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OBJECTIVE: We studied whether the use of hydroxychloroquine (HCQ) for COVID-19 resulted in supply shortages for patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). METHODS: We used US claims data (IQVIA PHARMETRICS® Plus for Academics [PHARMETRICS]) and hospital electronic records from Spain (Institut Municipal d'Assistència Sanitària Information System [IMASIS]) to estimate monthly rates of HCQ use between January 2019 and March 2022, in the general population and in patients with RA and SLE. Methotrexate (MTX) use was estimated as a control. RESULTS: More than 13.5 million individuals (13,311,811 PHARMETRICS, 207,646 IMASIS) were included in the general population cohort. RA and SLE cohorts enrolled 135,259 and 39,295 patients, respectively, in PHARMETRICS. Incidence of MTX and HCQ were stable before March 2020. On March 2020, the incidence of HCQ increased by 9- and 67-fold in PHARMETRICS and IMASIS, respectively, and decreased in May 2020. Usage rates of HCQ went back to prepandemic trends in Spain but remained high in the United States, mimicking waves of COVID-19. No significant changes in HCQ use were noted among patients with RA and SLE. MTX use rates decreased during HCQ approval period for COVID-19 treatment. CONCLUSION: Use of HCQ increased dramatically in the general population in both Spain and the United States during March and April 2020. Whereas Spain returned to prepandemic rates after the first wave, use of HCQ remained high and followed waves of COVID-19 in the United States. However, we found no evidence of general shortages in the use of HCQ for both RA and SLE in the United States.
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Antirreumáticos , Artritis Reumatoide , COVID-19 , Hidroxicloroquina , Lupus Eritematoso Sistémico , Humanos , Hidroxicloroquina/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/epidemiología , Antirreumáticos/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , COVID-19/epidemiología , Adulto , España/epidemiología , Estados Unidos/epidemiología , Tratamiento Farmacológico de COVID-19 , Anciano , Incidencia , SARS-CoV-2RESUMEN
Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution.
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Amidas , Norovirus , Pirazinas , Virus , Animales , Humanos , Norovirus/genética , Antivirales/farmacología , Antivirales/uso terapéutico , Pez Cebra , Mutagénesis , ARN Polimerasa Dependiente del ARN/genética , Huésped InmunocomprometidoRESUMEN
Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.
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Antifúngicos , Infecciones Fúngicas Invasoras , Adulto , Humanos , Niño , Niño Hospitalizado , Disponibilidad Biológica , Monitoreo de Drogas , Administración Oral , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Infecciones Fúngicas Invasoras/prevención & control , Comprimidos , SuspensionesRESUMEN
OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of MMF in juvenile idiopathic inflammatory myopathies (JIIMs). METHODS: Patients diagnosed with JIIM and treated with MMF enrolled in the Juvenile Dermatomyositis Research Group (JDRG) in the UK or followed at the Giannina Gaslini Institute in Genoa, Italy, were included. The following information was collected retrospectively at MMF initiation, at 3, 6 and 12 months after treatment start, and at last follow-up visit: clinical manifestations, laboratory data, physicians' subjective assessment of disease activity, standardized outcome measures of muscle strength/endurance, cutaneous disease activity, physical function, global disease activity, cumulative damage, and ongoing treatment. RESULTS: Of the 29 patients included, 23 had juvenile DM and 6 had overlap myositis. During administration of MMF, improvement in measures of muscle strength, skin disease activity, and overall disease activity was seen, with an increase in the frequency of normal scores for Manual Muscle Test-8 from 50.0% to 83.3%, Childhood Myositis Activity Score from 53.5% to 88.9%, muscle component of DAS from 55.2% to 84.2%, skin component of DAS from 31.0% to 42.1%, visual analogue scale for skin disease activity from 25.0% to 47.4%, and visual analogue scale for overall disease activity from 7.1% to 42.1%. The number of patients with inactive disease increased from 10.3% at baseline to 68.5% at last follow-up. CS dose was significantly reduced, from 0.3 to 0.1 mg/kg/day. No relevant side effects were reported. CONCLUSION: Our experience suggests that MMF is a valuable therapeutic option for the management of JIIM.
