Influence of (E)-5-(2-Bromovinyl)-2′-deoxyuridine on corneal epithelium healing

Maudgal, P C; Kimpe, N De; Clercq, Erik De; Descamps, J.; Missotten, Luc; Geysen, Astrid

doi:10.1007/bf02175897

Cited by 5 publications

(3 citation statements)

References 11 publications

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“…The marked antiviral activity exhibited following single or infrequent dosing appears to be a unique feature of the phosphonylmethoxyalkyl derivatives. In another study, HPMPC was found to be equally effective in the treatment of HSV-1 keratitis if instilled (as eyedrops) nine times daily, three times daily, or only once daily (24). Also, HPMPC has been to be found effective against murine cytomegalovirus and simian vari- cella-zoster virus when administered systemically at infrequent doses to mice and monkeys, respectively (21a, 29a).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Clercq

Holý

1991

Antimicrob Agents Chemother

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The phosphonylmethoxyalkyl derivative (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) was evaluated for its in vivo efficacy in several model infections for herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) and thymidine kinase-deficient (TK-) HSV-1 in mice. In hairless mice infected intracutaneously with HSV-1 or HSV-2, HPMPC completely suppressed all manifestations of the disease (skin lesions, paralysis of the hind legs, and mortality) if it was administered topically at a concentration of as low as 0.1, 0.3, or 1%. Similarly, HPMPC completely suppressed TK-HSV-1 infection in athymic nude mice if it was administered topically at 0.1 or 0.3% or intraperitoneally at 100 or 250 mg/kg/day. HPMPC was also effective against intraperitoneal HSV infection if it was given orally at a dose of 50 mg/kg/day or higher. In mice inoculated intracerebrally with HSV-2, intraperitoneal HPMPC treatment achieved a significant and dose-dependent protection at doses ranging from 5 to 400 mg/kg/day. The protective effect of HPMPC (at 200 mg/kg/day) was accompanied by a complete inhibition of virus multiplication in the brain. In all models of infections studied, the efficacy of HPMPC proved to be superior to that of acyclovir. The most remarkable feature of HPMPC was that a single administration of the compound, even as late as 4 days after infection, conferred significant protection against HSV-1 or HSV-2 infection. Topical or systemic HPMPC treatment is efficacious in murine models of HSV-1, HSV-2, and TK-HSV infections.The phosphonylmethoxyalkylpurines and -pyrimidines have been identified as new classes of antiviral agents with broad-spectrum activities against a wide variety of DNA viruses (13,14). (S)-9-(3-Hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA), the prototype of this class of compounds, has proved to be active against adenoviruses (2) 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), which can be considered as the truncated form of HPMPA in which the hydroxymethyl group has been deleted, is active against herpes-, hepadna-, and iridoviruses (13,14,19, 33) HPMPA, PMEA, and PMEDAP have been the subject of a previous study in which the efficacies of these phosphonylmethoxyalkyl derivatives were demonstrated in a variety of experimental HSV-1 and HSV-2 infections, including intracutaneous HSV-1 and HSV-2 infections in hairless mice; intracutaneous thymidine kinase-deficient (TK-) HSV-1 infections in athymic nude mice; systemic (intraperitoneal [i.p.]) HSV-1 infections in mice; and intracerebral HSV-1, HSV-2, or TK-HSV-1 infections in mice (12). These animal models for HSV infections have been used to * Corresponding author. assess the in vivo efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), another member of the class of phosphonylmethoxyalkyl derivatives (14), which, according to previous investigations (7), would be more efficacious than acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] in both the systemic and topical treatment of HSV infections in mice and guinea pigs. MATERIALS...

