Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Lenalidomida , Linfoma de Célula do Manto , Neoplasia Residual , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/terapia , Linfoma de Célula do Manto/patologia , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Neoplasia Residual/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/administração & dosagem , Imunoterapia/métodosRESUMO
OtezlaTM was first approved on March 21, 2014 for the treatment of psoriatic arthritis, on September 23, 2014 for moderate to severe plaque psoriasis and on July 19, 2019 for the treatment of oral ulcers associated with Behcet's disease (BD). Apremilast is an inhibitor of phosphodi-esterase-4, an enzyme involved in the pathogenesis of several dermatologic conditions. This review explores the potential utility of apremilast in the treatment of other unapproved dermatologic indications.
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Talidomida , Humanos , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Psoríase/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Comprimidos , Artrite Psoriásica/tratamento farmacológicoRESUMO
Pemphigus foliaceus (PF) is a superficial form of pemphigus. Treatment options for PF resemble pemphigus vulgaris, including glucocorticosteroids, immunosuppressive agents and rituximab et al. These treatment approaches can effectively improve the condition but may also be accompanied by high risks of side effects. Therefore, it is crucial to find a safe and effective treatment options for patients with PF. It will not only benefit/be necessary for patients who refuse glucocorticosteroids or immunosuppressive agents treatments, but also for patients who cannot be treated with glucocorticosteroids or immunosuppressive agents. Herein, we reported a case of PF that was treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. A 54-year-old woman presented with itchy erythema and erosions on the trunk for more than 1 month. The patient applied mometasonefuroate cream without improvement for a duration of two weeks. The past history of diabetes mellitus and atrophic gastritis was reported. Physical examination revealed scattered erythematous macules and erosions on the trunk. No mucosal involvement was observed. The condition was assessed by the pemphigus disease area index and numerical rating scale, with baseline scores of 7 and 8, respectively. Histopathological examination showed acantholysis and intraepithelial blister. Direct immunofluorescence revealed the presence of IgG and Complement 3 deposition between the acanthocytes with the reticular distribution. Based on enzyme-linked immunosorbent assay results, the levels of Dsg1 and Dsg3 antibodies were 28.18 and 0.26 kU/L respectively. The diagnosis of PF was made. This patient was successfully treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. The patient has continued with apremilast 30mg once daily for maintenance and no adverse events related to apremilast such as gastrointestinal side effects were observed during the 9-month follow-up period. In conclusion, apremilast therapy without systemic glucocorticosteroids nor immunosuppressive agents might provide an effective alternative to management of mild PF without obvious side effect.
Assuntos
Pênfigo , Talidomida , Humanos , Pênfigo/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Imunossupressores/uso terapêutico , Resultado do Tratamento , Glucocorticoides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêuticoRESUMO
A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Lenalidomida , Leucemia-Linfoma de Células T do Adulto , Recidiva , Indução de Remissão , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Leucemia-Linfoma de Células T do Adulto/terapia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Talidomida/análogos & derivados , Talidomida/uso terapêuticoRESUMO
BACKGROUND: To evaluate the risk of neutropenia during treatment with anti-IL-23 antibodies in patients with psoriasis. METHOD: We conducted an observational study with cohort design using MID-NET® in Japan. We identified patients with psoriasis who were newly prescribed anti-IL-23 antibodies, anti-IL-17-antibodies, adalimumab, or apremilast between January 1, 2009, and March 31, 2021. We estimated the adjusted hazard ratio (aHR) of anti-IL-23 antibodies compared to that of anti-IL-17 antibodies, adalimumab, or apremilast, for the risk of grade 2 (neutrophil count < 1,500/µL) or grade 3 (neutrophil count < 1,000/µL) neutropenia. RESULTS: Overall, 287 patients on anti-IL-23 antibodies, 189 patients on anti-IL-17 antibodies, 293 patients on adalimumab, and 540 patients on apremilast were included. Compared with anti-IL-17 antibodies, the aHR (95% confidence interval (CI)) of anti-IL-23 antibodies was 0.83 (0.27-2.51) for grade 2 and 0.40 (0.02-7.60) for grade 3 neutropenia; that when compared with adalimumab was 0.76 (0.28-2.06) for grade 2 but was not calculated for grade 3 as no cases were found; and that compared with apremilast was 3.88 (0.62-24.48) for grade 2 and 0.43 (0.02-11.63) for grade 3 neutropenia. CONCLUSION: No clear increase in the risk of neutropenia with anti-IL-23 antibodies was observed.
