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PURPOSE: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup. RESULTS: The plasma concentration showed a linear correlation with the daily dose taken ( r â =â 0.17; P â <â 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5â ±â 297.1 vs. 633.8â ±â 305.5â µg/ml; P â =â 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2â ±â 1.7 vs. 3.8â ±â 2.0; P â =â 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8â ±â 293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1â ±â 165.6 ng/ml and 260.0â ±â 36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8â ±â 285.6 vs. 433.0â ±â 227.2 ng/ml; P â =â 0.042). CONCLUSION: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy.
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Anticonvulsivantes , Citocromo P-450 CYP3A , Epilepsia , Nitrilos , Piridonas , Humanos , Citocromo P-450 CYP3A/genética , Niño , Femenino , Masculino , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Nitrilos/farmacocinética , Piridonas/farmacocinética , Piridonas/administración & dosificación , Piridonas/efectos adversos , Preescolar , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Polimorfismo de Nucleótido Simple/genética , Genotipo , Adolescente , Pueblo Asiatico/genética , Pueblos del Este de AsiaRESUMEN
BACKGROUND: Information on the efficacy and plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy is limited. Therefore, this real-world retrospective study aimed to assess the efficacy, tolerability, and plasma concentration of the maximum dose of PER for epilepsy treatment in Chinese pediatric patients. METHODS: A total of 107 pediatric patients from 2 hospitals in China were enrolled in this study. The plasma concentration of PER was determined using ultrahigh-performance liquid chromatography. The primary efficacy endpoint was the seizure reduction rate after PER treatment at the last follow-up. RESULTS: The response rate to PER therapy was 59.8% (64/107). The authors observed that patients younger than 6 years of age (n = 49) showed a significantly lower concentration-to-dose ratio than patients with ages between 6 and 14 years (n = 58) (2.2 ± 1.7 vs. 3.0 ± 1.8 mcg·mL -1 ·kg·mg -1 , respectively; P < 0.05). Patients who received enzyme-inducing antiseizure medication had significantly lower concentration-to-dose ratios than those who did not receive enzyme-inducing antiseizure medication (EIASM) (2.1 ± 1.8 vs. 3.1 ± 2.0 mcg·mL -1 ·kg·mg -1 , P < 0.05). A total of 37 patients (34.6%) reported treatment adverse events. Patients with somnolence and irritability had a significantly higher PER plasma concentration than the "no treatment-emergent adverse effect" groups ( P < 0.05). CONCLUSIONS: PER is an effective and well-tolerated treatment option for patients with epilepsy. To ensure the clinical efficacy and safety of PER in pediatric patients, it is necessary to monitor its plasma concentrations.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epilepsia , Humanos , Niño , Adolescente , Anticonvulsivantes/efectos adversos , Estudios Retrospectivos , Epilepsia/tratamiento farmacológico , Nitrilos , Piridonas/efectos adversos , Resultado del Tratamiento , Quimioterapia CombinadaRESUMEN
PURPOSE: We aimed to investigated the influencing risk factors of voriconazole-induced liver injury in Uygur pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: This was a prospective cohort design study. High-performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentration. First-generation sequencing was performed to detect gene polymorphisms. Indicators of liver function were detected at least once before and after voriconazole therapy. RESULTS: Forty-one patients were included in this study, among which, 15 patients (36.6%) had voriconazole-induced liver injury. The proportion of voriconazole trough concentration > 5.5 µg·mL-1 patients within the DILI group (40.0%) was significantly higher compared to the control group (15.4%) (p < 0.05). After administration of voriconazole, the values of ALT (103.3 ± 80.3 U/L) and AST (79.9 ± 60.6 U/L) in the DILI group were higher than that in the control group (24.3 ± 24.8 and 30.4 ± 8.6 U/L) (p < 0.05). There was no significant difference between the two groups in genotype and allele frequencies of CYP2C19*2, CYP2C19*3, CYP2C19*17, and UGT1A4 (rs2011425) (p > 0.05). CONCLUSION: There was a significant correlation between voriconazole-induced liver injury and voriconazole trough concentration in high-risk Uygur pediatric patients with allogeneic HSCT.