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Section: Methodsmentioning

confidence: 99%

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Clercq

Holý

1991

Antimicrob Agents Chemother

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“…A survey of previous corneal studies affirms that the time course of wound closure is clearly nonlinear [18,19,21,47,[56][57][58][59][60][61][62][63][64][65]. The piece-wise application of a first-order closure rate, over the first 18 h [47], or over two stages provides a better description than a single regression line analysis of the entire time course [66].…”

Section: Area Closure Ratementioning

confidence: 99%

Kinematics of epithelial wound closure in the rabbit cornea

Kwok

1991

Doc Ophthalmol

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The kinematics of wound closure in the healing rabbit corneal epithelium are modelled. The analysis is able to model the movement of the wound edge on the corneal surface. A unified formalism is described which embeds the surface velocity of the wound margin within the computational algorithm to enable calculation of the surface velocity of the wound margin from the time course of (1) planar wound area, or (2) wound diameter. The procedure can be implemented with the standard least-squares estimation procedure. A polynomial velocity function is discussed, but the model allows for any appropriate velocity function to be used to suit particular conditions of wound closure. Corneal curvature effects are incorporated to avoid the errors associated with a planar representation of wound closure on a curved corneal surface. The approach offers greater flexibility by avoiding the theoretical flaws of previous models which are often limited in scope and nonbiological in nature.

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“…56).Under both eye drop or ointment formulations, BVDU proved superior to the standard antiherpes drug, IDU, in promoting the healing of epithelial HSV1 keratitis in rabbits (Ref.57 & 58). BVDU eye drops were also effective in the topical treatment of stromal HSV1 keratitis, and in this regard BVDU proved superior to another classical antiherpes drug, TFT (if treatment was started one day after infection) (Ref 59)…”

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confidence: 99%

Antiviral activity of 5-substituted pyrimidine nucleoside analogues

Clercq¹

1983

Pure and Applied Chemistry

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From a large series of 5-substituted 1-(2-deoxy-D-ribofuranosyl)-uracil (dUrd) , 1-(2-deoxy-D-ribofuranosyl)-cytosine (dCyd) and 1-(-D-arabinofuranosyl)-uracil (araU) analogues that have been evaluated for their antiviral properties, the (E)-5-(2-bromovinyl)derivatives emerged as the most potent and most selective antiherpes agents. (E)-5-(2-Bromovinyl)-dUrd (BVDU) and its congeners, (E)-5-(2-bromovinyl)-dCyd (BVDC) and (E)-5-(2-bromovinyl)-araU (BVaraU) , inhibited the replication of herpes simplex virus type I (HSVI) and varicella-zoster virus (VZV) in cell culture at a concentration which was about 5,000-to 50,000-fold lower than the concentration required to affect normal cell growth or metabolism. For example, BVDU inhibited HSV1 replication in primary rabbit kidney cells and VZV in human embryonic lung cells at a concentration of 0.007 pg/ml (0.02 iM) and 0.003 pg/ml (0.01 pM), respectively. A series of sugar-modified analogues and 3'-O-or 5'-Oacyl esters of BVDU have been prepared, and some of these derivatives, i.e. 3'amino-BVDU and 5'-O-aminoacetyl-BVDU, proved almost as active as BVDU itself. Further studies revealed that the activity spectrum of BVDU includes, in addition to IISVI and VZV, several other herpesviruses such as pseudorabies virus, bovid herpesvirus type 1, simian varicella virus, herpesvirus saimiri and nuclear polyhedrosis virus. Its antiviral action would depend on a specific phosphorylation by the virusencoded thymidine kinase, a preferential inhibition of the viral DNA polymerase by the 5'-triphosphate of BVDU (BVDUTP), and, finally, the incorporation of BVDUTP into viral DNA. BVDU has demonstrated high efficacy in several animal model infections, and preliminary clinical studies point to the great promise of BVDU in the topical and systemic (i.e. oral) treatment of HSVI and VZV infections in humans.

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Influence of (E)-5-(2-Bromovinyl)-2′-deoxyuridine on corneal epithelium healing

Cited by 5 publications

References 11 publications

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Efficacy of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine in various models of herpes simplex virus infection in mice

Kinematics of epithelial wound closure in the rabbit cornea

Antiviral activity of 5-substituted pyrimidine nucleoside analogues

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