RESUMEN
Purpose: To determine the effect of telmisartan on intraocular pressure (IOP), blood pressure (BP), and ocular perfusion pressure (OPP) in normal and glaucomatous cats. Methods: A four-week study was conducted in six normal adult cats, followed by a longer six-month study performed in 37 cats with spontaneous glaucoma and 11 age-matched normal cats. Telmisartan (1 mg/kg/day) or placebo-vehicle were administered orally once daily. IOP was measured by rebound tonometry. BP readings were obtained by oscillometric method. OPP was calculated as mean arterial pressure (MAP) - IOP. IOP and BP were obtained three times a week for the first study and weekly for the second study. Results: Baseline IOP was significantly higher, and OPP was significantly lower in glaucomatous cats than in normal cats (P < 0.0001). These differences between glaucomatous and normal cats persisted throughout the study, regardless of treatment (P < 0.001). No significant differences in IOP, BP, or OPP were detected between any study phases in the first, normal feline cohort or between telmisartan- and placebo-treated glaucomatous cats at any timepoint in the second study. Conclusions: Oral telmisartan was well tolerated and did not have a detrimental effect on BP or OPP in cats but did not lower IOP or improve OPP in cats with glaucoma. Translational Relevance: While showing telmisartan could not be used as a sole therapy for IOP lowering, our data affirmed a lack of detrimental effects of telmisartan on BP and OPP in a translationally-relevant, spontaneous, large animal glaucoma model.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II , Presión Sanguínea , Presión Intraocular , Telmisartán , Animales , Telmisartán/farmacología , Telmisartán/uso terapéutico , Telmisartán/administración & dosificación , Presión Intraocular/efectos de los fármacos , Gatos , Presión Sanguínea/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Masculino , Femenino , Tonometría Ocular/veterinaria , Benzoatos/farmacología , Benzoatos/uso terapéutico , Benzoatos/administración & dosificación , Modelos Animales de Enfermedad , Glaucoma/tratamiento farmacológico , Glaucoma/veterinaria , Glaucoma/fisiopatología , Bencimidazoles/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Administración OralRESUMEN
Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.
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Anemia Aplásica , Suero Antilinfocítico , Benzoatos , Hidrazinas , Inmunosupresores , Pirazoles , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Benzoatos/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Humanos , Hidrazinas/uso terapéutico , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Inmunosupresores/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Adulto Joven , Anciano , Estudios Retrospectivos , Quimioterapia Combinada , Niño , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Preescolar , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , China/epidemiología , Tasa de SupervivenciaRESUMEN
Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.
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Anemia Aplásica , Benzoatos , Pirazoles , Humanos , Masculino , Femenino , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/terapia , Adulto , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Persona de Mediana Edad , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Adulto Joven , Adolescente , Pirazolonas/uso terapéutico , Hidrazonas/uso terapéutico , Receptores de Trombopoyetina/agonistas , Resultado del Tratamiento , Estudios Prospectivos , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Tiazoles , TiofenosRESUMEN
Thrombopoietin receptor agonists (TPO-Ras; romiplostim/eltrombopag/avatrombopag) have demonstrated high efficacy rates (59-88%) and a good safety profile in clinical trials with adult patients with immune thrombocytopenia (ITP). Similar efficacy and safety results have been observed with romiplostim and eltrombopag in paediatric cohorts. Continuous treatment with TPO-RAs has shown durable responses with long-term use, up to 3 years. The effect of TPO-RAs was generally considered transient, as platelet counts tended to drop to baseline values after a short period of time (about 2 weeks), unless treatment was maintained. Several groups have reported successful discontinuation