Publications by authors named "Paula Schaiquevich"

81 Publications

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.
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http://dx.doi.org/10.3390/cancers13040673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915502PMC
February 2021

An Ultra-fast UHPLC-MS/MS Method for Cannabidiol Monitoring in Pediatric Refractory Epilepsy.

Ther Drug Monit 2020 Dec 17;Publish Ahead of Print. Epub 2020 Dec 17.

Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP-CONICET), Hospital de Niños "Dr. Ricardo Gutiérrez," Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina. Medicina de Precisión, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan," Buenos Aires, Argentina. Unidad de Farmacocinética Clínica, Área Farmacia, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan," Buenos Aires, Argentina. Servicio de Neurología, Hospital de Pediatría "Prof. Dr. Juan P. Garrahan," Buenos Aires, Argentina. Laboratorio de estadística aplicada a ciencias de la salud. Departamento de Toxicología y Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. Division of Paediatric Clinical Pharmacology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Ontario, Canada.

Background: Cannabidiol (CBD) is a non-psychoactive natural product that has been used increasingly as a promising new drug for the management of neurological conditions such as refractory epilepsy. Development of rapid and sensitive methods to quantitate CBD is essential to evaluate its pharmacokinetics in humans, particularly in children.

Objectives: To develop and validate an ultra-fast ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for CBD quantitation that is capable of detecting major CBD and tetrahydrocannabinol (THC) metabolites in the plasma of pediatric refractory epilepsy patients.

Methods: Eight-point CBD calibration curves were prepared using 60 µL of plasma from healthy volunteers. Samples were analyzed in a Shimadzu Nexera X2 UHPLC system, which was coupled to a Sciex QTRAP 6500 mass spectrometer. Chromatography was optimized in acetonitrile (ACN)/water with a 70% to 90% gradient of ACN in 2 min. Multiple reaction monitoring transitions of major CBD and THC metabolites were optimized in patient plasma.

Results: The optimized UHPLC-MS/MS method was validated for the linear range (1-300 ng/mL) of CBD (r 2 =0.996). The limit of quantification and limit of detection were 0.26 and 0.86 ng/mL, respectively. Accuracy and precision met the acceptable validation limits. CBD recovery and matrix effects were 83.9 ± 13.9% and 117.4 ± 4.5%, respectively. The method was successfully applied to quantify CBD and detect the major CBD and THC metabolites in clinical samples. 7-COOH-CBD was the most intensely detected metabolite followed by glucuronide conjugates.

Conclusion: A simple and sensitive method for rapidly monitoring CBD and identifying relevant metabolites was developed. Its applicability in samples from children treated for epilepsy was demonstrated, making it an excellent alternative for performing pharmacokinetic studies.
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http://dx.doi.org/10.1097/FTD.0000000000000846DOI Listing
December 2020

Pharmacokinetics of cannabidiol in children with refractory epileptic encephalopathy.

Epilepsia 2021 01 6;62(1):e7-e12. Epub 2020 Dec 6.

Precision Medicine, Garrahan Pediatric Hospital, Buenos Aires, Argentina.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring.
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http://dx.doi.org/10.1111/epi.16781DOI Listing
January 2021

Therapeutic drug monitoring in developing nations: assessing the current state of affairs in South America.

Expert Opin Drug Metab Toxicol 2021 Mar 7;17(3):251-254. Epub 2021 Jan 7.

Precision Medicine, Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina.

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http://dx.doi.org/10.1080/17425255.2021.1859478DOI Listing
March 2021

A decision process for drug discovery in retinoblastoma.

Invest New Drugs 2021 Apr 16;39(2):426-441. Epub 2020 Nov 16.

Precision Medicine, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina.

Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.
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http://dx.doi.org/10.1007/s10637-020-01030-0DOI Listing
April 2021

Global Retinoblastoma Treatment Outcomes: Association with National Income Level.

Ophthalmology 2020 Sep 29. Epub 2020 Sep 29.

