1 Parker Hughes Institute, 2657 Patton Road, St Paul, MN 55113, USA; 2 Paradigm Pharmaceuticals, LLC, St Paul, MN, USA
![]() |
Abstract |
---|
Keywords: adenovirus , conjunctivitis , contact lens , HIV/AIDS , eye infections , stavudine , d4T
![]() |
Introduction |
---|
![]() |
Ocular and genital ADV serotypes |
---|
ADV serotypes 2, 8, 19 and 37 have been isolated from the genital tract of patients attending sexually transmitted disease clinics.3741 Genital ADV infections are associated with urethritis and penile ulcers in men,39,40 and cervicitis and labial ulcers in women3739,42 (Table 1). Some patients with genital ADV infection also have conjunctivitis caused by the same serotype.3844 Additionally, ADVs are associated with a significant number of human upper respiratory (B, C and E), gastrointestinal (A and F), and urinary tract (B) infections. The clinical manifestations of these ADV infections range from a symptomatic excretion of the virus to disseminated disease with multiorgan failure and death, especially in patients with immunological deficiencies.4552 Many HIV-infected patients with AIDS shed ADVs that are rarely or never isolated from immunocompetent individuals.4551 Typical AIDS-associated ADV serotypes include types 9, 17, 20, 22, 23, 26, 27 and 4251.45,47,51 Adenovirus subtypes 2/5 are also being used as vectors for gene delivery in clinical trials to treat a variety of acquired and inherited diseases.5357
|
![]() |
Ocular and genital ADV receptors |
---|
![]() |
Ocular manifestations of ADV infection |
---|
![]() |
Limitations of current anti-ADV agents |
---|
Ribavirin (Virazole®; 1-ß-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a guanosine analogue that inhibits the replication of many RNA and DNA viruses.77 The antiviral mechanism of ribavirin is due to inhibition of viral encoded polymerases, inhibition of genomic RNA capping, or inhibition of cellular encoded enzymes that control de novo synthesis of purine nucleosides. Cidofovir [HPMPC, Vistide, (S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine dihydrate] is a nucleotide analogue that contains a phosphonate group that does not require cellular phosphorylation. Both ribavirin and cidofovir exhibit inhibitory activity in vitro against several RNA and DNA viruses (adeno-, arena-, bunya-, cytomegalo-, EpsteinBarr-, hepadna-, herpes-, irido-, myxo-, papilloma-, paramyxo-, polyoma-, pox-, retroviruses or RNA tumour viruses).7780 Cellular enzymes convert cidofovir into the active diphosphate form. Cidofovir is currently being pursued in the topical/intravenous/intravesicular treatment of ADV infections.78,80,81 The momentum in the design of novel nucleoside analogues for anti-ADV therapy is their ability to discriminate between the viral DNA polymerase and cellular DNA polymerases. None of the currently available anti-HIV agents has potent anti-ADV activity and several experimental anti-ADV agents are associated with significant side effects. Development of nephrotoxicity is the major risk factor encountered with patients receiving cidofovir, whereas extravascular haemolysis, bone marrow suppression, and anaemia are the most common dose-limiting toxic effects seen with ribavirin.78,8184 The local toxicity of cidofovir to the skin of the eyelids and the conjunctiva is clinically similar to the signs of initial ADV inflammation. Consequently, there is an urgent need for selective anti-ADV agents with more favourable safety profiles than the available nucleoside and nucleotide analogues as well as dual-function anti-HIV agents with anti-ADV activity.
![]() |
Stampidine, a novel anti-ADV agent |
---|
Table 2 lists the anti-ADV activity of 12 structurally similar STV derivatives. All 12 derivatives of STV were substantially more potent than STV and inhibited ADV-induced plaque formation at nanomolar IC50 values. Compounds with an electron-withdrawing group (chloro, bromo or di-halogen) at the para position of the phenyl group, which led to enhanced rates of hydrolysis to yield Ala-STV-MP, were the most active compounds. In contrast, electron-donating substituents such as methoxy or methyl-substituted compounds showed a 5- to 10-fold decrease in activity. The position of the substituents on the phenyl ring did not alter the activity profiles. Cluster analysis of log IC50 values for the ADV strain versus Hammett sigma values and partition coefficient (P) values revealed bivariate plots.92 Compounds with higher log P values were more active. However, lipophilicity plays a minor role in predicting the anti-ADV activity of these phosphoramidate derivatives. Unsubstituted, as well as the electron-donating group substituted phosphoramidate derivatives had the highest solubility in water (1245 mg/mL).
