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1.
Cell Cycle ; 21(5): 501-513, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34989322

RESUMO

Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including SMC3, CdLS) and ESCO2 (RBS). Though ESCO2 activates cohesin, CdLS and RBS etiologies are currently considered non-synonymous and for which pharmacological treatments are unavailable. Here, we identify a unifying mechanism that integrates these genetic maladies to pharmacologically-induced teratogenicity via thalidomide. Our results reveal that Esco2 and cohesin co-regulate the transcription of a component of CRL4 ubiquitin ligase through which thalidomide exerts teratogenic effects. These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments.


Assuntos
Síndrome de Cornélia de Lange , Talidomida , Acetiltransferases/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Anormalidades Craniofaciais , Proteínas de Ligação a DNA/genética , Síndrome de Cornélia de Lange/genética , Ectromelia , Humanos , Hipertelorismo , Ligases/genética , Mutação , Receptores de Interleucina-17 , Talidomida/efeitos adversos , Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética
3.
Lancet Haematol ; 9(2): e98-e110, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35032434

RESUMO

BACKGROUND: Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. METHODS: In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. FINDINGS: Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). INTERPRETATION: Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. FUNDING: Oncopeptides AB.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , COVID-19/tratamento farmacológico , Dexametasona/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Melfalan/efeitos adversos , Melfalan/análogos & derivados , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Fenilalanina/efeitos adversos , Fenilalanina/análogos & derivados , SARS-CoV-2 , Talidomida/efeitos adversos , Talidomida/análogos & derivados
4.
J Natl Compr Canc Netw ; 20(1): 91-95, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34991076

RESUMO

Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.


Assuntos
Mieloma Múltiplo , Tromboembolia Venosa , Anticoagulantes/efeitos adversos , Humanos , Lenalidomida/efeitos adversos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Fatores de Risco , Talidomida/efeitos adversos , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
5.
Blood Cancer J ; 12(1): 9, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075109

RESUMO

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535-1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547-2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368-1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Boro/uso terapêutico , Dexametasona/uso terapêutico , Glicina/análogos & derivados , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Talidomida/análogos & derivados , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêutico
6.
J Oncol Pharm Pract ; 28(2): 453-456, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34590522

RESUMO

INTRODUCTION: Lenalidomide is an immunomodulatory agent with multiple mechanisms of action, and treatment with lenalidomide is associated with adverse events such as thrombosis and abdominal pain; nonetheless, other rarer adverse events do exist, with few knowledge from physicians and pharmacists. For such adverse events, pharmacovigilance databases are of great interest. CASE REPORT: A 71-year-old patient with no rheumatologic history, in complete remission of a mantle-cell lymphoma following rituximab, doxorubicin, vincristine, cyclophosphamide, and prednisone induction, received a maintenance treatment with rituximab and lenalidomide. After each course of lenalidomide and with no other new medication, the patient presented with fever and high inflammatory markers level, and a scapular-belt arthritis. MANAGEMENT AND OUTCOME: The patient was managed with non-steroidal anti-inflammatory drugs and colchicine, with symptomatology and inflammation improvement. After discontinuation of lenalidomide, he had no arthritis relapse; it was then concluded that the patient had a lenalidomide-induced arthritis. We interrogated the national and international (VigiBase®) pharmacovigilance databases and found that arthritis in the context of lenalidomide exposure is a rare finding, with only three reported cases in France; 0.13% of adverse events reported with lenalidomide in the international database VigiBase® were arthritis. DISCUSSION: Our case then reports an uncommon finding, of which both pharmacists and physicians should be aware due to the wide and increasing use of lenalidomide.


Assuntos
Artrite , Farmacovigilância , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Ciclofosfamida , Doxorrubicina , Humanos , Lenalidomida/efeitos adversos , Masculino , Recidiva Local de Neoplasia , Prednisona , Rituximab/efeitos adversos , Talidomida/efeitos adversos
7.
Clin Cancer Res ; 28(5): 840-850, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34862247

RESUMO

PURPOSE: Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes. PATIENTS AND METHODS: Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes. RESULTS: Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%-87%. Twelve of 18 HIV-positive (67%; 95% CI, 41-87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%-97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6-15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases. CONCLUSIONS: Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.


