M. N.; Kim, C. U.; Dougherty, J.; Mulato, A.; Oliyai, R.; Shaw, J. P.; Cundy, K. C.; Bischofberger, N. Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-[(phosphonomethoxy)propyl]adenine (PMPA) Prodrugs. Antivir. Chem. Chemother. 1997, 8, 557-564.
256. Arimilli, M. N.; Cundy, K. C.; Dougherty, J. P.; Kim, C. U.; Oliyai, R.; Stella, V. J. Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability (Patent to Gilead Sciences, Inc, United States) Patent: US 5,922, 695 33, Pp, 1999.
257. Tan, X.; Chu, C. K.; Boudinot, F. D. Development and optimization of anti-HIV nucleoside analogs and prodrugs: A review of their cellular pharmacology, structure-activity relationships and pharmacokinetics. Adv. Drug Deliv. Rev. 1999, 39, 117-151.
258. Beach, J. W. Chemotherapeutic agents for human immunodeficiency virus infection: mechanism of action, pharmacokinetics, metabolism, and adverse reactions. Clin. Ther. 1998, 20, 2-25.
259. Moodley, D.; Pillay, K.; Naidoo, K.; Moodley, J.; Johnson, M. A.; Moore, K. H.; Mudd, P. N. Jr.; Pakes, G. E. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. J. Clin. Pharmacol. 2001, 41, 732-741.
260. van Leeuwen, R.; Lange, J. M.; Hussey, E. K., Donn, K. H.; Hall, S. T.; Harker, A. J.; Jonker, P.; Danner, S. A. The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a Phase I study. AIDS. 1992, 6, 1471-1475.
261. van Leeuwen, R.; Katlama, C.; Kitchen, V.; Boucher, C. A.; Tubiana, R.; McBride, M.; Ingrand, D.; Weber, J.; Hill, A.; McDade, H.; Danner, S. A. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a Phase I/II study. J. Infect. Dis. 1995, 171, 1166-1171.
262. Retrovir Product Information. Glaxo Wellcome Inc., Research Triangle Prk, NC, 1996.
263. Epivir Product Information. Glaxo Wellcome Inc., Research Triangle Prk, NC, 1996.
264. Pelucio, M. T.; Rothenhaus, T.; Smith, M.; Ward, D. J. Fatal pancreatitis as a complication of therapy for HIV infection. J. Emerg. Med. 1995, 13, 633-637.
265. Viramune Product Information. Roxane Laboratories, Columbus, Ohio, 1996.
266. Pluda, J. M.; Cooley, T. P.; Montaner, J. S.; Shay, L. E.; Reinhalter, N. E.; Warthan, S. N.; Ruedy, J.; Hirst, H. M.; Vicary, C. A.; Quinn, J. B.; Yuen, G. J.; Wainberg, M. A.; Rubin, M.; Yarchoan, R. A phase I/II study of 2′-deoxy-3′-thiacytidine (lamivudine) in patients with advanced human immunodeficiency virus infection. J. Infect. Dis. 1995, 171, 1438-1447.
267. Videx Product Information. Bristol-Myers Squibb, Princeton, NJ, 1996.
268. Zerit Product Information. Bristol-Myers Squibb, Princeton, NJ, 1996.
269. Yarchoan, R.; Klecker, R. W.; Weinhold, K. J.; Markham, P. D.; Lyerly, H. K.; Durack, D. T.; Gelmann, E.; Lehrman, S. N.; Blum, R. M.; Barry, D. W.; Shearer, G. M.; Fischl, M. A.; Mitsuya, H.; Gallo, R. C.; Collins, J. M.; Bolognesi, D. P.; Myers, C. E.; Broder, S. Administration of 3′-azido-3′-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. Lancet. 1986, 1, 575-580.
270. Marchbanks, K.; Dudley, M. N.; Posner, M. R.; Darnowski, J. Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer. Pharmacotherapy. 1995, 15, 451-457.
271. Pizzo, P. A.; Butler, K.; Balis, F.; Brouwers, E.; Hawkins, M.; Eddy, J.; Einloth, M.; Falloon, J.; Husson, R.; Jarosinski P. Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection. J. Pediatr. 1990, 117, 799-808.
272. Paff, M. T.; Averett, D. R.; Prus, K. L.; Miller, W. H.; Nelson, D. J. Intracellular metabolism of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in HepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob. Agents Chemother. 1994, 38, 1230-1238.
273. Adkins, J. C.; Peters, D. H.; Faulds, D. Zalcitabine. An update of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of HIV infection. Drugs 1997, 53, 1054-80.
274. Zhu, Z.; Ho, H. T.; Hitchcock, M. J.; Sommadossi, J. P. Cellular pharmacology of 2′,3′-didehydro-2′,3′ -dideoxythymidine (D4T) in human peripheral blood mononuclear cells. Biochem. Pharmacol. 1990, 39, R15-19.
275. Wilde, M. I.; Langtry, H. D. Zidovudine. An update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1993, 46, 515-578.
276. Good, S. S.; de Miranda, P. Species differences in the metabolism and disposition of antiviral nucleoside analogues. Zidovudine. Antiviral Chemistry and Chemotherapy 1992, 3, 65-77.
277. Rollinski, B.; Wintergerst, U.; Sadri, I.; Bogner, J. R.; Goebel, F. D. Protein binding of zidovudine in the sera of healthy controls and patients infected with human immunodeficiency virus. Drug Investigation 1993, 5, 166-172.
278. Hoetelmans, R. M.; Kraaijeveld, C. L.; Meenhorst, P. L.; Mulder, J. W.; Burger, D. M.; Koks, C. H.; Beijnen, J. H. Penetration of 3′-amino-3′-deoxythymidine, a cytotoxic metabolite of zidovudine, into the cerebrospinal fluid of HIV-1-infected patients. 1997, 15, 131-136.
279. Langtry, H. D.; Campoli-Richards, D.M. Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1989, 37, 408-450.