Assuntos
Adalimumab , Interleucina-17 , Interleucina-23 , Neutropenia , Psoríase , Talidomida , Humanos , Adalimumab/efeitos adversos , Adalimumab/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Feminino , Masculino , Neutropenia/induzido quimicamente , Neutropenia/imunologia , Neutropenia/epidemiologia , Pessoa de Meia-Idade , Japão , Adulto , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Talidomida/efeitos adversos , Talidomida/análogos & derivados , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversosRESUMO
BACKGROUND/PURPOSE: The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. METHODS: This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. RESULTS: Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. CONCLUSION: In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.
Assuntos
Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/administração & dosagem , Idoso , Feminino , Masculino , Taiwan , Estudos Retrospectivos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Adulto , RecidivaRESUMO
Introduction: Although the treatment for pemphigus vulgaris (PV) has been revolutionized by the use of rituximab combined with corticosteroids, new effective therapies with a better safety profile are needed. Observation: A 67-year-old woman was diagnosed with severe mucosal PV, which was initially misdiagnosed as atypical Behçet's disease. Following an unsuccessful colchicine treatment, significant improvement was observed upon the introduction of apremilast: reduced pain, fewer lesions, and a stabilized weight. The discontinuation of apremilast led to a rapid relapse. Retrospective analysis through anti-Dsg3 ELISA indicated a gradual decrease in antibody levels during the apremilast treatment. Discussion: Apremilast, a phosphodiesterase 4 inhibitor approved for psoriasis and Behçet's disease's related oral ulcers treatment, demonstrated its efficacy in this PV case. This is the second case report highlighting the effectiveness of apremilast for PV treatment. Apremilast's ability to upregulate cyclic adenosine monophosphate (cAMP) levels appears to contribute to the stabilization of keratinocyte adhesion. Conclusion: Apremilast may be a promising therapeutic option for the treatment of pemphigus, with an innovative mechanism of action, no induced immunosuppression, and good tolerance. It could be a good alternative to steroids, in the treatment regimen of steroids combined with rituximab.
Assuntos
Pênfigo , Talidomida , Humanos , Pênfigo/tratamento farmacológico , Pênfigo/diagnóstico , Feminino , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Idoso , Resultado do Tratamento , Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêuticoRESUMO
BACKGROUND: Central nervous system involvement in chronic lymphocytic leukemia rarely occurs, and there is no standard therapy for central nervous system involvement in chronic lymphocytic leukemia. This article aims to analyze the diagnosis and treatment of central nervous system involvement in chronic lymphocytic leukemia. CASE PRESENTATION: It reports two cases of central nervous system involvement in chronic lymphocytic leukemia describing the clinical course, therapy, and prognosis. Case 1 is a 67-year-old Asian male patient, he experienced complications with central nervous system involvement after developing resistance to ibrutinib, bendamustine, and rituximab (BR) chemotherapies. The central nervous system lesion was controlled with high-dose methotrexate combined with pomalidomide, but Richter transformation occurred several months later. Case 2 is a 62-year-old Asian female patient, she had central nervous system involvement at initial diagnosis, and bone marrow and central nervous system lesions were controlled by ibrutinib therapy. CONCLUSION: Central nervous system involvement in chronic lymphocytic leukemia is rare and can be diagnosed on the basis of clinical features, cerebrospinal fluid testing, and radiographic evaluation. Ibrutinib, pomalidomide, and other drugs that can cross the blood-brain barrier may be effective for treating central nervous system involvement in chronic lymphocytic leukemia.
