Papers by Jorge González Borroto
Nitroethene in the Mouse Bone Marrow Micronucleus Test
Pharmacovigilance 2017: Impact of the polypill approach in the efficacy and safety of Trinomia: Post-marketing pharmacovigilance data after three-years- Jorge I Gonzalez Borroto- Grupo Ferrer Internacional
Pharmaceutical Biotechnology: Current Research, 2017
Impact of the polypill approach in the efficacy and safety of Trinomia: Post-marketing pharmacovigilance data after three-years
Journal of Pharmacovigilance, 2017
Toxicological Sciences, 2003
The compound 2-furyl-1-nitroethene (G-0) has been tested to determine its ability to induce clast... more The compound 2-furyl-1-nitroethene (G-0) has been tested to determine its ability to induce clastogenic or aneugenic effects in vivo, through the induction of micronucleated polychromatic erythrocytes (MNPCE) in mouse bone marrow. Groups of five CD-1 male mice were administered once intraperitoneally at a dose range of 5-20 mg/kg and bone marrow was sampled at 24 and 48 h after the treatment. G-0 was dissolved in corn oil, thus a vehicle control group received only corn oil at 10 ml/kg. The positive control group was administered with cyclophosphamide (40 mg/kg). All animals dosed with the highest concentration of the test agent (20 mg/kg) showed evident clinical symptoms of toxicity. Although evidences of bone marrow toxicity were observed, no statistically significant increases in the incidence of MNPCE over the vehicle control group were observed at any sampling time with any of the assayed doses of the G-0 compound. Cyclophosphamide treatment increased the incidence of MNPCE in all treated animals, demonstrating the sensitivity of the assay conditions in which it was carried out. From the results obtained, it is concluded that the test agent G-0 is neither clastogenic nor aneugenic in the erythrocytes from the bone marrow of treated mice at the doses tested.
EFSA Journal, 2022
In accordance with Art. 31(1) of Regulation (EC) No 178/2002, the Commission asked EFSA to provid... more In accordance with Art. 31(1) of Regulation (EC) No 178/2002, the Commission asked EFSA to provide a scientific review on the BfR opinion on the 'Health risk assessment of ethylene oxide residues in sesame seeds' (Opinion No 024/2021) regarding the toxicity of 2-chloroethanol. In addition, EFSA was asked to clarify under which circumstances the use of the MOE approach is considered appropriate. Based on the information available to EFSA, i.e. the studies assessed in the frame of the BfR opinion and additional data provided by stakeholders not assessed by BfR, EFSA considers the genotoxicity of 2-chloroethanol as inconclusive. On this basis, EFSA would not recommend setting reference points for risk assessment or health-based guidance values until the genotoxic potential of 2-chloroethanol is clarified. EFSA therefore recommends performing new in vitro gene mutation and in vitro micronucleus tests with 2-chloroethanol following the recommendations of the most recent OECD technical guidelines to clarify its genotoxic potential. If the result of any of the test is positive, the recommendations of the EFSA Scientific Committee (2011) should be followed. If the genotoxic potential of 2-chloroethanol is finally clarified and overall negative, EFSA would recommend setting the reference point for deriving health-based guidance values based on existing toxicity studies on 2-chloroethanol.
Se evaluó mediante la técnica de tinción ultravital con naranja de acridina el potencial del prod... more Se evaluó mediante la técnica de tinción ultravital con naranja de acridina el potencial del producto Bioplant para inducir reticulocitos micronucleados (RETsMN) en sangre periférica de ratones machos de la linea Cenp:NMRI. La sustancia se disolvió en agua destilada estéril, las dosis ensayadas fueron 0 3 ,l y 2 g/kg de peso corporal (pc) y se administró por vía oral en dosis única en un volumen de 10 mL/kg pc para todos los grupos de tratamiento. La frecuencia de RETsMN se evaluó a las 48 h y 72 h post-administración. Se encontraron diferencias estadísticas significativas para p < 0,05 en el número de RETsMN en el grupo de tratamiento con Bioplant a la dosis de 2 g/kg de p.c. en relación con el control con vehículo a las 48 h; además hubo una relación dosis-respuesta positiva, lo que permite concluir que la sustancia de ensayo mostró clastogenicidad en las condiciones de este experimento.The potential of Bioplant was assessed using ultravital staining technique with acridine ora...
