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2.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-33807944

RESUMEN

Phosphodiesterases (PDEs) are a heterogeneous superfamily of enzymes which catalyze the degradation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Among PDEs, PDE4 is the most widely studied and characterized isoenzyme. PDE4 blocking can lead to increased levels of intracellular cAMP, which results in down-regulation of inflammatory responses by reducing the expression of tumor necrosis factor (TNF), interleukin (IL)-23, IL-17, interferon-γ, while increasing regulatory cytokines, such as IL-10. Therefore, PDE4 has been explored as a therapeutic target for the treatment of different chronic inflammatory conditions such as psoriatic arthritis (PsA) and inflammatory bowel disease (IBD). PsA shares clinical, genetic, and pathogenic features with IBD such as ulcerative colitis (UC) and Crohn's disease (CD), and enteropathic spondyloarthritis (eSpA) represent a frequent clinical evidence of the overlap between gut and joint diseases. Current therapeutic options in PsA patients and underlying UC are limited to synthetic immunosuppressants and anti-TNF. Apremilast is an oral PDE4 inhibitor approved for the treatment of active PsA patients with inadequate response to synthetic immunosuppressants. The efficacy and a good safety profile observed in randomized clinical trials with apremilast in PsA patients have been confirmed by few studies in a real-life scenario. In addition, apremilast led to significant improvement in clinical and endoscopic features in UC patients in a phase II RCT. By now there are no available data regarding its role in eSpA patients. In view of the above, the use of apremilast in eSpA patients is a route that deserves to be deepened.


Asunto(s)
Artritis Psoriásica/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/inmunología , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Talidomida/análogos & derivados , Artritis Psoriásica/inmunología , Artritis Psoriásica/patología , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/patología , Citocinas/inmunología , Humanos , Talidomida/uso terapéutico
3.
Ann Hematol ; 100(6): 1417-1427, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33811502

RESUMEN

Hydroxyurea (HU) and thalidomide have been reported to improve clinical and hematological parameters in transfusion-dependent beta thalassemia (TDT). Therefore, we retrospectively analyzed the combination of HU and thalidomide in 140 transplant ineligible TDT, ≥ 10 years old, visiting our thalassemia clinic between October 2014 and November 2019. Responses were defined as maintenance of hemoglobin ≥9gm/dl without transfusion as complete response (CR) and with at least 50% reduction in transfusion burden as partial response (PR). Patients with less than 50% transfusion burden reduction for consecutive 6 months of therapy were defined as non-responders (NR), and treatment was discontinued thereafter. Primary end point was overall response rate (ORR) at last follow-up. At median follow-up of 22.6 (95% CI 16.4-28.7) months, 76 (57.2%) patients achieved CR and 19 (14.3%) achieved PR, accounting to an ORR of 71.5%. Among responders at last follow-up, a significant increase in the post-treatment hemoglobin (0.88±0.37gm/dl, p<0.0001) and drop in serum ferritin (-1490.5ng/ml, p<0.0001) were observed. Median time to CR was 124 (95% CI 75.3-172.6) days. Median longest continuous CR was 791 (95% CI 662.2-919.7) days. Common toxicities observed were sedation (25%), hyperbilirubinemia {(23.57%, grade 3/4 =17 (12.14%)}, and constipation (22.8%). Nearly three-fourth of the patients has responded with majority having CR. Adverse events are a concern; hence, regular close monitoring is a prerequisite.


