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Cyclosporine is an immunosuppressant used to prevent organ rejection in kidney, liver, and heart allogeneic transplants. This study aimed to assess the safety of cyclosporine through the analysis of adverse events (AEs) related to cyclosporine in the US Food and Drug Administration Adverse Event Reporting System (FAERS). To detect AEs associated with cyclosporine, a pharmacovigilance analysis was conducted using four algorithms on the FAERS database: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). A statistical analysis was performed on data extracted from the FAERS database, covering 19,582 case reports spanning from 2013 to 2022. Among these cases, 3,911 AEs were identified, with 476 linked to cyclosporine as the primary suspected drug. Cyclosporin-induced AEs targeted 27 System Organ Classes (SOCs). Notably, the highest case at the SOC level included eye disorders, injury, poisoning, and procedural complications, as well as immune system disorders, all of which are listed on the cyclosporine label. Furthermore, we discovered novel potential AEs associated with hepatobiliary disorders, among others. Moreover, unexpected adverse drug reactions (ADRs), such as biliary anastomosis complication and spermatozoa progressive motility decrease, were identified. Importantly, these newly identified ADRs were not mentioned on the cyclosporine label, which were involved in injury, poisoning, and procedural complications, and investigations at the SOC level. The study used pharmacovigilance analysis of FAERS database to identify new and unexpected potential ADRs relating to cyclosporine, which can provide safety tips for the safe use of cyclosporine.

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La hemosiderosis pulmonar idiopática (HPI) es una patología poco frecuente; su distribución geográfica, su incidencia y prevalencia se desconocen de manera exacta a nivel mundial. Tiene una fuerte asociación con condiciones autoinmunes y una adecuada respuesta al tratamiento inmunosupresor. A pesar de ser una patología grave, presenta una tasa de morbilidad y mortalidad mediana, siempre que se realice un diagnóstico y tratamiento precoz. Se presenta el caso clínico de una paciente femenina con diagnóstico de HPI quien cursó con la triada clásica de esta enfermedad: hemoptisis, anemia ferropénica e infiltrados pulmonares difusos. Se descartaron otras causas de hemorragia pulmonar difusa y se realizó el diagnóstico por biopsia pulmonar. Se trató con esteroides sistémicos e inhalados y azatioprina. Tras casi 2 años después del diagnóstico, estando sin tratamiento por 3 meses, presentó una exacerbación con hemorragia pulmonar masiva ocasionando el fallecimiento de la paciente.

Idiopathic pulmonary hemosiderosis (IPH) is a rare pathology; its geographic distribution, incidence and prevalence are not accurately known worldwide. It has a strong association with autoimmune conditions and has an adequate response to immunosuppressive treatment. Despite being a serious pathology, it has a medium morbidity and mortality rate, provided that early diagnosis and treatment is performed. We present the clinical case of a female patient diagnosed with IPH who presented with the classic triad of this disease: hemoptysis, iron deficiency anemia and diffuse pulmonary infiltrates. Other causes of diffuse pulmonary hemorrhage were ruled out and the diagnosis was made by lung biopsy. She was managed with systemic and inhaled steroids and azathioprine. After almost 2 years before the diagnosis, being without treatment for 3 month she had a massive pulmonary hemorrhage, causing the death of the patient.

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Thiopurine prodrugs (azathioprine, AZA, and 6-mercaptopurine, 6MP) are embryotoxic to rodents and rabbits. Little is known about the developmental toxicity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine drug metabolite that is thought to mediate its liver toxicity. A limb bud assay found that 6MMPr impairs the in vitro morphogenetic differentiation of mouse limb extremities, being more potent than 6MP in the assay. This study evaluated the embryotoxicity of 6MMPr (0, 7.5, 15, 30 mg/kg bw sc) in rats after single-dose exposure in mid organogenesis (GD10). One group of pregnant rats was similarly treated with 6MP (15 mg/kg bw sc). After C-section (GD21), fetuses were weighed, and examined for external abnormalities. One third of each litter was examined for soft-tissue abnormalities while the remaining fetuses were cleared and stained for skeleton evaluation. 6MMPr caused a dose-dependent maternal weight loss followed by recovery before term pregnancy. Except for a nonsignificant increase in embryolethality and slight reduction in fetal weight at 30 mg/kg bw, no indication of embryotoxicity was noted at this dose or at lower doses of 6MMPr. In contrast, 6MP led to nearly 98 % of post-implantation losses in the presence of slight-to-mild maternal toxicity. These results are consistent with the notion that maternal treatment with 6MMPr affects embryo development, causing a nonsignificant increase in embryolethality and a slight reduction in fetal weight at 30 mg/kg bw. However, there was no increase in abnormalities at this dose, which was severely toxic to the dams, as reflected in the maternal weight gain data.

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The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy.

