Anti-HIV drug distribution to the central nervous system

Current Pharmaceutical Design

Volumn 10, Issue 12, 2004, Pages 1313-1324

  Thomas, Sarah A ^a  

^a KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Blood brain barrier; Choroid plexus; CSF; HIV; Non nucleoside reverse transcriptase inhibitors; Nucleoside reverse transcriptase inhibitors; Protease inhibitors; Transport

Indexed keywords

ABACAVIR; AMPRENAVIR; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; BENZBROMARONE; CARBOVIR; DELAVIRDINE; DIDANOSINE; DIGOXIN; EFAVIRENZ; GLYCOPROTEIN P; INDINAVIR; LAMIVUDINE; LOPINAVIR; MULTIDRUG RESISTANCE PROTEIN; NELFINAVIR; NEVIRAPINE; PROBENECID; PROTEINASE INHIBITOR; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; ZALCITABINE; ZIDOVUDINE;

BLOOD BRAIN BARRIER; BLOOD CEREBROSPINAL FLUID BARRIER; CENTRAL NERVOUS SYSTEM; CLINICAL TRIAL; DRUG BLOOD LEVEL; DRUG CLASSIFICATION; DRUG DISTRIBUTION; DRUG PENETRATION; DRUG POTENCY; DRUG POTENTIATION; DRUG SOLUBILITY; DRUG TISSUE LEVEL; DRUG TRANSPORT; HEADACHE; HEMATOLOGIC DISEASE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIPOPHILICITY; LIVER DISEASE; MENTAL DISEASE; MOUSE; MYOPATHY; NEUROPATHY; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; SKIN DISEASE; VIRUS REPLICATION;

ANIMALS; ANTI-HIV AGENTS; CENTRAL NERVOUS SYSTEM; HIV INFECTIONS; HUMANS;

EID: 2342439868     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043384835     Document Type: Review

References (162)

1. Perelson AS, Essunger P, Cao Y, Vesanen M, Hurley A, Saksela K, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387: 188-191.
2. Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, et al. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 1997; 278: 1291-1295.
3. Schrager LK, D'Souza MP. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 1998; 280: 67-71.
4. Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 1999; 5:512-517.
5. Wiley CA, Achim CL, Christopherson C, Kidane Y, Kwok S, Masliah E, et al. HIV mediates a productive infection of the brain. AIDS 1999; 13: 2055-2059.
6. Lambotte O, Deiva K, Tardieu M. HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era. Brain Pathol 2003; 13: 95-103.
7. Cashion MF, Banks WA, Bost KL, Kastin AJ. Transmission routes of HIV-1 gp120 from brain to lymphoid tissues. Brain Res 1999; 822: 26-33.
8. Cunningham PH, Smith DG, Satchell C, Cooper DA, Brew B. Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid. AIDS 2000; 14: 1949-1954.
9. Venturi G, Catucci M, Romano L, Corsi P, Leoncini F, Valensin PE, et al. Antiretroviral resistance mutations in human immunodeficiency virus type 1 reverse transcriptase and protease from paired cerebrospinal fluid and plasma samples. J Infect Dis 2000; 181: 740-745.
10. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS 2002; 16: 1201-1215.
11. Bonnet F, Dequae-Merchadou L, Taupin JL, Sire S, Dupon M, Ragnaud JM, et al. Increase in CD3+ CD4- T lymphocytes in patients with AIDS and disseminated Mycobacterium avium-intracellulare complex infection: a prospective study. GECSA. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine. Microbes Infect 1999; 1: 771-776.
12. d'Arminio MA, Duca PG, Vago L, Grassi MP, Moroni M. Decreasing incidence of CNS AIDS-defining events associated with antiretroviral therapy. Neurology 2000; 54: 1856-1859.
13. Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A. Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 2000; 69: 376-380.
14. Resnick L, Berger JR, Shapshak P, Tourtellotte WW. Early penetration of the blood-brain-barrier by HIV. Neurology 1988; 38: 9-14.
15. Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ. Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 1999; 13: 1249-1253.
16. Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, et al. HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 2002; 8: 136-142.
17. Sacktor NC, Lyles RH, Skolasky RL, Anderson DE, McArthur JC, McFarlane G, et al. Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men. Multicenter AIDS Cohort Study (MACS). Neurology 1999; 52: 1640-1647.
18. Sacktor NC, Skolasky RL, Lyles RH, Esposito D, Selnes OA, McArthur JC. Improvement in HIV-associated motor slowing after antiretroviral therapy including protease inhibitors. J Neurovirol 2000; 6: 84-88.
19. Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I, et al. Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 1999; 53: 782-789.
20. Banks WA. Physiology and pathology of the blood-brain barrier: implications for microbial pathogenesis, drug delivery and neurodegenerative disorders. J Neurovirol 1999; 5: 538-555.
21. Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 2001; 53: 569-596.
22. de Boer AG, van dS, I, Gaillard PJ. The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 2003; 43: 629-656.
23. Sun H, Dai H, Shaik N, Elmquist WF. Drug efflux transporters in the CNS. Adv Drug Deliv Rev 2003; 55: 83-105.
24. Taylor EM. The impact of efflux transporters in the brain on the development of drugs for CNS disorders. Clin Pharmacokinet 2002; 41: 81-92.
25. Gibbs JE, Jayabalan P, Thomas SA. Mechanisms by which 2′,3′-dideoxyinosine (ddI) crosses the guinea-pig CNS barriers; relevance to HIV therapy. J Neurochem 2003; 84: 725-734.
26. Groothuis DR, Levy RM. The entry of antiviral and antiretroviral drugs into the central nervous system. J Neurovirol 1997; 3: 387-400.
27. Thomas SA, Segal MB. The transport of the anti-HIV drug, 2′,3′-didehydro-3′-deoxythymidine (D4T), across the blood-brain and blood-cerebrospinal fluid barriers. Br J Pharmacol 1998; 125: 49-54.
28. Bradbury M. The Concept of a Blood-Brain Barrier. Wiley and Sons 1979;
29. Voetman E. On the structure and surface area of the human choroid plexuses. Acta Anatomica 1949; 8:104-116.
30. Gibbs JE, Thomas SA. The distribution of the anti-HIV drug, 2′3′-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors. J Neurochem 2002; 80: 392-404.
31. Bouldin TW, Krigman MR. Differential permeability of cerebral capillary and choroid plexus to lanthanum ion. Brain Res 1975; 99: 444-448.
32. Sawchuk RJ, Yang Z. Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. Adv Drug Deliv Rev 1999; 39: 5-31.
33. Kandanearatchi A, Williams B, Everall IP. Assessing the efficacy of highly active antiretroviral therapy in the brain. Brain Pathol 2003; 13: 104-110.
34. Tarrago-Litvak L, Andreola ML, Fournier M, Nevinsky GA, Parissi V, de Soultrait VR, et al. Inhibitors of HIV-1 reverse transcriptase and integrase: classical and emerging therapeutical approaches. Curr Pharm Des 2002; 8: 595-614.
35. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. HIV Med 2001; 2: 276-313.
36. Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, et al. Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. JAMA 2002; 288: 222-235.
37. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Ann Intern Med 2002; 137: 381-433.
38. Curtis H, Sabin CA, Johnson MA. Findings from the first national clinical audit of treatment for people with HIV. HIV Med 2003; 4: 11-17.
39. Portegies P, de Gans J, Lange JM, Derix MM, Speelman H, Bakker M, et al. Declining incidente of AIDS dementia complex after introduction of zidovudine treatment. BMJ 1989; 299: 819-821.
40. Sidtis JJ, Gatsonis C, Price RW, Singer EJ, Collier AC, Richman DD, et al. Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol 1993; 33: 343-349.
41. Baldeweg T, Catalan J, Gazzard BG. Risk of HIV dementia and opportunistic brain disease in AIDS and zidovudine therapy. J Neurol Neurosurg Psychiatry 1998; 65: 34-41.
