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dc.contributor.author
Buitagro, Emiliano
dc.contributor.author
del Sole, Maria Jose
dc.contributor.author
Torbidoni, Ana Vanesa
dc.contributor.author
Fandino, Adriana
dc.contributor.author
Asprea, Marcelo
dc.contributor.author
Croxatto, Juan Oscar
dc.contributor.author
Chantada, Guillermo
dc.contributor.author
Bramuglia, Guillermo
dc.contributor.author
Schaiquevich, Paula Susana
dc.date.available
2016-03-08T18:42:37Z
dc.date.issued
2013-03
dc.identifier.citation
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
dc.identifier.issn
0014-4835
dc.identifier.uri
http://hdl.handle.net/11336/4683
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Intravitreal
dc.subject
Topotecan
dc.subject
Rabbits
dc.subject
Retinoblastoma
dc.subject.classification
Oftalmología
dc.subject.classification
Medicina Clínica
dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Ocular and systemic toxicity of intravitreal topotecan in rabbits for potential treatment of retinoblastoma
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-03-30 10:35:44.97925-03
dc.journal.volume
108
dc.journal.pagination
103-109
dc.journal.pais
Países Bajos
dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Buitagro, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
dc.description.fil
Fil: del Sole, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tandil. Centro de Investigacion Veterinaria de Tandil; Argentina
dc.description.fil
Fil: Torbidoni, Ana Vanesa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
dc.description.fil
Fil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
dc.description.fil
Fil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan"; Argentina
dc.description.fil
Fil: Croxatto, Juan Oscar. Fundacion Oftalmologia Argentina "j.malbran"; Argentina
dc.description.fil
Fil: Chantada, Guillermo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "juan P. Garrahan". Servicio de Hemato-oncología; Argentina
dc.description.fil
Fil: Bramuglia, Guillermo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
dc.description.fil
Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "juan P.garrahan". Unidad de Farmacocinetica Clinica. Laboratorio Farmacia; Argentina
dc.journal.title
Experimental Eye Research
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.sciencedirect.com/science/article/pii/S0014483513000043
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.exer.2013.01.002
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/issn/0014-4835
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