of TPO-RAs without the need for concomitant treatments. This is referred to as sustained remission off treatment (SROT). Both short- and medium-term treatment with TPO-RAs may reduce costs to our healthcare systems and, more importantly, may reduce the potential side effects that may be associated with continuous TPO-RA treatment. The issue of tapering and discontinuation of TPO-RAs in paediatric patients with ITP has received little attention to date. Given that paediatric ITP has much higher rates of spontaneous remission than ITP in adults, we consider that the possibility of SROT of TPO-RAs in paediatric patients with ITP is a neglected but very relevant issue in this subtype of the disease.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Receptores Fc , Receptores de Trombopoyetina , Proteínas Recombinantes de Fusión , Inducción de Remisión , Trombopoyetina , Humanos , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Trombopoyetina/uso terapéutico , Receptores Fc/uso terapéutico , Niño , Benzoatos/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Pirazoles/uso terapéutico , Hidrazinas/uso terapéutico , Esquema de Medicación , Recuento de Plaquetas , Resultado del Tratamiento , Tiazoles , TiofenosRESUMEN
Introduction. The international consensus and the American Society of Hematology guidelines from 2019 established thrombopoietin analogues as the second-line therapy for primary immune thrombocytopenia cases. Objectives. To describe romiplostim usefulness in patients with immune thrombocytopenia in a third-level hospital in Cuenca, Ecuador. Materials and methods. We conducted a descriptive and retrospective study in patients with immune thrombocytopenia treated with romiplostim. We evaluated the following variables: age, gender, previous therapies to romiplostim, dose, frequency, complications, change of thrombopoietin analogue, and treatment discontinuation. Results. We included 21 patients with immune thrombocytopenia treated with romiplostim, with a median age of 49 years. All patients received corticosteroids as first-line treatment. Three patients required longer administration intervals (over a week), with weekly doses lower than those recommended (< 1 µg/kg). Due to lack of efficacy, six patients replaced elthrombopag with romiplostim. Of the total, three suffered thrombotic complications: two had portal venous thrombosis, and one had pulmonary thromboembolism; five of the patients discontinued romiplostim scheme without resuming it. Conclusions. Romiplostim constitutes a convenient second-line therapy in immune thrombocytopenia. Despite the small sample size, romiplostim early use can minimize toxicities and infectious risks.
Introducción: El consenso internacional y la guía del 2019 de la American Society of Hematology, establecieron a los análogos de la trombopoyetina como medicamentos de segunda línea para tratar la trombocitopenia inmunitaria primaria. En Ecuador, se comercializan dos trombomiméticos: romiplostim y eltrombopag OBJETIVOS: Describir el uso de romiplostim en pacientes con trombocitopenia inmunitaria, en un hospital de tercer nivel en Cuenca (Ecuador). Materiales y métodos. Se adelantó un estudio descriptivo y retrospectivo en pacientes con trombocitopenia inmunitaria y tratamiento con romiplostim. Se evaluaron las siguientes variables: edad, sexo, tratamientos previos a romiplostim, dosis, frecuencia, complicaciones, cambio de análogo de trombopoyetina y discontinuación de la terapia. RESULTADOS: Veintiún pacientes con trombocitopenia inmunitaria fueron tratados con romiplostim, con una mediana de 49 años. Todos recibieron corticoides como tratamiento de primera línea. Tres precisaron de intervalos más prolongados que el semanal, con dosis semanales menores de las recomendadas (< 1 µg/kg). Por falta de eficacia, en seis pacientes se reemplazó la terapia con eltrombopag por romiplostim. Tres pacientes padecieron complicaciones trombóticas: dos, trombosis venosa portal, y uno, tromboembolia pulmonar. En cinco, se discontinuó el tratamiento con romiplostim, sin necesidad de reanudarlo. CONCLUSIONES: Romiplostim constituye un tratamiento de segunda línea para la trombocitopenia inmunitaria primaria. A pesar del reducido tamaño de la muestra, se observó que la administración temprana del medicamento puede minimizar toxicidades y riesgos infecciosos.