|
|
![]() |
Stampidine, a novel broad-spectrum anti-HIV agent |
---|
|
|
|
![]() |
Solubility and formulation studies |
---|
Stability
Based on accelerated stability studies conducted at 40°C, stampidine is a stable molecule at room temperature for more than 6 months. A comparison of the hydrolytic and biological activities of dual-function STV derivatives revealed that the introduction of electron-withdrawing substituents enhanced the antiviral activity of these compounds and the rate of hydrolysis predicted the potency of the compounds.91,92,95,109 All compounds were efficacious against HIV-1 (125 nM). Regression analysis revealed a significant linear relationship between anti-HIV (A17) IC50 values and Hammett sigma values (P = 0.036) or log 10 transformed hydrolysis rates (P = 0.014).92 However, these aryl phosphate derivatives differed more than 60-fold in the rates of alkaline hydrolysis.92,103 The presence of electron-withdrawing groups at the phenyl moiety enhanced the rate of hydrolysis of these phosphoramidate derivatives to yield Ala-STV-MP.91,109
In various tissue microenvironments, the metabolism of stampidine may occur through the action of hydrolytic enzymes. Accordingly, we demonstrated that stampidine and other halogen-substituted phosphoramidate derivatives of STV can be activated by esterase, lipase or protease-mediated hydrolysis.101103 The target site for the lipase appears to be the methyl ester group of the L-alanine side chain. As a result of the stereochemistry of its phosphorous chiral centre, stampidine exists as a mixture of two diastereoisomers. Molecular modelling studies and comparison of the lipase and protease-mediated hydrolysis rate constants indicated a chiral preference of the lipase active site for the putative S-stereoisomer.101104 Cellular metabolic studies of stampidine in COS-7 fibroblast cells revealed lipase or protease hydrolysis of the methyl ester group of the L-alanine side chain to form the cyclic intermediate in a stereoselective fashion.101,103 This intermediate was converted into the active metabolite, Ala-STV-MP. The superior antiviral activity of stampidine was attributed to the rapid formation of Ala-STV-MP. In addition, the presence of electron-withdrawing groups on the phenyl ring enhanced the activity of phosphoramidate derivatives by improving the rate of hydrolysis. Thus, the biological activity of these phosphoramidate derivatives is directly related to their rate of hydrolysis.
Solubility
Stampidine solubility in water was 3.0 mg/mL (Table 2). Solubility ranged from 4.6 mg/mL to 12 mg/mL in commonly utilized ophthalmic and topical formulations for human and veterinary use.108 In non-aqueous water miscible excipients containing polyethylene glycols and propylene glycol, the solubility was >20 mg/mL. The solubility values for stampidine with admixtures of varying amounts of water in hydroxylic excipients showed an exponential rather than a linear relationship.106,107 These solubility studies indicated that aqueous formulations of stampidine are feasible by adjusting the ratios of the excipients for preclinical and clinical studies. The presence of the nitrogen in the pyridine ring would be useful in preparing salt forms of stampidine for further improving its solubility for topical use.
Formulation
Development of stampidine as a topical agent for potential clinical use requires the evaluation of the design of appropriate ocular and genital drug delivery methods. Our initial work with stampidine has established its feasibility as a formulated drug product as a topical agent for mucosal bioavailability.105107 In a study of the accelerated excipient compatibility, stampidine was found to be stable in the presence of various formulation ingredients. The recovery of stampidine after 1 month of storage at 50°C in six excipients ranged from 71% to 94%.