42. Gray F, Belec L, Keohane C, De Truchis P, Clair B, Durigon M, et al. Zidovudine therapy and HIV encephalitis: a 10-year neuropathological survey. AIDS 1994; 8: 489-493.
43. Vago L, Castagna A, Lazzarin A, Trabattoni G, Cinque P, Costanzi G. Reduced frequency of HIV-induced brain lesions in AIDS patients treated with zidovudine. J Acquir Immune Defic Syndr 1993; 6: 42-45.
44. Terasaki T, Pardridge WM. Restricted transport of 3′-azido-3′-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J Infect Dis 1988; 158: 630-632.
45. de Miranda P, Burnette TC, Good SS. Tissue distribution and metabolic disposition of zidovudine in rats. Drug Metab Dispos 1990; 18: 315-320.
46. Ahmed AE, Jacob S, Loh JP, Samra SK, Nokta M, Pollard RB. Comparative disposition and whole-body autoradiographic distribution of [2-14C]azidothymidine and [2-14C]thymidine in mice. J Pharmacol Exp Ther 1991; 257: 479-486.
47. Galinsky RE, Hoesterey BL, Anderson BD. Brain and cerebrospinal fluid uptake of zidovudine (AZT) in rats after intravenous injection. Life Sci 1990; 47: 781-788.
48. Gallo JM, Sanzgiri Y, Howerth EW, Finco TS, Wilson J, Johnston J, et al. Zidovudine serum, cerebrospinal fluid, and brain concentrations following chronic administration of a new zidovudine formulation via an implantable pump in dogs [corrected]. J Pharm Sci 1992; 81: 11-15.
49. Fox E, Bungay PM, Bacher J, McCully CL, Dedrick RL, Balis FM. Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey. J Pharmacol Exp Ther 2002; 301: 1003-1011.
50. Thomas SA, Segal MB. The passage of azidodeoxythymidine into and within the central nervous system: does it follow the parent compound, thymidine? J Pharmacol Exp Ther 1997; 281: 1211-1218.
51. Takasawa K, Terasaki T, Suzuki H, Ooie T, Sugiyama Y. Distributed model analysis of 3′-azido-3′-deoxythymidine and 2′,3′-dideoxyinosine distribution in brain tissue and cerebrospinal fluid. J Pharmacol Exp Ther 1997; 282: 1509-1517.
52. Collins JM, Klecker RW Jr, Kelley JA, Roth JS, McCully CL, Balis FM, et al. Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid. J Pharmacol Exp Ther 1988; 245: 466-470.
53. Masereeuw R, Jaehde U, Langemeijer MW, de Boer AG, Breimer DD. In vitro and in vivo transport of zidovudine (AZT) across the blood-brain barrier and the effect of transport inhibitors. Pharm Res 1994; 11: 324-330.
54. Tuntland T, Ravasco RJ, al Habet S, Unadkat JD. Efflux of zidovudine and 2′,3′-dideoxyinosine out of the cerebrospinal fluid when administered alone and in combination to Macaca nemestrina. Pharm Res 1994; 11: 312-317.
55. Sawchuk RJ, Hedaya MA. Modeling the enhanced uptake of zidovudine (AZT) into cerebrospinal fluid. 1. Effect of probenecid. Pharm Res 1990; 7: 332-338.
56. Dykstra KH, Arya A, Arriola DM, Bungay PM, Morrison PF, Dedrick RL. Microdialysis study of zidovudine (AZT) transport in rat brain. J Pharmacol Exp Ther 1993; 267: 1227-1236.
57. Takasawa K, Terasaki T, Suzuki H, Sugiyama Y. In vivo evidence for carrier-mediated efflux transport of 3′-azido-3′-deoxythymidine and 2′-3′ -dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transpor system. J Pharmacol Exp Ther 1997; 281: 369-375.
58. Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H. Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 1997; 272: 18526-18529.
59. Sweet DH, Wolff NA, Pritchard JB. Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 1997; 272: 30088-30095.
60. Pritchard JB, Sweet DH, Miller DS, Walden R. Mechanism of organic anion transport across the apical membrane of choroid plexus. J Biol Chem 1999; 274: 33382-33387.
61. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, et al. Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther 2000; 294: 844-849.
62. Nagata Y, Kusuhara H, Endou H, Sugiyama Y. Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol 2002; 61: 982-988.
63. Strazielle N, Belin M-F, Gersi-Egea J-F. Choroid plexus controls brain availability of anti-HIV nucleoside analogs via pharmacologically inhibitable organic anion transporters. AIDS 2003; 17: 1473-1485.
64. Lin TS, Schinazi RF, Prusoff WH. Potent and selective in vitro activity of 3′-deoxythymidin-2′-ene (3′-deoxy-2′,3′-didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol 1987; 36: 2713-2718.
65. Skowron G. Biologic effects and safety of stavudine: overview of phase I and II clinical trials. J Infect Dis 1995; 171 Suppl 2: S113-Sl17.
66. Hurst M, Noble S. Stavudine: an update of its use in the treatment of HIV infection. Drugs 1999; 58: 919-949.
67. Hogg RS, Heath KV, Yip B, Craib KJ, O'Shaughnessy MV, Schechter MT, et al. Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. JAMA 1998; 279: 450-454.
68. Arendt G, von Giesen HJ, Hefter H, Theisen A. Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection. AIDS 2001; 15: 493-500.
69. Kandanearatchi A, Zuckerman M, Smith M, Vyakarnam A, Everall IP. Granulocyte-macrophage colony-stimulating factor enhances viral load in human brain tissue: amelioration with stavudine. AIDS 2002; 16: 413-420.
70. Haworth SJ, Christofalo B, Anderson RD, Dunkle LM. A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17: 235-238.
71. Foudraine NA, Hoetelmans RM, Lange JM, de Wolf F, van Benthem BH, Maas JJ, et al. Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine plus zidovudine or stavudine. Lancet 1998; 351: 1547-1551.
72. Schinazi RF, Boudinot FD, Doshi KJ, McClure HM. Pharmacokinetics of 3′-fluoro-3′-deoxythymidine and 3′-deoxy-2′,3′-didehydrothymidine in rhesus monkeys. Antimicrob Agents Chemother 1990; 34: 1214-1219.
73. Keller RD, Nosbisch C, Unadkat JD. Pharmacokinetics of stavudine (2′,3′-didehydro-3′-deoxythymidine) in the neonatal macaque (Macaca nemestrina). Antimicrob Agents Chemother 1995; 39: 2829-2831.
74. Yang Z, Brundage RC, Barbhaiya RH, Sawchuk RJ. Microdialysis studies of the distribution of stavudine into the central nervous system in the freely-moving rat. Pharm Res 1997; 14: 865-872.
75. Kaul S, Dandekar KA, Schilling BE, Barbhaiya RH. Toxicokinetics of 2′,3′-didehydro-3′-deoxythymidine, stavudine (D4T). Drug Metab Dispos 1999; 27: 1-12.
76. de Lange EC, de Boer AG, Breimer DD. Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 2000; 45: 125-148.
77. Raskino C, Pearson DA, Baker C J, Lifschitz MH, O'Donnell K, Mintz M, et al. Neurologic, neurocognitive, and brain growth outcomes in human immunodeficiency virus-infected children receiving different nucleoside antiretroviral regimens. Pediatric AIDS Clinical Trials Group 152 Study Team. Pediatrics 1999; 104: e32-
78. Portegies P, Enting RH, de Jong MD, Danner SA, Reiss P, Goudsmit J, et al. AIDS dementia complex and didanosine. Lancet 1994; 344: 759-
79. Stoltz M, Elhawari M, Litle L, Alm P, Tomaszewski J, Grieshaber C. Pharmacokinetics and bioavailability of the anti-AIDS drugs 2′,3′-dideoxyinosine (NSC-612049) in beagle dogs. Am Assoc Can Res 1988; 29: 505-
80. Anderson BD, Hoesterey BL, Baker DC, Galinsky RE. Uptake kinetics of 2′,3′-dideoxyinosine into brain and cerebrospinal fluid of rats: intravenous infusion studies. J Pharmacol Exp Ther 1990; 253: 113-118.