Asunto(s)
Antidrepanocíticos/uso terapéutico , Hidroxiurea/uso terapéutico , Inmunosupresores/uso terapéutico , Talidomida/uso terapéutico , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Antidrepanocíticos/administración & dosificación , Transfusión Sanguínea , Niño , Combinación de Medicamentos , Femenino , Ferritinas/sangre , Estudios de Seguimiento , Humanos , Hidroxiurea/administración & dosificación , Inmunosupresores/administración & dosificación , Masculino , Estudios Retrospectivos , Talidomida/administración & dosificación , Adulto Joven , Talasemia beta/sangre , Talasemia beta/terapia
5.
Blood ; 137(2): 232-237, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33443552

RESUMEN

Emergence of drug resistance to all available therapies is the major challenge to improving survival in myeloma. Cereblon (CRBN) is the essential binding protein of the widely used immunomodulatory drugs (IMiDs) and novel CRBN E3 ligase modulator drugs (CELMoDs) in myeloma, as well as certain proteolysis targeting chimeras (PROTACs), in development for a range of diseases. Using whole-genome sequencing (WGS) data from 455 patients and RNA sequencing (RNASeq) data from 655 patients, including newly diagnosed (WGS, n = 198; RNASeq, n = 437), lenalidomide (LEN)-refractory (WGS, n = 203; RNASeq, n = 176), and pomalidomide (POM)-refractory cohorts (WGS, n = 54; RNASeq, n = 42), we found incremental increases in the frequency of 3 CRBN aberrations, namely point mutations, copy losses/structural variations, and a specific variant transcript (exon 10 spliced), with progressive IMiD exposure, until almost one-third of patients had CBRN alterations by the time they were POM refractory. We found all 3 CRBN aberrations were associated with inferior outcomes to POM in those already refractory to LEN, including those with gene copy losses and structural variations, a finding not previously described. This represents the first comprehensive analysis and largest data set of CBRN alterations in myeloma patients as they progress through therapy. It will help inform patient selection for sequential therapies with CRBN-targeting drugs.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/genética , Mieloma Múltiple/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/genética , Variación Genética , Humanos , Lenalidomida/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico
6.
Dig Liver Dis ; 53(3): 277-282, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33423942

RESUMEN

BACKGROUND: Patients receiving biologic therapies are at risk for viral infections. This study investigated the impact of the SARS-CoV-2 infection and the serum prevalence of SARS-CoV-2 antibodies in patients with inflammatory bowel disease (IBD) treated with biologic drugs. METHODS: Information on demography, co-morbidities, clinical data regarding IBD, symptoms suggestive of the SARS-CoV-2 infection, close contacts with SARS-CoV-2 positive patients, hospitalization, and therapies administered for COVID-19 was collected for all patients who were being treated with biologic drugs. All patients underwent SARS-CoV-2 antibody testing. RESULTS: Two hundred and fifty-nine patients (27 children) with a mean age of 42.2 ±â€¯16.7 years (range 9 - 88) and a mean duration of disease of 13.4 ±â€¯10 years (range 0.2 - 49) were enrolled. One hundred four patients (40.2%) had ulcerative colitis, and 155 (59.8%) had Crohn's disease. About the therapy: 62 patients were receiving infliximab, 89 adalimumab, 20 golimumab, 57 vedolizumab, 27 ustekinumab, 1 thalidomide, and 3 an experimental compound. The mean Charlson Comorbidity Index was 2. Thirty-two patients (12.3%) reported respiratory symptoms, and 2 of them were hospitalized (0.77%). Two patients resulted positive for IgG against SARS-CoV-2 (0.77%). CONCLUSIONS: In patients with IBD, treatment with biologic drug does not represent a risk factor for the SARS-CoV-2 infection.


Asunto(s)
Productos Biológicos/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/epidemiología , Adalimumab/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antivirales/inmunología , /fisiopatología , Niño , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Ensayo de Inmunoadsorción Enzimática , Femenino , Hospitalización , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Talidomida/uso terapéutico , Ustekinumab/uso terapéutico , Adulto Joven
8.
Eur J Med Chem ; 209: 112912, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33328101