Bioavailability
Stampidine was developed to overcome the dependence of STV on intracellular nucleoside kinase activation. Consequently, the dual-function antiviral activity of stampidine is substantially more potent that that of STV. The presence of a single para-bromine group in the phenyl moiety of stampidine contributes to its ability to undergo rapid hydrolysis yielding the key active metabolites Ala-STV-MP and STV with longer elimination half-lives.91,92,109 Micromolar plasma concentrations of the active metabolites of stampidine were rapidly achieved and maintained for more than 4 h after parenteral as well as oral administration of non-toxic doses of GMP-grade stampidine in preclinical studies.98,99
![]() |
Utility as an ocular antiviral agent |
---|
The anti-adenoviral mechanism of action of stampidine is undefined but is probably not due to depletion of intracellular nucleotide pools that play an essential role in nucleic acid synthesis.111 Studies are currently in progress to assess the change in host cell RNA transcripts in response to virus-specific, stampidine-specific, and time-specific effects using DNA microarray (GeneChip Human Genome U95 set) that cross-examines the expression level of 12 625 genes. The effect of stampidine on the expression levels of genes associated with cell cycle regulation, apoptosis, oncogenesis, transcription, signalling and inflammation are being assessed using a Hierarchial Clustering algorithm. In agreement with our preclinical observations, stampidine did not affect the gene expression profile of inflammatory mediators. Our ongoing DNA microarray analysis has revealed that stampidine is a useful probe to develop new target sites relevant to the control of oculo-genital ADV/HIV pathogenesis.
![]() |
Conclusions |
---|
![]() |
Acknowledgements |
---|
![]() |
References |
---|
2. Warren D, Nelson KE, Farrar JA et al. A large outbreak of epidemic keratoconjunctivitis: problems in controlling nosocomial spread. J Infect Dis 1989; 160: 93843.[ISI][Medline]
3. McMinn PC, Stewart J, Burrell CJ. A community outbreak of epidemic keratoconjunctivitis in central Australia due to adenovirus type 8. J Infect Dis 1991; 164: 11138.[ISI][Medline]
4.
Takeuchi S, Itoh N, Uchio E et al. Adenovirus strains of subgenus D associated with nosocomial infection as new etiological agents of epidemic keratoconjunctivitis in Japan. J Clin Microbiol 1999; 37: 33924.
5. Chang CH, Lin KH, Sheu MM et al. The change of etiological agents and clinical signs of epidemic viral conjunctivitis over an 18-year period in southern Taiwan. Graefes Arch Clin Exp Ophthalmol 2003; 241: 55460.[CrossRef][ISI][Medline]
6. D'Angelo LJ, Hierholzer JC, Keenlyside RA et al. Pharyngoconjunctival fever caused by adenovirus type 4: report of a swimming pool-related outbreak with recovery of virus from pool water. J Infect Dis 1979; 140: 427.[ISI][Medline]
7. Uchio E, Matsuura N, Takeuchi S et al. Acute follicular conjunctivitis caused by adenovirus type 34. Am J Ophthalmol 1999; 128: 6806.[CrossRef][ISI][Medline]
8. Darougar S, Quinlan MP, Gibson JA et al. Epidemic keratoconjunctivitis and chronic papillary conjunctivitis in London due to adenovirus type 19. Br J Ophthalmol 1977; 61: 7685.[Abstract]
9. Martone WJ, Hierholzer JC, Keenlyside RA et al. An outbreak of adenovirus type 3 disease at a private recreation center swimming pool. Am J Epidemiol 1980; 111: 22937.[Abstract]
10. Mueller AJ, Klauss V. Main sources of infection in 145 cases of epidemic keratoconjunctivitis. Ger J Ophthalmol 1993; 2: 2247.[Medline]
11. Jernigan JA, Lowry BS, Hayden FG et al. Adenovirus type 8 epidemic keratoconjunctivitis in an eye clinic: risk factors and control. J Infect Dis 1993; 167: 130713.[ISI][Medline]
12. Chhabra BK. Nosocomial transmission of epidemic keratoconjunctivitis to food handlers in a nursing home. J Am Geriatr Soc 1995; 43: 13923.[ISI][Medline]
13. Koo D, Bouvier B, Wesley M et al. Epidemic keratoconjunctivitis in a university medical center ophthalmology clinic; need for re-evaluation of the design and disinfection of instruments. Infect Control Hosp Epidemiol 1989; 10: 54752.[ISI][Medline]
14. Azar MJ, Dhaliwal DK, Bower KS et al. Possible consequences of shaking hands with your patients with epidemic keratoconjunctivitis. Am J Ophthalmol 1996; 121: 7112.[ISI][Medline]
15. Harley D, Harrower B, Lyon M et al. A primary school outbreak of pharyngoconjunctival fever caused by adenovirus type 3. Commun Dis Intell 2001; 25: 912.[Medline]
16. Chaberny IE, Schnitzler P, Geiss HK et al. An outbreak of epidemic keratoconjunctivitis in a pediatric unit due to adenovirus type 8. Infect Control Hosp Epidemiol 2003; 24: 5149.[ISI][Medline]
17. Nauheim RC, Romanowski EG, Araullo-Cruz T et al. Prolonged recoverability of desiccated adenovirus type 19 from various surfaces. Ophthalmology 1990; 97: 14503.[ISI][Medline]
18. Kowalski RP, Romanowski EG, Waikhom B et al. The survival of adenovirus in multidose bottles of topical fluorescein. Am J Ophthalmol 1998; 126: 8356.[CrossRef][ISI][Medline]
19. Gordon YJ, Gordon RY, Romanowski E et al. Prolonged recovery of desiccated adenoviral serotypes 5, 8, and 19 from plastic and metal surfaces in vitro. Ophthalmology 1993; 100: 18359.[ISI][Medline]
20. Croes K. Contact lens market: higher-value products, favorable demographics and international expansion create an accelerating growth industry. OptiStock Optical Sector Report October 2003. http://www.optistock.com/mw/2003_10all.htm (15 April 2005, date last accessed).
