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1.
Bone ; 149: 115977, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33932619

RESUMEN

OBJECTIVE: Hypoparathyroidism has heterogeneous genetic and acquired etiologies with a broad spectrum of severity. Herein we describe the clinical outcomes of the largest cohort of hypoparathyroid patients reported to date, who were followed over 27-years. DESIGN: Pooled analysis of current and past studies describing the differential responses to PTH 1-34 injections vs conventional therapy among the varied hypoPT etiologies. METHODS: 192 participants (ages 2-74 years) with hypoparathyroidism who received either calcitriol and calcium or PTH 1-34 by subcutaneous injection. RESULTS: Among the 4 main etiologic categories of hypoparathyroidism (autoimmune polyglandular failure type 1, activating mutation of the calcium receptor, surgical, and idiopathic hypoparathyroidism), we reveal significant differences in PTH 1-34 dose requirements, prevalence of nephrocalcinosis, biomarkers of mineral homeostasis, and pharmacodynamic profiles. Serum 1,25-dihydroxyvitamin D3 increased significantly (P < 0.001) and 25-hydroxyvitamin D levels decreased during PTH 1-34 injections compared to calcitriol therapy (P < 0.01). Post-surgical patients achieved consistently lower urine calcium excretion over long-term PTH 1-34 therapy compared to conventional therapy (p < 0.001), but this was not achieved in the other etiologies. At study entry, patients had a high prevalence of renal insufficiency and nephrocalcinosis which were directly related to the duration of hypoparathyroidism (P < 0.03). Renal function remained stable during participation in our studies for both PTH 1-34 and conventional therapies. CONCLUSIONS: We conclude that the effects and dose-response of PTH 1-34 treatment differ according to the etiology of hypoparathyroidism. Postsurgical hypoPT maintained mean serum calcium levels in the mid- to low-normal range while concurrently maintaining normal mean urine calcium during long-term twice-daily PTH 1-34 therapy.


Asunto(s)
Calcio , Hipoparatiroidismo , Adolescente , Adulto , Anciano , Calcitriol/uso terapéutico , Niño , Preescolar , Humanos , Hipoparatiroidismo/tratamiento farmacológico , Persona de Mediana Edad , Hormona Paratiroidea , Fósforo , Centros de Atención Terciaria , Adulto Joven
2.
Clin Endocrinol (Oxf) ; 94(3): 377-383, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32955743

RESUMEN

CONTEXT: The monogenic disorder autoimmune polyendocrine syndrome type 1 (APS-1) or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifests frequently with hypoparathyroidism, which requires treatment with oral supplementation with calcium and active vitamin D analogs. The majority of APS-1/APECED patients also suffer from intestinal malabsorption, which complicates the management of hypoparathyroidism and may lead to refractory severe hypocalcaemia. In such situations, reliance on intravenous calcium carries a high risk of nephrocalcinosis and renal damage. METHODS: Here, we report our experience of periprocedural subcutaneous administration of recombinant human parathyroid hormone (rhPTH 1-34) in APS-1/APECED patients. Serum calcium was measured up to five times within the 36-hour period starting the evening before the scheduled procedure and ending the morning following the procedure. RESULTS: Twenty-seven APS-1/APECED patients with hypoparathyroidism (aged 4-67 years) underwent 31 invasive gastrointestinal and/or pulmonary procedures. The patients received an average rhPTH1-34 dose of 9.6 ± 1.4 µg by subcutaneous injection. 92% of the adults and 54% of children in our cohort had evidence of nephrocalcinosis. Mean calcium levels remained stable and ranged from 2.06 to 2.17 mmol/L with minimal fluctuation. None of our patients experienced periprocedural adverse events connected with hypocalcaemia. CONCLUSION: rhPTH 1-34 is an alternative to conventional therapy in patients with APS-1/APECED and hypoparathyroidism undergoing invasive procedures. Subcutaneous PTH1-34 given directly before and after procedures resulted in well-controlled serum calcium levels maintained in the low-normal range and avoided the need for intravenous calcium which may contribute to renal calcifications and tubular damage.