81. Ray GF, Mason WD, Badr MZ. Pharmacokinetics of the anti-AIDS drug 2′,3′-dideoxyinosine in the rat. Drug Metab Dispos 1990; 18: 654-658.
82. Wientjes MG, Placke ME, Chang MJ, Page JG, Kluwe WM, Tomaszewski JE. Pharmacokinetics of 2′,3′-dideoxyadenosine in dogs. Invest New Drugs 1991; 9: 159-168.
83. Hartman NR, Yarchoan R, Pluda JM, Thomas RV, Marczyk KS, Broder S, et al. Pharmacokinetics of 2′,3′-dideoxyadenosine and 2′,3′-dideoxyinosine in patients with severe human immunodeficiency virus infection. Clin Pharmacol Ther 1990; 47: 647-654.
84. Burger DM, Kraayeveld CL, Meenhorst PL, Mulder JW, Hoetelmans RM, Koks CH, et al. Study on didanosine concentrations in cerebrospinal fluid. Implications for the treatment and prevention of AIDS dementia complex. Pharm World Sci 1995; 17: 218-221.
85. Petito CK, Cash KS. Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol 1992; 32: 658-666.
86. Hoesterey BL, Galinsky RE, Anderson BD. Dose dependence in the plasma pharmacokinetics and uptake kinetics of 2′,3′-dideoxyinosine into brain and cerebrospinal fluid of rats. Drug Metab Dispos 1991; 19: 907-912.
87. Kang HJ, Wientjes MG, Au JL. Tissue pharmacokinetics of 2′,3′-dideoxyinosine in rats. Biochem Pharmacol 1994; 48: 2109-2116.
88. Li JY, Boado RJ, Pardridge WM. Differential kinetics of transport of 2′,3′-dideoxyinosine and adenosine via concentrative Na+ nucleoside transporter CNT2 cloned from rat blood-brain barrier. J Pharmacol Exp Ther 2001; 299: 735-740.
89. Chen H, Wood C, Petito CK. Comparisons of HIV-1 viral sequences in brain, choroid plexus and spleen: potential role of choroid plexus in the pathogenesis of HIV encephalitis. J Neurovirol 2000; 6: 498-506.
90. Banks WA, Freed EO, Wolf KM, Robinson SM, Franko M, Kumar VB. Transport of human immunodeficiency virus type 1 pseudoviruses across the blood-brain barrier: role of envelope proteins and adsorptive endocytosis. J Virol 2001; 75: 4681-4691.
91. Noe B, Hagenbuch B, Stieger B, Meier PJ. Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci USA 1997; 94: 10346-10350.
92. Gao B, Stieger B, Noe B, Fritschy JM, Meier PJ. Localization of the organic anion transporting polypeptide 2 (Oatp2) in capillary endothelium and choroid plexus epithelium of rat brain. J Histochem Cytochem 1999; 47:1255-1264.
93. Sugiyama D, Kusuhara H, Shitara Y, Abe T, Sugiyama Y. Effect of 17 beta-estradiol-D-17 beta-glucuronide on the rat organic anion transporting polypeptide 2-mediated transport differs depending on substrates. Drug Metab Dispos 2002; 30: 220-223.
94. Galinsky RE, Flaharty KK, Hoesterey BL, Anderson BD. Probenecid enhances central nervous system uptake of 2′,3′-dideoxyinosine by inhibiting cerebrospinal fluid efflux. J Pharmacol Exp Ther 1991; 257: 972-978.
95. Shelton MJ, O'Donnell AM, Morse GD. Zalcitabine. Ann Pharmacother 1993; 27: 480-489.
96. Yarchoan R, Perno CF, Thomas RV, Klecker RW, Allain JP, Wills RJ, et al. 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.