21. Mah-Sadorra JH, Yavuz SG, Najjar DM et al. Trends in contact lens-related corneal ulcers. Cornea 2005; 24: 518.[CrossRef][ISI][Medline]
22. Pepose JS. Contact lens disinfection to prevent transmission of viral disease. CLAO J 1988; 14: 1658.[Medline]
23. Gordon JS, Aoki K, Kinchington PR. Adenovirus keratoconjunctivitis. In: Pepose JS, Holland GN, Wilhelmus KR, eds. Ocular Infection & Immunity. St Louis, MO, USA: Mosby, 1996; 87794.
24. Wadell G. Molecular epidemiology of human adenoviruses. Curr Top Microbiol Immunol 1984; 110: 191220.[ISI][Medline]
25. Horwitz MS. Adenoviruses. In: Fields BN, Knipe DM, eds. Virology 2nd edn. New York, NY, USA: Raven Press, 1990; 172340.
26. Shenk T. Adenoviridae: the viruses and their replication. In: Fields BN, Knipe DM, Howley PM, eds. Fields Virology 3rd edn. Philadelphia, PA, USA: Lippincott-Raven Publishers, 1996; 211148.
27. Jawetz EA, Kimura A, Nicholas N et al. New type of APC virus from keratoconjunctivitis. Science 1955; 122: 11902.[Medline]
28. Aoki K, Tagawa Y. A twenty-one year surveillance of adenoviral conjunctivitis in Sapporo, Japan. Int Ophthalmol Clin 2002; 42: 4954.[Medline]
29. Gordon JS. Adenovirus and other non-herpetic viral diseases. In: Smolin G, Thoft RA, eds. The Cornea 3rd edn. New York, NY, USA: Little, Brown and Company, 1994; 21522.
30. Darourgor S, Walpita P, Thaker U et al. Adenovirus serotypes isolated from ocular infections in London. Br J Ophthalmol 1983; 67: 1114.[Abstract]
31. Kinchington PR, Turse SE, Kowalski RP et al. Use of polymerase chain amplification reaction for the detection of adenoviruses in ocular swab specimens. Invest Ophthalmol Vis Sci 1994; 35: 412634.[Abstract]
32. Corsaro D, Gut JP, Venard V et al. Molecular epidemiology of ocular isolates of adenovirus 8 obtained over nine years. J Clin Pathol 1999; 52: 8601.[Abstract]
33. Chang CH, Sheu MM, Lin KH et al. Hemorrhagic viral keratoconjunctivitis in Taiwan caused by adenovirus types 19 and 37: applicability of polymerase chain reaction-restriction fragment length polymorphism in detecting adenovirus genotypes. Cornea 2001; 20: 295300.[CrossRef][ISI][Medline]
34. Pring-Akerblom P, Adrian T. Characterization of adenovirus subgenus D fiber genes. Virology 1995; 206: 56471.[CrossRef][ISI][Medline]
35. O'Donnell B, McCruden EA, Desselberger U. Molecular epidemiology of adenovirus conjunctivitis in Glasgow 19811991. Eye 1993; 7: 814.[ISI][Medline]
36. Harley D, Harrower B, Lyon M et al. A primary school outbreak of pharyngoconjunctival fever caused by adenovirus type 3. Commun Dis Intell 2001; 25: 912.[Medline]
37. Harnett GB, Newnham WA. Isolation of adenovirus type 19 from the male and female genital tracts. Br J Vener Dis 1981; 57: 557.[ISI][Medline]
38.