Assuntos
Infecções por HIV , Herpesvirus Humano 8 , Sarcoma de Kaposi , Tromboembolia Venosa , Anticoagulantes/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/análogos & derivados
8.
Clin Exp Dermatol ; 47(4): 667-674, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34779533

RESUMO

Thalidomide is a medication that has been in existence for over half a century, and has proven to be useful and effective in severe dermatological conditions. For dermatologists, the ability of thalidomide to reduce the levels of the cytokine tumour necrosis factor-α, along with its immunomodulatory and anti-angiogenic properties, is of great significance, with the added advantage of being an oral medication. Its use is of course strictly monitored, owing to its potential adverse effects (AEs), particularly teratogenicity, with precautions taken to ensure its safe and correct use by both prescriber and patient. In this review, we look at the background and mechanism of action of thalidomide, provide an overview of conditions it can be used for with case examples, explain the potential AEs and monitoring requirements, and discuss future developments.


Assuntos
Dermatologia , Talidomida , Citocinas , Humanos , Talidomida/efeitos adversos , Talidomida/uso terapêutico
9.
Dermatol Ther ; 35(2): e15253, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34877758

RESUMO

Palmoplantar psoriasis (PP) is a type of psoriasis that involves the skin of the palms and soles and can present as hyperkeratotic, similar to the vulgaris psoriasis of the body. Apremilast, as an oral inhibitor of phosphodiesterase 4 (PDE4), is currently approved for the treatment of psoriatic arthritis and for moderate-to-severe psoriasis in adult patients who have not responded or have contraindications or do not tolerate other systemic treatments. We evaluated the efficacy and safety of apremilast in the treatment of non-pustular palmo-plantar psoriasis in a cohort of 12 patients. We found a clinical response of clear/almost clear palmoplantar psoriasis (PPPGA score 0/1) in 83.33% of our patients, at week 16. No significant safety issues were reported and none of our patients had to discontinue the drug.


Assuntos
Inibidores da Fosfodiesterase 4 , Psoríase , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Humanos , Inibidores da Fosfodiesterase 4/efeitos adversos , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Estudos Retrospectivos , Índice de Gravidade de Doença , Talidomida/efeitos adversos , Talidomida/análogos & derivados
10.
J Oral Pathol Med ; 51(1): 106-112, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34773292

RESUMO

BACKGROUND: Recurrent aphthous stomatitis (RAS) is the most common oral mucosal disease, and ulcer-free periods are a major concern for patients. Thalidomide has been shown to be an effective systemic drug in the treatment of RAS, but the value of undertaking a trial to evaluate various maintenance doses was warranted. METHODS: We performed this randomized controlled clinical trial with a two-stage design. Firstly, all the 125 cases of RAS received prednisone at a starting dose of 15 mg/d for one week as an initial therapeutic drug. Secondly, the 100 cases of RAS in the experimental group received thalidomide (50 mg/d vs. 25 mg/d) as a maintenance drug to observe its efficacy and safety. RESULTS: During maintenance medication at the fourth and eighth weekend, the two doses (50 and 25 mg/d) of thalidomide were equivalent in reducing the incidence of ulcers, ulcer number, and ulcer pain, respectively (all p > 0.05). Notably, the ulcer-free period in the group using 25 mg/d thalidomide for eight weeks was longer (mean, >3 months) than those in the other groups (all p < 0.05). Importantly, the total adverse events in the group using 25 mg/d thalidomide were significantly less than those in the group using 50 mg/d (p < 0.001). Moreover, the effect of 50 mg/d thalidomide on the levels of various salivary cytokines was not superior to 25 mg/d medication (p > 0.05). CONCLUSION: This dose optimization study concluded that 25 mg/d thalidomide had a long-term effect on extending the recurrence interval of RAS with better safety.