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Dermatomiositis , Miositis , Humanos , Niño , Ácido Micofenólico/uso terapéutico , Estudios Retrospectivos , Miositis/diagnóstico , Dermatomiositis/diagnóstico , PielRESUMEN
Most non-polio enterovirus infections in immunocompetent individuals are acute and self-limiting in nature; however, infection can be severe, chronic and have devastating outcomes in immunocompromised hosts. Therapeutic strategies have predominantly involved supportive care, with the lack of approved antiviral treatments proving challenging for management. We report a case of an 8-month-old child who presented with severe enterovirus encephalitis following gene therapy for X-linked severe combined immunodeficiency (X-SCID) and who demonstrated clinical and microbiological improvement after a novel regimen of favipiravir, fluoxetine, and high-dose intravenous immunoglobulin (IVIg). The patient presented 6 weeks post-gene therapy with rapid neurological deterioration in the context of incomplete immune reconstitution, with microbiological and radiological evidence confirming enterovirus encephalitis. His neurologic examination stabilised 8 weeks after treatment, and he subsequently demonstrated excellent immune recovery. This is the first case report of combined therapy with favipiravir, fluoxetine, and high-dose IVIg in the context of severe enterovirus encephalitis in an immunocompromised host. This case highlights the importance of considering enterovirus encephalitis in immunocompromised patients presenting with both acute and chronic neurological signs, as well as developmental regression. The demonstrated treatment success and the associated low risk of toxicity warrant further investigation of this therapeutic regimen.
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Encefalitis Viral , Infecciones por Enterovirus , Enterovirus , Amidas , Antivirales/uso terapéutico , Encefalitis Viral/diagnóstico , Encefalitis Viral/tratamiento farmacológico , Infecciones por Enterovirus/diagnóstico , Infecciones por Enterovirus/tratamiento farmacológico , Fluoxetina , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Masculino , PirazinasAsunto(s)
Queratinocitos/inmunología , Biología Molecular , Terapia Molecular Dirigida/métodos , Nevo Sebáceo de Jadassohn/genética , Nevo Sebáceo de Jadassohn/terapia , Biopsia , Proteínas Adaptadoras de Señalización CARD/genética , Estudios de Casos y Controles , Niño , Preescolar , Conexina 43/genética , Femenino , Guanilato Ciclasa/genética , Humanos , Lactante , Inflamación , Queratinocitos/metabolismo , Masculino , Proteínas de la Membrana/genética , Mosaicismo , Mutación Missense , Resultado del TratamientoRESUMEN
BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disease, caused by gain of function mutation in NLRP3 resulting in excess production of interleukin-1 (IL-1). Canakinumab is a human monoclonal antibody against Interleukin-1 beta (IL-1ß), licensed for the treatment of CAPS. The objective of the study was to describe the feasibility and cost-effectiveness of a canakinumab vial-sharing programme for paediatric patients with CAPS. METHOD: Retrospective case series and clinical service description of a national specially commissioned CAPS clinic at Great Ormond Street Hospital (GOSH). Effectiveness was assessed using a CAPS disease activity score (DAS) and serum amyloid A protein (SAA). Adverse events were collected to determine safety. The number of canakinumab vials saved was considered when investigating the cost-effectiveness of vial-sharing. RESULTS: Nineteen/20 (95%) of our paediatric patients achieved minimally active clinical disease activity with canakinumab monotherapy; and 75% achieved both minimally active clinical disease and serological remission using a pre-specified definition based on the CAPS DAS and SAA level. Canakinumab was well tolerated, with only one child developing an infection requiring hospitalisation during the study. Canakinumab vial sharing resulted in 117 vials of canakinumab saved over a 24-month period, equating to a direct drug-related cost saving of £1,385,821, and a conservative estimated 5-year cost-saving of £3,464,552.50. CONCLUSION: We provide further evidence for the effectiveness and safety of canakinumab in children with CAPS, and highlight the cost-effectiveness of a vial-sharing programme for this high cost medicine. We suggest that this could have important implications for the delivery of other high cost medicines used in paediatric practice.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Síndromes Periódicos Asociados a Criopirina/tratamiento farmacológico , Fármacos Dermatológicos/administración & dosificación , Adolescente , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/economía , Niño , Preescolar , Análisis Costo-Beneficio , Síndromes Periódicos Asociados a Criopirina/economía , Fármacos Dermatológicos/efectos adversos , Fármacos Dermatológicos/economía , Costos de los Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Compartición de Agujas/economía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
