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1.
Brasília; s.n; 5 jun. 2020.
No convencional en Portugués | LILACS, BRISA/RedTESA, PIE | ID: biblio-1100288

RESUMEN

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 11 artigos e 7 protocolos.


Asunto(s)
Humanos , Neumonía Viral/tratamiento farmacológico , Infecciones por Coronavirus/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Ácido Ascórbico/uso terapéutico , Ribavirina/uso terapéutico , Evaluación de la Tecnología Biomédica , Talidomida/uso terapéutico , Ceftriaxona/uso terapéutico , Metilprednisolona/uso terapéutico , Cloroquina/uso terapéutico , Interferones/uso terapéutico , Enoxaparina/uso terapéutico , Azitromicina/uso terapéutico , Ritonavir/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Lopinavir/uso terapéutico , Inhibidores de las Vasopeptidasas/uso terapéutico , Hidroxicloroquina/uso terapéutico
2.
Medicine (Baltimore) ; 99(21): e20221, 2020 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-32481292

RESUMEN

RATIONALE: Behcets disease (BD) is a type of chronic systemic vasculitis that typically manifests as a mucocutaneous disease with orogenital ulcers, skin damage, and uveitis. The clinical diagnosis is often difficult because of the diversity of organs that may be involved and lack of specific pathological diagnosis. PATIENT CONCERNS: A 26-year-old woman presented as a nearly 2-week history of hoarseness with throat pain. DIAGNOSES: In the present case, Fiber laryngoscopy showed multiple ulcers involving the epiglottic tubercle, bilateral false vocal cord, middle area of the left vocal cord, and full length of the right vocal cord. Multidisciplinary physicians combined the patients clinical manifestations and pathological findings to make the Behcets disease diagnosis. INTERVENTIONS: As the diagnosis confirmed, immediately began appropriate medical therapy (prednisolone at 30 mg once per day and thalidomide at 50 mg once per night in a month). OUTCOMES: The ulcer on the right vocal cord disappeared but left a scar. Therefore, the patient experienced only partial recovery from the hoarseness. LESSONS: Behcets disease can cause damage to multiple organs. Although the combination of vocal cord ulcers and hoarseness is rare in patients with BD and has not been previously reported to date, such patients should be treated with caution in clinical practice.


Asunto(s)
Síndrome de Behçet/complicaciones , Ronquera/etiología , Faringitis/etiología , Pliegues Vocales/patología , Adulto , Síndrome de Behçet/diagnóstico por imagen , Síndrome de Behçet/tratamiento farmacológico , Quimioterapia Combinada/métodos , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Laringoscopía/métodos , Faringitis/diagnóstico , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Resultado del Tratamiento , Pliegues Vocales/diagnóstico por imagen
3.
Lancet Haematol ; 7(5): e381-e394, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32171061

RESUMEN

BACKGROUND: Treatment of multiple myeloma is not curative, but targeting CD38 improves patient survival. To further explore this therapeutic approach, we investigated the safety and activity of MOR202, a novel monoclonal antibody targeting CD38, in patients with multiple myeloma. METHODS: This is a multicentre, open-label, phase 1-2a trial done at ten hospitals in Germany and Austria. Enrolled patients were aged 18 years or older with relapsed or refractory multiple myeloma and Karnofsky performance status of 60% or higher. Patients were assigned to the different treatment regimens with MOR202 ranging between 0·01 mg/kg and 16 mg/kg in a 3 + 3 design. Dose-escalation and expansion was done either with MOR202 intravenous infusions alone (MOR202 q2w [twice a week] and q1w [weekly] groups) or in combination with dexamethasone (MOR202 with dexamethasone group), with dexamethasone plus pomalidomide (MOR202 with dexamethasone plus pomalidomide group) or plus lenalidomide (MOR202 with dexamethasone plus lenalidomide group). Primary endpoints were safety, MOR202 maximum tolerated dose (or recommended dose) and regimen, and immunogenicity. The primary analysis was assessed in the safety population, which included patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, NCT01421186. FINDINGS: Between Aug 24, 2011, and Aug 1, 2017, 91 patients were treated, 35 with MOR202 monotherapy, and 56 with MOR202 combination regimens (18 in the MOR202 with dexamethasone group, 21 in the MOR202 with dexamethasone plus pomalidomide group, and 17 in the MOR202 with dexamethasone plus lenalidomide group). MOR202 intravenous infusions were safely administered within 30 min. Infusion-related reactions occurred in 14 (40%) of 35 patients receiving MOR202 monotherapy without steroids, and in four (7%) of 56 patients receiving MOR202 combination treatment. MOR202 maximum tolerated dose was not reached and the recommended regimens were MOR202 administered as an intravenous infusion for 30 min at doses up to 16 mg/kg with dexamethasone (40 mg), or in combination with dexamethasone plus lenalidomide (25 mg) or pomalidomide (4 mg). 35 (38%) of 91 patients developed lymphopenia, 30 (33%) developed neutropenia, and 27 (30%) developed leukopenia; these were the most common grade 3 or higher treatment-emergent adverse events. Serious adverse events were reported in 51 (56%) of 91 patients. None of the deaths were associated with MOR202. One pomalidomide-associated death occurred in the MOR202 with dexamethasone plus pomalidomide group. No anti-MOR202 antibodies were detected in patients. INTERPRETATION: MOR202 is safe and its clinical activity in patients with relapsed or refractory multiple myeloma is promising. Further clinical investigations of combinations with an immunomodulatory drug and dexamethasone are recommended. FUNDING: MorphoSys AG.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Anciano , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/uso terapéutico , Femenino , Humanos , Lenalidomida/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Resultado del Tratamiento
5.
Medicine (Baltimore) ; 99(5): e18991, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000436