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Benzoatos , Púrpura Trombocitopénica Idiopática , Pirazoles , Receptores Fc , Proteínas Recombinantes de Fusión , Trombopoyetina , Humanos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Trombopoyetina/uso terapéutico , Trombopoyetina/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Femenino , Masculino , Receptores Fc/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Anciano , Pirazoles/uso terapéutico , Benzoatos/uso terapéutico , Benzoatos/administración & dosificación , Hidrazinas/uso terapéutico , Adulto Joven , Receptores de Trombopoyetina/agonistas , Corticoesteroides/uso terapéuticoAsunto(s)
Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Esplenectomía , Humanos , Masculino , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/cirugía , Pirazoles/uso terapéutico , PreescolarAsunto(s)
Benzoatos , Trasplante de Células Madre Hematopoyéticas , Hidrazinas , Pirazoles , Terapia Recuperativa , Humanos , Hidrazinas/uso terapéutico , Benzoatos/uso terapéutico , Pirazoles/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Terapia Recuperativa/métodos , Antígenos CD19/inmunología , Células T de Memoria/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta , Complejo CD3 , Masculino , Antígenos Comunes de Leucocito , Femenino , Depleción Linfocítica , Trasplante Homólogo , NiñoRESUMEN
PURPOSE: This study evaluates the long-term adjunctive use of netarsudil ophthalmic solution 0.02% in lowering IOP in patients with refractory glaucoma. METHODS: This retrospective chart review study was conducted at a tertiary care center. Patients who were prescribed add-on netarsudil therapy and on ≥ 3 topical glaucoma medications from 01/01/2018 to 08/31/2020 were reviewed. 47 patients (69 eyes) met the inclusion criteria. Baseline IOPs prior to the addition of netarsudil were compared to IOPs measured at 3-, 6-, and 12-month intervals. Any patients with inadequate follow-up or who had glaucoma surgery after netarsudil initiation were excluded. RESULTS: Median baseline IOP (± SD) was 21 ± 5.8 mmHg (median of 2 visits prior to initiation of netarsudil). At 3-month follow-up, 64 eyes had a median IOP of 16 ± 6.7 mmHg (p < 0.01). At 6-month follow-up, 56 eyes had a median IOP of 18 ± 4.6 mmHg (p < 0.01). At 12-month follow-up, 44 eyes had a median IOP of 15 ± 6.8 mmHg (p < 0.01). At the conclusion of the study, 64% of eyes reached 1 year follow-up due to several reasons. CONCLUSIONS: Patients with refractory glaucoma showed statistically and clinically significant IOP reductions on netarsudil. IOP reduction was stable long-term with the largest decrease in IOP seen at 12 months. Although some patients will still go on to require further laser or incisional surgery, for most patients netarsudil is an effective treatment for adjunctive use in refractory glaucoma.
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Benzoatos , Presión Intraocular , Soluciones Oftálmicas , beta-Alanina , Humanos , Estudios Retrospectivos , Masculino , Femenino , Presión Intraocular/fisiología , Presión Intraocular/efectos de los fármacos , beta-Alanina/análogos & derivados , beta-Alanina/administración & dosificación , beta-Alanina/uso terapéutico , Anciano , Soluciones Oftálmicas/administración & dosificación , Persona de Mediana Edad , Benzoatos/administración & dosificación , Benzoatos/uso terapéutico , Estudios de Seguimiento , Resultado del Tratamiento , Glaucoma/tratamiento farmacológico , Glaucoma/fisiopatología , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Tonometría Ocular , Agudeza Visual , Anciano de 80 o más AñosRESUMEN
Background and Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by the autoantibody-mediated destruction of platelets. The treatment of ITP aims to maintain a sufficient platelet count to prevent bleeding. First-line treatment options include corticosteroids and intravenous immunoglobulin (IVIg), while second-line treatments include splenectomy, rituximab and other immunosuppressive agents, and thrombopoietin (TPO) receptor agonists. This study aims to discuss the treatment methods and results from 100 patients with ITP at the Mugla Training and Research Hospital through a pharmacological approach. Materials and Methods: Demographic characteristics, clinical findings, bone marrow aspiration and biopsy results, and treatments and treatment responses at the time of diagnosis of the 100 patients with ITP who were treated and followed up in the period 2015-2023 were evaluated retrospectively. Results: In the third month after treatment, the overall response percentage was 100% in patients who received steroids only and 88% in patients who received IVIg treatment alone or in combination with steroids (p > 0.05). The most preferred second-line treatments were splenectomy (41%), eltrombopag (26%), and rituximab (10%). Bone marrow biopsy was performed in 54% of patients, where 35.1% showed increased megakaryocytes, 44.4% adequate megakaryocytes, and 14.8% decreased megakaryocytes. It is noted that eltrombopag and rituximab, in particular, yield higher complete remission rates than immunosuppressive drugs. Conclusions: Considering the side effects of immunosuppressive medications, IVIg, splenectomy, and steroid therapy, the use of new agents such as eltrombopag, which are easily tolerated and have a lower risk of side effects, is expected to increase.