AIMS: Rituximab is a chimeric IgG-1 monoclonal antibody that depletes B cells, aiding in the treatment of several conditions including autoimmune diseases. It is not licensed for use in children. This study aimed to quantify the B cell-related pharmacodynamics of rituximab in children with autoimmune disease. METHODS: Routine electronic health record data were collected at a large paediatric tertiary hospital in London, UK. Dosing protocols were either 2 × 750 mg/m2 intravenous infusions of rituximab on days 1 and 15, or 4 × 375 mg/m2 infusions on days 1, 8, 15 and 22. Rituximab pharmacokinetics (PK) were not measured but CD19+ lymphocyte counts were taken before and after rituximab treatment. A dose-response model was constructed describing the life cycle of CD19+ lymphocytes, with rituximab assumed to increase the death rate. Rituximab effect was assumed to decay by first-order kinetics. RESULTS: In total, 258 measurements of CD19+ lymphocyte counts were collected from 39 children with 8 autoimmune diseases. The elimination rate constant (% relative standard error) of rituximab effect decay was 0.036 (22.7%) days-1 and CD19+ turnover was 0.02 (41%) days-1 corresponding to half-lives of 19 and 35 days respectively. Rituximab increased CD19+ death rate 35-fold, with methotrexate and cyclophosphamide associated with further increases. Simulations suggested that a single infusion of 750 mg/m2 provides similar 6-month suppression of CD19+ lymphocytes to current dosing. CONCLUSIONS: Rituximab pharmacodynamics (PD) in paediatric autoimmune diseases has been described. Compared with rituximab alone, the additional effect of methotrexate or cyclophosphamide was statistically significant but small.
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Enfermedades Autoinmunes/tratamiento farmacológico , Linfocitos B/efectos de los fármacos , Inmunosupresores/farmacología , Depleción Linfocítica/métodos , Rituximab/farmacología , Adolescente , Antígenos CD19/metabolismo , Apoptosis/efectos de los fármacos , Enfermedades Autoinmunes/sangre , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Preescolar , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada/métodos , Femenino , Semivida , Humanos , Inmunosupresores/uso terapéutico , Infusiones Intravenosas , Recuento de Linfocitos , Masculino , Metotrexato/farmacología , Metotrexato/uso terapéutico , Modelos Biológicos , Estudios Retrospectivos , Rituximab/uso terapéuticoRESUMEN
OBJECTIVES: The objectives of this study were to investigate the population pharmacokinetics of posaconazole in immunocompromised children, evaluate the influence of patient characteristics on posaconazole exposure and perform simulations to recommend optimal starting doses. METHODS: Posaconazole plasma concentrations from paediatric patients undergoing therapeutic drug monitoring were extracted from a tertiary paediatric hospital database. These were merged with covariates collected from electronic sources and case-note reviews. An allometrically scaled population-pharmacokinetic model was developed to investigate the effect of tablet and suspension relative bioavailability, nonlinear bioavailability of suspension, followed by a step-wise covariate model building exercise to identify other important sources of variability. RESULTS: A total of 338 posaconazole plasma concentrations samples were taken from 117 children aged 5 months to 18 years. A one-compartment model was used, with tablet apparent clearance standardised to a 70-kg individual of 15 L/h. Suspension was found to have decreasing bioavailability with increasing dose; the estimated suspension dose to yield half the tablet bioavailability was 99 mg/m2. Diarrhoea and proton pump inhibitors were also associated with reduced suspension bioavailability. CONCLUSIONS: In the largest population-pharmacokinetic study to date in children, we have found similar covariate effects to those seen in adults, but low bioavailability of suspension in patients with diarrhoea or those taking concurrent proton pump inhibitors, which may in particular limit the use of posaconazole in these patients.