Assuntos
Adenina , Leucemia Linfocítica Crônica de Células B , Piperidinas , Talidomida , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Masculino , Feminino , Pessoa de Meia-Idade , Adenina/análogos & derivados , Piperidinas/uso terapêutico , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Pirazóis/uso terapêutico , Metotrexato/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
INTRODUCTION: The treatment of multiple myeloma (MM) is evolving rapidly. Quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies have emerged as standard-of-care options for newly diagnosed MM, and numerous novel therapies have been approved for relapsed/refractory MM. However, there remains a need for novel options in multiple settings, including refractoriness to frontline standards of care. AREAS COVERED: Targeting degradation of IKZF1 and IKZF3 - Ikaros and Aiolos - through modulation of cereblon, an E3 ligase substrate recruiter/receptor, is a key mechanism of action of the IMiDs and the CELMoD agents. Two CELMoD agents, iberdomide and mezigdomide, have demonstrated substantial preclinical and clinical activity in MM and have entered phase 3 investigation. Using a literature search methodology comprising searches of PubMed (unlimited time-frame) and international hematology/oncology conference abstracts (2019-2023), this paper reviews the importance of Ikaros and Aiolos in MM, the mechanism of action of the IMiDs and CELMoD agents and their relative potency for targeting Ikaros and Aiolos, and preclinical and clinical data on iberdomide and mezigdomide. EXPERT OPINION: Emerging data suggest that iberdomide and mezigdomide have promising activity, including in IMiD-resistant settings and, pending phase 3 findings, may provide additional treatment options for patients with MM.
Assuntos
Fator de Transcrição Ikaros , Mieloma Múltiplo , Talidomida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Fator de Transcrição Ikaros/metabolismo , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Talidomida/farmacologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proteólise/efeitos dos fármacos , Terapia de Alvo Molecular , Agentes de Imunomodulação/uso terapêutico , Agentes de Imunomodulação/farmacologia , Ensaios Clínicos como Assunto , Animais , Piperidonas , Morfolinas , Receptores de Interleucina-17 , Proteínas Adaptadoras de Transdução de Sinal , FtalimidasRESUMO
BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50â¯%, while non-cholinergic contractions were inhibited up to 80â¯% and 60â¯% for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75â¯%. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.
Assuntos
Proliferação de Células , Contração Muscular , Miócitos de Músculo Liso , Bexiga Urinária , Humanos , Contração Muscular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Animais , Suínos , Masculino , Talidomida/farmacologia , Talidomida/análogos & derivados , Músculo Liso/efeitos dos fármacos , Agentes de Imunomodulação/farmacologia , Células Cultivadas , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Lenalidomida/farmacologiaRESUMO
BACKGROUND: Understanding the economic value of deucravacitinib and apremilast could assist treatment decision-making for patients with moderate to severe plaque psoriasis. OBJECTIVE: This study compared the cost per response (CPR) for US patients initiating deucravacitinib versus apremilast for moderate to severe plaque psoriasis. METHODS: A CPR model using pharmacy and administration costs was developed from a US payer perspective. Response was defined as a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at weeks 16 and 24. Long-term response was defined as the cumulative benefit over 52 weeks, measured as area under the curve; subsequent treatment was included. Scenario analyses explored varying the efficacy measure or choices of subsequent treatments and limiting discontinuation. RESULTS: The CPR for deucravacitinib versus apremilast was lower at 16 weeks (difference: -$3796 [95% confidence interval (CI): -$6140 to -$1659]) and 24 weeks (difference: -$12,784 [95% CI: -$16,674 to -$9369]). At 52 weeks, the cost per cumulative benefit was lower for patients who initiated deucravacitinib, regardless of initial treatment period duration (16 or 24 weeks). CONCLUSIONS: Scenario analyses found mainly consistent results. This study showed that the CPR is lower when initiating deucravacitinib versus apremilast in moderate to severe plaque psoriasis.
