8 research outputs found

    Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine mode

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    Purpose: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). Methods: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. Results: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9–138.7] vs. 13.6 ng/mL [5.5–15.3], respectively; P , 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 nghour/mL [247.6–347.2] and 48.9 nghour/mL [11.8–63.4], respectively; P , 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 nghour/mL [6.8–13.4] vs. 18.7 nghour/mL [6.3–21.7]; P = 0.54). Conclusion: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires; ArgentinaFil: Ceciliano, Alejandro. No especifĂ­ca;Fil: Fandino, Adriana C.. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Sierre, Sergio. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. No especifĂ­ca;Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; Argentin

    Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine mode

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    Purpose: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). Methods: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. Results: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9–138.7] vs. 13.6 ng/mL [5.5–15.3], respectively; P , 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 nghour/mL [247.6–347.2] and 48.9 nghour/mL [11.8–63.4], respectively; P , 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 nghour/mL [6.8–13.4] vs. 18.7 nghour/mL [6.3–21.7]; P = 0.54). Conclusion: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires; ArgentinaFil: Ceciliano, Alejandro. No especifĂ­ca;Fil: Fandino, Adriana C.. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Sierre, Sergio. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. No especifĂ­ca;Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; Argentin

    Application of microdialysis for pharmacokinetic-pharmacodynamic modelling

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    Pharmacokinetic–pharmacodynamic (PK–PD) modelling describes the relationship between the pharmacokinetics and pharmacodynamics of a drug allowing the prediction of clinically relevant parameters. PK–PD modelling has several advantages over classical dose–response studies because it allows a better pharmacodynamic characterisation of drugs and screening of dosage– regimen. However, PK–PD studies are limited by the need for simultaneous measurement of drug tissue levels and corresponding pharmacological effects at multiple time points. The microdialysis technique is a unique research tool that allows the simultaneous determination of unbound concentrations of drugs at several tissues and its action on biochemical and clinical markers during several hours and days. Therefore, microdialysis sampling is an attractive methodology for PK–PD studies. The aim of this review is to describe the applicability of the microdialysis technique for PK–PD modelling of therapeutic agents, including the description of PK–PD modelling concepts, an overview of the microdialysis technique and the analysis of PK–PD studies using microdialysis sampling both in the preclinical and clinical setting.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay; ArgentinaFil: Opezzo, Javier. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica; ArgentinaFil: Taira, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay; Argentin

    Application of Microdialysis in Clinical Pharmacology

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    Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites in different laboratory animals. However, in the last ten years microdialysis sampling has been introduced as a versatile technique in the clinical setting. Although, microdialysis sampling has been extensively used for metabolic monitoring in patients, it was also employed for the study of distribution of different therapeutic agents especially anti-infective and antineoplasic drugs. In addition, clinical effect of drugs in patients could be also determined by means of microdialysis. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs in the clinical setting.Microdialysis has been developed during the last 25 years by several authors primarily to study brain function and changes in levels of endogenous compounds such as neurotransmitters or metabolites in different laboratory animals. However, in the last ten years microdialysis sampling has been introduced as a versatile technique in the clinical setting. Although, microdialysis sampling has been extensively used for metabolic monitoring in patients, it was also employed for the study of distribution of different therapeutic agents especially anti-infective and antineoplasic drugs. In addition, clinical effect of drugs in patients could be also determined by means of microdialysis. So, this article reviewed the vast applications of the microdialysis technique for the study of pharmacokinetic and pharmacodynamic properties of drugs in the clinical setting.Fil: Höcht, Christian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Opezzo, Javier. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentin

    Pharmacokinetic-pharmacodynamic (PK-PD) modeling of cardiovascular effects of metoprolol in spontaneously hypertensive rats: a microdialysis study

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    The present work addressed possible alterations inthe pharmacokinetics and the in vivo pharmacodynamic ofmetoprolol (MET) in spontaneously hypertensive (SH) ratsand Wistar Kyoto (WKY) animals by means of the microdialysistechnique. The correlation between MET unboundplasma concentrations and its pharmacological effects, such asheart rate and blood pressure change,was also examined in SHand WKY rats by the application of a PK-PD model. METdialysate concentrations and its chronotropic and bloodpressure effect were determined during 3 h after theadministration of 3 and 10 mg.kg−1 of the drug. A PK-PDmodel with a separate effect compartment was used toanalyse the data. A good correlation between plasma METconcentrations and its hypotensive and chronotropic effectwas found in all experimental groups. Although a greatermaximal effect (Emax) for the antihypertensive effect of METwas observed in SH rats (WKY: Emax: −17±1 mmHg; SH:Emax: −28±4 mmHg; P<0.05 versus WKY rats), no differenceswere found in the concentration yielding half-maximalresponse (IC50) comparing SH (IC50: 583±146 ng.ml−1) andWKY animals (IC50: 639±187 ng.ml−1). The bradycardiceffect of MET was greater in SH rats (Emax: −29±1%, P<0.05versus WKY rats) than in WK animals (Emax: −22±2%), butno differences were observed in the IC50 comparing bothexperimental groups (WKY: IC50: 187±53 ng.ml−1; SH: IC50:216±62 ng.ml−1). Pharmacokinetic analysis shows that thevolume of distribution of MET was greater in SH rats (Vd:3.4±0.5 l, P<0.05 versus WKY rats) with regard to WistarKyoto (WKY) animals (Vd: 1.9±0.2 l). The results suggestthat the pharmacokinetic behaviour of metoprolol aremodified in SH rats, resulting in an increased volume ofdistribution. A greater maximal efficacy to the hypotensiveeffect of metoprolol was observed in SH rats, suggestingparticipation of Ăą-adrenoceptors in the maintenance of thehypertension. Also, a greater chronotropic response tometoprolol was found in the hypertensive group comparedwith WKY animals, suggesting that, at least in part, thegreater cardiac effect of metoprolol explained the enhancedhypotensive response of the beta blocker in the SH animals.Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a; ArgentinaFil: Di Verniero, Carla. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a; ArgentinaFil: Opezzo, Javier A.. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a; ArgentinaFil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a; Argentin