RESUMEN

INTRODUCTION: Hidradenitis suppurativa is a complex, chronic, difficult to treat condition belonging to the spectrum of cutaneous immune-mediated inflammatory diseases. Systemic treatment options for moderate-severe disease are limited to TNF-alpha antagonists and other biologic agents, with limited clinical evidence. PATIENT CONCERNS: We report two adult patients with severe hidradenitis suppurativa presenting concomitant psoriatic arthritis and multiple medical comorbidities. Both were ineligible or resistant to adalimumab, the only biologic drug approved for the treatment of hidradenitis. DIAGNOSIS: Both patients were diagnosed with severe Hurley III-stage disease and psoriatic arthritis, showing resistance to first-line systemic treatments and a complex comorbidity profile. INTERVENTIONS: Patients underwent treatment with apremilast, an oral phosphodiesterase-4 inhibitor, approved for the treatment of psoriatic arthritis. OUTCOMES: After 16 weeks of treatment, a clinically relevant improvement of inflammatory lesions, skin- and arthritis-related pain, and patient-reported outcomes was achieved in both patients. Apremilast was well tolerated and continued up to 48 weeks of treatment. CONCLUSION: We report the "real-life" use of apremilast in the treatment of multimorbid patients with hidradenitis suppurativa and review its potential role in the management of this severe condition.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Hidradenitis Supurativa/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Artritis Psoriásica/complicaciones , Hidradenitis Supurativa/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Talidomida/uso terapéutico
6.
Expert Opin Pharmacother ; 21(7): 785-796, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32057269

RESUMEN

INTRODUCTION: In recent years, different studies regarding psoriatic arthritis (PsA) have shown the pathogenetic role of dysfunction of signaling pathways involving the phosphodiesterase-4 enzyme and transcription factors or enzymes belonging to the kinase (JAK)-signal family pathway. These also represent the target of several drugs known as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). AREAS COVERED: The authors performed a systematic literature search using the PubMed database, as well as through retrieving data from randomized controlled trials, their post-hoc analysis, and pooled data analysis on the efficacy and safety profile of the PDE4 inhibitor (PDE4i), apremilast, and the inhibitors of JAK (JAKis), tofacitinib, filgotinib, baricitinib, and upadacitinib, in PsA. EXPERT OPINION: In PsA, the PDE4i, apremilast, and the JAKi, tofacitinib, are effective across multiple clinical domains and have an acceptable tolerability profile, thus expanding the treatment options available for PsA patients. Apremilast and tofacitinib show several advantages mainly represented by their oral administration, a fast onset of action, and a short half-life. Data on tsDMARDs in PsA are still limited, and randomized trials and real-life studies are advocated.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Quinasas Janus/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Administración Oral , Artritis Psoriásica/enzimología , Azetidinas/uso terapéutico , Humanos , Terapia Molecular Dirigida , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sulfonamidas/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Resultado del Tratamiento
7.
J Dermatolog Treat ; 31(3): 245-253, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-30935254