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Antifúngicos , Enfermedad Hepática Inducida por Sustancias y Drogas , Trasplante de Células Madre Hematopoyéticas , Voriconazol , Humanos , Voriconazol/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Niño , Masculino , Femenino , Estudios Prospectivos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Factores de Riesgo , Antifúngicos/efectos adversos , Preescolar , China , Adolescente , Citocromo P-450 CYP2C19/genética , Trasplante Homólogo/efectos adversosRESUMEN
PURPOSE: We aimed to evaluate the effect of the ABCC2 1249G>A (rs2273697) and -24C>T (rs717620) polymorphisms on lacosamide (LCM) plasma concentrations and the efficacy of LCM in Uygur pediatric patients with epilepsy. METHODS: We analyzed 231 pediatric patients with epilepsy, among which 166 were considered to be LCM responsive. For drug assays, 2-3 mL of venous blood was collected from each patient just before the morning LCM dose was administered (approximately 12 hours after the evening dose, steady-state LCM concentrations). The remaining samples after routine therapeutic drug monitoring were used for genotyping analysis. The χ 2 test and Fisher exact test were utilized for comparative analysis of the allelic and genotypic distribution of ABCC2 polymorphisms between the LCM-resistant and LCM-responsive groups. The Student t test or Mann-Whitney U test was conducted to analyze differences in plasma LCM concentration among pediatric patients with epilepsy with different genotypes. RESULTS: Patients with the ABCC2 1249G>A GA genotype (0.7 ± 0.3 mcg/mL per kg/mg) and AA genotype (0.5 ± 0.3 mcg/mL per kg/mg) showed significantly ( P < 0.001) lower LCM concentration-to-dose (CD) ratios than patients with the GG genotype (1.0 ± 0.4 mcg/mL per kg/mg). Moreover, patients with the ABCC2 -24C>T CT genotype (0.6 ± 0.2 mcg/mL per kg/mg) and TT genotype (0.6 ± 0.3 mcg/mL per kg/mg) presented a significantly ( P < 0.001) lower LCM CD ratio than patients with the CC genotype (1.1 ± 0.4 mcg/mL per kg/mg). CONCLUSIONS: The ABCC2 1249G>A (rs2273697) and ABCC2 -24C>T (rs717620) polymorphisms can affect plasma LCM concentrations and treatment efficacy among a population of Uygur pediatric patients with epilepsy, causing these patients to become resistant to LCM. In clinical practice, ABCC2 polymorphisms should be identified before LCM treatment, and then, the dosage should be adjusted for pediatric patients with epilepsy accordingly.
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Epilepsia , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Humanos , Niño , Lacosamida/uso terapéutico , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Genotipo , Anticonvulsivantes/uso terapéuticoRESUMEN
PURPOSE: The effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China. METHODS: Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders. RESULTS: 105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg- 1·d- 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg- 1·d- 1) (p < 0.05). At first follow-up, 44 patients (41.9%) reported experiencing at least one treatment-emergent adverse events. CONCLUSION: This real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy.