RESUMEN

Lenalidomide and its analogs are well-known for treating multiple myeloma. In this work, designed sulfide-modified lenalidomide and pomalidomide were synthesized and evaluated. The anti-proliferative activity against MM.1S cell line of 3ak (IC50 = 79 nM) was similar to lenalidomide (IC50 = 81 nM). Compared to benzylic thioether substituted lenalidomide 3a, the half-live (T1/2) of 4-F-phenyl-thioether analogs 3ak in human liver microsomes was promoted from 3 min to 416.7 min. The corresponding metabolic factor of 3ak was increased from 2.8% to 79.5%, which was slightly lower than lenalidomide (91.5%). Moreover, the IKZF1 degradation of 3y and 3ak was well related with corresponding IC50 values, which suggested the IKZF1 degradation efficiency is correlated to the responses of MM1. S cells. Furthermore, the oral administration of compounds 3y and 3ak at dosages of 60 mg/kg could delay tumor growth in female CB-17 SCID mice. This research helped to prompt the stability of thioether lenalidomide analogs, which paved the way for developing better molecules for treating multiple myeloma.


Asunto(s)
Diseño de Fármacos , Lenalidomida/química , Lenalidomida/farmacología , Mieloma Múltiple/tratamiento farmacológico , Talidomida/análogos & derivados , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Lenalidomida/síntesis química , Lenalidomida/uso terapéutico , Ratones , Ratones SCID , Sulfuros/química , Talidomida/síntesis química , Talidomida/química , Talidomida/farmacología , Talidomida/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Lancet Haematol ; 7(12): e874-e883, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33242444

RESUMEN

BACKGROUND: In part 1 of the two-part CASSIOPEIA study, treatment before and after autologous haematopoietic stem-cell transplantation (HSCT) with daratumumab plus bortezomib, thalidomide, and dexamethasone (D-VTd) significantly improved rates of stringent complete response and progression-free survival versus bortezomib, thalidomide, and dexamethasone (VTd) in patients with newly diagnosed multiple myeloma. METHODS: CASSIOPEIA is an ongoing randomised, open-label, active-controlled, parallel-group, phase 3 trial done at 111 academic and community practice centres in Europe. Transplantation-eligible adults with newly diagnosed multiple myeloma were randomly assigned (1:1) to D-VTd or VTd. Treatment consisted of four 28-day cycles of induction therapy before autologous HSCT and two 28-day cycles of consolidation therapy after. In this prespecified secondary analysis, patient-reported outcomes were assessed using the European Organization for Research and Treatment of Cancer quality of life questionnaire-core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire at baseline, after induction (cycle 4, day 28), and after consolidation (day 100 after autologous HSCT). The analysis was done in all patients in the intention-to-treat population with a baseline and at least one post-baseline patient-reported outcome assessment. The trial is registered at ClinicalTrials.gov (NCT02541383). FINDINGS: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled and randomly assigned D-VTd (n=543) or VTd (n=542). Questionnaire completion rates were high at baseline (511 [94%] of 543 in the D-VTd group vs 510 [94%] of 542 in the VTd group). Compliance rates (calculated from the number of completed surveys as a proportion of the predicted number of participants still on study treatment) were high at post-induction (431 [84%] of 513 vs 405 [80%] of 509) and post-consolidation (414 [90%] of 460 vs 386 [88%] of 438) assessments and were similar between treatment groups. Mean changes in global health status scores from baseline to post-induction were not different between the D-VTd group (3·8 [95% CI 1·6 to 6·0]) and VTd group (2·9 [0·7 to 5·1]; p=0·43), or from baseline to post-consolidation between the two groups (D-VTd group, 9·7 (95% CI 7·4 to 11·9) vs VTd group, 8·7 (6·5 to 11·0; p=0·45). Improvements from baseline in EORTC QLQ-C30 global health status and EQ-5D-5L visual analogue scale scores were observed in post-consolidation scores in both groups. Post-consolidation scores showed significantly greater mean decreases in pain (-23·3 [95% CI -26·6 to -20·0] in the D-VTd group vs -19·7 [-23·0 to -16·3] in the VTd group; p=0·042), significantly smaller reductions in cognitive functioning (-5·0 [-7·6 to -2·4] vs -7·9 [-10·6 to -5·3]; p=0·036), and significantly greater improvements in emotional functioning (13·0 [10·4 to 15·5] vs 9·5 [6·9 to 12·1]; p=0·013) and in constipation (-3·2 [-7·3 to 0·9] vs 1·8 [-2·4 to 6·0]; p=0·025) with D-VTd versus VTd. Between-group differences in change from baseline for all other scales were not significant. INTERPRETATION: D-VTd and VTd were associated with on-treatment health-related quality of life improvements from baseline in transplantation-eligible patients with newly diagnosed multiple myeloma. The significantly greater reductions in pain, less deterioration of cognitive functioning, and greater emotional functioning improvements complement the clinical benefits observed with D-VTd versus VTd, and support the addition of daratumumab to standard regimens in patients with newly diagnosed multiple myeloma. FUNDING: Intergroupe Francophone du Myélome, The Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research and Development.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Calidad de Vida/psicología , Talidomida/uso terapéutico , Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib/farmacología , Dexametasona/farmacología , Femenino , Humanos , Masculino , Talidomida/farmacología
10.
Lancet Haematol ; 7(12): e861-e873, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33242443