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Introducción: La infección por el SARS-COV-2 afecta en su evolución a diferentes órganos, entre ellos, el riñón. Objetivo: Examinar el inusual caso de un paciente afectado por COVID-19, que exhibió un cuadro clínico y humoral compatible con síndrome nefrótico. Presentación del caso: Paciente de un año con antecedente de buena salud, sin enfermedad renal previa, remitido al Hospital Pediátrico Cerro por manifestaciones respiratorias, edema marcado y test de antígeno positivo al SARS-COV-S. Al ingreso se constató un peso 14 kg, anasarca, tensión arterial de 100/60 mm Hg. En los análisis complementarios se comprobó PCR positivo al SARS-COV-2, hipoproteinemia, proteinuria e hipercolesterolemia. Ultrasonido abdominal y torácico mostraron ascitis y derrame pleural. Conclusiones: Paciente preescolar, ingresado por síndrome respiratorio e hidropígeno y PCR positivo al SARS-COV-2. Muestra los indicadores clínicos y humorales compatibles con síndrome nefrótico, con óptima respuesta al tratamiento esteroideo. Este caso podría constituir una coincidencia o una inusual forma de presentación de COVID-19 y ayudar, por tanto, a un mejor conocimiento del síndrome y del cuadro clínico inicial que pudiera originar este nuevo morbo.

Introduction: SARS-COV-2 infection affects different organs in its evolution, including the kidney. Objective: To examine the unusual case of a patient affected by COVID-19, who showed a clinical and humoral picture compatible with nephrotic syndrome. Case presentation: One-year-old patient with a history of good health, without previous kidney disease, referred to Cerro Pediatric Hospital due to respiratory manifestations, marked edema and positive to SARS-COV-S antigen test. On admission, a weight of 14 kg, anasarca, blood pressure of 100/60 mmHg were observed. In the complementary tests, positive PCR to SARS-COV-2, hypoproteinemia, proteinuria and hypercholesterolemia were verified. Abdominal and thoracic ultrasound showed ascites and pleural effusion. Conclusions: Preschool patient, admitted due to respiratory and hydropygenic syndrome and positive PCR to SARS-COV-2. The patient showed the clinical and humoral indicators compatible with nephrotic syndrome, with optimal response to steroid treatment. This case could constitute a coincidence or an unusual form of presentation of COVID-19 and therefore help a better knowledge of the syndrome and the initial clinical picture that could cause this new morbidity.

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Methanol dried over powdered 4 Å molecular sieves can be used for a selective mono-de-O-acetylation of the phenolic acetyl group of the per-O-acetyl protected brasilicardin A carbohydrate side chain. This reaction opens a practical procedure for a synthetic access to derivates of the immunosuppressive and cytotoxic natural product brasilicardin A.

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The aim of this study was to develop and validate a UHPLC-MS/MS assay to quantify cyclosporin (CYC), tacrolimus (TAC), sirolimus (SIR) and everolimus (EVE) in human whole blood for therapeutic drug monitoring. Analytes were extracted from 50 µL human whole blood by protein precipitation. The separation of the drugs was performed on an Acquity UPLC BEH C18 column. Analytes were eluted with a mobile phase consisting of 2 mM ammonium acetate with 0.1% formic acid (v/v) in deionised water and 2 mM ammonium acetate with 0.1% formic acid (v/v) in methanol at a flow rate of 300 µL/min in gradient elution. The method performance was evaluated by analysing patient blood samples and/or external quality control samples [proficiency testing (PT) scheme]. The method was linear from 23.75 to 1094.0, 1.3 to 42.4, 1.3 to 47.0 and 1.2-41.6 µg/mL for CYC, TAC, SIR and EVE, respectively. The within- and between-assay reproducibility results were ˂ 11%. Results from PT and patient sample quantification were comparable to those obtained previously by an in-house validated method using protein precipitation and liquid-liquid extraction. This method showed good analytical performance for quantifying CYC, TAC, SIR and EVE in whole blood over their respective calibration ranges.

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This study presents, for the first time, the development and validation of a liquid chromatography and time-of-flight mass-spectrometry (LC-TOF-MS) based assay to quantify mycophenolic acid (MPA) in patient samples as part of a routine therapeutic drug monitoring service. MPA was extracted from 50 µl human plasma by protein precipitation, using sulindac as internal standard (IS). Separation was obtained on a Luna™ Omega polar C18 column kept at 40°C. The mobile phase consisted of a mixture of acetonitrile-deionized water (50:50, v/v) with 0.1% formic acid at a flow rate of 350 µl/min. Analyte and IS were monitored on a TOF-MS using a Jet-Stream™ (electrospray) interface running in positive mode. Assay performance was evaluated by analysing patient plasma (N = 69) and external quality assessment (N = 6) samples. The retention times were 2.66 and 2.18 min for MPA and IS, respectively. The lower limit of quantification of MPA was 0.1 µg/ml. The within- and between-assay reproducibility results ranged from 1.81 to 10.72%. Patient and external quality assessment sample results were comparable with those obtained previously by an in-house validated LC-MS/MS method. This method showed satisfactory analytical performance for the determination of MPA in plasma over the calibration range of 0.1-15.0 µg/ml.