Retinoblastoma Unit, Department of Oncology, Hospital Sant Joan de Déu. Esplugues de Llobregat, Barcelona, Spain.

Purpose: To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels.

Design: International, multicenter, registry-based retrospective case series.

Participants: Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents.

Methods: Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes.

Main Outcome Measures: Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy).

Results: Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001).

Conclusions: This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.
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http://dx.doi.org/10.1016/j.ophtha.2020.09.032DOI Listing
September 2020

Clinical, Genomic, and Pharmacological Study of -Amplified Wild-Type Metastatic Retinoblastoma.

Cancers (Basel) 2020 09 22;12(9). Epub 2020 Sep 22.

Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina.

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in gene with high-level amplification of (ampl+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of ampl+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common high amplification and chromosome 16q and 17p loss. A somatic mutation in , in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient's poor response but sensitivity to the synergistic effects of panobinostat-bortezomib and carboplatin-panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic ampl+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.
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http://dx.doi.org/10.3390/cancers12092714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565107PMC
September 2020

Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain.

Biomed Res Int 2020 13;2020:3902740. Epub 2020 Aug 13.

Medicina de Precisión, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.

Choosing an appropriate treatment for chronic pain remains problematic, and despite the available medication for its treatment, still, many patients complain about pain and appeal to the use of cannabis derivatives for pain control. However, few data have been provided to clinicians about the pharmacokinetic drug-drug interactions of cannabinoids with other concomitant administered medications. Therefore, the aim of this brief review is to assess the interactions between cannabinoids and pain medication through drug transporters (ATP-binding cassette superfamily members) and/or metabolizing enzymes (cytochromes P450 and glucuronyl transferases).
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http://dx.doi.org/10.1155/2020/3902740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443220PMC
August 2020

Clinical pharmacology of cannabidiol in refractory epilepsy.

Farm Hosp 2020 06 30;44(5):222-229. Epub 2020 Jun 30.

Unit of Clinical Pharmacokinetics, Pharmacy, Hospital de Pediatría JP Garrahan, Buenos Aires. Argentina..

Objective: The aim of this article is to provide a systematic and updated review  on the pharmacology of cannabidiol in the context of refractory epilepsy, with  special emphasis on its pharmacokinetics, adverse drug reactions and drug-drug interactions.

Method: A review of the literature related to cannabidiol pharmacokinetics, adverse drug reactions and drug-drug interactions was  carried out in the context of refractory epilepsy, through a search in PubMed and LILACS.

Results: Original studies that exhaustively describe the pharmacokinetics of  cannabidiol are limited but informative. Cannabidiol is rapidly absorbed and its  bioavailability increases when administered with high fat meals. Cannabidiol  exhibits a linear pharmacokinetic profile for doses up to 3,000 mg/day and  accumulates after multiple administrations. Elimination half-life has been  reported between 14 h and 60 h depending on the sampling times of each  study; changes in cannabidiol elimination due to continuous administration  cannot be discarded. Of all reported drugdrug interactions with anticonvulsants  or other co-administered drugs in patients with epilepsy, the strongest evidence  is provided with clobazam. The most frequent cannabidiol-related adverse drug  reactions were low to moderate and included somnolence, mainly related to  concomitant administration of clobazam, and gastrointestinal alterations. Also,  liver function abnormalities were reported during the use of cannabidiol and valproic acid.

Conclusions: Given the increased use of cannabidiol in refractory epilepsy, a  comprehensive understanding of its pharmacological profile is essential for the  clinical team. Specifically, clinical pharmacists play an important role in  monitoring cannabidiol's safety and efficacy. This approach leads to treatment  optimization, allowing to maximizing the pharmacological activity and minimizing the occurrence of adverse events as well as drug-to-drug interactions. Clinical  follow-up is essential to avoid discontinuation of treatment or exacerbation of  adverse events, which may impair the patients' quality of life.
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http://dx.doi.org/10.7399/fh.11390DOI Listing
June 2020

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part II: Treatment Success and Globe Salvage.