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Benzoatos , Hidrazinas , Inmunoglobulinas Intravenosas , Púrpura Trombocitopénica Idiopática , Rituximab , Esplenectomía , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/mortalidad , Adulto , Estudios Transversales , Rituximab/uso terapéutico , Benzoatos/uso terapéutico , Hidrazinas/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Esplenectomía/estadística & datos numéricos , Anciano , Pronóstico , Pirazoles/uso terapéutico , Adolescente , Inmunosupresores/uso terapéutico , Corticoesteroides/uso terapéutico , Análisis de SupervivenciaRESUMEN
Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Niño , Masculino , Femenino , Preescolar , Adolescente , Lactante , Resultado del Tratamiento , Estudios Retrospectivos , Inducción de Remisión , RecurrenciaRESUMEN
AIM: The present study compared the safety, efficacy, and tolerability of the new fixed-dose combination (FDC) of telmisartan 40 mg + bisoprolol 5 mg (TBP) tablets with the existing comparator FDC telmisartan 40 mg + metoprolol succinate ER 50 mg (TMS) tablets in patients with stage 1 and stage 2 hypertension. METHODOLOGY: The multicentric, double-blind, parallel-group, comparative, prospective, phase-III clinical study involved 264 subjects with stage 1 and stage 2 hypertension from 10 centres across India. The selected subjects were randomized into two groups: group A received the TMS and group B received the new FDC TBP. The primary endpoint was the mean change in seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) from baseline to week 12 in both the control and study arms. The secondary endpoint was achieving the target of SeSBP <140 mmHg and SeDBP <90 mmHg from baseline to week 12 in both groups. Safety and tolerability parameters were evaluated in both groups based on adverse effects (AEs) reported by the patients and the physician. RESULTS: Both treatment groups exhibited a reduction in BP after 2 weeks of treatment, which was sustained until 12 weeks. The mean change in SeSBP and SeDBP at weeks 2, 6, and 12 compared to the previous visit showed statistical significance (p < 0.001) in all cases for both groups A and B. The mean changes in SeSBP and SeDBP from baseline to study end were numerically higher in group B than in group A. The mean difference in SeSBP from baseline to study end was significantly higher in group B compared to group A (p = 0.029). By week 12, 88.28 % and 89.84 % of subjects in group B achieved SeSBP <140 mmHg and SeDBP <90 mmHg respectively, while 86.71 % and 91.40 % of subjects in group A achieved the same targets. Reported AEs were mostly mild to moderate in both treatment groups, and no serious AEs or deaths were reported. Tolerability was rated as 'excellent' by 93.75 % of subjects in group B and 91.40 % of subjects in group A. CONCLUSION: Both the new FDC TBP and the existing comparator TMS combination therapy have comparable efficacy, tolerability, and safety for the management of stage 1 and stage 2 hypertension. TRIAL REGISTRY NAME: Clinical Trials Registry of India (CTRI) TRIAL REGISTRATION NO: CTRI/2021/11/037,926 PROTOCOL NO: MLBTL/05/2021 PROTOCOL URL: https://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=62069&EncHid=&userName=bisoprolol.