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Anticonvulsivantes , Epilepsia Refractaria , Humanos , Niño , Adolescente , Lacosamida/uso terapéutico , Anticonvulsivantes/efectos adversos , Epilepsia Refractaria/tratamiento farmacológico , Acetamidas/efectos adversos , Resultado del Tratamiento , Convulsiones/tratamiento farmacológico , Quimioterapia CombinadaRESUMEN
BACKGROUND: P-glycoprotein, encoded by ABCB1 (or MDR1), may contribute to drug resistance in epilepsy by limiting gastrointestinal absorption and brain access to antiseizure medications. The study aimed to evaluate the impact of ABCB1 polymorphisms on lacosamide (LCM) serum concentrations in Uygur pediatric patients with epilepsy. METHODS: The serum concentrations of LCM were determined by ultrahigh performance liquid chromatography, and the ABCB1 polymorphism was analyzed through polymerase chain reaction-fluorescence staining in situ hybridization. The χ2 test and the Fisher exact test were used to analyze the allelic and genotypic distributions of ABCB1 polymorphisms between the drug-resistant and drug-responsive patient groups. Differences in steady-state and dose-corrected LCM serum concentrations between different genotypes were analyzed using the one-way analysis of variance and the Mann-Whitney test. RESULTS: A total of 131 Uygur children with epilepsy were analyzed, and of them, 41 demonstrated drug resistance. The frequency of the GT genotype of ABCB1 G2677T/A was significantly higher in the drug-resistant group than that in the drug-responsive group (P < 0.05, OR = 1.966, 95% CI, 1.060-3.647). Patients with the G2677T/A-AT genotype had a statistically significantly lower concentration-to-dose (CD) value than patients with the G2677T/A-GG genotype (mean: 0.6 ± 0.2 versus 0.8 ± 0.5 mcg/mL per mg/kg, P < 0.001). Significantly lower LCM serum concentrations were observed in ABCB1 C3435T CT and TT genotype carriers than those in the CC carriers (P = 0.008 and P = 0.002), and a significantly lower LCM CD value was observed in ABCB1 C3435T CT genotype carriers than that in the CC carriers (P = 0.042). CONCLUSIONS: ABCB1 G2677T/A and C3435T polymorphisms may affect LCM serum concentrations and treatment efficacy in Uygur pediatric patients with epilepsy, leading to drug resistance in pediatric patients.
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Epilepsia , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Niño , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Lacosamida/uso terapéutico , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
This study has developed and validated a novel LC-MS/MS assay method to quantify perampanel in pediatric patients with epilepsy in Xinjiang, China. Our assay reduces current specimen volume requirements and decreases the turnaround time for results. Samples were separated by gradient elution and then injected into the mass spectrometer with a total run time of 3 min per sample. The ions from the analytes were detected using multiple reactions by monitoring transitions of m/z 350.2-219.0 for perampanel and m/z 359.1-323.1 for the internal standard, as precursor ion and product ion, respectively. The peak area ratios of perampanel with internal standard within the plasma samples were linear in the concentration range of 0.1-3.2 µg/mL (y = 2.87x + 0.61; r2 ≥ 0.99). The within-run and between-run precision coefficient of variation (%) did not exceed 11.03%, and the accuracy (bias) ranged from -1.07 to 6.69%. The mean absolute recoveries of perampanel for four QC levels (lower limit of quantification, low quality control, middle quality control, and high quality control) determined by this method were 87.69, 94.04, 107.50, and 95.15%, respectively. The stability results for this method showed that the plasma samples of perampanel were stable under all tested conditions (86.43-104.81%), with a coefficient of variation (%) maximum of 8.74%.
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Epilepsia , Espectrometría de Masas en Tándem , Niño , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Epilepsia/tratamiento farmacológico , Humanos , Nitrilos , Piridonas , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
BACKGROUND: Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). METHODS: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. RESULTS: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 µM for QGY7703and 4.04 µM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. CONCLUSIONS: The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.