RESUMEN

Background: Hair loss encompasses a group of scarring and nonscarring diseases with limited treatment options. Understanding the pathogenesis of alopecias has led to the experimental use of phosphodiesterase inhibitors (PDEi).Objective: To perform a systematic review of literature surrounding the use of PDEi for alopecia.Materials and methods: A search was conducted using PubMed in February 2019 on PDEi and alopecia. Inclusion criteria were clinical trials, prospective or retrospective studies, case series and case reports written in English, using PDEi in human subjects for the treatment of alopecia.Results: Fifteen articles were included for review - eight discussing the use of topical caffeine 0.2%-2.5% for the treatment of androgenetic alopecia (AGA) and telogen effluvium (TE), one using injectable caffeine for AGA, one using topical sildenafil for pediatric alopecia areata (AA), and five using oral apremilast for adult AA.Conclusions: Preliminary results using topical caffeine for AGA or TE are promising with minimal adverse events. However, these studies are primarily single-center trials with few patients. Studies using topical or systemic PDEi for AA demonstrate limited success. Current research using PDEi for alopecia is limited, however new clinical trials are being conducted.


Asunto(s)
Alopecia/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Cafeína/uso terapéutico , Cicatriz/patología , Ensayos Clínicos como Asunto , Humanos , Citrato de Sildenafil/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico
8.
J Dermatolog Treat ; 31(2): 131-140, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30935262

RESUMEN

Purpose: Apremilast is a phosphodiesterase-4 inhibitor FDA approved for psoriatic arthritis and moderate to severe plaque psoriasis. In recent years, multiple studies have suggested other potential uses for apremilast in dermatology. A summary of these various studies will be a valuable aid to dermatologists considering apremilast for an alternative indication.Materials and methods: The PubMed/MEDLINE and ClinicalTrials.gov databases were queried with the term 'apremilast,' with results manually screened to identify published data on off-label uses of apremilast. The article was structured by the quality of evidence available.Results: Apremilast use in dermatology beyond plaque psoriasis and psoriatic arthritis is frequently described in the literature, with a mixture of positive and negative results. Randomized controlled data is available for Behçet's disease, hidradenitis suppurativa, nail/scalp/palmoplantar psoriasis, alopecia areata, and atopic dermatitis.Conclusion: The relatively safe adverse effect profile of apremilast and its broad immunomodulatory characteristics may make it a promising option in the future for patients with difficult to treat diseases in dermatology, refractory to first line therapies, but further studies will be necessary to clarify its role.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Talidomida/análogos & derivados , Alopecia Areata/tratamiento farmacológico , Antiinflamatorios no Esteroideos/efectos adversos , Síndrome de Behçet/tratamiento farmacológico , Hidradenitis Supurativa/tratamiento farmacológico , Humanos , Náusea/etiología , Uso Fuera de lo Indicado , Ensayos Clínicos Controlados Aleatorios como Asunto , Talidomida/efectos adversos , Talidomida/uso terapéutico
12.
Klin Onkol ; 32(6): 445-452, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31842563

RESUMEN

BACKGROUND: Thalidomide-and bortezomib-containing regimens are widely used for transplant-ineligible newly diagnosed multiple myeloma patients. The aim of this study was to analyse the efficiency of thalidomide-or bortezomib-based regimens in long-term follow-up. MATERIALS AND METHODS: From 2008 to 2012, 142 transplant-ineligible newly diagnosed multiple myeloma patients were analysed retrospectively. Bortezomib was administered at the standard dosing of 1.3mg/m2 weekly, and thalidomide was administered at a daily dose of 100mg. Both drugs were combined with cyclophosphamide and dexamethasone. A total of 95 patients were treated with thalidomide and 47 with bortezomib. A median four cycles of treatment were administered in both groups. RESULTS: In the thalidomide group, the overall response rate was 60.6%, the median progression-free survival (PFS) was 10.3 months (95% CI 7.4-13.2) and the median overall survival (OS) was 35.1 months (95% CI 23.9-46.3). In the bortezomib group, the overall response rate was 51.1%, the median PFS was 11.9 months (95% CI 8.8-15) and the median OS was 25.4 months (95% CI 9.3-41.6). There was a statistically significant difference in OS (p = 0.027), favouring the cyclophosphamide/thalidomide/dexamethasone group, but the response rates and PFS intervals were not significantly different between both groups. The median follow-up in the thalidomide group was 35.1 months (95% CI 0.2-95.9) compared to 25.1 months (95% CI 0.4-60.6) in the bortezomib group (p = 0.004). The incidence of serious adverse events was comparable in both groups. CONCLUSION: In conclusion, the results of bortezomib treatment are comparable to thalidomide treatment under conditions of short administration. According to other clinical trials, long-term bortezomib treatment provides an additional advantage for PFS and OS.