Asunto(s)
Hipocalcemia , Hipoparatiroidismo , Hormona Paratiroidea , Poliendocrinopatías Autoinmunes , Adulto , Calcio/sangre , Niño , Humanos , Hipocalcemia/tratamiento farmacológico , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/administración & dosificación , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/tratamiento farmacológico
3.
Sci Immunol ; 5(48)2020 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-32503877

RESUMEN

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Benzamidas/farmacología , Benzamidas/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Pirazinas/farmacología , Pirazinas/uso terapéutico , Agammaglobulinemia Tirosina Quinasa/metabolismo , Anciano , Anciano de 80 o más Años , COVID-19 , Infecciones por Coronavirus/virología , Enfermedad Crítica , Femenino , Estudios de Seguimiento , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Interleucina-6/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Pandemias , Neumonía Viral/virología , Estudios Prospectivos , Respiración Artificial , SARS-CoV-2 , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19
4.
Virulence ; 1(6): 488-99, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21178494

RESUMEN

Despite considerable progress over recent years, the prognosis of invasive aspergillosis (IA) remains unfavorable, reflecting an incomplete understanding of Aspergillus pathogenesis and suboptimal antifungal efficacy in vivo. Mammalian host systems including rodents and rabbits are important tools in elucidating antifungal drug activity and the immunopathogenesis of IA. Nonetheless, they are hampered by limitations that impose a "bottleneck" in mass screening of novel antifungal compounds and putative Aspergillus virulence factors including their cost, labor intensity and ethical constraints. Drosophila melanogaster is an invertebrate host with a long tract record of genetic studies and a simple, yet highly conserved innate immune system. Herein, we describe our experience using this fly model as a facile, non-laborious, inexpensive pathosystem for high-throughput screening of novel antifungal compounds and putative Aspergillus mutants, and studying antifungal innate immunity. We present three infection protocols (i.e., injection, rolling, ingestion) that introduce Aspergillus either directly into the hemolymph or at different epithelial surfaces of Toll-deficient Drosophila flies. As a proof of principle, we demonstrate attenuated virulence of known hypovirulent Aspergillus strains and protection of Aspergillus-infected flies given oral Aspergillus-active agents such is voriconazole. These protocols can be adapted for similar studies of other fungal pathogens. Crossing and generation of Toll-deficient Drosophila flies takes 3 weeks; Aspergillus conidial preparation takes 3 days; fly inoculation depending on the infection assay takes 1 to 6-8 hours; and assessment of fly survival, Aspergillus strain virulence, Drosophila innate host parameters and/or drug activity takes 4-8 days.


Asunto(s)
Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Aspergillus/patogenicidad , Proteínas de Drosophila/genética , Drosophila melanogaster/microbiología , Receptores Toll-Like/genética , Animales , Proteínas de Drosophila/deficiencia , Drosophila melanogaster/genética , Drosophila melanogaster/inmunología , Ingestión de Alimentos , Eliminación de Gen , Ensayos Analíticos de Alto Rendimiento , Inyecciones , Pruebas de Sensibilidad Microbiana , Modelos Animales , Receptores Toll-Like/deficiencia , Virulencia
5.
Antimicrob Agents Chemother ; 50(1): 294-7, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16377700

RESUMEN

We studied the efficacy of pentamidine (PNT) as prophylaxis or early treatment in acute pulmonary fusariosis in neutropenic mice. PNT-preexposed mice had significantly improved survival and reduced fungal burden compared to amphotericin B-preexposed and untreated mice. PNT-treated mice had increased survival but no difference in fungal burden versus untreated mice.


Asunto(s)
Antifúngicos/uso terapéutico , Fusarium/efectos de los fármacos , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Pentamidina/uso terapéutico , Animales , Antifúngicos/farmacocinética , Modelos Animales de Enfermedad , Fusarium/aislamiento & purificación , Enfermedades Pulmonares Fúngicas/patología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Neutropenia/complicaciones , Neutropenia/metabolismo , Infecciones Oportunistas , Pentamidina/farmacología
6.
Pharmacotherapy ; 25(9): 1174-80, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16164392

RESUMEN

STUDY OBJECTIVES: As the failure of amphotericin B therapy in patients with invasive aspergillosis often exceeds 50%, we sought to determine the relationship between in vitro amphotericin B resistance and clinical failure of amphotericin B against invasive aspergillosis. DESIGN: Retrospective study. SETTING: University cancer center. PATIENTS: One hundred sixteen patients with cancer and invasive aspergillosis. MEASUREMENTS AND MAIN RESULTS: The correlation between in vitro amphotericin B susceptibility, defined by both the National Committee for Clinical Laboratory Standards and Etest methods, and other prognostic factors with failure of initial amphotericin B therapy was retrospectively evaluated. Data for correlation could be clearly assessed in only 18 (16%) of the 116 patients. Admission to the intensive care unit was the only prognostic factor associated with failure of initial amphotericin B treatment in these 18 patients (p = 0.01). CONCLUSIONS: Several important obstacles underlie the correlation of in vitro susceptibility testing with in vivo efficacy of individual antifungal agents in the treatment of invasive aspergillosis. Such correlations could be determined in only a small subset of patients.