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Carcinoma Hepatocelular/tratamiento farmacológico , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Fluorouracilo/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Piperazinas/administración & dosificación , Animales , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Regulación hacia Abajo , Sinergismo Farmacológico , Femenino , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inyecciones Subcutáneas , Neoplasias Hepáticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Levetiracetam is approved as an add-on therapy to treat refractory partial seizures in pediatric patients over four years old. The efficacy and safety in pediatric patients with epilepsy in Uygur, China, is unknown. Therefore, the objective of this study was to investigate the safety, efficacy, and tolerability of levetiracetam in pediatric patients with epilepsy in Uygur, China. METHODS: This retrospective study compared the efficacy and safety of levetiracetam monotherapy and in combination with other antiseizure medications (ASMs) in 1055 pediatric patients with epilepsy treated with levetiracetam. The seizure frequencies at 1, 2, and 3â¯years after starting levetiracetam therapy were recorded and compared with the baseline yearly frequency. Safety variables included the incidence and type of adverse reactions. RESULTS: A total of 680 (64%) pediatric patients responded to levetiracetam therapy with a more than 50% reduction in the frequency of seizures. Seizure-free rates increased over time, 13%, 15%, and 18% at 1, 2, and 3â¯years, respectively. The number of baseline ASMs and the order of levetiracetam introduction were highly significant, impacting the likelihood of seizure remission during a 3-year follow-up period (pâ¯<â¯0.001). During levetiracetam treatment, 233 pediatric patients (22%) experienced at least one adverse reaction. CONCLUSION: These significant findings indicate that levetiracetam is likely to become a widely prescribed ASM for epilepsy in pediatric clinical practice because of its long-term safety, efficacy, and tolerability.
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Epilepsia , Piracetam , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , China , Epilepsia/tratamiento farmacológico , Humanos , Levetiracetam/uso terapéutico , Piracetam/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Lacosamide (LCM) was approved in China in 2018. However, the safety of LCM has not been established in pediatric patients. Therefore, the objective of this study was to investigate its safety, efficacy, and tolerability in pediatric patients living in Uygur, Northwest China. METHODS: This is a retrospective analysis of pediatric patients diagnosed with epilepsy and on LCM therapy at a medical center. The seizure frequencies at 3, 6, and 12â¯months after starting LCM therapy were recorded and compared with the baseline monthly frequency. The primary outcome variables were the 50% responder and seizure-free rates. The secondary outcome variables included the terminal 6-month seizure remission and percentages of discontinuation due to a lack of efficacy and tolerability. Safety variables included the incidence and type of adverse reactions. RESULTS: Seventy-two pediatric patients with epilepsy living in Uygur, China and receiving LCM treatment were included in the present study. Fifty (69%) children responded to LCM therapy with a more than 50% reduction in the frequency of seizures. Seizure-free rates increased over time, at 14%, 19%, and 20% at 3, 6, and 12 months, respectively. The number of baseline anti-seizure medications (ASMs) and order of LCM introduction significantly impacted the likelihood of seizure remission during the 12-month follow-up period (pâ¯<â¯0.05). During the entire period of LCM treatment, twenty-two children (30.5%) experienced at least one adverse reaction. CONCLUSION: This retrospective study of 72 pediatric patients with epilepsy in Uygur, China, showed that LCM therapy is safe and effective for epilepsy in children, resulting in a reduction in the seizure rate.
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Epilepsias Parciales , Epilepsia , Anticonvulsivantes/uso terapéutico , Niño , China , Epilepsias Parciales/tratamiento farmacológico , Epilepsia/tratamiento farmacológico , Humanos , Lacosamida/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
This study has developed and validated a novel UPLC method to quantify lacosamide (LCM), oxcarbazepine (OXC), and lamotrigine (LTG) in children with epilepsy in Xinjiang, China. Phenytoin sodium was used as the internal standard. The mobile phase contained ammonium dihydrogen phosphate solution (10 mmol/L, pH = 4.0) and methanol (55:45, v/v). The flow rate, injection volume, column temperature, and detection wavelength were 0.2 mL/min, 2 µL, 30°C, and 240 nm, respectively. The method was linear within 0.5-40, 2.5-80, and 2.5-40 µg/mL for LCM, 10-hydroxycarbazepine (MHD), and LTG, respectively (r2 ≥ 0.998). The intra- and inter-day precision as measured by the relative standard deviation values was between 1.36 and 4.50, 0.54 and 1.91, and 0.58 and 1.56%. Recovery ranged from 96.58 to 106.22%. All serum samples could be maintained for up to 3 h at ambient temperature, 24 h at 4°C, 30 days at -30°C, and after successive freeze-thaw cycles (24 h per cycle) in the absence of significant degradation.