Swenson PD, Lowens MS, Celum CL et al. Adenovirus types 2, 8, and 37 associated with genital infections in patients attending a sexually transmitted disease clinic. J Clin Microbiol 1995; 33: 272831.
39. Cevenini R, Donati M, Landini MP et al. Adenoviruses associated with an oculo-genital infection. Microbiologica 1979; 2: 4257.[ISI]
40. Harnett GB, Phillips PA, Gollow MM. Association of genital adenovirus infection with urethritis in men. Med J Aust 1984; 141: 3378.[ISI][Medline]
41. Laverty CR, Russell P, Black J et al. Adenovirus infection of the cervix. Acta Cytol 1977; 21: 1147.[ISI][Medline]
42. Phillips PA, Harnett GB, Gollow MM. Adenovirus type 19 and a closely related new serotype in genital infection. Br J Vener Dis 1982; 58: 1312.[ISI][Medline]
43.
Arnberg N, Pring-Akerblom P, Wadell G. Adenovirus type 37 uses sialic acid as a cellular receptor on Chang C cells. J Virol 2002; 76: 883441.
44. Arnberg N, Mei Y, Wadell G. Fiber genes of adenoviruses with tropism for the eye and the genital tract. Virology 1997; 227: 23944.[CrossRef][ISI][Medline]
45. Hierholzer JC, Wigand R, Anderson LJ et al. Adenoviruses from patients with AIDS: a plethora of serotypes and a description of five new serotypes of subgenus D (types 4347). J Infect Dis 1988; 158: 80413.[ISI][Medline]
46. Green WR, Greaves WL, Frederick WR et al. Renal infection due to adenovirus in a patient with human immunodeficiency virus infection. Clin Infect Dis 1994; 18: 98991.[ISI][Medline]
47. Khoo SH, Bailey AS, de Jong JC et al. Adenovirus infections in human immunodeficiency virus-positive patients: clinical features and molecular epidemiology. J Infect Dis 1995; 172: 62937.[ISI][Medline]
48. Carrigan DR. Adenovirus infections in immunocompromised patients. Am J Med 1997; 102: 714.[CrossRef][Medline]
49.
De Jong JC, Wermenbol AG, Verweij-Uijterwaal MW et al. Adenoviruses from human immunodeficiency virus-infected individuals, including two strains that represent new candidate serotypes Ad50 and Ad51 of species B1 and D, respectively. J Clin Microbiol 1999; 37: 39405.
50. Sabin CA, Clewley GS, Deayton JR et al. Shorter survival in HIV-positive patients with diarrhoea who excrete adenovirus from the GI tract. J Med Virol 1999; 58, 2805.[CrossRef][ISI][Medline]
51. Koopmann J, Dombrowski F, Rockstroh JK et al. Fatal pneumonia in an AIDS patient coinfected with adenovirus and Pneumocystis carinii. Infection 2000; 28: 3235.[CrossRef][ISI][Medline]
52. Kojaoghlanian T, Flomenberg P, Horwitz MS. The impact of adenovirus infection on the immunocompromised host. Rev Med Virol 2003; 13: 15571.[CrossRef][ISI][Medline]
53. Perricone MA, Morris JE, Pavelka K et al. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. II. Transfection efficiency in airway epithelium. Hum Gene Ther 2001; 12: 138394.[CrossRef][ISI][Medline]
54. Urabe M, Ding C, Kotin RM. Insect cells as a factory to produce adeno-associated virus type 2 vectors. Hum Gene Ther 2002; 13: 193543.[CrossRef][Medline]
55. Galanis E, Okuno SH, Nascimento AG et al. Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther 2005; 12: 43745.[CrossRef][ISI][Medline]
56.
Sangro B, Mazzolini G, Ruiz J et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 2004; 22: 138997.