Assuntos
Estomatite Aftosa , Talidomida , Método Duplo-Cego , Humanos , Dor , Recidiva , Estomatite Aftosa/tratamento farmacológico , Talidomida/efeitos adversos
11.
Acta Derm Venereol ; 102: adv00665, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-34806759

RESUMO

Drug survival reflects treatment effectiveness and safety in real life. There is limited data on the variation of drug survival with the availability of systemic treatments with additional biological disease-modifying antirheumatic drugs (bDMARDs) or synthetic disease-modifying antirheumatic drugs (sDMARDs). The aim of this study was to determine whether the increasing number of available systemic treatments for psoriasis affects drug survival over time. Patients were selected from the PsoBioTeq cohort, a French prospective observational cohort enrolling patients with moderate to severe psoriasis. All patients initiating a first bDMARD or sDMARD were included. The primary outcome was comparison of drug survival over time. A multivariate Cox proportional hazard ratio model was computed. A total of 1,866 patients were included; 739 females (39%), median age 47 years. In the multivariate Cox model, no association was found between the calendar year of initiation and drug survival (hazard ratio) overlapping from 0.80 (0.42-1.52) to 1.17 (0.64-2.17), p = 0.633). In conclusion, drug survival in psoriasis is not affected by the year of initiation.


Assuntos
Antirreumáticos , Produtos Biológicos , Psoríase , Antirreumáticos/uso terapêutico , Fatores Biológicos/uso terapêutico , Produtos Biológicos/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/análogos & derivados
12.
Gynecol Endocrinol ; 38(1): 90-93, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34486922

RESUMO

INTRODUCTION: Thalidomide is an immunomodulatory drug and first choice in the treatment of erythema nodosum leprosum. Given its teratogenic potential, it is essential that an effective contraceptive method is used, especially a long-acting reversible contraceptive (LARC) method. The subdermal etonogestrel (ENG)-releasing implant is an adequate method due to the high effectiveness and long-term use. However, interaction between thalidomide and ENG has not been well documented. Concern arises because thalidomide interacts with cytochrome P450 (CYP450) enzymes that metabolize sexual steroids. AIM: We aimed to study the effectiveness and safety of the ENG-implant in a thalidomide user. METHODS: Case report of a sexually active 21-year-old patient with both Hansen's disease and leprosy reaction type 2 treated with thalidomide requiring effective contraception. Follow-up was up to 36 months after implant placement. RESULTS: Contraception with ENG-implant was effective and safe, based on clinical parameters (reduction of menstrual flow and cervical mucus thickening) and laboratory parameters (gonadotropins and sexual steroids). CONCLUSION: To the best of our knowledge, this is the first case reported which presents a patient in simultaneous use of thalidomide and ENG-implant. Although this case report preliminary supports effectiveness and safety of ENG-implant as a contraceptive option in women using thalidomide, rigorous drug-drug interaction research is needed to better characterize the interaction between thalidomide and the ENG-implant.


Assuntos
Anticoncepcionais Femininos/administração & dosagem , Desogestrel/administração & dosagem , Eritema Nodoso/tratamento farmacológico , Hanseníase Virchowiana/tratamento farmacológico , Teratógenos , Talidomida/uso terapêutico , Adulto , Desogestrel/efeitos adversos , Implantes de Medicamento , Interações Medicamentosas , Feminino , Humanos , Talidomida/efeitos adversos , Adulto Jovem
13.
J Am Acad Dermatol ; 86(1): 77-85, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34343599

RESUMO

BACKGROUND: Patients with mild-to-moderate psoriasis may have substantial quality-of-life impairment. OBJECTIVE: To evaluate apremilast 30 mg twice daily for mild-to-moderate psoriasis. METHODS: Phase 3, double-blind, placebo-controlled study in adults with mild-to-moderate psoriasis inadequately controlled or intolerant to ≥ 1 topical psoriasis therapy (NCT03721172). The primary endpoint was the achievement of static Physician Global Assessment score of 0 (clear) or 1 (almost clear) and ≥ 2-point reduction at week 16. RESULTS: Five hundred ninety-five patients were randomized (apremilast: 297; placebo: 298). The primary endpoint was met, with a significantly greater static Physician Global Assessment response rate observed at week 16 in the apremilast group compared with the placebo group (21.6% vs 4.1%; P < .0001). All secondary endpoints were met with the achievement of body surface area-75 (33.0% vs 7.4%), body surface area ≤ 3% (61.0% vs 22.9%), ≥ 4-point reduction in Whole Body Itch Numeric Rating Scale (43.2% vs 18.6%), Scalp Physician Global Assessment 0 or 1 and ≥ 2-point reduction (44.0% vs 16.6 %), and changes from baseline in body surface area, Psoriasis Area and Severity Index, and Dermatology Life Quality Index (all P < .0001). The most commonly reported adverse events (≥ 5%) with apremilast were diarrhea, headache, nausea, nasopharyngitis, and upper respiratory tract infection, consistent with prior studies. LIMITATIONS: The study lacked an active-comparator arm. CONCLUSION: Apremilast demonstrated efficacy in mild-to-moderate psoriasis and safety consistent with the established safety profile of apremilast.


