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Anticuerpos Monoclonales Humanizados/uso terapéutico , Dermatitis Exfoliativa/tratamiento farmacológico , Interleucina-17/antagonistas & inhibidores , Queratodermia Palmoplantar/tratamiento farmacológico , Linfocitos T Colaboradores-Inductores/fisiología , Dermatitis Exfoliativa/inmunología , Insuficiencia de Crecimiento/tratamiento farmacológico , Femenino , Humanos , Hipotricosis/tratamiento farmacológico , Lactante , Interleucina-17/inmunología , Queratodermia Palmoplantar/inmunología , Recuento de Linfocitos , Uñas Malformadas/tratamiento farmacológico , SíndromeRESUMEN
Background and objectives: Glycerol phenylbutyrate (GPB) has demonstrated safety and efficacy in patients with urea cycle disorders (UCDs) by means of its clinical trial program, but there are limited data in clinical practice. In order to analyze the efficacy and safety of GPB in clinical practice, here we present a national Spanish experience after direct switching from another nitrogen scavenger to GPB. Methods: This observational, retrospective, multicenter study was performed in 48 UCD patients (age 11.7 ± 8.2 years) switching to GPB in 13 centers from nine Spanish regions. Clinical, biochemical, and nutritional data were collected at three different times: prior to GPB introduction, at first follow-up assessment, and after one year of GPB treatment. Number of related adverse effects and hyperammonemic crisis 12 months before and after GPB introduction were recorded. Results: GPB was administered at a 247.8 ± 102.1 mg/kg/day dose, compared to 262.6 ± 126.1 mg/kg/day of previous scavenger (46/48 Na-phenylbutyrate). At first follow-up (79 ± 59 days), a statistically significant reduction in ammonia (from 40.2 ± 17.3 to 32.6 ± 13.9 µmol/L, p < 0.001) and glutamine levels (from 791.4 ± 289.8 to 648.6 ± 247.41 µmol/L, p < 0.001) was observed. After one year of GPB treatment (411 ± 92 days), we observed an improved metabolic control (maintenance of ammonia and glutamine reduction, with improved branched chain amino acids profile), and a reduction in hyperammonemic crisis rate (from 0.3 ± 0.7 to less than 0.1 ± 0.3 crisis/patients/year, p = 0.02) and related adverse effects (RAE, from 0.5 to less than 0.1 RAEs/patients/year p < 0.001). Conclusions: This study demonstrates the safety of direct switching from other nitrogen scavengers to GPB in clinical practice, which improves efficacy, metabolic control, and RAE compared to previous treatments.
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Introduction Urea cycle disorders (UCDs) form a group of metabolic pathological conditions that might develop serious neurological consequences. Early diagnosis, before irreversible damage is established, is the most important prognostic and morbidity factor. Case Report We present the case of a 5-day newborn with high blood pressure and respiratory distress. Diagnosis was type I citrullinemia. With appropriate citrullinemia guided-treatment blood pressure returned to normal. Conclusion High blood pressure has been rarely described as a lead symptom for the debut of a UCD. We must take this into consideration as an early recognition and treatment of these disorders are of the utmost importance.
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PURPOSE: Salts of phenylacetic acid (PAA) and phenylbutyric acid (PBA) have been used for nitrogen elimination as a treatment for hyperammonaemia caused by urea cycle disorders (UCD). A new analytical method for PBA measurement in urine which helps to evaluate the drug adherence has been implemented. METHODS: Urine specimens from UCD patients receiving PBA were analysed by tandem mass spectrometry to measure urine phenylacetylglutamine (PAGln). Some clinical and biochemical data for each patient were collected. RESULTS: Our study included 87 samples from 40 UCD patients. The PAGln levels did not correlate with height, weight or age. However, the PAGln values showed correlation with PBA dose (râ¯=â¯0.383, Pâ¯=â¯0.015). Plasma glutamine and ammonia levels presented a positive correlation (râ¯=â¯0.537, Pâ¯<â¯0.001). The stability for PAGln in urine was determined at different storage temperatures. CONCLUSIONS: We have developed a simple method for the determination of PAGln in urine, which acts as useful biomarker of effective drug delivery. PAGln in urine is stable at room temperature at least for 15 days, and for several months when frozen at -20⯰C. This procedure is useful for the optimization and monitorization of the drug dose allowing the use of spot urine samples.
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Benzoatos/farmacocinética , Monitoreo de Drogas/métodos , Glutamina/análogos & derivados , Fenilbutiratos/farmacocinética , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Adolescente , Adulto , Benzoatos/uso terapéutico , Biomarcadores/orina , Niño , Preescolar , Cromatografía Líquida de Alta Presión/métodos , Femenino , Glutamina/metabolismo , Glutamina/orina , Humanos , Lactante , Recién Nacido , Masculino , Cumplimiento de la Medicación , Fenilbutiratos/uso terapéutico , Espectrometría de Masas en Tándem/métodos , Trastornos Innatos del Ciclo de la Urea/orina , Adulto JovenRESUMEN
The present work describes the value of genetic analysis as a confirmatory measure following the detection of suspected inborn errors of metabolism in the Spanish newborn mass spectrometry screening program. One hundred and forty-one consecutive DNA samples were analyzed by next-generation sequencing using a customized exome sequencing panel. When required, the Illumina extended clinical exome panel was used, as was Sanger sequencing or transcriptional profiling. Biochemical tests were used to confirm the results of the genetic analysis. Using the customized panel, the metabolic disease suspected in 83 newborns (59%) was confirmed. In three further cases, two monoallelic variants were detected for two genes involved in the same biochemical pathway. In the remainder, either a single variant or no variant was identified. Given the persistent absence of biochemical alterations, carrier status was assigned in 39 cases. False positives were recorded for 11. In five cases in which the biochemical pattern was persistently altered, further genetic analysis allowed the detection of two variants affecting the function of BCAT2, ACSF3, and DNAJC12, as well as a second, deep intronic variant in ETFDH or PTS. The present results suggest that genetic analysis using extended next-generation sequencing panels can be used as a confirmatory test for suspected inborn errors of metabolism detected in newborn screening programs. Biochemical tests can be very helpful when a diagnosis is unclear. In summary, simultaneous genomic and metabolomic analyses can increase the number of inborn errors of metabolism that can be confirmed following suggestive newborn screening results.