Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats

Boujemla, Imene; Fakhoury, May; Nassar, Michel; Adle‐Biassette, Homa; Hurteaud, Marie Françoise; Jacqz-Aigrain, Évelyne; Gressèns, Pierre; Teissier, Natacha

doi:10.1016/j.antiviral.2016.05.019

Cited by 10 publications

(11 citation statements)

References 23 publications

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“…7 Findings in this animal model were consistent with the results of these studies and infer a correlation between murine population treatment and GCV treatment in children experiencing SNHL from a congenital CMV infection. Although GCV has previously been shown to enter the cochlea, 13 this study confirms this medication's efficacy in reducing viral load within the temporal bone. It is likely that this reduction plays an important role in GCV's ability to ameliorate hearing loss both in murine and human populations.…”

Section: Discussionsupporting

confidence: 78%

“…Neutropenia was not observed in murine populations treated with GCV after 7 days (10 mg/kg dose given twice a day). Although this is contrary to documented neutropenic findings in GCV‐treated mice, the chosen dose was significantly lower than was used in previous murine studies (50 mg/kg dose) . It is also possible that 7 days of treatment did not allow for this side effect to fully manifest.…”

Section: Discussionmentioning

confidence: 78%

“…Although this is contrary to documented neutropenic findings in GCV-treated mice, the chosen dose was significantly lower than was used in previous murine studies (50 mg/kg dose). 13 It is also possible that 7 days of treatment did not allow for this side effect to fully manifest. Because neutropenia is a common side effect of GCV treatment, affecting up to 30% of treated children, 8 this dose was chosen to more closely mimic clinical dosing of GCV (6 mg/kg dose).…”

Section: Discussionmentioning

confidence: 99%

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Effects of ganciclovir treatment in a murine model of cytomegalovirus‐induced hearing loss

et al. 2019

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Objective To determine whether ganciclovir (GCV) treatment reduces sensorineural hearing loss in cytomegalovirus (CMV)‐infected mice. The effects of GCV on viral load, absolute neutrophil count (ANC), and outer hair cell (OHC) integrity were also investigated. Methods Infected BALB/c mice were inoculated with murine CMV on postnatal day 3. Those treated with GCV received an intraperitoneal injection twice a day for 14 days. Auditory thresholds were assessed using distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) testing 4 weeks after inoculation. Temporal bones were used for determination of viral load by quantitative polymerase chain reaction and hair cell quantification by scanning electron microscopy. ANCs were completed by an automated hematology analyzer, with manual review for confirmation. Results GCV‐treated CMV‐infected mice had lower ABR (P < 0.0001, Kruskal‐Wallis test) and DPOAE (P < 0.0001) thresholds compared to CMV‐infected untreated mice, indicating that GCV protected mice from CMV‐induced hearing loss. Viral load in infected populations undergoing GCV treatment was significantly decreased (P = 0.03) relative to untreated mice. GCV treatment alone had no effect on ABR and DPOAE compared to untreated, uninfected controls (P = 0.1, P = 0.24, respectively). GCV‐treated mice received increased protection from OHC loss when compared to untreated groups, with total OHC losses of approximately 7% and 14%, respectively (P < 0.05). Neutropenia was absent after 7 days of GCV treatment. Conclusion Ganciclovir effectively ameliorated SNHL and partially protected from OHC loss in a preclinical model of congenital CMV infection, seemingly by reducing viral load. Level of Evidence NA Laryngoscope, 130:1064–1069, 2020

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Effects of ganciclovir treatment in a murine model of cytomegalovirus‐induced hearing loss

et al. 2019

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“…We generated an animal model in which tumor cell death can be induced specifically in target cells using the HSV‐tk/GCV system to examine the immune response triggered by tumor cell death in the absence of immune system dysfunction from cancer chemotherapy. Recent studies have shown that GCV is maintained above the effective concentration for only a limited time (less than 1 h) following injection due to its short biological half‐life and dose‐limiting toxicity 27,28 . Thus, direct tumor cell death induced by the system was only a small fraction in vivo.…”

Section: Discussionmentioning

confidence: 99%

Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system

et al. 2023

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Immune cells can recognize tumor-associated antigens released from dead tumor cells, which elicit immune responses, potentially resulting in tumor regression. Tumor cell death induced by chemotherapy has also been reported to activate immunity.However, various studies have reported drug-induced immunosuppression or suppression of inflammation by apoptotic cells. Thus, this study aimed to investigate whether apoptotic tumor cells trigger antitumor immunity independent of anticancer treatment. Local immune responses were evaluated after direct induction of tumor cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/ GCV) system. The inflammatory response was significantly altered at the tumor site after apoptosis induction. The expression of cytokines and molecules that activate and suppress inflammation simultaneously increased. The HSV-tk/GCV-induced tumor cell apoptosis resulted in tumor growth suppression and promoted T lymphocyte infiltration into tumors. Therefore, the role of T cells after inducing tumor cell death was explored. CD8 T cell depletion abrogated the antitumor efficacy of apoptosis induction, indicating that tumor regression was mainly dependent on CD8 T cells.Furthermore, CD4 T cell depletion inhibited tumor growth, suggesting the potential role of CD4 T cells in suppressive tumor immunity. Tumor tissues were evaluated after tumor cell apoptosis and CD4 T cell depletion to elucidate this immunological mechanism. Foxp3 and CTLA4, regulatory T-cell markers, decreased. Furthermore, arginase 1, an immune-suppressive mediator induced by myeloid cells, was significantly downregulated. These findings indicate that tumors accelerate CD8 T cell-dependent antitumor immunity and CD4 T cell-mediated suppressive immunity. These findings could be a therapeutic target for immunotherapy in combination with cytotoxic chemotherapy.

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“…Pharmacokinetic studies have demonstrated that, upon i.p. administration, systemic GCV concentrations peak 1 hour after injection and are undetectable by 2 hours (22).…”

Section: Ganciclovir (Gcv) Treatmentmentioning

confidence: 99%

Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

Torrance

Panier

Cadar

et al. 2023

Preprint

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Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective deletion of p16-expressing senescent cells upon administration of ganciclovir (GCV). While p16-expressing senescent cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although deletion of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV treated mice. GCV treated mice were unable to mount an optimal memory response and demonstrated increased viral load following a heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.

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Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats

Abstract: Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.

Cited by 10 publications

References 23 publications

Effects of ganciclovir treatment in a murine model of cytomegalovirus‐induced hearing loss

Effects of ganciclovir treatment in a murine model of cytomegalovirus‐induced hearing loss

Distinct role of CD8 cells and CD4 cells in antitumor immunity triggered by cell apoptosis using a Herpes simplex virus thymidine kinase/ganciclovir system

Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

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