Dipyridamole Potentiates the Activity of Various Acyclic Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus

Snoeck, Robert; Andrei, Gracíela; Balzarini, Jan; Reymen, D.; Clercq, Erik De

doi:10.1177/095632029400500505

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…Only a slight antiviral effect of DPM in a dose-dependent pattern was noted, and significant cellular toxicity was unlikely. In addition, the 25 M DPM concentration used was similar to that used in other HSV studies, where there was no apparent cellular toxicity with 20 M DPM (14). It does remain possible that DPM is particularly toxic to neurons and that destruction of neurons led to reactivation in ganglia.…”

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confidence: 68%

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Inhibition of Herpes Simplex Virus Reactivation by Dipyridamole

Tenser

Gaydos

Hay

2001

Antimicrob Agents Chemother

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Herpes simplex virus (HSV) reactivation from latency was investigated. Reactivation of thymidine kinasenegative HSV, which is defective for reactivation, was greatly enhanced by thymidine (TdR). The reactivationenhancing effect of TdR was blocked by dipyridamole (DPM), a known nucleoside transport inhibitor. DPM also inhibited wild-type HSV reactivation, suggesting potential antiviral use.In experimental models of herpes simplex virus (HSV) infection, expression of viral thymidine kinase (TK) has been shown to be important for viral latency. This was first suggested in studies of mice infected with TK-negative HSV. It was shown that in cases of acute infection, HSV replicated well in ocular tissues but not in trigeminal ganglia (TG) and that HSV reactivated poorly in ganglia during latency. Subsequently it was shown that establishment of latency was intact, i.e., latency-associated transcript (LAT) was readily detected in ganglion neurons, but reactivation was impaired (4, 5, 16). The defect of reactivation was explored in studies which showed that TKnegative HSV could in fact readily reactivate in ganglia if explant medium was supplemented with thymidine (TdR) (17). The present study extended this observation in three ways. First, it was shown that if a nucleoside transport inhibitor is added along with supplemental TdR, the effect of TdR on enhancing TK-negative HSV reactivation is blocked. This suggests the specific roles of TdR and phosphorylation by TK in the reactivation process. Second, it is shown that the nucleoside transport inhibitor also blocks wild-type HSV reactivation from latency. Lastly, supplemental TdR decreased the dipyridamole (DPM) block of wild-type HSV reactivation.Latent infection of TG and lumbar dorsal root ganglia (DRG) was established in randomly bred CD-1 mice (Charles River Laboratories, Wilmington, Mass.) by standard methods. In brief, mice were anesthetized (methoxyflurane), and corneal inoculation (5 l) or footpad inoculation (25 l) was performed (17). Inoculation was performed with either TK-positive wild-type HSV type 1 (HSV-1; strain KOS, 5 ϫ 10 8 PFU/ ml) or with mutant TK-negative HSV-1 (dlsactk, 4 ϫ 10 8 PFU/ml). The titers of the viruses were determined on Vero cells using standard methods. The KOS virus had been used previously (16,17). It readily established latency (i.e., LAT expression) and reactivated from latency in explants with a frequency of 90 to 100%. The dlsactk mutant strain was kindly provided by D. Coen (Harvard Medical School, Boston, Mass.). It was shown to express less than 1% of parental TK activity (4, 7). LAT expression during latency in mice inoculated with dlsactk was similar to that in mice with the TKpositive KOS strain, but reactivation from latency occurred at a frequency of 0 to 10% (4,7,17).After 28 to 30 days, mice were anesthetized (methoxyflurane) and exsanguinated by cardiac puncture. HSV inoculation of mice, as well as housing and eventual sacrifice, were done in accordance with institutional and federal guidelines. TG and DRG (from lumb...

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confidence: 68%

“…DPM has been used occasionally in antiviral studies (18), including investigations of HSV (14). In the latter study, it was not shown to be a potent antiviral.…”

mentioning

confidence: 99%

Inhibition of Herpes Simplex Virus Reactivation by Dipyridamole

Tenser

Gaydos

Hay

2001

Antimicrob Agents Chemother

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“…In addition, it would be of interest to investigate the effect of these drugs on wild-type TK ϩ HSV reactivation. While a significant antiviral effect has not been ascribed to these drugs, a synergistic effect with antiviral agents has been reported (37). In addition, while these drugs may not inhibit replication of HSV during lytic infection, inhibition of reactivation, a point of vulnerability when HSV replication is initially very limited, may be sufficient for a clinical effect to be noted.…”