1The mutagenic potential of the furylethylene derivative 2-furyl-1-
Evaluation of the genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) in a battery of in vitro and in vivo genotoxicity assays
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2007
The genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) was evaluated in a battery o... more The genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) was evaluated in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, an in vivo mouse bone-marrow micronucleus assay and an in vivo rat-liver UDS assay. Maximum test concentrations in in vitro assays were determined by the TTX limit of solubility in the formulation vehicle (0.02% acetic acid solution). In the Ames test, TTX was tested at concentrations of up to 200 microg/plate. In the chromosome-aberration assay human lymphocytes were exposed to TTX at concentrations of up to 50 microg/ml for 3 and 20 h in the absence of S9, and for 3h in the presence of S9. For the in vivo assays, maximum tested dose levels were determined by the acute lethal toxicity of TTX after subcutaneous administration. In the mouse micronucleus assay TTX dose levels of 2, 4 and 8 microg/kg were administered to male and female animals, and bone-marrow samples taken 24 and 48 h (high-dose animals only) after administration. In the UDS assay, male rats were given TTX on two occasions with a 14-h interval at dose levels of 2.4 and 8 microg/kg, the last dose being administered 2h before liver perfusion and hepatocyte culturing. Relevant vehicle and positive control cultures and animals were included in all assays. TTX was clearly shown to lack in vitro or in vivo genotoxic activity in the assays conducted in this study. The results suggest that administration of TTX as a therapeutic analgesic agent would not pose a genotoxic risk to patients.
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2001
The compound 2-furyl-1-nitroethene (G-0) was evaluated for genotoxicity in cultured human periphe... more The compound 2-furyl-1-nitroethene (G-0) was evaluated for genotoxicity in cultured human peripheral blood lymphocytes, at concentrations ranging from 1 to 15 g/ml. Micronuclei (MN) and sister-chromatid exchanges (SCEs) were scored as genetic endpoints. In order to detect the role of metabolic enzymes on the genotoxicity of this furylethylenic derivative, the cultures for MN and SCE demonstrations were also treated with S9 microsomal fraction. The results indicate that, under the conditions of the study, the test agent does not seem to induce significant increases in the frequency of micronucleated cells, irrespective of the presence of metabolic activation. Nevertheless, a slight increase in the SCE frequency was observed in those cultures treated without the S9 mix; although this increase disappeared in presence of the microsomal fraction. In addition, cytostatic effects of 2-furyl-1-nitroethene were observed mainly in cultures without S9 fraction, as indicated by the reduction of cell proliferation.
Mutagenesis, 2005
The genotoxicity of three 2-furylethylene derivatives and four 5-nitrofurans was evaluated by usi... more The genotoxicity of three 2-furylethylene derivatives and four 5-nitrofurans was evaluated by using the comet assay in human lymphoblastoid cultured TK6 cells. The 2-furylethylene derivatives were 2-furyl-1-nitroethene, 1-(5-bromofur-2-yl)-2-nitroethene and 1-(5-bromofur-2yl)-2-bromo-2-nitroethene, while the 5-nitrofurans were nitrofurantoin, nitrofurazone, furazolidone and 5-nitro-2-furanacrolein. The treatments lasted for 3 h in the absence of metabolic activation. No genotoxic effects were observed for two of the 2-furylethylene compounds, while the derivative 1-(5-bromofur-2-yl)-2-nitroethene showed a statistically significant response mainly at the highest concentration tested; this effect was considered biologically relevant and the compound was classified as slightly genotoxic. On the other hand, for the classical 5-nitrofurans tested there is a tendency towards a dose-related increase of the DNA damage in the comet assay and the observed increases for the parameters analysed (Olive tail moment, tail % DNA and tail length) were significant for all compounds. Then, the four 5-nitrofurans tested were considered genotoxic. These results show that the position of the nitro group influences the genotoxicity of the assayed compounds. Thus, in this comet assay, the 2-furylethylene derivatives having the nitro group attached outside the furan ring appear to be much less genotoxic than the 5-nitrofurans.