RESUMEN

BACKGROUND: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. METHODS: In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. FINDINGS: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group. INTERPRETATION: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy. FUNDING: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Talidomida/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/métodos , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bortezomib/farmacología , Dexametasona/farmacología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Talidomida/farmacología , Adulto Joven
12.
Medicine (Baltimore) ; 99(40): e22639, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019487

RESUMEN

INTRODUCTION: Tuberculous meningitis (TBM) is the most fatal type of tuberculosis in which corticosteroids are added with antitubercular therapy to prevent permanent brain damage. However, this treatment may produce paradoxical reactions. In such cases, thalidomide use might reduce central nervous system inflammation and improve the outcome. We present the case of a human immunodeficiency virus-negative patient with TBM who developed paradoxical reactions manifesting as multiple intracranial tuberculomas that were resistant to standard care (antitubercular drugs and corticosteroids) but responded well to thalidomide. PATIENT'S MAIN CONCERN AND CLINICAL FINDINGS: The patient was a 40-year-old Chinese female, who was admitted with a 10-day history of headaches, night sweats, and cough. She was healthy before contracting the infection and had no history of contact with tuberculosis patients. DIAGNOSES, INTERVENTION, AND OUTCOME: We diagnosed the patient with TBM complicated by the occurrence of pulmonary tuberculosis. Positive results were obtained from Gram and Ziehl-Neelsen staining of the sputum and acid-fast bacilli sputum culture. Standard treatment was initiated with antitubercular drugs (daily isoniazid, rifampicin, ethionamide, and pyrazinamide) and corticosteroids (dexamethasone). However, 3 months later the magnetic resonance imaging of the head revealed some new tuberculoma lesion. Thus, a specific therapy of antitubercular drugs and thalidomide was introduced. On completion of a 12-month course of antitubercular drugs with 2 months of thalidomide, the patient showed favorable outcomes without neurologic sequelae. Moreover, thalidomide appeared safe and well tolerated in the patient. CONCLUSION: In addition to the specific anti-tubercular and adjuvant corticosteroid therapies for TBM, thalidomide can be used as a "salvage" antitubercular drug in cases that are unresponsive to corticosteroids.