97. Kelley JA, Litterst CL, Roth JS, Vistica DT, Poplack DG, Cooney DA, et al. The disposition and metabolism of 2′,3′-dideoxycytidine, an in vitro inhibitor of human T-lymphotrophic virus type III infectivity, in mice and monkeys. Drug Metab Dispos 1987; 15: 595-601.
98. Tomaszewski J, Grieshaber C, Balzarini J, Johns DG, Smith AC, Liao JT. Toxicological and pharmacokinetic evaluation of 2′,3′-dideoxycytidine (ddCyd, NSC-606170), a potential drug to treat AIDS. Proc Am Assoc Canc Res 1987; 28: 440-
99. Borg N, Stahle L. Pharmacokinetics and distribution over the blood-brain barrier of zalcitabine (2′,3′-dideoxycytidine) and BEA005 (2′, 3′-dideoxy-3′-hydroxymethylcytidine) in rats, studied by microdialysis. Antimicrob Agents Chemother 1998; 42: 2174-2177.
100. Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC. Inhibition of the replication of hepatitis B virus in vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues. Proc Natl Acad Sci USA 1991; 88: 8495-8499.
101. Coates JA, Cammack N, Jenkinson HJ, Jowett AJ, Jowett MI, Pearson BA, et al. (-)-2′-deoxy-3′-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother 1992; 36: 733-739.
102. Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharmacokinetics of lamivudine. Clin Pharmacokinet 1999; 36: 41-66.
103. van Leeuwen R, Katlama C, Kitchen V, Boucher CA, Tubiana R, McBride M, et al. 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.
104. Mueller BU, Lewis LL, Yuen GJ, Farley M, Keller A, Church JA, et al. Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother 1998; 42: 3187-3192.
105. Blaney SM, Daniel MJ, Harker AJ, Godwin K, Balis FM. Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates. Antimicrob Agents Chemother 1995; 39: 2779-2782.
106. Wu D, Clement JG, Pardridge WM. Low blood-brain barrier permeability to azidothymidine (AZT), 3TC, and thymidine in the rat. Brain Res 1998; 791: 313-316.
107. Gibbs JE, Rasheed T, Thomas SA. Effect of transport inhibitors and additional anti-HIV drugs on the movement of lamivudine (3TC), across the guinea-pig brain-barriers. J Pharm Exp Ther 2003; 306: 1035-1041.
108. Saag MS, Sonnerborg A, Torres RA, Lancaster D, Gazzard BG, Schooley RT, et al. Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults. Abacavir Phase 2 Clinical Team. AIDS 1998; 12: F203-F209.
109. Hughes W, McDowell JA, Shenep J, Flynn P, Kline MW, Yogev R, et al. Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother 1999; 43: 609-615.
110. Kumar PN, Sweet DE, McDowell JA, Symonds W, Lou Y, Hetherington S, et al. 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.
111. Simpson DM. Human immunodeficiency virus-associated dementia: review of pathogenesis, prophylaxis, and treatment studies of zidovudine therapy. Clin Infect Dis 1999; 29: 19-34.
112. Colebunders R, Hilbrands R, De Roo A, Pelgrom J. Neuropsychiatric reaction induced by abacavir. Am J Med 2002; 113: 616-
113. McDowell JA, Chittick GE, Ravitch JR, Polk RE, Kerkering TM, Stein DS. Pharmacokinetics of [(14)C]abacavir, a human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, administered in a single oral dose to HIV-1-infected adults: a mass balance study. Antimicrob Agents Chemother 1999; 43: 2855-2861.
114. Daluge SM, Good SS, Faletto MB, Miller WH, St Clair MH, Boone LR, et al. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob Agents Chemother 1997; 41: 1082-1093.
115. Thomas SA, Bye A, Segal MB. Transport characteristics of the anti-human immunodeficiency virus nucleoside analog, abacavir, into brain and cerebrospinal fluid. J Pharmacol Exp Ther 2001; 298: 947-953.