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ABSTRACT Background: Systemic sclerosis (SSc) is an immune-mediated disease characterized by small vessel vasculopathy and fibroblast dysfunction that leads to increased production of extracellular matrix. Interstitial lung disease represents one of the most common complications, by affecting almost 70% of patients with SSc. Objective: To evaluate the effectiveness of the pharmacological treatments available for systemic sclerosis-associated interstitial lung disease (SSc-ILD) based on pulmonary function tests and radiologic findings. Materials and methods: A systematic literature review and meta-analysis were conducted. A thorough literature search was made in EMBASE, PUBMED, and Cochrane CENTRAL to collect studies published between January 2015 and July 31 of 2019. The primary outcomes were forced vital capacity (FVC), diffusion capacity of carbon monoxide (DLCO), and high-resolution computed tomography findings (HR-CT). Studies using medications for the treatment of SSc-ILD including cyclophosphamide (CYC), mycophenolate mofetil (MMF), nintedanib, pirfenidone, or rituximab (RTX) were included. Effect measures were calculated based on available data, and a meta-analysis was made with these results. Results: We found a total of 312 studies. 49 studies were selected for full-text assessment after reading the abstracts. Finally, 14 studies were selected to be included in the final review. 2 meta-analyses, 8 clinical trials, 3 retrospective cohorts, and one nested case-control study were identified. The available evidence supports the use of CYC and MMF as the best options for the treatment of SSc-ILD, with MMF being the preferred option based on a better safety profile. Other medications such as RTX, pirfenidone, and nintedanib show potential as alternatives to CYC. The overall quality of evidence available is adequate based on generally well-designed studies. Meta-analysis was done by assessing >5% or >10% decrease of FVC when comparing pharmacological agents vs. placebo. Results show that the use of pharmacological agents is negatively associated with the worsening of FVC. However, high heterogeneity limits the number of studies used during quantitative analysis, affecting the overall results. Conclusions: Immunosuppressive therapies remain as the cornerstone of treatment of SSc-ILD, as most evidence show improvement or slow progression of pulmonary function tests by using them, especially CYC and MMF. However, more evidence is required regarding the use of alternative pharmacological agents, in search of an improvement in the quality of life of these patients.

RESUMEN Antecedentes: La esclerosis sistémica (ES) es una enfermedad mediada por el sistema inmunitario, caracterizada por vasculopatía de pequeños vasos y disfunción de los fibroblastos, que da lugar a una mayor producción de matriz extracelular. La enfermedad pulmonar intersticial representa una de las complicaciones más comunes, ya que afecta a cerca del 70% de los pacientes con ES. Objetivo: Evaluar la efectividad de los tratamientos farmacológicos disponibles para la enfermedad pulmonar intersticial asociada a la esclerosis sistémica (EPI-ES) basándonos en las pruebas de función pulmonar y los hallazgos radiológicos. Materiales y métodos: Se llevó a cabo una revisión sistemática de la literatura y un metaanálisis. Se hizo una búsqueda exhaustiva de literatura en EMBASE, MEDLINE PubMed y Cochrane (CENTRAL) con el fin de recopilar los estudios publicados entre enero de 2015 y el 31 de julio de 2019. Los resultados primarios fueron la capacidad vital forzada (CVF), la capacidad de difusión del monóxido de carbono (diffusing capacity of the lungs for carbon monoxide, DLCO), y los hallazgos de la tomografía computarizada de alta resolución (TCAR). Se incluyeron los estudios que utilizaron medicamentos para el tratamiento de la EPI-ES, incluyendo ciclofosfamida (CYC), micofenolato de mofetilo (MMF), nintedanib, pirfenidona o rituximab (RTX). Las medidas de efecto se calcularon con base en los datos disponibles, y se hizo un metaanálisis con estos resultados. Resultados: Encontramos un total de 312 estudios. Después de leer los resúmenes, se seleccionaron 49 estudios para la evaluación del texto completo. Finalmente, se seleccionaron 14 estudios para incluirlos en la revisión final. Se identificaron dos metaanálisis, ocho ensayos clínicos, tres cohortes retrospectivas y un estudio de casos y controles anidado. La evidencia disponible respalda el uso de CYC y MMF como las mejores opciones para el tratamiento de la EPI-ES, siendo el MMF la opción preferida basada en un mejor perfil de seguridad. Otros medicamentos como RTX, pirfenidona y nintedanib muestran potencial como alternativas a la CYC. La calidad global de la evidencia disponible es adecuada ya que parte de estudios por lo general bien diseñados. El metaanálisis se realizó evaluando una disminución > 5% o > 10% de la CVF al comparar los agentes farmacológicos vs. placebo. Los resultados muestran que el uso de agentes farmacológicos se asocia negativamente con el empeoramiento de la CVF. Sin embargo, la alta heterogeneidad limita el número de estudios utilizados durante el análisis cuantitativo, afectando los resultados generales. Conclusiones: Las terapias inmunosupresoras, especialmente la CYC y el MMF, siguen siendo la piedra angular del tratamiento de la EPI-ES, ya que la mayoría de la evidencia muestra una mejoría o una progresión lenta de las pruebas de función pulmonar al usarlas. Sin embargo, se requiere más evidencia con respecto al uso de agentes farmacológicos alternativos, en busca de una mejora de la calidad de vida de estos pacientes.

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