Assuntos
Análise Custo-Benefício , Psoríase , Índice de Gravidade de Doença , Talidomida , Humanos , Psoríase/tratamento farmacológico , Psoríase/economia , Estados Unidos , Talidomida/análogos & derivados , Talidomida/economia , Talidomida/uso terapêutico , Produtos Biológicos/economia , Produtos Biológicos/uso terapêutico , Resultado do Tratamento , Custos de Medicamentos , Masculino , FemininoRESUMO
Purpose: This noninterventional, cross-sectional survey estimated the prevalence and consequences of residual disease in apremilast-treated US adults with moderate to severe psoriasis. Materials and Methods: Residual disease was defined as experiencing moderate, severe, or very severe psoriasis over the past week or having ≥3% body surface area affected, despite treatment. Factors associated with residual disease and its effects on flare-ups, humanistic burden, and health care resource utilization (HCRU) were evaluated. Results: Of the 344 apremilast users (mean age, 44.9 years; female, 65.4%), 174 (50.6%) had residual disease. It was more prevalent in Black versus White participants (OR, 4.5; 95% CI, 1.6-12.2), those receiving apremilast for ≥1 versus <1 year (OR, 16.5; 95% CI, 7.9-34.4), those reporting ≥2 versus 0 to 1 flare-ups during the past 3 months (OR, 10.0; 95% CI, 5.0-20.1), and those with ≥4 versus 1 to 3 body regions affected at time of survey (OR, 8.6; 95% CI, 3.8-19.8). Participants with versus without residual disease self-reported more psoriasis flare-ups over the past 3 months (mean, 4.7 vs 0.9; p < .001) and more anxiety (89.7% vs 50.0%; p < .001) and depression (69.0% vs 23.6%; p < .001) over the past 30 days. Conclusion: Generally, participants with versus without residual disease also had significantly more comorbidities and greater HCRU.
Assuntos
Psoríase , Índice de Gravidade de Doença , Talidomida , Humanos , Psoríase/tratamento farmacológico , Psoríase/epidemiologia , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Feminino , Masculino , Estudos Transversais , Adulto , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Prevalência , Anti-Inflamatórios não Esteroides/uso terapêutico , Inquéritos e Questionários , Exacerbação dos SintomasRESUMO
Multiple myeloma (MM) is a haematological lymphoid malignancy involving tumoural plasma cells and is usually characterized by the presence of a monoclonal immunoglobulin protein. MM is the second most common haematological malignancy, with an increasing global incidence. It remains incurable because most patients relapse or become refractory to treatments. MM is a genetically complex disease with high heterogeneity that develops as a multistep process, involving acquisition of genetic alterations in the tumour cells and changes in the bone marrow microenvironment. Symptomatic MM is diagnosed using the International Myeloma Working Group criteria as a bone marrow infiltration of ≥10% clonal plasma cells, and the presence of at least one myeloma-defining event, either standard CRAB features (hypercalcaemia, renal failure, anaemia and/or lytic bone lesions) or biomarkers of imminent organ damage. Younger and fit patients are considered eligible for transplant. They receive an induction, followed by consolidation with high-dose melphalan and autologous haematopoietic cell transplantation, and maintenance therapy. In older adults (ineligible for transplant), the combination of daratumumab, lenalidomide and dexamethasone is the preferred option. If relapse occurs and requires further therapy, the choice of therapy will be based on previous treatment and response and now includes immunotherapies, such as bi-specific monoclonal antibodies and chimeric antigen receptor T cell therapy.
Assuntos
Mieloma Múltiplo , Mieloma Múltiplo/terapia , Mieloma Múltiplo/fisiopatologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Humanos , Dexametasona/uso terapêutico , Lenalidomida/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Talidomida/uso terapêutico , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Immunomodulatory imide drugs (IMiDs) play a crucial role in the treatment landscape across various stages of multiple myeloma. Despite their evident efficacy, some patients may exhibit primary resistance to IMiD therapy, and acquired resistance commonly arises over time leading to inevitable relapse. It is critical to develop novel therapeutic options to add to the treatment arsenal to overcome IMiD resistance. We designed, synthesized, and screened a new class of polyfluorinated thalidomide analogs and investigated their anti-cancer, anti-angiogenic, and anti-inflammatory activity using in vitro and ex vivo biological assays. We identified four lead compounds that exhibit potent anti-myeloma, anti-angiogenic, anti-inflammatory properties using three-dimensional tumor spheroid models, in vitro tube formation, and ex vivo human saphenous vein angiogenesis assays, as well as the THP-1 inflammatory assay. Western blot analyses investigating the expression of proteins downstream of cereblon (CRBN) reveal that Gu1215, our primary lead candidate, exerts its activity through a CRBN-independent mechanism. Our findings demonstrate that the lead compound Gu1215 is a promising candidate for further preclinical development to overcome intrinsic and acquired IMiD resistance in multiple myeloma.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Mieloma Múltiplo , Talidomida , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Humanos , Talidomida/análogos & derivados , Talidomida/farmacologia , Talidomida/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Linhagem Celular Tumoral , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Avaliação Pré-Clínica de MedicamentosRESUMO
Peptide separations that combine high sensitivity, robustness, peak capacity, and throughput are essential for extending bottom-up proteomics to smaller samples including single cells. To this end, we have developed a multicolumn nanoLC system with offline gradient generation. One binary pump generates gradients in an accelerated fashion to support multiple analytical columns, and a single trap column interfaces with all analytical columns to reduce required maintenance and simplify troubleshooting. A high degree of parallelization is possible, as one sample undergoes separation while the next sample plus its corresponding mobile phase gradient are transferred into the storage loop and a third sample is loaded into a sample loop. Selective offline elution from the trap column into the sample loop prevents salts and hydrophobic species from entering the analytical column, thus greatly enhancing column lifetime and system robustness. With this design, samples can be analyzed as fast as every 20 min at a flow rate of just 40 nL/min with close to 100% MS utilization time and continuously for as long as several months without column replacement. We utilized the system to analyze the proteomes of single cells from a multiple myeloma cell line upon treatment with the immunomodulatory imide drug lenalidomide.