Ophthalmology 2020 12 8;127(12):1733-1746. Epub 2020 Jun 8.

Retinoblastoma Unit, Department of Oncology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.

Purpose: To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB).

Design: International, multicenter, registry-based retrospective case series.

Participants: A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.

Methods: International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included.

Main Outcome Measures: Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC).

Results: Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year Kaplan-Meier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of local treatment failure in categories cT1b (hazard ratio [HR], 3.5; P = 0.004), cT2a (HR, 15.1; P < 0.001), cT2b (HR, 16.4; P < 0.001), and cT3 (HR, 45.0; P < 0.001) compared with category cT1a. Use of plaque brachytherapy and IAC improved local tumor control in categories cT1a (P = 0.031) and cT1b (P < 0.001).

Conclusions: Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB.
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http://dx.doi.org/10.1016/j.ophtha.2020.05.051DOI Listing
December 2020

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma: Part I: Metastasis-Associated Mortality.

Ophthalmology 2020 12 6;127(12):1719-1732. Epub 2020 Jun 6.

Retinoblastoma Unit, Department of Oncology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.

Purpose: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB).

Design: International, multicenter, registry-based retrospective case series.

Participants: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.

Methods: Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied.

Main Outcome Measures: Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan-Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait.

Results: Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n = 92) from diagnosis to metastasis was 9.50 months. The 5-year Kaplan-Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97-99) for cT1b and cT2a, 96% (95% CI, 95-97) for cT2b, 89% (95% CI, 88-90) for cT3 tumors, and 45% (95% CI, 31-59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55-25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease.

Conclusions: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.
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http://dx.doi.org/10.1016/j.ophtha.2020.05.050DOI Listing
December 2020

Genomic and Transcriptomic Tumor Heterogeneity in Bilateral Retinoblastoma.

JAMA Ophthalmol 2020 05;138(5):569-574

Precision Medicine, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina.

Importance: Comprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics.

Objective: To compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma.

Design, Setting, And Participants: In this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation. Tumor samples were subjected to genomic and gene-expression analysis. Primary cell cultures were established from both of the tumors of 1 patient and were used for gene-expression studies.

Main Outcomes And Measures: Whole-exome sequencing was performed on an Illumina platform for fresh tumor samples and DNA arrays (CytoScan or OncoScan) were used for paraffin-embedded samples and cell lines. Gene-expression analysis was performed using Agilent microarrays. Germinal and somatic alterations, copy number alterations, and differential gene expression were assessed.

Results: After initial bilateral enucleation, patient 1 showed massive choroidal and laminar optic nerve infiltration, while patient 2 showed choroidal and laminar optic nerve invasion. Patient 1 developed left-eye orbital recurrence and bone marrow metastasis less than 1 year after enucleation. Both ocular tumors showed gains on 1q and 6p but presented other distinct genomic alterations, including an additional gain in 2p harboring the N-myc proto-oncogene (MYCN) in the left tumor and orbital recurrence. Similar copy number alterations between the orbital recurrence and the left eye supported the origin of the relapse, with an additional 11q loss only detected in the orbital relapse. Specimens from patient 2 showed common copy number gains and losses, but further evolution rendered a 2p gain spanning MYCN in the left tumor. For this patient, microarray expression analysis showed differential expression of the MYCN and the forkhead box protein G1 (FOXG1) gene pathways between the left and right tumors.

Conclusions And Relevance: Differential genomic and gene expression features were observed between tumors in 2 patients with bilateral disease, confirming intereye heterogeneity that might be considered if targeted therapies are used in such patients. Chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient. Loss in chromosome 11q may have been associated with extraocular relapse in this patient.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.0427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082772PMC
May 2020

Medicinal cannabis in Latin America: History, current state of regulation, and the role of the pharmacist in a new clinical experience with cannabidiol oil.

J Am Pharm Assoc (2003) 2020 Jan - Feb;60(1):212-215. Epub 2019 Nov 6.