    Ocular pharmacology of topotecan and its activity in retinoblastoma

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    Purpose: To review the ocular pharmacology and antitumor activity of topotecan for the treatment of retinoblastoma by an evaluation of different routes of administration. Methods: Systematic review of studies available at PubMed using the keywords retinoblastoma, topotecan, and camptothecins, including preclinical data such as cell lines and animal models, as well as clinical studies in patients with retinoblastoma. Results: Forty-two available studies were reviewed. Evidence of antitumor activity against retinoblastoma as a single agent is based on data on cell lines and a limited number of affected patients with intraocular and extraocular disease when given in a protracted schedule. Evidence of additive or synergistic activity in combination with other agents such as carboplatin, melphalan, and vincristine was reported in preclinical and clinical models. In animal models, pharmacokinetic evaluation of topotecan administered by the periocular route shows that most of the drug reaches the vitreous through the systemic circulation. Topotecan administered by intravitreal injection shows high and sustained vitreal concentrations with limited systemic exposure and lack of retinal toxicity at a dose of up to 5 ÎŒg. Topotecan administered intraophthalmic artery shows higher passage to the vitreous compared with periocular administration in a swine model. Conclusion: Topotecan alone or in combination is active against retinoblastoma. It shows a favorable passage to the vitreous when given intravenously and intraarterially, and ocular toxicity is minimal by all routes of administration. However, its clinical role, optimal dose, and route of administration for the treatment of retinoblastoma are to be determined.Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a ; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Montero Carcaboso, Angel. Hospital Sant Joan de DĂ©u, Departamento de OncologĂ­a; España. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Buitrago, Emiliano. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Taich, Paula Juliana. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a ; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Opezzo, Javier. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a ; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentin

    Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

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    Background: Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children. Methods: Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (Ctrough) and between 1 and 2 h after (Cpost-dose) the administration of the next dose of drug. CD4+ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r. Results: MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~ 50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV Cpost-dose than homozygotes 1236TT (median Cpost-dose = 3.04 ÎŒg/ml and 6.50 ÎŒg/ml, respectively; p = 0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes = − 0.50 log10 copies/ml and − 2.08 log10 copies/ml, respectively; p = 0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR. Conclusions: Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4+ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.Fil: Bellusci, Carolina Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan". Laboratorio de BiologĂ­a Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Rocco, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan". Laboratorio de BiologĂ­a Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Aulicino, Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan". Laboratorio de BiologĂ­a Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Mecikovsky, Debora. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Curras, VerĂłnica. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Hegoburu, Soledad. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y BioquĂ­mica. Departamento de FarmacologĂ­a. CĂĄtedra de FarmacologĂ­a; ArgentinaFil: Bologna, Rosa. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan"; ArgentinaFil: Sen, Luisa. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan". Laboratorio de BiologĂ­a Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; ArgentinaFil: Mangano, Andrea MarĂ­a Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital de PediatrĂ­a "Juan P. Garrahan". Laboratorio de BiologĂ­a Celular y Retrovirus; Argentina. Consejo Nacional de Investigaciones CientĂ­ficas y TĂ©cnicas; Argentin

    Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier

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    Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P = 0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P = 0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.Fil: Pascual-Pasto, Guillem. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Olaciregui, Nagore G.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Opezzo, Javier A. W.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Castillo Ecija, Helena. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Cuadrado Vilanova, Maria. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Paco, Sonia. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Rivero, Ezequiel Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vila Ubach, Monica. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Restrepo Perdomo, Camilo A.. Hospital Sant Joan de Deu Barcelona; EspañaFil: Torrebadell, Montserrat. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Suñol, Mariona. Hospital Sant Joan de Deu Barcelona; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; EspañaFil: Carcaboso, Angel M.. Hospital Sant Joan de Deu Barcelona; España. Institut de Recerca Sant Joan de Deu; Españ
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