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Antifúngicos/administración & dosificación , Antifúngicos/farmacocinética , Huésped Inmunocomprometido , Modelos Biológicos , Triazoles/administración & dosificación , Triazoles/farmacocinética , Administración Oral , Adolescente , Antifúngicos/sangre , Disponibilidad Biológica , Niño , Preescolar , Monitoreo de Drogas , Humanos , Lactante , Suspensiones , Comprimidos , Triazoles/sangreRESUMEN
However, the Original article has been updated with the Open Access under Commercial License.
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BACKGROUND: We previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE. CASE PRESENTATION: All three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency. CONCLUSIONS: PKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Proteína Quinasa C-delta/genética , Trombocitopenia/complicaciones , Anticuerpos Monoclonales Humanizados , Humanos , Riñón/patología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/genética , Mutación , Linaje , Rituximab/efectos adversos , Rituximab/uso terapéuticoRESUMEN
Radiotherapy for malignancies in the head and neck can cause common complications that can result in tooth damage that are also known as radiation caries. The aim of this study was to examine damage to the surface topography and calculate changes in friction behavior and the nano-mechanical properties (elastic modulus, nanohardness and friction coefficient) of enamel and dentine from extracted human third molars caused by exposure to radiation. Enamel and dentine samples from 50 human third molars were randomly assigned to four test groups or a control group. The test groups were exposed to high energy X-rays at 2 Gy/day, 5 days/week for 5 days (10 Gy group), 15 days (30 Gy group), 25 days (50 Gy group), 35 days (70 Gy group); the control group was not exposed. The nanohardness, elastic modulus, and friction coefficient were analyzed using a Hysitron Triboindenter. The nano-mechanical properties of both enamel and dentine showed significant dose-response relationships. The nanohardness and elastic modulus were most variable between 30-50 Gy, while the friction coefficient was most variable between 0-10 Gy for dentine and 30-50 Gy for enamel. After exposure to X-rays, the fracture resistance of the teeth clearly decreased (rapidly increasing friction coefficient with increasing doses under the same load), and they were more fragile. These nano-mechanical changes in dental hard tissue may increase the susceptibility to caries. Radiotherapy caused nano-mechanical changes in dentine and enamel that were dose related. The key doses were 30-50 Gy and the key time points occurred during the 15th-25th days of treatment, which is when application of measures to prevent radiation caries should be considered.
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Esmalte Dental/efectos de la radiación , Dentina/efectos de la radiación , Traumatismos por Radiación/etiología , Radioterapia de Alta Energía/efectos adversos , Análisis de Varianza , Caries Dental/etiología , Esmalte Dental/química , Dentina/química , Módulo de Elasticidad/efectos de la radiación , Fricción/efectos de la radiación , Dureza/efectos de la radiación , Humanos , Ilustración Médica , Dosis de Radiación , Valores de Referencia , Propiedades de Superficie/efectos de la radiación , Factores de TiempoRESUMEN
Abstract Radiotherapy for malignancies in the head and neck can cause common complications that can result in tooth damage that are also known as radiation caries. The aim of this study was to examine damage to the surface topography and calculate changes in friction behavior and the nano-mechanical properties (elastic modulus, nanohardness and friction coefficient) of enamel and dentine from extracted human third molars caused by exposure to radiation. Enamel and dentine samples from 50 human third molars were randomly assigned to four test groups or a control group. The test groups were exposed to high energy X-rays at 2 Gy/day, 5 days/week for 5 days (10 Gy group), 15 days (30 Gy group), 25 days (50 Gy group), 35 days (70 Gy group); the control group was not exposed. The nanohardness, elastic modulus, and friction coefficient were analyzed using a Hysitron Triboindenter. The nano-mechanical properties of both enamel and dentine showed significant dose-response relationships. The nanohardness and elastic modulus were most variable between 30-50 Gy, while the friction coefficient was most variable between 0-10 Gy for dentine and 30-50 Gy for enamel. After exposure to X-rays, the fracture resistance of the teeth clearly decreased (rapidly increasing friction coefficient with increasing doses under the same load), and they were more fragile. These nano-mechanical changes in dental hard tissue may increase the susceptibility to caries. Radiotherapy caused nano-mechanical changes in dentine and enamel that were dose related. The key doses were 30-50 Gy and the key time points occurred during the 15th-25th days of treatment, which is when application of measures to prevent radiation caries should be considered.