Asunto(s)
Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Ciclofosfamida/uso terapéutico , Dexametasona/uso terapéutico , Inmunosupresores/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Talidomida/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Bortezomib/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Trasplante de Células Madre , Análisis de Supervivencia , Talidomida/efectos adversos , Resultado del Tratamiento
13.
Thromb Res ; 183: 69-75, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31670229

RESUMEN

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by immune-mediated platelet destruction, leading to lower platelet count. Thalidomide is considered as a novel immunomodulatory drug for treating several autoimmune diseases. Whether thalidomide can ameliorate ITP remains unclear. This study aims to evaluate the effect of thalidomide on ITP mouse model. ITP mouse model was established through intraperitoneal injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin. Thalidomide (10, 20 or 50 mg/kg body weight) was intraperitoneally injected into mice followed by antibody injection. Then, peripheral blood and plasma was isolated for analysis of platelet count and the level of IFN-γ and IL-17 in plasma. Meanwhile, spleen was extracted to measure the expression of CD68, a macrophage marker. In addition, macrophage cell line RAW264.7 was cultured and treated with thalidomide followed by analysis of cell viability, apoptosis as well as cell cycle. Thalidomide prevented antiplatelet antibody-mediated platelet destruction in ITP mouse model. Compared with vehicle (phosphate-buffered saline), thalidomide significantly inhibited the secretion of IFN-γ and IL-17 in ITP mouse and reduced the expression of CD68 in spleen. After thalidomide treatment, the cell viability of RAW264.7 cell was significantly reduced and the cell number in S phase was also significantly decreased. In addition, the expression of cyclin E2 was significantly reduced. In conclusion, thalidomide prevents antiplatelet antibody-mediated platelet destruction in ITP mouse possibly through reducing the number of macrophages, suggesting that it might be a novel approach for treating ITP.


Asunto(s)
Inmunosupresores/uso terapéutico , Talidomida/uso terapéutico , Trombocitopenia/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Inmunosupresores/farmacología , Ratones , Talidomida/farmacología , Trombocitopenia/patología
14.
Curr Opin Pediatr ; 31(6): 747-753, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31693582

RESUMEN

PURPOSE OF REVIEW: To provide an update of vascular malformation syndromes by reviewing the most recent articles on the topic and following the new International Society for the Study of Vascular Anomalies (ISSVA) 2018 classification. RECENT FINDINGS: This review discusses the main features and diagnostic approaches of the vascular malformation syndromes, the new genetic findings and the new therapeutic strategies developed in recent months. SUMMARY: Some vascular malformations can be associated with other anomalies, such as tissue overgrowth. PIK3CA-related overgrowth spectrum (PROS) is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic mutations in PI3K-AKT-mTOR pathway that encompass a heterogeneous group of rare disorder that are associated with the appearance of overgrowth. CLOVES syndrome and Klippel-Trénaunay syndrome are PROS disease. Proteus syndrome is an overgrowth syndrome caused by a somatic activating mutation in AKT1. CLOVES, Klippel-Trénaunay and Proteus syndromes are associated with high risk of thrombosis and pulmonary embolism. Hereditary hemorrhagic telangiectasia is an autosomic dominant disorder characterized by the presence of arteriovenous malformations. New therapeutic strategies with bevacizumab and thalidomide have been employed with promising results.