116. Mahony WB, Domin K., Daluge WH, Miller WH, Zimmerman TP. Membrane permeation characteristics of the structurally related anti-HIV agents 1592 and ()-carbovir in human erythrocytes and human T-lymphoblastoid CD4+ CEM cells (Abstract). Proc Am Assoc Cancer Res 1995; 36:2211.
117. Wang LH, Chittick GE, McDowell JA. Single-dose 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.
118. Hong M, Schlichter L, Bendayan R. A Na(+)-dependent nucleoside transporter in microglia. J Pharmacol Exp Ther 2000; 292: 366-374.
119. Wu X, Yuan G, Brett CM, Hui AC, Giacomini KM. Sodium-dependent nucleoside transport in choroid plexus from rabbit. Evidence for a single transporter for purine and pyrimidine nucleosides. J Biol Chem 1992; 267: 8813-8818.
120. Faletto MB, Miller WH, Garvey EP, St Clair MH, Daluge SM, Good SS. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother 1997; 41:1099-1107.
121. Mahony WB, Domin BA, Daluge SM, Miller WH, Zimmerman TP. Enantiomeric selectivity of carbovir transport. J Biol Chem 1992; 267: 19792-19797.
122. Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu JC, et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990; 250:1411-1413.
123. Moyle G. The emerging roles of non-nucleoside reverse transcriptase inhibitors in antiretroviral therapy. Drugs 2001; 61: 19-26.
124. Cheeseman SH, Havlir D, McLaughlin MM, Greenough TC, Sullivan JL, Hall D, et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8: 141-151.
125. Harris M, Durakovic C, Rae S, Raboud J, Fransen S, Shillington A, et al. A pilot study of nevirapine, indinavir, and lamivudine among patients with advanced human immunodeficiency virus disease who have had failure of combination nucleoside therapy. J Infect Dis 1998; 177: 1514-1520.
126. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354: 795-802.
127. von Giesen HJ, Koller H, Theisen A, Arendt G. Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1-infected patients. J Acquir Immune Defic Syndr 2002; 29: 363-367.
128. Wise ME, Mistry K, Reid S. Drug points: Neuropsychiatric complications of nevirapine treatment. BMJ 2002; 324: 879-
129. Enting RH, Hoetelmans RM, Lange JM, Burger DM, Beijnen JH, Portegies P. Antiretroviral drugs and the central nervous system. AIDS 1998; 12: 1941-1955.
130. Moyle G. Efavirenz: shifting the HAART paradigm in adult HIV-1 infection. Exp Opin Invest Drugs 1999; 8: 473-486.
131. Glynn SL, Yazdanian M. In vitro blood-brain barrier permeability of nevirapine compared to other HIV antiretroviral agents. J Pharm Sci 1998; 87: 306-310.
132. Hartmann M, Rump A, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Evaluation of an efavirenz-containing regimen: an open-label, multicenter study. HIV Clin Trials 2001; 2: 421-428.
133. Lochet P, Peyriere H, Lotthe A, Mauboussin JM, Delmas B, Reynes J. Long-term assessment of neuropsychiatric adverse reactions associated with efavirenz. HIV Med 2003; 4: 62-66.
134. Tashima KT, Caliendo AM, Ahmad M, Gormley JM, Fiske WD, Brennan JM, et al. Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J Infect Dis 1999; 180: 862-864.
135. Albright AV, Erickson-Viitanen S, O'Connor M, Frank I, Rayner MM, Gonzalez-Scarano F. Efavirenz is a potent nonnucleoside reverse transcriptase inhibitor of HIV type 1 replication in microglia in vitro. AIDS Res Hum Retroviruses 2000; 16: 1527-1537.
136. Gulick RM, Hu XJ, Fiscus SA, Fletcher CV, Haubrich R, Cheng H, et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 2000; 182: 1375-1384.
137. Fletcher CV, Acosta EP, Cheng H, Haubrich R, Fischl M, Raasch R, et al. Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV- infected subjects: ACTG 884. AIDS 2000; 14: 2495-2501.
138. Chang M, Sood VK, Wilson GJ, Kloosterman DA, Sanders PE, Hauer MJ, et al. Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdine in mice. Drug Metab Dispos 1997; 25: 828-839.