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Bisoprolol , Presión Sanguínea , Hipertensión , Metoprolol , Telmisartán , Humanos , Masculino , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Femenino , Bisoprolol/administración & dosificación , Bisoprolol/uso terapéutico , Método Doble Ciego , Persona de Mediana Edad , Estudios Prospectivos , Resultado del Tratamiento , Presión Sanguínea/efectos de los fármacos , Telmisartán/administración & dosificación , Telmisartán/uso terapéutico , Metoprolol/administración & dosificación , Metoprolol/uso terapéutico , Benzoatos/administración & dosificación , Benzoatos/uso terapéutico , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , India , Relación Dosis-Respuesta a Droga , Antihipertensivos/uso terapéutico , Antihipertensivos/administración & dosificación , Quimioterapia Combinada , Adulto , Combinación de Medicamentos , Estudios de SeguimientoRESUMEN
This review summarizes the rationale and current data on the use of thrombopoietin receptor agonists (TPO-RAs) for treating severe thrombocytopenia in infants, children, and adolescents. It focuses on substances that have been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for pediatric patients. Romiplostim and eltrombopag are already established as second-line treatment for persistent or chronic immune thrombocytopenia (ITP). As in adults, TPO-RAs are currently also evaluated in severe aplastic anemia (SAA), chemotherapy-induced thrombocytopenia (CIT), myelodysplastic syndromes (MDS), and poor engraftment after hematopoietic stem cell transplantation in pediatric and adolescent patients. Moreover, studies on the implication of TPO-RA in treating rare inherited thrombocytopenias, such as Wiskott-Aldrich syndrome (WAS), congenital amegakaryocytic thrombocytopenia (CAMT), or MYH9-associated thrombocytopenia, deserve future attention. Current developments include testing of avatrombopag and lusutrombopag that are approved for the treatment of thrombocytopenia associated with chronic liver disease (CLD) in adult patients. In pediatric and adolescent medicine, we expect in the near future a broader use of TPO-RAs as first-line treatment in primary ITP, thereby considering immunomodulatory effects that increase the rate of sustained remission off-treatment, and a selective use in rare inherited thrombocytopenias based on current clinical trials.
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Receptores Fc , Receptores de Trombopoyetina , Proteínas Recombinantes de Fusión , Trombocitopenia , Trombopoyetina , Humanos , Receptores de Trombopoyetina/agonistas , Niño , Trombopoyetina/uso terapéutico , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Adolescente , Pirazoles/uso terapéutico , Hidrazinas/uso terapéutico , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Lactante , Preescolar , Púrpura Trombocitopénica Idiopática/tratamiento farmacológicoRESUMEN
While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Pirazolonas , Receptores de Trombopoyetina , Humanos , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Pirazoles/administración & dosificación , Masculino , Femenino , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Benzoatos/administración & dosificación , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/sangre , Persona de Mediana Edad , Adulto , Anciano , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Hidrazinas/administración & dosificación , Receptores de Trombopoyetina/agonistas , Pirazolonas/uso terapéutico , Sustitución de Medicamentos , Recuento de Plaquetas , Resultado del Tratamiento , HidrazonasRESUMEN
A recent study investigated the correlation between telmisartan (TEL) exposure and Alzheimer's disease (AD) risk among African Americans (AAs) and European Americans. Their findings indicated that moderate-to-high TEL exposure was linked to a decreased incidence of AD among AAs. These results suggest a potential association between TEL and a reduced risk of AD specifically within the AA population. Here, we investigated the effects of TEL, either alone or in combination with ranolazine (Ran) or dapagliflozin (Dapa), on voltage-gated Na + currents ( INa ) in Neuro-2a cells. TEL, primarily used for treating hypertension and cardiovascular disorders, showed a stimulatory effect on INa , while Ran and Dapa reversed this stimulation. In Neuro-2a cells, we demonstrated that with exposure to TEL, the transient ( INa(T) ) and late ( INa(L) ) components of INa were differentially stimulated with effective EC 50 's of 16.9 and 3.1 µM, respectively. The research implies that TEL's impact on INa might be associated with enhanced neuronal excitability. This study highlights the complex interplay between TEL, Ran, and Dapa on INa and their potential implications for AD, emphasizing the need for further investigation to understand the mechanisms involved.