Asunto(s)
VIH/inmunología , Inmunosupresores/uso terapéutico , Talidomida/uso terapéutico , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Pulmonar/complicaciones , Corticoesteroides/uso terapéutico , Adulto , Antituberculosos/uso terapéutico , Grupo de Ascendencia Continental Asiática/etnología , Encéfalo/patología , Quimioterapia Combinada , Femenino , Hospitalización , Humanos , Imagen por Resonancia Magnética/métodos , Terapia Recuperativa , Resultado del Tratamiento , Tuberculoma/diagnóstico por imagen , Tuberculosis Meníngea/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico
14.
PLoS Negl Trop Dis ; 14(8): e0008329, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32760161

RESUMEN

The drug thalidomide has resurged in the world market under restrictive conditions for marketing and use. In Brazil, there are still cases of pregnant women using thalidomide even after the implementation of laws that regulate the control of use (Law No. 10.651/2003 and Collegiate Board Resolution No. 11/2011). The objective of this study was to discuss the control of thalidomide use in Brazil, based on a scoping review of the scientific literature, documents, and data from the Ministry of Health. A total of 51 studies and documents related to the following subthemes were selected: (1) organization of access and use of thalidomide in the health system; (2) epidemiological and population characteristics of people affected by leprosy; and (3) occurrence of pregnancy and cases of embryopathy with the use of thalidomide. The results showed that Brazil has no unified information database about thalidomide patients. Furthermore, there is inconsistency in the accreditation of public health centers that dispense this medicine, in a country that has a high consumption of thalidomide in the Unified Health System. A large part of this amount of dispensed medicine is intended for the treatment of erythema nodosum leprosum, mainly in the North, Northeast, and Central-West regions of the country, which are endemic for leprosy. This disease is the only one among the clinical indications of the medicine approved in Brazil that does not have a Clinical Protocol and Therapeutic Guidelines. The control of thalidomide use in Brazil presents historical regulatory failures. These are currently linked to the organization and structure of primary healthcare in the country, as well as to the lack of leadership of the Ministry of Health and National Health Surveillance Agency when it comes to managing the process of control of this use.


Asunto(s)
Lepra/tratamiento farmacológico , Talidomida/efectos adversos , Talidomida/uso terapéutico , Anomalías Inducidas por Medicamentos/epidemiología , Brasil/epidemiología , Eritema Nudoso/tratamiento farmacológico , Femenino , Humanos , Leprostáticos/efectos adversos , Leprostáticos/uso terapéutico , Lepra/epidemiología , Lepra Lepromatosa/tratamiento farmacológico , Masculino , Embarazo
15.
Scott Med J ; 65(3): 72-75, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32638647

RESUMEN

Cytokine storm is a life-threatening complication of Covid-19 infection. Excessive cytokines are the products of hyperactive immune inflammatory response mounted by the host against the virus. There is no agreed treatment for cytokine storm. Three therapeutic agents with proven immune-modulatory properties in regular use in a wide range of inflammatory disorders (high dose intravenous immunoglobulin, Rituximab and thalidomide) are proposed for the treatment of cytokine storm. Safety and efficacy of the proposed treatment should be assessed by randomised controlled clinical trials. The use of the proposed treatment is expected to reduce the mortality rate and alter the overall management of the pandemic.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Rituximab/uso terapéutico , Talidomida/uso terapéutico , Administración Intravenosa , Infecciones por Coronavirus/complicaciones , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/etiología , Quimioterapia Combinada/métodos , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Factores Inmunológicos/administración & dosificación , Pandemias , Neumonía Viral/complicaciones , Rituximab/administración & dosificación , Talidomida/administración & dosificación
16.
Zhonghua Er Ke Za Zhi ; 58(7): 570-575, 2020 Jul 02.
Artículo en Chino | MEDLINE | ID: mdl-32605341