Asunto(s)
Bevacizumab/uso terapéutico , Trastornos del Crecimiento/genética , Anomalías Musculoesqueléticas/diagnóstico , Anomalías Musculoesqueléticas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/genética , Talidomida/uso terapéutico , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/tratamiento farmacológico , Anomalías Múltiples , Fosfatidilinositol 3-Quinasa Clase I , Trastornos del Crecimiento/complicaciones , Humanos , Anomalías Musculoesqueléticas/genética , Mutación , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Síndrome , Serina-Treonina Quinasas TOR , Malformaciones Vasculares/genética
15.
Cochrane Database Syst Rev ; 2019(11)2019 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-31765002

RESUMEN

BACKGROUND: Multiple myeloma is a bone marrow-based hematological malignancy accounting for approximately two per cent of cancers. First-line treatment for transplant-ineligible individuals consists of multiple drug combinations of bortezomib (V), lenalidomide (R), or thalidomide (T). However, access to these medicines is restricted in many countries worldwide. OBJECTIVES: To assess and compare the effectiveness and safety of multiple drug combinations of V, R, and T for adults with newly diagnosed transplant-ineligible multiple myeloma and to inform an application for the inclusion of these medicines into the World Health Organization's (WHO) list of essential medicines. SEARCH METHODS: We searched CENTRAL and MEDLINE, conference proceedings and study registries on 14 February 2019 for randomised controlled trials (RCTs) comparing multiple drug combinations of V, R and T for adults with newly diagnosed transplant-ineligible multiple myeloma. SELECTION CRITERIA: We included RCTs comparing combination therapies of V, R, and T, plus melphalan and prednisone (MP) or dexamethasone (D) for first-line treatment of adults with transplant-ineligible multiple myeloma. We excluded trials including adults with relapsed or refractory disease, trials comparing drug therapies to other types of therapy and trials including second-generation novel agents. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias of included trials. As effect measures we used hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and risk ratios (RRs) for adverse events. An HR or RR < 1 indicates an advantage for the intervention compared to the main comparator MP. Where available, we extracted quality of life (QoL) data (scores of standardised questionnaires). Results quoted are from network meta-analysis (NMA) unless stated. MAIN RESULTS: We included 25 studies (148 references) comprising 11,403 participants and 21 treatment regimens. Treatments were differentiated between restricted treatment duration (treatment with a pre-specified amount of cycles) and continuous therapy (treatment administered until disease progression, the person becomes intolerant to the drug, or treatment given for a prolonged period). Continuous therapies are indicated with a "c". Risk of bias was generally high across studies due to the open-label study design. Overall survival (OS) Evidence suggests that treatment with RD (HR 0.63 (95% confidence interval (CI) 0.40 to 0.99), median OS 55.2 months (35.2 to 87.0)); TMP (HR 0.75 (95% CI 0.58 to 0.97), median OS: 46.4 months (35.9 to 60.0)); and VRDc (HR 0.49 (95% CI 0.26 to 0.92), median OS 71.0 months (37.8 to 133.8)) probably increases survival compared to median reported OS of 34.8 months with MP (moderate certainty). Treatment with VMP may result in a large increase in OS, compared to MP (HR 0.70 (95% CI 0.45 to 1.07), median OS 49.7 months (32.5 to 77.3)), low certainty). Progression-free survival (PFS) Treatment withRD (HR 0.65 (95% CI0.44 to 0.96), median PFS: 24.9 months (16.9 to 36.8)); TMP (HR 0.63 (95% CI 0.50 to 0.78), median PFS:25.7 months (20.8 to 32.4)); VMP (HR 0.56 (95% CI 0.35 to 0.90), median PFS: 28.9 months (18.0 to 46.3)); and VRDc (HR 0.34 (95% CI 0.20 to 0.58), median PFS: 47.6 months (27.9 to 81.0)) may result in a large increase in PFS (low certainty) compared to MP (median reported PFS: 16.2 months). Adverse events The risk of polyneuropathies may be lower with RD compared to treatment with MP (RR 0.57 (95% CI 0.16 to 1.99), risk for RD: 0.5% (0.1 to 1.8), mean reported risk for MP: 0.9% (10 of 1074 patients affected), low certainty). However, the CIs are also compatible with no difference or an increase in neuropathies. Treatment with TMP (RR 4.44 (95% CI1.77 to 11.11), risk: 4.0% (1.6 to 10.0)) and VMP (RR 88.22 (95% CI 5.36 to 1451.11), risk: 79.4% (4.8 to 1306.0)) probably results in a large increase in polyneuropathies compared to MP (moderate certainty). No study reported the amount of participants with grade ≥ 3 polyneuropathies for treatment with VRDc. VMP probably increases the proportion of participants with serious adverse events (SAEs) compared to MP (RR 1.28 (95% CI 1.06 to 1.54), risk for VMP: 46.2% (38.3 to 55.6), mean risk for MP: 36.1% (177 of 490 patients affected), moderate certainty). RD, TMP, and VRDc were not connected to MP in the network and the risk of SAEs could not be compared. Treatment with RD (RR 4.18 (95% CI 2.13 to 8.20), NMA-risk: 38.5% (19.6 to 75.4)); and TMP (RR 4.10 (95% CI 2.40 to 7.01), risk: 37.7% (22.1 to 64.5)) results in a large increase of withdrawals from the trial due to adverse events (high certainty) compared to MP (mean reported risk: 9.2% (77 of 837 patients withdrew)). The risk is probably slightly increased with VMP (RR 1.06 (95% CI 0.63 to 1.81), risk: 9.75% (5.8 to 16.7), moderate certainty), while it is much increased with VRDc (RR 8.92 (95% CI 3.82 to 20.84), risk: 82.1% (35.1 to 191.7), high certainty) compared to MP. Quality of life QoL was reported in four studies for seven different treatment regimens (MP, MPc, RD, RMP, RMPc, TMP, TMPc) and was measured with four different tools. Assessment and reporting differed between studies and could not be meta-analysed. However, all studies reported an improvement of QoL after initiation of anti-myeloma treatment for all assessed treatment regimens. AUTHORS' CONCLUSIONS: Based on our four pre-selected comparisons of interest, continuous treatment with VRD had the largest survival benefit compared with MP, while RD and TMP also probably considerably increase survival. However, treatment combinations of V, R, and T also substantially increase the incidence of AEs, and lead to a higher risk of treatment discontinuation. Their effectiveness and safety profiles may best be analysed in further randomised head-to-head trials. Further trials should focus on consistent reporting of safety outcomes and should use a standardised instrument to evaluate QoL to ensure comparability of treatment-combinations.