Objective: Cannabis sativa was introduced in Latin America in the 16th century. Nevertheless, many years have elapsed, and scientific progress and the medicinal use of C sativa have been restricted by the national laws of the countries in the region.

Summary: In Argentina, the first law on medical cannabis, approved in 2017 (#17,350), establishes a regulatory framework for the medical use and scientific research of this plant and its derivatives. In 2018, the first clinical research protocol in Latin America was approved at Hospital de Pediatria Garrahan (Buenos Aires, Argentina) to evaluate the efficacy and safety of cannabidiol (CBD) oil for the treatment of pediatric patients with refractory epilepsy. In this context, the role of pharmacists in the health care system related to the study protocol and the medicinal use of CBD has evolved from dispensing to active participation in clinical follow-up and research protocols.

Conclusion: Considering this experience, here we discuss the active role of the clinical pharmacist in the use of medicinal cannabis. Medicinal cannabis should be controlled in a legal framework based on clinical evidence, and the participation of the pharmacist in research and clinical protocols, as well as the dispensing and provision of information on the medicinal products should be emphasized in the clinical setting.
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http://dx.doi.org/10.1016/j.japh.2019.09.012DOI Listing
November 2019

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis.

Pediatr Pulmonol 2019 11 12;54(11):1801-1810. Epub 2019 Aug 12.

Clinical Pharmacokinetics Unit, Hospital de Pediatria JP Garrahan, Buenos Aires, Argentina.

Introduction: Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF.

Methods: CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg  kg  day every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite-2018R1 (Lixoft).

Results: A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours and 0.451 L/kg, respectively. Between-subject and between-occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg  kg  day every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective.

Conclusions: The regimen of 30  mg  kg  day every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse-events profile, further studies are necessary to redefine the optimal treatment strategy.
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http://dx.doi.org/10.1002/ppul.24468DOI Listing
November 2019

Conservative management of retinoblastoma: Challenging orthodoxy without compromising the state of metastatic grace. "Alive, with good vision and no comorbidity".

Prog Retin Eye Res 2019 11 5;73:100764. Epub 2019 Jun 5.

Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, Lausanne, Switzerland.

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated. Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy. Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.
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http://dx.doi.org/10.1016/j.preteyeres.2019.05.005DOI Listing
November 2019

Identification of Factors Affecting Tacrolimus Trough Levels in Latin American Pediatric Liver Transplant Patients.

Liver Transpl 2019 09 25;25(9):1397-1407. Epub 2019 Jun 25.

Liver Transplant Service, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina.

Tacrolimus is the cornerstone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to characterize the clinical, pharmacological, and genetic variables associated with systemic tacrolimus exposure in pediatric liver transplant patients. De novo transplant patients with a survival of more than 1 month were considered for inclusion and were genotyped for cytochrome P450 3A5 (CYP3A5). Peritransplant clinical factors and laboratory covariates were recorded retrospectively between 1 month and 2 years after transplant, including alanine aminotransferase (ALT), aspartate aminotransferase, hematocrit, and tacrolimus predose steady-state blood concentrations collected 12 hours after tacrolimus dosing. A linear mixed effect (LME) model was used to assess the association of these factors and the log-transformed tacrolimus dose-normalized trough concentration (logC0/D) levels. Bootstrapping was used to internally validate the final model. External validation was performed in an independent group of patients who matched the original population. The developed LME model described that logC0/D increases with increases in time after transplant (β = 0.019, 95% confidence interval [CI], 0.010-0.028) and ALT values (β = 0.00030, 95% CI, 0.00002-0.00056), whereas logC0/D is significantly lower in graft CYP3A5 expressers compared with nonexpressers (β = -0.349, 95% CI, -0.631 to -0.062). In conclusion, donor CYP3A5 genotype, time after transplant, and ALT values are associated with tacrolimus disposition between 1 month and 2 years after transplant. A better understanding of tacrolimus exposure is essential to minimize the occurrence of an out-of-range therapeutic window that may lead to adverse drug reactions or acute rejection.
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http://dx.doi.org/10.1002/lt.25495DOI Listing
September 2019

Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration.