RESUMEN

Objective: To analyze the clinical characteristics and efficacy of drug treatment in children with inflammatory bowel disease (IBD) at different ages of onset. Methods: The clinical data of 87 children with IBD admitted to Department of Gastroenterology in Children's Hospital, Capital Institute of Pediatrics from January 2009 to December 2018 were collected. The patients were divided into four groups according to the age of onset: 0 -<2 years old group (36 cases), 2 -<6 years old group (10 cases), 6 -<10 years old group (12 cases) and 10 -<18 years old group (29 cases). The clinical manifestations, laboratory examination, endoscopic findings, pathologic and genetic changes, and treatment were compared among different age groups with chi-square test or Fisher's exact text. Results: (1) A total of 87 patients were diagnosed with IBD, including 50 Crohn's disease (CD) (57%), 25 ulcerative colitis (UC) (29%) and 12 unclassified inflammatory bowel disease (IBD-U) (14%). (2) Patients with fever accounted for 78% (28/36) and 8/10 in the 0 -<2 years old group and 2 -<6 years old group, respectively. Patients with abdominal pain and perianal diseases accounted for 6% (2/36) and 47% (17/36) in the 0 -<2 years old group, and their proportions were significantly different among the four groups (χ(2)=8.369, 40.317 and 13.130, all P<0.05). (3) Leukocytosis, thrombocytosis and anemia were more common in the 0-<2 years old group, seen in 72% (26/36), 31% (11/36) and 81% (29/36), respectively. There were significant differences in the changes of complete blood count among the four groups (χ(2)=21.919, 8.095 and 11.520, all P<0.05). (4) Colonic involvement accounted for 85% (17/20) in the 0 -<2 years old CD patients. While in the CD patients over 6 years old, 61% (14/23) had inflammation of ileum and colon, with a significant difference compared to that in patients under 6 years old (19% (5/27) , χ(2)=9.455, P=0.003). Also, the location of bowel inflammation among the four groups were significantly different (χ(2)=21.120, P<0.01). (5) Noncaseating granulomas were found in 15 (30%) CD patients, and crypt abscess was found in 11 (44%) UC patients. (6) Among the 24 patients whose genes were analyzed by high throughput sequencing, 12 had pathogenic single gene mutation. (7) There were 25 patients treated with total enteral nutrition. Among the 25 patients treated with thalidomide, 20 (80%) had clinical remission or partial remission. Among the 19 CD patients treated with infliximab (IFX), 14 had clinical remission at the 6(th) week of treatment, and the proportion of remission maintenance at the 30(th) week of treatment was 12/14. (8) The rate of clinical remission or partial remission was 64% (23/36) in the 0 -<2 years old group, 8/10 in the 2 -<6 years old group, 11/12 in the 6 -<10 years old group, and 83% (24/29) in the 10 -<18 years old group. Conclusions: The proportion of CD was higher than that of UC in this study. Infant onset inflammatory bowel disease was more likely to present with perianal lesions, and was usually associated with leukocytosis, thrombocytosis and anemia, and has high possibility of single gene mutation. IFX may be effective in treating CD.


Asunto(s)
Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Adolescente , Niño , Preescolar , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/tratamiento farmacológico , Nutrición Enteral , Fármacos Gastrointestinales/uso terapéutico , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/epidemiología , Infliximab/uso terapéutico , Talidomida/uso terapéutico
17.
Drugs Aging ; 37(9): 657-663, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32696432