Asunto(s)
Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bortezomib/uso terapéutico , Humanos , Lenalidomida/uso terapéutico , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , Talidomida/uso terapéutico
16.
BMC Cancer ; 19(1): 1147, 2019 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-31775673

RESUMEN

BACKGROUND: The advent of the immunomodulatory imide drugs (IMiDs) lenalidomide and thalidomide for the treatment of patients with plasma cell myeloma (PCM), has contributed to more than a doubling of the overall survival of these individuals. As a result, PCM patients join survivors of other malignancies such as breast and prostate cancer with a relatively new clinical problem - second primary malignancies (SPMs) - many of which are a result of the treatment of the initial cancer. PCM patients have a statistically significant increased risk for acute myeloid leukemia (AML) and Kaposi sarcoma. IMiD treatment has also been associated with an increased risk of myelodysplastic syndrome (MDS), AML, and squamous cell carcinoma of the skin. However, within these overlapping groups, acute lymphoblastic leukemia (ALL) is much less common. CASE PRESENTATION: Herein, we describe an elderly man with PCM and a 14-year cumulative history of IMiD therapy who developed persistent pancytopenia and was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). He joins a group of 17 other patients documented in the literature who have followed a similar sequence of events starting with worsening cytopenias while on IMiD maintenance for PCM. These PCM patients were diagnosed with B-ALL after a median time of 36 months after starting IMiD therapy and at a median age of 61.5 years old. CONCLUSIONS: PCM patients with subsequent B-ALL have a poorer prognosis than their de novo B-ALL counterparts, however, the very low prevalence rate of subsequent B-ALL and high efficacy of IMiD maintenance therapy in PCM should not alter physicians' current practice. Instead, there should be a low threshold for bone marrow biopsy for unexplained cytopenias.


Asunto(s)
Lenalidomida/efectos adversos , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/etiología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Talidomida/efectos adversos , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Médula Ósea , Humanos , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Lenalidomida/uso terapéutico , Masculino , Talidomida/uso terapéutico
17.
N Engl J Med ; 381(20): 1918-1928, 2019 11 14.
Artículo en Inglés | MEDLINE | ID: mdl-31722152