Assuntos
Proteoma , Análise de Célula Única , Humanos , Proteoma/análise , Nanotecnologia , Proteômica/métodos , Cromatografia Líquida/métodos , Linhagem Celular Tumoral , Lenalidomida/farmacologia , Talidomida/farmacologia , Talidomida/análogos & derivados , Mieloma Múltiplo/metabolismoRESUMO
Introduction of fluorine into bioactive molecules has attracted much attention in drug development. For example, tetrafluorination of the phthalimide moiety of immunomodulatory drugs (IMiDs) has a strong beneficial effect on the ability to inhibit angiogenesis. The neomorphic activity of E3 ligase complexes is induced by the binding of IMiDs to cereblon. We investigated that a set of eight thalidomide analogs, comprising non- and tetrafluorinated counterparts, did not induce the degradation of neomorphic substrates (IKZF3, GSPT1, CK1α, SALL4). Hence, the antiangiogenic activity of fluorinated IMiDs was not triggered by neosubstrate degradation features. A fluorine scanning of non-traditional IMiDs of the benzamido glutarimide chemotype was performed. By measuring the endothelial cell tube formation, no angiogenesis inhibitors were identified, confirming the narrow structure-activity window of IMiD-induced antiangiogenesis.
Assuntos
Inibidores da Angiogênese , Talidomida , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Talidomida/farmacologia , Talidomida/química , Talidomida/análogos & derivados , Talidomida/síntese química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Halogenação , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismoRESUMO
We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico , Etanol , Camundongos Endogâmicos C57BL , Inibidores da Fosfodiesterase 4 , Receptores de GABA-A , Talidomida , Animais , Talidomida/farmacologia , Talidomida/análogos & derivados , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Masculino , Feminino , Etanol/farmacologia , Camundongos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Receptores de GABA-A/efeitos dos fármacos , Técnicas de Introdução de Genes , Fosforilação/efeitos dos fármacos , Ataxia/genética , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/genética , Camundongos Transgênicos , Diazepam/farmacologiaRESUMO
Targeted protein degradation is the selective removal of a protein of interest through hijacking intracellular protein cleanup machinery. This rapidly growing field currently relies heavily on the use of the E3 ligase cereblon (CRBN) to target proteins for degradation, including the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide which work through a molecular glue mechanism of action with CRBN. While CRBN recruitment can result in degradation of a specific protein of interest (e.g., efficacy), degradation of other proteins (called CRBN neosubstrates) also occurs. Degradation of one or more of these CRBN neosubstrates is believed to play an important role in thalidomide-related developmental toxicity observed in rabbits and primates. We identified a set of 25 proteins of interest associated with CRBN-related protein homeostasis and/or embryo/fetal development. We developed a targeted assay for these proteins combining peptide immunoaffinity enrichment and high-resolution mass spectrometry and successfully applied this assay to rabbit embryo samples from pregnant rabbits dosed with three IMiDs. We confirmed previously reported in vivo decreases in neosubstrates like SALL4, as well as provided evidence of neosubstrate changes for proteins only examined in vitro previously. While there were many proteins that were similarly decreased by all three IMiDs, no compound had the exact same neosubstrate degradation profile as another. We compared our data to previous literature reports of IMiD-induced degradation and known developmental biology associations. Based on our observations, we recommend monitoring at least a major subset of these neosubstrates in a developmental test system to improve CRBN-binding compound-specific risk assessment. A strength of our assay is that it is configurable, and the target list can be readily adapted to focus on only a subset of proteins of interest or expanded to incorporate new findings as additional information about CRBN biology is discovered.