Assuntos
Anti-Inflamatórios não Esteroides , Psoríase , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Método Duplo-Cego , Humanos , Psoríase/induzido quimicamente , Psoríase/diagnóstico , Psoríase/tratamento farmacológico , Índice de Gravidade de Doença , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Resultado do Tratamento
14.
Arthritis Rheumatol ; 74(2): 244-252, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34279061

RESUMO

OBJECTIVE: To investigate whether the initiation of treatment with an interleukin-17 inhibitor (IL-17i) in real life is associated with a higher risk of inflammatory bowel disease (IBD) in patients who had both psoriasis (PsO) and psoriatic arthritis (PsA)/ankylosing spondylitis (AS). METHODS: This nationwide cohort study was conducted using the French National Health Data System database. All adult patients with PsO and PsA/AS who were identified as having newly initiated treatment with an IL-17i during 2016-2019 were included. As controls, patients with PsO and PsA/AS who had newly initiated either 1) apremilast or 2) etanercept (ETN) during this period but had not received IL-17i were included. The follow-up end date was September 30, 2019. The primary end point was the risk of occurrence of IBD associated with exposure to an IL-17i compared to exposure to the other treatments, as determined in a time-to-event analysis with propensity score-weighted Cox and Fine-Gray proportional hazards models. RESULTS: The study included a total of 16,793 new IL-17i users (mean ± SD age 48.4 ± 13 years, 45% men), 20,556 new apremilast users (age 52.6 ± 15 years, 54% men), and 10,294 new ETN users (age 46.3 ± 15 years, 44% men). New IL-17i users and new ETN users had received more biologics for their underlying disease compared to new apremilast users. IBD occurred in 132 patients: 72 new IL-17i users (0.43%), 11 new apremilast users (0.05%), and 49 new ETN users (0.48%). Most IBD cases occurred after 6 months of exposure (82%, 55%, and 76%, respectively). After propensity score weighting, the risk of IBD was significantly greater among patients initiating an IL-17i compared to those initiating apremilast (weighted hazard ratio [HR] 3.8 [95% confidence interval (95% CI) 2.1-6.8]). No difference in the risk of IBD between new IL-17i users and new ETN users was observed (weighted HR 0.8 [95% CI 0.5-1.2]). CONCLUSION: Patients with PsO and PsA/AS who initiate treatment with an IL-17i do not have a higher risk of developing IBD when compared to patients initiating ETN who display the same severity of underlying disease. These results need to be confirmed in other large studies of patients with PsO and PsA/AS.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Etanercepte/efeitos adversos , Doenças Inflamatórias Intestinais/induzido quimicamente , Interleucina-17/antagonistas & inibidores , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Talidomida/análogos & derivados , Adulto , Idoso , Artrite Psoriásica/complicações , Estudos de Coortes , Etanercepte/uso terapêutico , Feminino , França , Humanos , Doenças Inflamatórias Intestinais/epidemiologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Espondilite Anquilosante/complicações , Talidomida/efeitos adversos , Talidomida/uso terapêutico
15.
Expert Opin Drug Saf ; 21(1): 67-81, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34232089

RESUMO

INTRODUCTION: One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED: This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION: This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.