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confidence: 99%

Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside

Tenser

Gaydos

Hay

1996

J Virol

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Herpes simplex virus (HSV) mutants defective for thymidine kinase expression (TK ؊ ) have been reported to establish latent infection of sensory ganglia of mice, in that HSV latency-associated transcript is expressed, but to be defective for reactivation. In the present study, the mechanism of defective reactivation by TK ؊ HSV was investigated. Latent infection established by each of three reactivation-defective HSV type 1 mutants was studied. Reactivation in explant culture was markedly enhanced by the addition of thymidine (dTdR) to the explant culture medium. Without added dTdR, reactivation occurred in 0 of 32 ganglia, while when dTdR (200 M) was present, reactivation occurred in 32 of 37 ganglia (86%). Reactivation was minimal or did not occur after treatment with other nucleosides; specificity for dTdR would suggest the importance of dTdR nucleotide levels rather than more general nucleotide pool imbalance. Enhanced reactivation by dTdR was dose dependent and was blocked by acyclovir. While some degree of inhibition of TK ؊ HSV by acyclovir may be expected, the complete block of dTdR-enhanced reactivation was unexpected. This result may suggest that HSV is particularly vulnerable during initial reactivation events. The mechanism of dTdR-enhanced reactivation of TK ؊ HSV was further evaluated during in vivo infection by TK ؊ HSV. For mice infected with TK ؊ HSV, virus was undetectable in ganglia 3 days later. However, for mice infected with TK ؊ HSV and treated with dTdR, virus was readily detected (2.8 ؋ 10 3 PFU per ganglion). This result suggested that in vivo treatment with dTdR enhanced replication of TK ؊ HSV in ganglion neurons. In turn, this suggests that in latently infected ganglia, dTdR-enhanced reactivation of TK ؊ HSV occurred as a result of viral replication in neurons following initial reactivation events.

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“…13 Dipyridamole has been found to be able to potentiate the action of acyclic nucleotides in the treatment of herpes viruses, probably through its immunomodulating interferonogenic effect. [14][15][16] Papaverine also has a number of additional immunotropic properties that have not been previously used in pharmacological practice. For example, papaverine has antiviral properties against a broad spectrum of viruses, due to both its direct antiviral effect and its ability to stimulate the production of endogenous interferons.…”

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confidence: 99%

Non-Classical Effects of the cAMP Accumulation Activators In Vivo

Martynov¹,

Bomko²,

Nosalskaya³

et al. 2020

Adv Pharm Bull

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Purpose : Wound-healing dipyridamole- and papaverine-based aerosols (D1/D2) as activators of the accumulation of cyclic adenosine monophosphate are promising drugs that can accelerate wound healing in wound processes of various origins. Methods: 128 rats were used in the study, including 38 in a pharmacological experiment on a model of stencil wounds and 90 in an experiment that studied the effect of spray on the number of CD34 cells in the blood of rats with chemically induced immunodeficiency. Immunodeficiency was caused by the fivefold administration of cyclophosphamide and prednisone. The expression level of CD34 was determined using flow cytofluorimeter. Results: Dipyridamole- and papaverine-based aerosols of two compositions (with and without ascorbic acid) have pronounced reparative properties, significantly accelerating epithelialization and healing of stencil wounds in rats. In terms of this type of action, they are somewhat superior to dexpanthenol. Dipyridamole- and papaverine-based aerosols have the ability to produce beneficial effect on the entire body’s immune system by stimulating the division of pluripotent CD34 cells. The combined effect of papaverine and dipyridamole on tissues leads to selective stimulation of the division of pluripotent cells in the wound, and contributes to a six-fold acceleration of restoration of the animal’s immune system after induced immunodeficiency. Conclusion: Topical application of D1/D2 aerosol samples on the skin of rats contributed to a statistically significant acceleration of regeneration processes. In terms of the appearance of granulations and epithelialization of wounds, D1/D2 aerosols were superior to dexpanthenol ointment.

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Dipyridamole Potentiates the Activity of Various Acyclic Nucleoside Phosphonates against Varicella-Zoster Virus, Herpes Simplex Virus and Human Cytomegalovirus

Cited by 13 publications

References 30 publications

Inhibition of Herpes Simplex Virus Reactivation by Dipyridamole

Inhibition of Herpes Simplex Virus Reactivation by Dipyridamole

Reactivation of thymidine kinase-defective herpes simplex virus is enhanced by nucleoside

Non-Classical Effects of the cAMP Accumulation Activators In Vivo

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