57. Tsubota K, Inoue H, Ando K et al. Adenovirus-mediated gene transfer to the ocular surface epithelium. Exp Eye Res 1998; 67: 5318.[CrossRef][ISI][Medline]
58. Wu E, Fernandez J, Fleck SK et al. A 50-kDa membrane protein mediates sialic acid-independent binding and infection of conjunctival cells by adenovirus type 37. Virology 2001; 279: 7889.[CrossRef][ISI][Medline]
59. Gaggar A, Shayakhmetov DM, Lieber A. CD46 is a cellular receptor for group B adenoviruses. Nature Med 2003; 9: 140812.[CrossRef][ISI][Medline]
60.
Wu E, Trauger SA, Pache L et al. Membrane cofactor protein is a receptor for adenoviruses associated with epidemic keratoconjunctivitis. J Virol 2004; 78: 3897905.
61. Gipson IK, Argueso P. Role of mucins in the function of the corneal and conjunctival epithelia. Int Rev Cytol 2003; 231: 149.[ISI][Medline]
62. D'Cruz OJ, Wild RA, Medders DE et al. Antigenic similarities between respiratory and reproductive tract mucins: heterogeneity of mucin expression by human endocervix and endometrium. Fertil Steril 1993; 60: 10119.[ISI][Medline]
63. D'Cruz OJ, Dunn TS, Pichan P et al. Antigenic cross-reactivity of human tracheal mucin with human sperm and trophoblasts correlates with the expression of mucin 8 gene messenger ribonucleic acid in reproductive tract tissues. Fertil Steril 1996; 66: 31626.[ISI][Medline]
64. D'Cruz OJ, Wild RA. Evaluation of endometrial tissue specific complement activation in women with endometriosis. Fertil Steril 1992; 57: 78795.[ISI][Medline]
65. Bora NS, Gobleman CL, Atkinson JP et al. Differential expression of the complement regulatory proteins in the human eye. Invest Ophthalmol Vis Sci 1993; 34: 357984.[Abstract]
66. D'Cruz OJ, Haas GG Jr. The expression of the complement regulators CD46, CD55, and CD59 by human sperm does not protect them from antisperm antibody- and complement-mediated immune injury. Fertil Steril 1993; 59; 87684.[ISI][Medline]
67. Cocuzzi E, Szczotka LB, Brodbeck WG et al. Tears contain the complement regulator CD59 as well as decay-accelerating factor (DAF). Clin Exp Immunol 2001; 123: 18895.[CrossRef][ISI][Medline]
68. Duke-Elder S. System of Ophthalmology, Vol. VIII, Diseases of the Outer Eye, Part 1. St Louis, MO, USA: CV Mosby, 1965; 33748.
69. Gottsch JD. Surveillance and control of epidemic keratoconjunctivitis. Trans Am Ophthalmol Soc 1996; 94: 53987.[Medline]
70.
Chodosh J, Astley RA, Butler MG et al. Adenovirus keratitis: a role for Interleukin 8. Invest Ophthalmol Vis Sci 2000; 41: 7839.
71. Trousdale MD, Nobrega R, Wood RL et al. Role of adenovirus type 5 early region in the pathogenesis of ocular disease and cell culture infection. Cornea 1995; 14: 2809.[ISI][Medline]
72. Jones BR. The clinical features of viral keratitis and a concept of their pathogenesis. Proc R Soc Med 1958; 51: 1320.
73. Reefschlager J, Brwolff D, Barwolff D et al. Efficiency and selectivity of (E)-5-(2-bromovinyl)-2'-deoxyuridine and some other 5-substituted 2'-deoxypyrimidine nucleosides as anti-herpes agents. Antiviral Res 1982; 2: 4152.[CrossRef][ISI][Medline]
74. van der Vliet PC, Kwant MM. Role of DNA polymerase gamma in adenovirus DNA replication. Mechanism of inhibition by 2',3'-dideoxynucleoside 5'-triphosphates. Biochemistry 1981; 20: 262832.[CrossRef][ISI][Medline]
75. Mentel R, Kinder M, Wegner U et al. Inhibitory activity of 3'-fluoro-2' deoxythymidine and related nucleoside analogues against adenoviruses in vitro. Antiviral Res 1997; 34: 1139.[CrossRef][ISI][Medline]
76. Mentel R, Kurek S, Wegner U et al. Inhibition of adenovirus DNA polymerase by modified nucleoside triphosphate analogs correlate with their antiviral effects on cellular level. Med Microbiol Immunol 2000; 189; 915.[CrossRef][ISI][Medline]
77. Allen LB, Boswell KH, Khwaja TA et al. Synthesis and antiviral activity of some phosphates of the broad-spectrum antiviral nucleoside, 1-ß-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin). J Med Chem 1978; 21: 7426.[CrossRef][ISI][Medline]
78.