Asunto(s)
Acetanilidas , Compuestos de Bencidrilo , Bencimidazoles , Benzoatos , Glucósidos , Neuroblastoma , Piperazinas , Ranolazina , Telmisartán , Telmisartán/farmacología , Telmisartán/uso terapéutico , Glucósidos/farmacología , Glucósidos/uso terapéutico , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Ranolazina/farmacología , Ranolazina/uso terapéutico , Benzoatos/farmacología , Benzoatos/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/patología , Línea Celular Tumoral , Animales , Acetanilidas/farmacología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Ratones , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Activación del Canal Iónico/efectos de los fármacosRESUMEN
Objective: This study aimed at investigating the efficacy and safety of eltrombopag in the treatment of adult primary immune thrombocytopenia (ITP) and evaluated the factors influencing its efficacy and side effects. Methods: A total of 198 patients with adult ITP who were admitted to Tianjin Medical University General Hospital between January 2018 and March 2022 were retrospectively analyzed. The efficacy of each starting dose of eltrombopag was evaluated, and adverse events were analyzed. The factors influencing efficacy were investigated, including sex, age, adult ITP type, platelet antibodies, and combined drug treatments. Results: Of the 198 patients, 70 males and 128 females with a median age of 45 years (18-88 years) were included; 130 (65.7%) had newly diagnosed adult ITP, 25 (12.6%) had persistent adult ITP, and 43 (21.7%) had chronic adult ITP. The bleeding event scores at baseline were assessed; 84.3% had scores of<4 and 15.7% had scores of ≥4. The eltrombopag response rate (initial response) at 6 weeks was 78.8% (complete response [CR]: 49.0%; CR1: 14.6%; CR2: 15.2%). The median response time to eltrombopag was 7 (7, 14) days. The initial response rates to 25, 50, and 75 mg eltrombopag were 74.1%, 85.9%, and 60.0%, respectively (P=0.031). The initial response rate to the 50 mg dose was significantly higher than that of the 25-mg and 75-mg doses. Two patients received 100 mg as the starting dose, and their initial response was 0. Regarding dose adjustment, 70.7% of the patients remained on the starting dose, 8.6% underwent dose adjustment to 50 mg, and 6.1% underwent dose adjustment to 75 mg. Another two patients underwent dose adjustment to 100 mg. After dose adjustment, the persistent response rates were 83.6%, 85.3%, and 85.7% for the 25-, 50-, and 75-mg doses, respectively, with no significant difference. After dose adjustment, the sustained efficacy rate for the 100-mg dose (4 patients) was 100.0%. After 6 weeks of treatment with eltrombopag, the overall bleeding score of patients with ITP decreased. The number of patients with a score of ≥4 decreased to 0, the number of patients with a score of<4 decreased, and there was no significant change in the number of patients with a score of 1-2. The most common adverse event associated with eltrombopag was impaired liver function (7.7%). No thrombosis events or other adverse events were observed. ITP type and number of megakaryocytes significantly affected the initial response to eltrombopag. The initial response rates to eltrombopag for newly diagnosed adult ITP, persistent adult ITP, and chronic adult ITP were 85.3%, 56.0%, and 76.2%, respectively (P=0.003). For megakaryocytes, the initial response rates were 61.8%, 87.1%, and 84.3% (P=0.009) for the decreased, normal, and increased megakaryocyte groups, respectively. Conclusion: Eltrombopag, as a second-line or higher treatment for adult ITP, has a rapid onset of action and good safety. The initial response rate is significantly higher with a dose of 50 mg than with a dose of 25 mg. Patients with newly diagnosed ITP and those with normal or increased megakaryocyte numbers have a higher initial response rate to eltrombopag.
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Benzoatos , Hidrazinas , Púrpura Trombocitopénica Idiopática , Pirazoles , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Adulto , Anciano , Pirazoles/administración & dosificación , Pirazoles/uso terapéutico , Benzoatos/administración & dosificación , Benzoatos/uso terapéutico , Benzoatos/efectos adversos , Hidrazinas/uso terapéutico , Hidrazinas/administración & dosificación , Adolescente , Anciano de 80 o más Años , Resultado del Tratamiento , Niño , Adulto Joven , HemorragiaRESUMEN
We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.