Assuntos
Monitoramento de Medicamentos/métodos , Hansenostáticos/administração & dosagem , Talidomida/administração & dosagem , Brasil , Eritema Nodoso/tratamento farmacológico , Feminino , Humanos , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Hanseníase Virchowiana/tratamento farmacológico , Gravidez , Talidomida/efeitos adversos
16.
Cancer ; 128(7): 1467-1474, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34910297

RESUMO

BACKGROUND: This multicenter clinical trial was designed to evaluate the efficacy and safety of thalidomide (THD) in preventing oral mucositis (OM) in patients with nasopharyngeal carcinoma (NPC) undergoing concurrent chemoradiotherapy (CCRT). METHODS: Patients with locally advanced NPC were randomly assigned to either a THD group or a control group. All 160 patients received radical intensity-modulated radiotherapy plus cisplatin-based concurrent chemotherapy and basic oral hygiene guidance. Patients in the THD group received additional THD at the beginning of CCRT. The primary end points were the latency period and the incidence of OM. The secondary end points were mouth and throat soreness (MTS), weight loss, short-term efficacy, and adverse events. RESULTS: The median latency period of OM was 30 and 14 days in the THD and control groups, respectively (hazard ratio, 0.32; 95% confidence interval, 0.23-0.35; P < .0001). The incidence of OM and severe OM (World Health Organization grade 3 or higher) was significantly lower in the THD group than the control group (87.5% vs 97.5% [P = .016] and 27.5% vs 46.3% [P = .014], respectively). THD treatment also remarkably reduced the intensity of MTS and the degree of weight loss. In comparison with the control group, the incidence of nausea, vomiting, and insomnia was significantly decreased, whereas the incidence of dizziness and constipation was obviously increased in the THD group. The objective response rates 3 months after CCRT were similar between the groups. CONCLUSIONS: THD prolonged the latency period, reduced the incidence of OM, and did not affect the short-term efficacy of CCRT in patients with NPC. LAY SUMMARY: Oral mucositis is the most common complication of nasopharyngeal carcinoma during chemoradiotherapy; it decreases the patient's quality of life, and ideal mucosal protective agents are lacking. A few basic research and preclinical studies have shown that thalidomide may be an approach to ameliorating oral mucositis. The results of the current study confirm that thalidomide has a protective effect against oral mucositis in patients who have received chemoradiotherapy for nasopharyngeal carcinoma.


Assuntos
Neoplasias Nasofaríngeas , Estomatite , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Cisplatino , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Qualidade de Vida , Estomatite/etiologia , Estomatite/prevenção & controle , Talidomida/efeitos adversos
19.
JAMA Dermatol ; 157(12): 1472-1476, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757396

RESUMO

IMPORTANCE: Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM. OBJECTIVE: The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission). RESULTS: Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration. CONCLUSIONS AND RELEVANCE: In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.


Assuntos
Eritema Multiforme , Talidomida , Adolescente , Adulto , Estudos de Coortes , Eritema Multiforme/induzido quimicamente , Eritema Multiforme/diagnóstico , Eritema Multiforme/tratamento farmacológico , Feminino , Humanos , Indução de Remissão , Estudos Retrospectivos , Talidomida/efeitos adversos , Resultado do Tratamento
20.
Signal Transduct Target Ther ; 6(1): 405, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34795208

RESUMO

Thalidomide induces γ-globin expression in erythroid progenitor cells, but its efficacy on patients with transfusion-dependent ß-thalassemia (TDT) remains unclear. In this phase 2, multi-center, randomized, double-blind clinical trial, we aimed to determine the safety and efficacy of thalidomide in TDT patients. A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks, followed by an extension phase of at least 36 weeks. The primary endpoint was the change of hemoglobin (Hb) level in the patients. The secondary endpoints included the red blood cell (RBC) units transfused and adverse effects. In the placebo-controlled period, Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0 (range, 2.5 to 37.5) g/L, whereas Hb in patients treated with placebo did not significantly change. Within the 12 weeks, the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4 ± 5.0 U and 10.3 ± 6.4 U, respectively (P < 0.001). Adverse events of drowsiness, dizziness, fatigue, pyrexia, sore throat, and rash were more common with thalidomide than placebo. In the extension phase, treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9 ± 19.0 g/L, without blood transfusion. Significant increase in Hb concentration and reduction in RBC transfusions were associated with non ß0/ß0 and HBS1L-MYB (rs9399137 C/T, C/C; rs4895441 A/G, G/G) genotypes. These results demonstrated that thalidomide is effective in patients with TDT.


Assuntos
Transfusão de Eritrócitos , Talidomida/administração & dosagem , Talassemia beta/terapia , Adolescente , Adulto , Criança , Método Duplo-Cego , Feminino , Humanos , Masculino , Talidomida/efeitos adversos
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