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Anticonvulsivantes/sangre , Cromatografía Líquida de Alta Presión/métodos , Lacosamida/sangre , Lamotrigina/sangre , Oxcarbazepina/sangre , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , China , Epilepsia/tratamiento farmacológico , Humanos , Lactante , Lacosamida/uso terapéutico , Lamotrigina/uso terapéutico , Límite de Detección , Modelos Lineales , Oxcarbazepina/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Interindividual variations in the efficacy of antiseizure medications make epilepsy treatment challenging. This is due to genetic factors such as gene polymorphisms in Adenosine-triphosphate (ATP)-binding cassette sub-family B member 1 (ABCB1). In this article, the impact of polymorphisms in the P-glycoprotein-encoding gene, ABCB1 (C1236T, G2677T/A, and C3435T), on levetiracetam disposition was evaluated in Uygur Chinese children with epilepsy. METHODS: MDR1 C3435T polymorphism was analyzed by polymerase chain reaction-fluorescence staining in situ hybridization. The χ test and Fisher exact test were used to analyze the allelic and genotypic distribution of ABCB1, C1236T, G2677T, and C3435T between the drug-resistant and drug-responsive groups. Differences in steady-state and dose-corrected levetiracetam serum concentrations between the different genotypes were analyzed using 1-way analysis of variance and Mann-Whitney test. RESULTS: Total 245 Uygur children with epilepsy were analyzed [drug-resistant, n = 117 (males:females = 53:64) and drug-responsive, n = 128 (males:females = 76:52)]. The frequency of ABCB1 C1236T, G2677T/A, and ABCB1 C3435T genotypes, alleles, haplotypes, or diplotypes did not differ significantly between the 2 groups (P > 0.05). Significantly higher levetiracetam concentrations and serum concentration/body mass dose were seen in ABCB1 2677-GT, TT, GA, and AT genotypes and 3435-TT carriers compared with GG and CC carriers (P = 0.021 and P = 0.002 versus P = 0.001 and P = 0.000, respectively). CONCLUSIONS: ABCB1 G2677T/A and C3435T may affect levetiracetam disposition and therapeutic efficacy in Uygur children with epilepsy. Genetic analysis could be a valuable tool for predicting the response to antiseizure medications before the start of treatment and could contribute to personalized medicine for Uygur children with epilepsy.
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Anticonvulsivantes/sangre , Epilepsia/tratamiento farmacológico , Levetiracetam/sangre , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , China , Epilepsia/etnología , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Levetiracetam/uso terapéutico , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Despite recent results of deletion experiments showing that open reading frame (ORF) UL49 of human cytomegalovirus (HCMV) is essential, the expression, function and functional location of its encoded protein remain unknown. We generated an antibody specific for pUL49 to investigate the protein product encoded by the UL49 ORF and identified its function in HCMV-infected host foreskin fibroblasts. A bacterial artificial chromosome (BAC) of HCMV strain Towne (pRV-Towne) and the UL49-deleted mutant pRV-delUL49Towne were used to observe virus growth by plaque assay. Using a UL49-protein-binding antibody, we located pUL49 in the fibroblast cytoplasm. pUL49 exhibited expression kinetics resembling those of the class ß-2 proteins and was detected in the virion tegument. Following deletion of UL49 ORF, the virus failed to replicate, but it could be recovered by addition of pUL49 from pCDNA3.1 (+)-UL49. Our findings indicate that UL49 ORF is essential for HCMV replication in host foreskin fibroblasts.