RESUMEN

INTRODUCTION: Apremilast is a drug recently developed for psoriasis. Few data are available on its use in the elderly. We evaluated the tolerance and effectiveness of apremilast used in daily practice for psoriasis treatment in older patients. METHODS: We performed a multicenter, retrospective study involving patients aged ≥ 65 years who had received apremilast as a psoriasis treatment. Demographic data and details regarding psoriasis and adverse events (AEs) were collected from patient medical records. RESULTS: 135 patients were included (mean age: 73.5 years). Treatment was stopped in 74 patients (54.8%) for AEs (n = 43, 56.6%), primary failures (n = 18, 23.4%), and relapses (n = 7, 9.2%). When patients were stratified by age at treatment initiation, the main cause of discontinuation in patients ≥ 75 years was AEs, whereas in patients aged 65-74 years it was primary failures (28.3%). Sixty-one patients reported AEs, mainly digestive (n = 49). Regarding effectiveness, 45.2% of patients reached PGA 0/1 between 3 and 6 months after treatment initiation. One-year apremilast continuation rates were better in the 65-74 and 75-84 years subgroups than in the > 85 years subgroup (p = 0.01). CONCLUSION: Apremilast seems to be an effective and safe therapeutic option for psoriasis in the elderly. The main AEs reported by patients did not seem to differ from those reported previously in younger populations. However, AEs were more frequent in patients > 75 years old leading to more frequent discontinuation of apremilast compared with younger patients, suggesting a higher level of vigilance is needed in the elderly.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Psoriasis/tratamiento farmacológico , Talidomida/análogos & derivados , Administración Oral , Factores de Edad , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Femenino , Humanos , Masculino , Registros Médicos , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/efectos adversos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/uso terapéutico , Resultado del Tratamiento
18.
Dermatol Ther ; 33(4): e13722, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32475036

RESUMEN

Time to improvement is a crucial characteristic for effective treatments of chronic inflammatory conditions, such as psoriasis. Apremilast is a recently approved drug, belonging to the small molecule phosphodiesterase 4 inhibitors, whose optimal safety and efficacy profile is somewhat affected by slow activity rate in clinical trials. Real world case series are suggesting a more consistent improvement, and with this additional personal investigation on 48 patients, we signal that 58% of patients achieved Psoriasis Area and Severity Index (PASI) 50, and 19% PASI 75 improvement in the first 8 weeks of treatment. Results at 16-week are remarkable, with overall 55% of patients achieving PASI 75, 21% PASI 90 and 14% PASI 100. Only 8 patients (18, 6%) had slightly improved, although satisfied with the regimen, and determined to continue. Noteworthy, our population was rather problematic in terms of comorbidities (86%), and resistance to other treatments, with only 28% naïve to systemics, including biologics. Moreover, the observation period includes the Italian outbreak of COVID-19 epidemic, and further information on apremilast safety are provided, no one of the patients having stopped treatment. In such a critical period, the apremilast satisfactory speed of therapeutic response in a real-world setting has further strengthens patient's compliance to remain safely at home, which is the best strategy to limit contagion.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Infecciones por Coronavirus/epidemiología , Neumonía Viral/epidemiología , Psoriasis/tratamiento farmacológico , Talidomida/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Talidomida/uso terapéutico
19.
PLoS One ; 15(6): e0232068, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32559187

RESUMEN

Cyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cells in vitro. Short-hairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells both in vitro and in vivo with insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.


Asunto(s)
Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas/metabolismo , Proteolisis/efectos de los fármacos , Animales , Azepinas/farmacología , Azepinas/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 9 Dependiente de la Ciclina/genética , Quinasa 9 Dependiente de la Ciclina/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Ratones , Ratones SCID , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Interferencia de ARN , ARN Polimerasa II/metabolismo , ARN Interferente Pequeño/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacología , Talidomida/uso terapéutico , Trasplante Heterólogo
20.
Front Immunol ; 11: 1248, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32574274

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic is a worldwide threatening health issue. The progression of this viral infection occurs in the airways of the lungs with an exaggerated inflammatory response referred to as the "cytokine storm" that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications of COVID-19 and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs is Thalidomide; a historically emblematic controversial molecule that harbors an FDA approval for treating erythema nodosum leprosum (ENL) and multiple myeloma (MM). Based on just one-case report that presented positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Yet, the absence of substantial evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases, might cause a significant obstacle for carrying out further clinical evaluations. Herein, we will discuss the theoretical effectiveness of Thalidomide in attenuating inflammatory complications that are encountered in COVID-19 patients while pinpointing the lack of the needed evidences to move forward with this drug.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Talidomida/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Progresión de la Enfermedad , Humanos , Inflamación/tratamiento farmacológico , Inflamación/etiología , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/inmunología
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