Int J Mol Sci 2019 Mar 2;20(5). Epub 2019 Mar 2.

National Scientific and Technical Research Council (CONICET), Buenos Aires CP1425, Argentina.

A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core ( < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.
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http://dx.doi.org/10.3390/ijms20051077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429414PMC
March 2019

Minimally disseminated disease and outcome in overt orbital retinoblastoma.

Pediatr Blood Cancer 2019 06 25;66(6):e27662. Epub 2019 Feb 25.

Scientific and Technical Research Council, CONICET, Buenos Aires, Argentina.

In this retrospective study of patients with overt orbital retinoblastoma, we evaluated minimally disseminated disease (MDD) in bone marrow and cerebrospinal fluid (CSF) using CRX and/or GD2 synthase as markers. Ten patients were evaluated-five (50%) at diagnosis and five upon relapse. MDD was detected in four cases (one in the bone marrow, two in the CSF, and in one case in both sites). All patients received chemotherapy and four received orbital radiotherapy. Seven patients relapsed or progressed and all of them died. Three patients remain in complete remission. There was no apparent correlation between MDD and the outcome.
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http://dx.doi.org/10.1002/pbc.27662DOI Listing
June 2019

Comparison of the pharmacological activity of idarubicin and doxorubicin for retinoblastoma.

Pediatr Blood Cancer 2019 01 5;66(1):e27441. Epub 2018 Sep 5.

Unit of Clinical Pharmacokinetics, Hospital de Pediatría Prof. Dr. JP Garrahan, Buenos Aires, Argentina.

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http://dx.doi.org/10.1002/pbc.27441DOI Listing
January 2019

Combined high-dose intra-arterial and intrathecal chemotherapy for the treatment of a case of extraocular retinoblastoma.

Pediatr Blood Cancer 2018 12 13;65(12):e27385. Epub 2018 Aug 13.

Department of Hematology-Oncology, Hospital de Pediatría Prof. Dr. JP Garrahan, Buenos Aires, Argentina.

Patients with retinoblastoma and central nervous system (CNS) involvement are rarely curable with available treatments. We designed a high-dose intra-arterial regimen targeting the ophthalmic artery and chiasm combined with intrathecal chemotherapy to treat a 4-year-old patient with retinoblastoma metastasized to the CNS. After three cycles of this regimen, including carboplatin, melphalan, and intrathecal topotecan, a partial response of the orbital tumor mass and chiasmatic lesion, and complete response in the cerebrospinal fluid and bone marrow were achieved. This new treatment strategy may be explored as a treatment component for patients with overt extraocular retinoblastoma and CNS dissemination.
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http://dx.doi.org/10.1002/pbc.27385DOI Listing
December 2018

Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina.

Pediatr Blood Cancer 2018 08 25;65(8):e27086. Epub 2018 Apr 25.

Pediatric Hemato-Oncology Service, Hospital Universitario Austral, Pilar, Argentina.

Background: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported.

Procedure: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015.

Results: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation.

Conclusions: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.
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http://dx.doi.org/10.1002/pbc.27086DOI Listing
August 2018

Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation.

Ther Drug Monit 2018 08;40(4):401-410

Unit of Clinical Pharmacokinetics, Hospital de Pediatría J.P. Garrahan.

Background: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients.

Methods: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR-free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models.

Results: Cox-proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR.

Conclusions: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results.
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http://dx.doi.org/10.1097/FTD.0000000000000517DOI Listing
August 2018

Assessment of retinoblastoma RNA reflux after intravitreal injection of melphalan.

Br J Ophthalmol 2018 03 31;102(3):415-418. Epub 2017 Oct 31.

Unit of Clinical Pharmacokinetics, Hospital de Pediatría JP Garrahan, Buenos Aires, Argentina.