Assuntos
Proteólise , Proteômica , Talidomida , Ubiquitina-Proteína Ligases , Animais , Coelhos , Proteômica/métodos , Ubiquitina-Proteína Ligases/metabolismo , Talidomida/análogos & derivados , Talidomida/farmacologia , Proteólise/efeitos dos fármacos , Feminino , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Lenalidomida/farmacologia , GravidezRESUMO
AIM: In the global phase 3 POETYK PSO-1 and PSO-2 trials, significantly greater proportions of deucravacitinib-treated patients met the coprimary endpoints (PASI 75, sPGA 0/1) at Week 16 versus placebo or apremilast-treated patients. This analysis evaluated onset of action and maintenance of response in patients randomized to deucravacitinib and placebo only. METHODS: Adults with moderate to severe plaque psoriasis at baseline were randomized 1:2:1 to oral placebo, deucravacitinib, or apremilast. Onset of action was determined through changes from baseline in mean PASI, BSA, BSA × sPGA, and DLQI. Maintenance of response was assessed using PASI 75, PASI 90, PASI 100, sPGA 0/1, and sPGA 0 response rates through Week 52 in patients who were treated continuously with deucravacitinib, crossed over from placebo to deucravacitinib at Week 16, or received deucravacitinib and achieved PASI 75 by Week 24. RESULTS: Deucravacitinib showed significantly higher increases in mean percent change from baseline in PASI versus placebo by Week 1. Significant improvement versus placebo was observed in all other efficacy measures by Week 8. Efficacy with deucravacitinib was maintained through Week 52. CONCLUSION: Deucravacitinib displayed efficacy as early as 1 week and clinical responses were maintained over 52 weeks in patients with moderate to severe plaque psoriasis.
Assuntos
Psoríase , Índice de Gravidade de Doença , Humanos , Psoríase/tratamento farmacológico , Psoríase/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Método Duplo-Cego , Resultado do Tratamento , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Talidomida/farmacologia , Estudos Cross-OverRESUMO
OBJECTIVE: Poor adherence to oral chemotherapy adversely impacts clinical outcomes and escalates overall healthcare costs. Despite barriers to medication adherence, a significant gap remains in assessing adherence to oral chemotherapy among multiple myeloma (MM) patients with lower socioeconomic status. Hence, our study aims to evaluate immunomodulator adherence in MM patients at a county hospital, primarily serving underrepresented and indigent individuals with low socioeconomic status across the greater Houston area. METHODS: Inclusion criteria composed of patients diagnosed with MM, aged at least 18 years, and treated with lenalidomide or pomalidomide-two widely used immunomodulators-for a minimum of 2 months or having two or more records of dispensation between May 2019 and May 2021. Adherence was gauged using an adjusted version of the medication possession ratio (MPR). RESULTS: Sixty-two patients were enrolled, yielding a mean MPR value of 88% (SD, ± 18.9). Of these, 43 patients (69.3%) demonstrated adherence with an MPR of ≥ 0.90. A significant difference was found in treatment duration between the adherent (mean 8.8 months; SD, ± 7.2) and non-adherent (mean 13.4 months; SD, ± 7.9) groups (p = 0.027). Notably, race/ethnicity demonstrated a significant difference (p = 0.048), driven by disparities in African American and Hispanic representation across adherence levels. CONCLUSION: In summary, our findings highlight race and treatment duration to be predictors of immunomodulator adherence among MM patients with lower socioeconomic status. Further research is imperative to devise and test innovative interventions aimed at enhancing medication adherence, thereby contributing to improved survival and healthcare quality in this population.