RESUMEN

BACKGROUND: The small-molecule phosphodiesterase 4 inhibitor apremilast modulates cytokines that are up-regulated in Behçet's syndrome. In a phase 2 trial involving patients with Behçet's syndrome, apremilast reduced the incidence and severity of oral ulcers. Data on the efficacy and safety of apremilast in patients with Behçet's syndrome who had active oral ulcers and had not previously received biologic agents are limited. METHODS: In a phase 3 trial, we randomly assigned, in a 1:1 ratio, patients who had Behçet's syndrome with active oral ulcers but no major organ involvement to receive either apremilast at a dose of 30 mg or placebo, administered orally, twice daily for 12 weeks, followed by a 52-week extension phase. The primary end point was the area under the curve (AUC) for the total number of oral ulcers during the 12-week placebo-controlled period (with lower values indicating fewer ulcers). There were 13 secondary end points, including complete response of oral ulcers, change from baseline in pain associated with oral ulcers, disease activity, and change from baseline in the Behçet's Disease Quality of Life score (range, 0 to 30, with higher scores indicating greater impairment in quality of life). Safety was also assessed. RESULTS: A total of 207 patients underwent randomization (104 patients to the apremilast group and 103 to the placebo group). The AUC for the number of oral ulcers was 129.5 for apremilast, as compared with 222.1 for placebo (least-squares mean difference, -92.6; 95% confidence interval [CI], -130.6 to -54.6; P<0.001). The change from baseline in the Behçet's Disease Quality of Life score was -4.3 points in the apremilast group, as compared with -1.2 points in the placebo group (least-squares mean difference, -3.1 points; 95% CI, -4.9 to -1.3). Adverse events with apremilast included diarrhea, nausea, and headache. CONCLUSIONS: In patients with oral ulcers associated with Behçet's syndrome, apremilast resulted in a greater reduction in the number of oral ulcers than placebo but was associated with adverse events, including diarrhea, nausea, and headache. (Funded by Celgene; ClinicalTrials.gov number, NCT02307513.).


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Síndrome de Behçet/tratamiento farmacológico , Úlceras Bucales/tratamiento farmacológico , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Talidomida/análogos & derivados , Administración Oral , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Área Bajo la Curva , Síndrome de Behçet/complicaciones , Método Doble Ciego , Femenino , Humanos , Masculino , Úlceras Bucales/etiología , Inhibidores de Fosfodiesterasa 4/efectos adversos , Calidad de Vida , Talidomida/efectos adversos , Talidomida/uso terapéutico
19.
Drugs R D ; 19(4): 329-338, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31598889

RESUMEN

BACKGROUND: Apremilast, an oral phosphodiesterase (PDE) 4 inhibitor, has demonstrated efficacy in psoriasis, while its efficacy in atopic dermatitis (AD) was found to be modest. AD is a chronic inflammatory skin disease associated with activation of T helper (Th) 2 and Th17 immunity and a compromised epidermal barrier. OBJECTIVE: The objectives of this study were to examine the expression of PDE4 isoforms in skin from healthy subjects and AD patients, and to determine the effects of apremilast on AD-related inflammatory markers in vitro and in murine models of AD. METHODS: The expression of PDE4 isoforms (A, B, C, and D) in skin biopsies from healthy subjects and AD patients was evaluated using immunohistochemistry and digital image analysis. Using quantitative real-time reverse-transcriptase polymerase chain reaction, we evaluated the effects of apremilast on gene expression in adult human epidermal keratinocytes (HEKa) stimulated by Th2 and Th17 cytokines, and in two mouse models of antigen-induced AD. RESULTS: Expression of PDE4 isoforms increased up to three-fold in the epidermis of AD patients versus healthy skin. In interleukin (IL)-4 and IL-17-stimulated HEKa cells, apremilast significantly changed the expression of ILs, including IL-12/IL-23p40 and IL-31, and alarmins S100A7, S100A8, and S100A12. In mouse models of AD, apremilast significantly reduced ear swelling and monocyte chemoattractant protein-1 expression. CONCLUSION: PDE4 is overexpressed in AD skin compared with normal skin, and inflammatory gene expression by human keratinocytes and mouse dermatitis can be modulated by apremilast.


Asunto(s)
Citocinas/genética , Dermatitis Atópica/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Queratinocitos/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/uso terapéutico , Talidomida/análogos & derivados , Adulto , Animales , Células Cultivadas , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Dermatitis Atópica/inmunología , Modelos Animales de Enfermedad , Voluntarios Sanos , Humanos , Interleucina-17/genética , Interleucina-4/genética , Queratinocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Cultivo Primario de Células , Isoformas de Proteínas , Talidomida/uso terapéutico
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