Naesens L, Lenaerts L, Andrei G et al. Antiadenovirus activities of several classes of nucleoside and nucleotide analogues. Antimicrob Agents Chemother 2005; 49: 10106.
79. Mul YM, van Miltenburg RT, De Clercq E et al. Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein. Nucleic Acids Res 1989; 17: 891729.[Abstract]
80.
De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 2003; 16: 56996.
81. Fanourgiakis P, Georgala A, Vekemans M et al. Intravesical instillation of cidofovir in the treatment of hemorrhagic cystitis caused by adenovirus type 11 in a bone marrow transplant recipient. Clin Infect Dis 2005; 40: 199201.[CrossRef][ISI][Medline]
82. Ljungman P. Treatment of adenovirus infections in the immunocompromised host. Eur J Clin Microbiol Infect Dis 2004; 23: 5838.[ISI][Medline]
83.
Maslo C, Girard PM, Urban T et al. Ribavirin therapy for adenovirus pneumonia in an AIDS patient. Am J Respir Crit Care Med 1997; 156; 12634.
84. De Clercq E. Antiviral drugs in current clinical use. J Clin Virol 2004; 30: 11533.[CrossRef][ISI][Medline]
85. Anekthananon T, Ratanasuwan W, Techasathit W et al. Safety and efficacy of a simplified fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-VIR) for the treatment of advanced HIV-infected patients: a 24-week study. J Med Assoc Thailand 2004; 87: 7607.[Medline]
86. Laurent C, Kouanfack C, Koulla-Shiro S et al. Effectiveness and safety of a generic fixed-dose combination of nevirapine, stavudine, and lamivudine in HIV-1-infected adults in Cameroon: open-label multicentre trial. Lancet 2004; 364: 2934.[CrossRef][ISI][Medline]
87.
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; 612733.
88. McIntee EJ, Remmel RP, Schinazi RF et al. Probing the mechanism of action and decomposition of amino acid phosphomonoester amidates of antiviral nucleoside prodrugs. J Med Chem 1997; 40: 332331.[CrossRef][ISI][Medline]
89. McGuigan C, Cahard D, Sheeka M et al. Aryl phosphoramidate derivatives of d4T have improved anti-HIV efficacy in tissue culture and may act by the generation of a novel intracellular metabolite. J Med Chem 1996; 39: 174853.[CrossRef][ISI][Medline]
90.
D'Cruz OJ, Venkatachalam TK, Uckun FM. Thymidine kinase-independent intracellular delivery of bioactive nucleotides by aryl phosphate derivatives of bromo-methoxy zidovudine (compounds WHI-05 and WHI-07) in normal human female genital tract epithelial cells and sperm. Biol Reprod 2001; 64: 519.
91. Vig R, Venkatachalam TK, Uckun FM. d4T-5'-[p-bromophenyl methoxyalaninyl phosphate] as a potent and non-toxic anti-human immunodeficiency virus agent. Antivir Chem Chemother 1998; 9: 4458.[ISI][Medline]
92. Uckun FM, Pendergrass S, Qazi S et al. Phenyl phosphoramidate derivatives of stavudine as anti-HIV agents with potent and selective in-vitro antiviral activity against adenovirus. Eur J Med Chem 2004; 39: 22534.[CrossRef][ISI][Medline]
93. Uckun FM, Pendergrass S, Qazi S et al. In vitro activity of stampidine against primary clinical human immunodeficiency virus isolates. Arzneimittelforschung 2004; 54: 6977.[ISI][Medline]
94.
Uckun FM, Pendergrass S, Venkatachalam TK et al. Stampidine is a potent inhibitor of zidovudine and NRTI-resistant primary clinical HIV-1 isolates with thymidine analog mutations. Antimicrob Agents Chemother 2002; 46, 36136.