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Citomegalovirus/fisiología , Proteínas Virales/fisiología , Secuencia de Bases , Línea Celular , Citomegalovirus/genética , Citomegalovirus/crecimiento & desarrollo , Infecciones por Citomegalovirus/virología , Fibroblastos/virología , Prepucio/citología , Prepucio/virología , Regulación Viral de la Expresión Génica/fisiología , Humanos , Masculino , Microscopía Fluorescente , Datos de Secuencia Molecular , Proteínas Virales/genética , Virión/crecimiento & desarrollo , Virión/fisiología , Replicación Viral/genética , Replicación Viral/fisiologíaRESUMEN
Ag nanowires (Ag NWs) are synthesized by polyol method under the conditions of different temperature of reaction solution, different addition amount and injection rate of polyvinylpyrrolidone (PVP). The structure and the process of lateral growth of Ag NWs were observed and analyzed by X-ray diffraction (XRD), ultraviolet-visible absorption spectrum (UV-VIS), scanning electron microscopy (SEM) and transmission electron microscope (TEM). It showed that the lateral growth of Ag NWs and longitudinal growth of Ag NWs occurrs at the same time by UV-VIS. And in the later stage of synthesis of Ag NWs, the peak in UV-VIS, which indicated the lateral growth of Ag NWs, red-shifted obviously from 384 nm to 388 nm. This rapid redshift implied that the diameters of Ag NWs increased quickly. In other words, rapid lateral growth of Ag NWs occurred in the later stage of synthesis of Ag NWs. According to the SEM of Ag NWs, in the early stage of the reaction (15~23 min), the diameter of Ag NWs increased by only 20 nm, but in the later stage of reaction (23~30 min), the diameter of Ag NWs increased by nearly 150 nm. The result of SEM observation is consistent with the analysis of UV-VIS. It was also found that the lateral growth of Ag NWs is related not only to the sizes of seeds but also to the thicknesses of the outer Ag layers. Tiny Ag particles with diameters of several nanometers adsorbed onto the side facets of Ag NWs and acted as adsorption points for Ag source. The lateral growth of Ag NWs was caused by the continuous multipoint adsorption of Ag source on the side of Ag NWs. Decreasing the temperature of the reaction solution (from 165 to 155 degree), reducing the injection rate (from 67 to 49 mL·h-1) and the addition amount of PVP in the later stage could inhibit the lateral growth of Ag NWs and increase the aspect ratios of Ag NWs remarkably. The diameters of Ag NWs decreased from 200 nm to 100 nm, but their lengths still maintained above 100 µm.
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Borne paint was studied in the article in which the solvent water was regarded as a variable factor. A series of paint samples with different percentage of water were configured before observing their storage performance and microstructures by using Fourier-transform infrared (FTIR) ATR (attenuated total reflection) spectroscopy and diffuse reflectance (DF) FTIR spectroscopy. The effects of construction process and solvent water on the coating film were examined through analyzing the changes of internal functional groups before and after coating. The results indicated that as the amount of solvent water was increased, the characteristic peak of nu(C=O) in 1 727 cm(-1) turned into acromion, the absorption peakin 871 cm(-1) was blue shifted, the intensity of the peak of hydroxyl (nu(OH)) in 3400 cm(-1) and unsaturated absorption peak of nu-CH in 3030 cm(-1) gradually weakened, the absorption peaks strengths of nu-CH3 and nu-CH2 in 2962 and 2871 cm(-1) increased, respectively. The absorption peak in 2516 cm(-1) was shifted to 2603 cm(-1) then form the acromion, the absorption peak of 1647 cm(-1) gradually changed to 1455 cm(-1), the stretching vibration absorption peak of nu(C-O) in 1107 cm(-1) was red-shifted. During the coating process of paint, the solvent water and paint molecules interacted with each other, having a significant impact on the electron cloud density distribution of the paint molecules. The results obtained in the article have an important significance for the production and construction of paint.