Environmental Toxicology and Pharmacology, 2005
The genotoxic potential of the compound 1-(5-bromofur-2-yl)-2-nitroethene (2-NF) has been tested... more The genotoxic potential of the compound 1-(5-bromofur-2-yl)-2-nitroethene (2-NF) has been tested by using the in vivo mouse bone marrow micronucleus assay. Its ability to induce clastogenicity or aneugenicity, through the induction of micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow cells has been evaluated. Treatment groups of five CD-1 male mice were administered once intraperitoneally at the doses of 10, 20, and 30 mg/kg, and their bone marrows were sampled at 24 and 48 h after the administration, at the first sampling time animals administered with the three doses were used, and in the second sampling time, only animals administered with the highest dose were used. All animals treated with the highest dose of the test compound (30 mg/kg) showed evident clinical symptoms of toxicity such as irritation, hunched posture, slight ataxia, dyspnoea, piloerection, and palpebral ptosis. However, no marked depression of bone marrow cell proliferation was observed, and no significant increases in the frequency of MNPCE were obtained in any of the concentrations tested at any sampling times. The positive control treated-animals were administered with cyclophosphamide at the dose of 40 mg/mL. The compound caused a significant increase in the number of MNPCE in all treated animals, demonstrating the sensitivity of the mouse strain used. From the results obtained, it is concluded that the compound 2-NF is neither clastogenic nor aneugenic in the erythrocytes from the bone marrow of treated mice at the doses tested.
Food and Chemical Toxicology, 2004
The genotoxic potential of the compound 1-(5-bromofur-2-yl)-2-bromo-2-nitroethene (G-1) was evalu... more The genotoxic potential of the compound 1-(5-bromofur-2-yl)-2-bromo-2-nitroethene (G-1) was evaluated in peripheral blood lymphocytes cultured in vitro, at concentrations ranging from 1 to 20 mg/ml. Micronuclei (MN) and sister-chromatid exchanges (SCE) were scored as biomarkers of genotoxic effects. To detect the role of metabolic enzymes on the genotoxicity of this furylethylenic derivative, cultures for MN and SCE demonstrations were treated for 3 h with and without the S9 microsomal fraction as well as for 48 h without S9. Under the conditions of the study, the test agent did not induce significant increases in the frequency of micronucleated cells, irrespective of the presence/absence of the metabolic fraction. Nevertheless, a slight/moderate increase in the SCE frequency was observed in those cultures treated without the S9 mix. In addition, cytotoxic/cytostatic effects of the G-1 compound were observed mainly in cultures without S9 fraction, as indicated by the reduction of cell proliferation measured by the cytokinesis block proliferation index (CBPI) and the proliferative rate index (PRI).
Future Microbiology, 2018
Ozenoxacin is a nonfluorinated quinolone antibacterial approved for topical treatment of impetigo... more Ozenoxacin is a nonfluorinated quinolone antibacterial approved for topical treatment of impetigo. Because quinolones have known chondrotoxic effects in juvenile animals, the potential toxicity of ozenoxacin was assessed in preclinical studies. Materials & methods: Ozenoxacin or ofloxacin (300 mg/kg/day for 5 days, for each compound) was orally administered to juvenile rats, and oral ozenoxacin (10-100 mg/kg/day for 14 days) was administered to juvenile dogs. Results: In juvenile rats, ozenoxacin showed no chondrotoxicity, whereas ofloxacin produced typical quinolone-induced lesions in articular cartilage in three of ten rats. Oral ozenoxacin administration to juvenile dogs showed no chondrotoxicity or toxicologically relevant findings in selected target organs. Conclusion: Ozenoxacin was generally well-tolerated in juvenile rats and dogs, with no evidence of quinolone-induced arthropathy.