Asunto(s)
Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergillus/efectos de los fármacos , Neoplasias Hematológicas/complicaciones , Aspergilosis/etiología , Aspergillus/aislamiento & purificación , Farmacorresistencia Fúngica , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Estudios Retrospectivos , Resultado del Tratamiento
7.
Diagn Microbiol Infect Dis ; 52(1): 15-20, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15878437

RESUMEN

Invasive aspergillosis (IA) can occur despite prior prophylactic or empiric use of triazoles or amphotericin B (AMB). Although profound immunosuppression may account for breakthrough IA, resistance of Aspergillus to antifungals may also play a role. To examine this question, we measured the minimal inhibitory concentration of 105 Aspergillus isolates recovered from 105 cancer patients (64 with IA, 41 with Aspergillus colonization) to AMB, itraconazole (ITC), and voriconazole (VRC) using the National Committee for Clinical Laboratory Standards (NCCLS) M38-A microdilution and E-test methods. We also determined the minimal fungicidal concentration (MFC) of these agents and the minimal effective concentration (MEC) of caspofungin (CAS) using standardized methods. We then collected information regarding pre-exposure to AMB or triazoles (fluconazole, ITC, VRC) within 3 months before Aspergillus isolation. Pre-exposure of cancer patients to AMB or triazoles was associated with increased frequency of non-fumigatus Aspergillus species. Aspergillus isolates recovered from patients who previously received AMB exhibited higher E-test AMB MICs compared with isolates from patients without prior AMB exposure (P = 0.01). In addition, the AMB MICs by E-test were higher in triazole-pre-exposed patients compared with those not exposed to triazoles (P = 0.001). The ITC and VRC MICs by E-test were not affected by prior AMB or triazole exposure. Finally, neither the AMB, ITC, and VRC MICs and MFCs by NCCLS method nor CAS MECs showed such changes. In conclusion, cancer patients with positive Aspergillus cultures who are pre-exposed to AMB or triazoles have high frequency of non-fumigatus Aspergillus species. These Aspergillus isolates were found to be AMB-resistant by the more sensitive E-test method.


Asunto(s)
Anfotericina B/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Aspergilosis/prevención & control , Aspergillus/clasificación , Neoplasias/tratamiento farmacológico , Triazoles/uso terapéutico , Anfotericina B/farmacología , Aspergillus/efectos de los fármacos , Aspergillus/aislamiento & purificación , Quimioprevención , Medios de Cultivo , Farmacorresistencia Fúngica , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Triazoles/farmacología
8.
J Infect Dis ; 191(7): 1188-95, 2005 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-15747256

RESUMEN

Invasive aspergillosis (IA) is the most important opportunistic mycosis in immunosuppressed patients. The lack of a sufficient number of effective antifungals and our incomplete understanding of the pathogenesis of IA contribute to its overall unfavorable prognosis. Studies of drug efficacy against IA and Aspergillus virulence rely on conventional animal models that are laborious and use limited numbers of animals; alternative, less cumbersome in vivo models are desirable. Using different inoculation models of IA, we found that Toll-deficient Drosophila flies exposed to voriconazole (VRC), the preferred drug for the treatment of IA in humans, had significantly better survival rates and lower tissue fungal burdens than did those not exposed to VRC. Furthermore, Toll-deficient Drosophila flies infected with an alb1-deleted hypovirulent Aspergillus mutant had significantly better survival rates than did those infected with a wild-type Aspergillus strain. Therefore, the Drosophila fly is a fast, high-throughput in vivo model for the study of drug efficacy against IA and Aspergillus virulence.


Asunto(s)
Antifúngicos/farmacología , Aspergilosis/tratamiento farmacológico , Aspergillus/efectos de los fármacos , Proteínas de Drosophila/genética , Drosophila/microbiología , Evaluación Preclínica de Medicamentos/métodos , Receptores de Superficie Celular/genética , Animales , Aspergilosis/microbiología , Aspergillus/genética , Aspergillus/crecimiento & desarrollo , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Drosophila/genética , Eliminación de Gen , Receptores Toll-Like
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