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Purpose: This study aimed to investigate the alteration trends and overlaps of positive features in benign and malignant thyroid nodules of different sizes based on the Chinese Thyroid Imaging Reporting and Data System (C-TIRADS). Patients and Methods: 1337 patients with 1558 thyroid nodules were retrospectively recruited from November 2021 to December 2023. These nodules were divided into three groups according to maximum diameter: A (≤10 mm), B (10-20 mm), and C (≥20 mm). C-TIRADS positive features were compared between benign and malignant thyroid nodules of different sizes. In addition, the trends of positive features with changes in nodule size among malignant thyroid nodules were analyzed. Results: The incidence of positive features in malignant thyroid nodules was higher than that in benign. As benign nodules grow, the incidence of all positive features showed a linear decreasing trend (Z values were 72.103, 101.081, 17.344, 33.909, and 129.304, P values < 0.001). With the size of malignant thyroid nodules increased, vertical orientation, solid, marked hypoechogenicity, and ill-defined/irregular margins/extrathyroidal extension showed a linear decreasing trend (Z = 148.854, 135.378, 8.590, and 69.239, respectively; P values < 0.05), while suspicious microcalcifications showed a linear increasing trend (Z = 34.699, P<0.001). In terms of overlapping characteristics, group A had a significantly higher overlapping rate than the other two groups, and the overlapping rate of solid indicators remained the highest among all three groups (P < 0.05). Conclusion: Differences in positive features were observed between thyroid nodules of different sizes. Except for suspicious microcalcifications, the incidence of other four positive features decreased with increasing nodule size. In addition, a negative correlation was observed between the overlap rate and nodule size. These results may provide a basis for sonographers to upgrade or downgrade thyroid nodules based on their own experience.
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OBJECTIVE: This study was the first to evaluate the effect of CYP3A4 gene polymorphisms on the plasma concentration and effectiveness of perampanel (PER) in Chinese pediatric patients with epilepsy. METHODS: We enrolled 102 patients for this investigation. The steady-state concentration was determined after patients maintained a consistent PER dosing regimen for at least 21 days. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final check-up. RESULTS: The CYP3A4×10 GC phenotype exhibited the highest average plasma concentration of PER at 491.1⯱â¯328.1â¯ng/mL, in contrast to the CC phenotype at 334.0⯱â¯161.1â¯ng/mL. The incidence of adverse events was most prominent in the CYP3A4×1â¯G TT and CYP3A4×10 GC groups, with rates of 77.8â¯% (7 of 9 patients) and 50.0â¯% (46 of 92 patients), respectively. Moreover, the percentage of patients for whom PER was deemed ineffective was least in the CYP3A4×1â¯G TT and CYP3A4×10 CC groups, recorded at 11.1â¯% (1 of 9 patients) and 10.0â¯% (1 of 10 patients), respectively. There was a significant correlation between PER plasma concentration and either exposure or toxicity (both with pâ¯<â¯0.05). We suggest a plasma concentration range of 625-900â¯ng/mL as a suitable reference for PER in Chinese patients with epilepsy. CONCLUSION: The CYP3A4×10 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A4 genetic phenotype should be factored in when prescribing PER to patients with epilepsy.
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Anticonvulsivantes , Citocromo P-450 CYP3A , Epilepsia , Nitrilos , Piridonas , Humanos , Citocromo P-450 CYP3A/genética , Niño , Femenino , Masculino , Piridonas/farmacocinética , Piridonas/uso terapéutico , Piridonas/sangre , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Nitrilos/farmacocinética , Preescolar , Adolescente , Polimorfismo Genético/genética , China , Pueblo Asiatico/genética , Genotipo , Resultado del Tratamiento , Pueblos del Este de AsiaRESUMEN
Objective: This study aimed to understand the epidemic status and phylogenetic relationships of rotavirus group A (RVA) in the Pearl River Delta region of Guangdong Province, China. Methods: This study included individuals aged 28 days-85 years. A total of 706 stool samples from patients with acute gastroenteritis collected between January 2019 and January 2020 were analyzed for 17 causative pathogens, including RVA, using a Gastrointestinal Pathogen Panel, followed by genotyping, virus isolation, and complete sequencing to assess the genetic diversity of RVA. Results: The overall RVA infection rate was 14.59% (103/706), with an irregular epidemiological pattern. The proportion of co-infection with RVA and other pathogens was 39.81% (41/103). Acute gastroenteritis is highly prevalent in young children aged 0-1 year, and RVA is the key pathogen circulating in patients 6-10 months of age with diarrhea. G9P[8] (58.25%, 60/103) was found to be the predominant genotype in the RVA strains, and the 41 RVA-positive strains that were successfully sequenced belonged to three different RVA genotypes in the phylogenetic analysis. Recombination analysis showed that gene reassortment events, selection pressure, codon usage bias, gene polymorphism, and post-translational modifications (PTMs) occurred in the G9P[8] and G3P[8] strains. Conclusion: This study provides molecular evidence of RVA prevalence in the Pearl River Delta region of China, further enriching the existing information on its genetics and evolutionary characteristics and suggesting the emergence of genetic diversity. Strengthening the surveillance of genotypic changes and gene reassortment in RVA strains is essential for further research and a better understanding of strain variations for further vaccine development.