Background: Intravitreal injection of chemotherapy in retinoblastoma eyes with vitreous seeds may lead to a risk of extraocular tumour dissemination that has not been assessed so far.

Aims: To develop a sensitive and clinically feasible technique to assess for potential retinoblastoma cell reflux after intravitreal injection of melphalan.

Methods: Filter papers were cut in 6 mm diameter circles and sterilised before use. Eyes with retinoblastoma vitreous seeds (group D, International Classification) received weekly intravitreal melphalan injections (20 µg or 30 µg/dose) followed by cryotherapy as part of local treatment. Immediately after finishing the injection and cryotherapy, filter papers were placed on the injection site and on the cryoprobe tip to assess for the expression of the cone-rod homeobox gene (CRX) by real-time qPCR as a surrogate of retinoblastoma RNA. The assay was developed and validated to determine sensitivity, linearity, recovery, repeatability and reproducibility.

Results: The assay for quantitation of CRX expression was linear in the range of 1 to 1000 cells. The lowest limit of detection was one retinoblastoma cell and allowed to recover 100% of the cell load in external supplementation. A total of 14 eyes received 22 cycles of intravitreal melphalan and were evaluated for potential extraocular tumour cell dissemination using the developed technique. None of the cycles were positive for CRX in samples from the scar or from the cryoprobe tip.

Conclusions: A sensitive and simple method of tumour cell assessment has been developed that can be used in the clinics to assess for potential extraocular dissemination after intravitreal injections to assure its performance.
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http://dx.doi.org/10.1136/bjophthalmol-2017-310574DOI Listing
March 2018

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

J Control Release 2017 Oct 19;264:34-44. Epub 2017 Aug 19.

Institut de Recerca Sant Joan de Deu, Barcelona, Spain; Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain. Electronic address:

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.

Chemical Compounds Included In This Manuscript: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).
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http://dx.doi.org/10.1016/j.jconrel.2017.08.018DOI Listing
October 2017

Pharmacoepidemiology of tacrolimus in pediatric liver transplantation.

Pediatr Transplant 2017 Aug 2;21(5). Epub 2017 Jun 2.

Liver Transplantation, Hospital de Pediatría J.P. Garrahan, Buenos Aires, Argentina.

AEs during immunosuppressive treatment with tacrolimus are very common. We retrospectively evaluated FK safety and efficacy in a large pediatric liver transplant cohort in Latin America. During 2-year follow-up, we analyzed data from patients who underwent liver transplantation over the period 2010-2012 and recorded FK exposure, AEs, and AR episodes. AEs were classified according causality and severity. Tacrolimus exposure before and during AE was compared using Wilcoxon matched-pairs test. Kaplan-Meier curves were used for survival analysis. In total, 46 patients (out of 72 patients) experienced 69 AEs, such as hypomagnesemia (49%), PTLD (6%), hypertension (6%), and/or nephrotoxicity (22%). 43% of AEs were classified as moderate or serious, and 89% were assigned as probable or definitive. Patients who had one or more AR episodes accounted for 65%. The 12-month acute rejection-free survival was 41% (95% CI, 30.1%-53.1%). A significant difference was observed in FK trough concentrations before and during hypomagnesemia and nephrotoxicity (P<.05). This study is the first report of FK safety in a large group of pediatric liver transplant patients in Latin America. Children experience AEs, even in protocols with low FK doses. Therapeutic monitoring is an important tool to manage immunosuppressive schemes containing tacrolimus in vulnerable populations.
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http://dx.doi.org/10.1111/petr.12982DOI Listing
August 2017

Pharmacokinetics of a novel spot-on formulation of praziquantel for dogs.

Vet Parasitol 2017 May 17;239:46-49. Epub 2017 Apr 17.