Asunto(s)
Transfusión Sanguínea , Deferasirox , Deferiprona , Deferoxamina , Quelantes del Hierro , Hierro , Piridonas , Talasemia beta , Humanos , Quelantes del Hierro/uso terapéutico , Talasemia beta/mortalidad , Talasemia beta/terapia , Talasemia beta/tratamiento farmacológico , Talasemia beta/complicaciones , Femenino , Masculino , Adulto , Estudios Retrospectivos , Deferoxamina/uso terapéutico , Deferiprona/uso terapéutico , Hierro/metabolismo , Deferasirox/uso terapéutico , Piridonas/uso terapéutico , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/tratamiento farmacológico , Benzoatos/uso terapéutico , Ferritinas/sangre , Adolescente , Triazoles/uso terapéutico , Adulto Joven , Niño , Resultado del Tratamiento , Persona de Mediana Edad , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Estudios de CohortesRESUMEN
Atopic dermatitis is a multi-pathogenic disease characterized by chronic skin inflammation and barrier dysfunction. Therefore, improving the skin's ability to form an epidermal barrier and suppressing the production of cytokines that induce type 2 inflammatory responses are important for controlling atopic dermatitis symptoms. (-)-Blebbistatin, a non-muscle myosin II inhibitor, has been suggested to improve pulmonary endothelial barrier function and control inflammation by suppressing immune cell migration; however, its efficacy in atopic dermatitis is unknown. In this study, we investigated whether (S)-(-)-blebbistatin O-benzoate, a derivative of (-)-blebbistatin, improves dermatitis symptoms in a mite antigen-induced atopic dermatitis model using NC/Nga mice. The efficacy of the compound was confirmed using dermatitis scores, ear thickness measurements, serum IgE levels, histological analysis of lesions, and filaggrin expression analysis, which is important for barrier function. (S)-(-)-Blebbistatin O-benzoate treatment significantly reduced the dermatitis score and serum IgE levels compared to those in the vehicle group (p < 0.05). Furthermore, the histological analysis revealed enhanced filaggrin production and a decreased number of mast cells (p < 0.05), indicating that (S)-(-)-blebbistatin O-benzoate improved atopic dermatitis symptoms in a pathological model. In vitro analysis using cultured keratinocytes revealed increased expression of filaggrin, loricrin, involucrin, and ceramide production pathway-related genes, suggesting that (S)-(-)-blebbistatin O-benzoate promotes epidermal barrier formation. Furthermore, the effect of (S)-(-)-blebbistatin O-benzoate on type 2 alarmin cytokines, which are secreted from epidermal cells upon scratching or allergen stimulation and are involved in the pathogenesis of atopic dermatitis, was evaluated using antigens derived from mite feces. The results showed that (S)-(-)-blebbistatin O-benzoate inhibited the upregulation of these cytokines. Based on the above, (S)-(-)-blebbistatin O-benzoate has the potential to be developed as an atopic dermatitis treatment option that controls dermatitis symptoms by suppressing inflammation and improving barrier function by acting on multiple aspects of the pathogenesis of atopic dermatitis.
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Benzoatos , Citocinas , Dermatitis Atópica , Epidermis , Proteínas Filagrina , Compuestos Heterocíclicos de 4 o más Anillos , Animales , Humanos , Masculino , Ratones , Antígenos Dermatofagoides/inmunología , Benzoatos/farmacología , Benzoatos/uso terapéutico , Citocinas/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/patología , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Proteínas Filagrina/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inmunoglobulina E/sangre , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas de Filamentos Intermediarios/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Alarminas/efectos de los fármacosRESUMEN
MRD-HSCT is the first-line therapy for children with SAA, while it is not easy to find a compatible donor due to the Chinese one-child policy. IST has a high recurrence rate, a risk of clonal transformation. Thus, Haplo-HSCT, as a first-line treatment, has gradually attracted clinicians' attention. To evaluate the efficacy of Haplo-HSCT in children with SAA, we performed a retrospective study (2006.06-2021.01) of 210 patients with AA who received HSCT or IST in Beijing Children's Hospital. The OS and FFS rates were analyzed to evaluate the efficacy of Haplo-HSCT and IST. We found that from 2006 to 2021, 3- and 5-year cumulative survival rates were both 85.3% in the first-line Haplo group, 98.1% and 96.8% in the first-line IST group, both 85.7% in the ATG group (P = 0.866), both 100% in the ATG + TPO group (P = 0.016), and 99.1% and 97.2% in the ATG + eltrombopag group (P = 0.056). 3- and 5-year cumulative FFS rates were both 85.3% in the first-line Haplo-HSCT group and 67.5% and 66.2% in the first-line IST group (P = 0.033). Therefore, we believe that Haplo-HSCT can be a first-line treatment for paediatric SAA.