95. Uckun FM, Samuel P, Qazi S et al. Effects of aryl substituents on the anti-HIV activity of the arylphosphoramidate derivatives of stavudine. Antivir Chem Chemother 2002; 13: 197203.[Medline]
96.
Uckun FM, Qazi S, Pendergrass S et al. In vivo toxicity, pharmacokinetics, and anti-human immunodeficiency virus activity of stavudine-5'-(p-bromophenyl methoxyalaninyl phosphate) (stampidine) in mice. Antimicrob Agents Chemother 2002; 46: 342836.
97.
Uckun FM, Chen CL, Samuel P et al. In vivo antiretroviral activity of stampidine in chronically feline immunodeficiency virus-infected cats. Antimicrob Agents Chemother 2003; 47: 123340.
98.
Chen CL, Yu G, Venkatachalam TK et al. Metabolism of stavudine-5'-[p-bromophenyl methoxyalaninyl phosphate], stampidine, in mice, dogs, and cats. Drug Metab Dispos 2002; 30: 152331.
99. Uckun FM, Chen CL, Lisowski E et al. Toxicity and pharmacokinetics of stampidine in mice and rats. Arzneimittelforschung 2003; 53: 35767.[ISI][Medline]
100. Qazi S, Samuel NK, Venkatachalam TK et al. Evaluating dissolution profiles of an anti-HIV agent using ANOVA and non-linear regression models in JMP software. Int J Pharm 2003; 252: 2739.[CrossRef][ISI][Medline]
101. Venkatachalam TK, Samuel P, Li G et al. Lipase-mediated stereoselective hydrolysis of stampidine and other phosphoramidate derivatives of stavudine. Bioorg Med Chem 2004; 12: 337181.[CrossRef][ISI][Medline]
102. Venkatachalam TK, Yu G, Samuel P et al. A comparative study of the hydrolysis pathways of substituted aryl phosphoramidate vs aryl thiophosphoramidate derivatives of stavudine. Eur J Med Chem 2004; 39: 66583.[CrossRef][ISI][Medline]
103. Venkatachalam TK, Samuel P, Uckun FM. Stereochemical influence on lipase-mediated hydrolysis and biological activity of stampidine and other stavudine phosphoramidates. Bioorg Med Chem 2005; 13: 176373.[CrossRef][ISI][Medline]
104. Venkatachalam TK, Samuel P, Uckun FM. Enzymatic hydrolysis of stampidine and other stavudine phosphoramidates in the presence of mammalian proteases. Bioorg Med Chem 2005; 13: 26515.[CrossRef][ISI][Medline]
105. D'Cruz OJ, Uckun FM. Stampidine is a nonspermicidal broad-spectrum anti-human immunodeficiency virus microbicide Fertil Steril 2003; 81: 83141.[CrossRef][ISI]
106. D'Cruz OJ, Samuel P, Waurzyniak B et al. In vivo evaluation of a gel formulation of stampidine, a novel nonspermicidal broad-spectrum anti-HIV microbicide. Am J Drug Deliv 2003; 1: 27585.
107.
D'Cruz OJ, Samuel P, Waurzyniak B et al. Development and evaluation of a thermoreversible ovule formulation of stampidine, a novel nonspermicidal broad-spectrum anti-HIV microbicide. Biol Reprod 2003; 69: 184351.
108. D'Cruz OJ, Samuel P, Uckun FM. Conceival, a novel non-contraceptive vaginal vehicle for lipophilic microbicides. AAAPS PharmSciTech 2005; 6: in press. http://www.aapspharmscitech.org/prepub/prepub.asp (15 April 2005, date last accessed).
109. Venkatachalam TK, Tai HL, Vig R et al. Enhancing effects of a mono-bromo substitution at the para position of the phenyl moiety on the metabolism and anti-HIV activity of D4T-phenyl methoxyalaninyl phosphate derivatives. Bioorg Med Chem Lett 1998; 8: 31216.[CrossRef][ISI][Medline]
110. Saviola JF, Hilmantel G, Rosenthal AR. The U.S. Food and Drug Administration's role in contact lens development and safety. Eye Contact Lens 2003; 29: S1605.[Medline]
111. Uckun FM, Tai HL, D'Cruz OJ. Antileukemic activity and cellular metabolism of the aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07). Arzneimittelforschung 2005; 55: 5065.[ISI][Medline]
|