CONICET, Argentina; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, C1121ABF Ciudad Autónoma de Buenos Aires, Argentina; Plataforma Tecnológica EBAL, Paraguay 2155, C1121ABF Ciudad Autónoma de Buenos Aires, Argentina. Electronic address:

Praziquantel (PZQ) is an anthelmintic drug used both in humans and animals that can be administered through various routes. There are transdermal formulations for cats, but only oral or subcutaneous dosage forms for dogs. Given the fact that the cat's skin and the dog's skin have different characteristics, which in turn affect bioavailability, we developed a PZQ spot-on formulation for dogs. This study was aimed at determining the plasmatic behavior of topically administered PZQ (Labyes) in adult dogs. Dogs were administered PZQ (14.5mg/kg PZQ, from a solution of 100mg/ml). Blood samples were drawn before treatment onset and at the following time points after PZQ administration: 1, 2, 4, 6, 12, 24 and 48h. PZQ plasma concentration was determined by ultra-high performance liquid chromatography (UPLC) coupled to tandem mass spectrometry (MS/MS). Observed maximum concentration (C), area under the concentration-time curve from the time of drug administration to infinity (AUC) and time to maximum concentration (T) were calculated for each animal, and mean±SD for each parameter was obtained. Results were as follows: C=56.0±15ng/ml; AUC=910.2±220ng*h/ml, T=5.0±1.1h. This is the first study to provide pharmacokinetic data of a praziquantel spot-on formulation for dogs.
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http://dx.doi.org/10.1016/j.vetpar.2017.04.022DOI Listing
May 2017

Comparison of two sedation protocols for short electroretinography in cats.

J Feline Med Surg 2018 02 5;20(2):172-178. Epub 2017 Apr 5.

1 Laboratory of Pharmacology, Tandil Center of Veterinary Investigation (CIVETAN, CONICET-CICPBA), Faculty of Veterinary Science, National University of the Center of Buenos Aires Province, University Campus, Tandil, Argentina.

Objectives The objectives were to compare two different sedative combinations, xylazine-ketamine and dexmedetomidine-ketamine, for the short electroretinography (ERG) protocol and their impact on sedative effect, reversal times and physiological variables in cats. Methods Six healthy spayed female domestic cats were sedated using one of two ketamine-containing protocols: intramuscular xylazine hydrochloride (1 mg/kg) plus ketamine hydrochloride (3 mg/kg) (XK), and dexmedetomidine hydrochloride (5 µg/kg) plus ketamine hydrochloride (3 mg/kg) (DK). A short ERG protocol was recorded from the left eye of each cat under XK and DK sedation. Thirty minutes later, the effects were reversed with yohimbine or atipamezole for the XK and DK treatment, respectively. The cats were evaluated for time to recumbency, time to head elevation, and time to standing position after reversal treatments. Other variables recorded were: systolic blood pressure, cardiac rhythm, heart rate, pulse oximetry and respiratory rate. Recorded ERG variables included a- and b-wave amplitudes and implicit times under photopic, scotopic and scotopic mixed ERG conditions. Results Time to lateral recumbency with XK was shorter than for DK ( P <0.05). After reversal, head elevation and standing position times were significantly longer for the XK than the DK group ( P <0.05). Heart rate increased and systolic blood pressure decreased from baseline in both groups ( P <0.05), but there were no significant differences between treatment groups. The b-wave amplitude recorded in the photopic study of cats treated with XK was lower than in animals treated with DK ( P <0.05). No other significant differences in ERG variables were observed between treatment groups ( P >0.05). Conclusions and relevance The present study shows that XK and DK treatments are chemical restraint alternatives for ERG recording in cats, with significant differences only in the photopic b-wave amplitude.
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http://dx.doi.org/10.1177/1098612X17703011DOI Listing
February 2018

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

Farm Hosp 2017 Mar 1;41(2):150-168. Epub 2017 Mar 1.

Clinical Pharmacokinetics Department, J.P. Garrahan Children's Hospital, Buenos Aires. National Scientific and Technological Research Council (CONICET)..

Objective: Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution.

Method: Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test.

Results: In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017- 0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed.

Conclusion: In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.
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http://dx.doi.org/10.7399/fh.2017.41.2.10534DOI Listing
March 2017