139. Chaput AJ, D'Ambrosio R, Morse GD. In vitro protein-binding characteristics of delavirdine and its N-dealkylated metabolite. Antiviral Res 1996; 32: 81-89.
140. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A review for clinicians. JAMA 1997; 277: 145-153.
141. Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 1996; 334:1011-1017.
142. Aweeka F, Jayewardene A, Staprans S, Bellibas SE, Kearney B, Lizak P, et al. Failure to detect nelfinavir in the cerebrospinal fluid of HIV-1 - infected patients with and without AIDS dementia complex. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 39-43.
143. Filippi CG, Sze G, Farber SJ, Shahmanesh M, Selwyn PA. Regression of HIV encephalopathy and basal ganglia signal intensity abnormality at MR imaging in patients with AIDS after the initiation of protease inhibitor therapy. Radiology 1998; 206: 491-498.
144. Gisolf EH, Enting RH, Jurriaans S, de Wolf F, van der Ende ME, Hoetelmans RM, et al. Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine. AIDS 2000; 14: 1583-1589.
145. Kravcik S, Gallicano K, Roth V, Cassol S, Hawley-Foss N, Badley A, et al. Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr 1999; 21: 371-375.
146. Solas C, Lafeuillade A, Halfon P, Chadapaud S, Hittinger G, Lacarelle B. Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients. Antimicrob Agents Chemother 2003; 47: 238-243.
147. Zhou XJ, Havlir DV, Richman DD, Acosta EP, Hirsch M, Collier AC, et al. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS 2000; 14: 2869-2876.
148. Lin JH, Chiba M, Balani SK, Chen IW, Kwei GY, Vastag KJ, et al. Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996; 24:1111-1120.
149. Sadler BM, Chittick GE, Polk RE, Slain D, Kerkering TM, Studenberg SD, et al. Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects. J Clin Pharmacol 2001; 41:386-396.
150. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101: 289-294.
151. Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, et al. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos 2000; 28: 655-660.
152. Huisman MT, Smit JW, Schinkel AH. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS 2000; 14: 237-242.
153. Huisman MT, Smit JW, Wiltshire HR, Hoetelmans RM, Beijnen JH, Schinkel AH. P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol Pharmacol 2001; 59: 806-813.
154. Polli JW, Jarrett JL, Studenberg SD, Humphreys JE, Dennis SW, Brouwer KR, et al. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), an HIV protease inhibitor. Pharm Res 1999; 16: 1206-1212.
155. Srinivas RV, Middlemas D, Flynn P, Fridland A. Human immunodeficiency virus protease inhibitors serve as substrates for
156. van dS, I, Vos CM, Nabulsi L, Blom-Roosemalen MC, Voorwinden HH, de Boer AG, et al. Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood-brain barrier. AIDS 2001; 15: 483-491.
157. Huisman MT, Smit JW, Crommentuyn KM, Zelcer N, Wiltshire HR, Beijnen JH, et al. Multidrug resistance protein 2 (MRP2) transports HIV protease inhibitors, and transport can be enhanced by other drugs. AIDS 2002; 16: 2295-2301.
158. Miller DS, Nobmann SN, Gutmann H, Toeroek M, Drewe J, Fricker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol Pharmacol 2000; 58: 1357-1367.
159. Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 1999; 57:1147-1152.
160. Bourinbaiar AS, Jirathitikal V. Low-cost anti-HIV compounds: potential application for AIDS therapy in developing countries. Curr Pharm Design 2003; 9(18): 1419-31.
161. Morris-Natschke SL, Ishaq KS, Kucera LS. Phospholipid analogs against HIV-1 infection and disease. Curr Pharm Design 2003; 9(18): 1441-51.
162. Tarrago-Litvak L, Andreola ML, Fournier M, Nevinsky GA, Parissi V, de Soultrait VR, et al. Inhibitors of HIV-1 reverse transcriptase and integrase: classical and emerging therapeutical approaches. Curr Pharm Design 2002; 8(8): 595-614.