RESUMEN. Se evaluo mediante la tecnica de tincion ultravital con naranja de acridina el potencial... more RESUMEN. Se evaluo mediante la tecnica de tincion ultravital con naranja de acridina el potencial del producto Bioplant para inducir reticulocitos micronucleados (RETsMN) en sangre periferica de ratones machos de la linea Cenp:NMRI. La sustancia se disolvio en agua destilada esteril, las dosis ensayadas fueron 0 3 ,l y 2 g k g de peso corporal (pc) y se administro por via oral en dosis unica en un volumen de 10 mLIkg pc para todos los grupos de tratamiento. La frecuencia de RETsMN se evaluo a las 48 h y 72 h post-administracion. Se encontraron diferencias estadisticas significativas para p < 0,05 en el numero de RETsMN en el grupo de tratamiento con Bioplant a la dosis de 2 glkg de p.c. en relacion con el control con vehiculo a las 48 h; ademas hubo una relacion dosis-respuesta positiva, lo que permite concluir que la sustancia de ensayo mostro clastogenicidad en las condiciones de este experimento. SUMMARY."Geiiotoxic evaluation of Bioplaiit by ineans of the micronuclei ass...
Evaluación del potencial genotóxico de derivados furiletilénicos aplicando ensayos in vitro e in vivo
Tdx, Oct 27, 2010
LA TESIS DOCTORAL DESARROLLADA SE AJUSTA PERFECTAMENTE AL DISENO Y A LOS OBJETIVOS QUE SE PLANTEA... more LA TESIS DOCTORAL DESARROLLADA SE AJUSTA PERFECTAMENTE AL DISENO Y A LOS OBJETIVOS QUE SE PLANTEARON DESDE SU INICIO MOSTRANDO UN TRABAJO COHERENTE Y DE CONTINUIDAD EN LA LINEA DE INVESTIGACION SELECCIONADA. LA EVALUACION DE LA SEGURIDAD TOXICOLOGICA DE LAS SUSTANCIAS QUIMICAS ES UN ASPECTO DE GRAN IMPORTANCIA PARA PODER ESTABLECER LOS POSIBLES EFECTOS ADVERSOS SOBRE LA SALUD DEL SER HUMANO. DENTRO DE ESTE PROCESO DE EVALUACION ES CLAVE LA DETERMINACION Y ESTIMACION DEL RIESGO O POTENCIAL GENOTOXICO O MUTAGENICO DE LOS COMPUESTOS QUIMICOS, CON UN ESPECIAL INTERES EN EL CASO DE MOLECULAS QUE SEAN DE INTERES PARA LA INDUSTRIA FARMACEUTICA. EN LA TESIS SE LLEVA A CABO LA EVALUACION DEL POTENCIAL GENOTOXICO DE COMPUESTOS FURILETILENICOS LOS CUALES POSEEN UN GRAN INTERES POR SUS PROPIEDADES BIOLOGICAS PARA SER APLICADOS EN LA MEDICINA HUMANA Y VETERINARIA. LA EVALUACION SE HA DESARROLLADO MEDIANTE UNA BATERIA DE ENSAYOS IN VITRO E IN VIVO SIGUIENDO LOS REQUERIMIENTOS TECNICOS MAS ACTUALES Y LAS RECOMENDACIONES DE LAS NORMATIVAS INTERNACIONALES LO QUE DEMUESTRA LA RIGUROSIDAD CIENTIFICA DE LOS RESULTADOS OBTENIDOS. DICHOS RESULTADOS BRINDAN DATOS IMPORTANTES SOBRE LOS COMPUESTOS EVALUADOS Y SOBRE SU POTENCIAL GENOTOXICO QUE EN CONJUNTO CON OTROS RESULTADOS GARANTIZAN QUE SE PUEDA SEGUIR AVANZANDO EN EL PROCESO DE DESARROLLO DE POSIBLES FARMACOS BASADOS EN ESTAS MOLECULAS Y QUE PUEDAN LLEGAR A SER MEDICAMENTOS QUE POSEAN UNA MAYOR EFICACIA TERAPEUTICA Y A LA VEZ UNA MAYOR SEGURIDAD DESDE EL PUNTO DE VISTA TOXICOLOGICO Y GENOTOXICO SOBRE LA SALUD DEL SER HUMANO. LOS RESULTADOS OBTENIDOS EN LA TESIS DOCTORAL HAN SIDO PUBLICADOS EN PRESTIGIOSAS REVISTAS INTERNACIONALES RELACIONADAS CON LA TEMATICA DE INVESTIGACION DE LA TESIS, LO CUAL ES OTRO ASPECTO FAVORABLE ACERCA DE LA CALIDAD CIENTIFICA DEL TRABAJO DE TESIS PRESENTADO
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Papers by Jorge González Borroto