Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma

Autores
Buitagro, Emiliano; del Sole, Maria Jose; Torbidoni, Ana Vanesa; Fandino, Adriana; Asprea, Marcelo; Croxatto, Juan Oscar; Chantada, Guillermo; Bramuglia, Guillermo; Schaiquevich, Paula Susana
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5–5 μg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment.
Fil: Buitagro, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: del Sole, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina
Fil: Torbidoni, Ana Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
Fil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
Fil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
Fil: Croxatto, Juan Oscar. Fundacion Oftalmologia Argentina "j.malbran"; Argentina
Fil: Chantada, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
Fil: Bramuglia, Guillermo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Unidad de Farmacocinetica Clinica. Laboratorio Farmacia; Argentina
Materia
Intravitreal
Topotecan
Rabbits
Retinoblastoma
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4683

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network_name_str CONICET Digital (CONICET)
spelling Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastomaBuitagro, Emilianodel Sole, Maria JoseTorbidoni, Ana VanesaFandino, AdrianaAsprea, MarceloCroxatto, Juan OscarChantada, GuillermoBramuglia, GuillermoSchaiquevich, Paula SusanaIntravitrealTopotecanRabbitsRetinoblastomahttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5–5 μg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment.Fil: Buitagro, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: del Sole, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; ArgentinaFil: Torbidoni, Ana Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; ArgentinaFil: Croxatto, Juan Oscar. Fundacion Oftalmologia Argentina "j.malbran"; ArgentinaFil: Chantada, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; ArgentinaFil: Bramuglia, Guillermo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Unidad de Farmacocinetica Clinica. Laboratorio Farmacia; ArgentinaElsevier2013-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4683Buitagro, Emiliano; del Sole, Maria Jose; Torbidoni, Ana Vanesa; Fandino, Adriana; Asprea, Marcelo; et al.; Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma; Elsevier; Experimental Eye Research; 108; 3-2013; 103-1090014-4835enginfo:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0014483513000043info:eu-repo/semantics/altIdentifier/doi/10.1016/j.exer.2013.01.002info:eu-repo/semantics/altIdentifier/issn/0014-4835info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:27Zoai:ri.conicet.gov.ar:11336/4683instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:10:27.958CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
title Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
spellingShingle Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
Buitagro, Emiliano
Intravitreal
Topotecan
Rabbits
Retinoblastoma
title_short Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
title_full Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
title_fullStr Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
title_full_unstemmed Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
title_sort Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
dc.creator.none.fl_str_mv Buitagro, Emiliano
del Sole, Maria Jose
Torbidoni, Ana Vanesa
Fandino, Adriana
Asprea, Marcelo
Croxatto, Juan Oscar
Chantada, Guillermo
Bramuglia, Guillermo
Schaiquevich, Paula Susana
author Buitagro, Emiliano
author_facet Buitagro, Emiliano
del Sole, Maria Jose
Torbidoni, Ana Vanesa
Fandino, Adriana
Asprea, Marcelo
Croxatto, Juan Oscar
Chantada, Guillermo
Bramuglia, Guillermo
Schaiquevich, Paula Susana
author_role author
author2 del Sole, Maria Jose
Torbidoni, Ana Vanesa
Fandino, Adriana
Asprea, Marcelo
Croxatto, Juan Oscar
Chantada, Guillermo
Bramuglia, Guillermo
Schaiquevich, Paula Susana
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Intravitreal
Topotecan
Rabbits
Retinoblastoma
topic Intravitreal
Topotecan
Rabbits
Retinoblastoma
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5–5 μg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment.
Fil: Buitagro, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: del Sole, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina
Fil: Torbidoni, Ana Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
Fil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
Fil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
Fil: Croxatto, Juan Oscar. Fundacion Oftalmologia Argentina "j.malbran"; Argentina
Fil: Chantada, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
Fil: Bramuglia, Guillermo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Unidad de Farmacocinetica Clinica. Laboratorio Farmacia; Argentina
description Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 μg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 μg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 μg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 μg/dose; Group B, 0.5 μg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5–5 μg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 μg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 μg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 μg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 μg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment.
publishDate 2013
dc.date.none.fl_str_mv 2013-03
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4683
Buitagro, Emiliano; del Sole, Maria Jose; Torbidoni, Ana Vanesa; Fandino, Adriana; Asprea, Marcelo; et al.; Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma; Elsevier; Experimental Eye Research; 108; 3-2013; 103-109
0014-4835
url http://hdl.handle.net/11336/4683
identifier_str_mv Buitagro, Emiliano; del Sole, Maria Jose; Torbidoni, Ana Vanesa; Fandino, Adriana; Asprea, Marcelo; et al.; Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma; Elsevier; Experimental Eye Research; 108; 3-2013; 103-109
0014-4835
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.exer.2013.01.002
info:eu-repo/semantics/altIdentifier/issn/0014-4835
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publisher.none.fl_str_mv Elsevier
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