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Gastroenteritis , Infecciones por Rotavirus , Rotavirus , Niño , Humanos , Lactante , Preescolar , Rotavirus/genética , Infecciones por Rotavirus/epidemiología , Filogenia , Heces , Gastroenteritis/epidemiología , Genotipo , China/epidemiología , Polimorfismo GenéticoRESUMEN
BACKGROUND AND OBJECTIVE: The impact of individual patient variables on drug metabolism is particularly important for antiseizure medication, and lacosamide has not been studied in Chinese pediatric patients with epilepsy. This study evaluated the effects of dose, age, sex, medication time, seizure type, and concomitant enzyme-inducing antiseizure medications (EIASMs) on the plasma concentration of lacosamide. METHODS: A total of 500 pediatric patients from two hospitals in China were enrolled in this study. Lacosamide plasma concentration was processed using an ultra-performance liquid chromatography assay. Efficacy was evaluated based on the four-grade therapeutic effect criteria developed by the first National Epilepsy Academic Conference of the Chinese Medical Association. RESULTS: The responder rate to lacosamide therapy was 72.2% (361/500). There was a weaker relationship between the lacosamide daily dose and lacosamide plasma concentration (r = 0.238). Lacosamide plasma concentrations of patients ranged from 1.5 to 19.7 µg/mL, with a mean of 6.9 ± 3.2 µg/mL. The study results showed a significant contribution of age, body mass index, epilepsy duration, medication time, and EIASMs to the lacosamide plasma concentration (p < 0.05). Patients taking concomitant EIASMs with lacosamide had a significantly lower mean lacosamide plasma concentration (5.9 ± 2.6 µg/mL) than patients taking concomitant non-EIASMs (7.5 ± 3.5 µg/mL, p < 0.001). CONCLUSION: To ensure the clinical efficacy and safety of lacosamide therapy in pediatric patients, it is necessary to monitor the plasma concentration.
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Anticonvulsivantes , Epilepsia , Humanos , Niño , Lacosamida , Anticonvulsivantes/efectos adversos , Monitoreo de Drogas , Acetamidas/uso terapéutico , Epilepsia/tratamiento farmacológicoRESUMEN
Aim: To evaluate the association between CYP2C19, CYP3A4 and ABCC2 polymorphisms and voriconazole plasma concentrations in Uygur pediatric patients with allogeneic hematopoietic stem cell transplantation. Materials & methods: High performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentrations. First-generation sequencing was performed to detect gene polymorphisms. Results: Voriconazole concentrations of normal metabolizers were significantly higher than those of intermediate (p < 0.05) and ultrafast (p < 0.001) metabolizers. Patients with ABCC2 GG and GA genotypes exhibited significantly lower voriconazole concentrations compared with patients with the AA genotype (p < 0.05). Conclusion: These results demonstrate a significant association between voriconazole concentrations and the CYP2C19 phenotype in Uygur pediatric patients with allogeneic hematopoietic stem cell transplantation.