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1.
Physiol Behav ; 208: 112572, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31175889

RESUMO

BACKGROUND: Thalidomide is a sedative/hypnotic agent that is currently used to treat patients suffering from multiple myeloma, myelodysplastic syndromes and erythema nodosum leprosum. Although previous studies have demonstrated that thalidomide possesses anti-depressant-like properties, the exact mechanism that thalidomide exerts this effect is not understood. In this study, we used two mouse models of depression and investigated the possible role of nitric oxide (NO), NO synthase (NOS) and inducible NOS (iNOS) in the ant-depressant-like effects of thalidomide. METHODS: Male mice were injected with different doses of thalidomide intraperitoneally. In order to assess the anti-depressant-like properties of thalidomide, the immobility time of mice was assessed in the forced swimming test (FST) and tail suspension test (TST). Locomotor activity was assessed using the open-field test. To assess the role of nitric oxide, N(G)-nitro-L-arginine methyl ester (L-NAME, non-specific NOS inhibitor), aminoguanidine (selective iNOS inhibitor) or L-arginine (NO precursor) were administered intraperitoneally along with specific doses of thalidomide. RESULTS: Thalidomide (10 mg/kg) significantly reduced immobility time in FST and TST. Aminoguanidine (50 mg/kg) and L-NAME (10 mg/kg) significantly augmented the anti-immobility effects of thalidomide (5 mg/kg). L-arginine (750 mg/kg) significantly inhibited the anti-immobility effects of thalidomide (10 mg/kg). None of the treatment groups demonstrated alteration of locomotor activity. CONCLUSION: Thalidomide exerts its anti-depressant-like effects through a mechanism dependent upon NO inhibition.


Assuntos
Antidepressivos/farmacologia , Óxido Nítrico/metabolismo , Talidomida/farmacologia , Animais , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Locomoção/efeitos dos fármacos , Redes e Vias Metabólicas , Camundongos , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
2.
J Hand Surg Eur Vol ; 44(1): 88-95, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30335598

RESUMO

Thalidomide remains notorious as a result of the damage it caused to children born to mothers who used it to treat morning sickness between 1957 and 1961. The re-emergence of the drug to treat a range of conditions including erythema nodosum leprosum (a complication of leprosy) has led to a new generation of thalidomide damaged children being born in Brazil. Although thalidomide affects most of the developing tissues and organs of the body, the damage to the limbs is striking. Indeed phocomelia, the severe reduction or loss of the proximal long bones with retention of the distal hand/foot plate remains the stereotypical image of thalidomide. This review focuses on the type and range of damage thalidomide caused to the limbs, reviews current understanding of the mechanisms underlying thalidomide-induced limb malformations and outlines some of the challenges remaining in elucidating its teratogenicity.


Assuntos
Deformidades Congênitas dos Membros/induzido quimicamente , Teratógenos/farmacologia , Talidomida/efeitos adversos , Anormalidades Induzidas por Medicamentos/história , Extremidades/embriologia , Feminino , História do Século XX , História do Século XXI , Humanos , Botões de Extremidades/embriologia , Gravidez , Teratogênese/efeitos dos fármacos , Talidomida/farmacologia
3.
Curr Med Chem ; 24(25): 2736-2744, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28571559

RESUMO

Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, antiinflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNFα-mRNA, thalidomide reduces the production of TNFα by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNFα alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn';s disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease.


Assuntos
Inibidores da Angiogênese/farmacologia , Mieloma Múltiplo/irrigação sanguínea , Mieloma Múltiplo/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Humanos , Talidomida/química , Fator de Necrose Tumoral alfa/biossíntese , Fatores de Crescimento do Endotélio Vascular/biossíntese
4.
Trends Mol Med ; 23(4): 348-361, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28285807

RESUMO

Thalidomide and its derivatives are immunomodulatory drugs (IMiDs) known for their sedative, teratogenic, anti-angiogenic, and anti-inflammatory properties. Commonly used in the treatment of cancers such as multiple myeloma and myelodysplastic syndrome (MDS), IMiDs have also been used in the treatment of an inflammatory skin pathology associated with Hansen's disease/leprosy. They have also shown promise in the treatment of autoimmune disorders including systemic lupus erythmatosus (SLE) and inflammatory bowel disease (IBD). Recent structural and experimental observations have revolutionized our understanding of these properties by revealing the fundamental molecular events underpinning IMiD activity. We review these findings, their relevance to IMiD therapy in immunological disorders, and discuss how further research might unlock the vast clinical potential of these compounds.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Hanseníase/tratamento farmacológico , Talidomida/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Doenças Autoimunes/imunologia , Humanos , Hanseníase/imunologia , Modelos Moleculares , Talidomida/farmacologia
5.
Oncotarget ; 7(22): 33237-45, 2016 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-27120781

RESUMO

Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.


Assuntos
Inibidores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Embrião de Galinha/efeitos dos fármacos , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala , Talidomida/farmacologia , Peixe-Zebra/embriologia , Anormalidades Induzidas por Medicamentos/etiologia , Inibidores da Angiogênese/toxicidade , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios/toxicidade , Relação Dose-Resposta a Droga , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Neovascularização Fisiológica/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Medição de Risco , Talidomida/análogos & derivados , Talidomida/toxicidade , Fluxo de Trabalho , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
6.
Pharmacol Res ; 99: 185-93, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26117428

RESUMO

Drug repositioning refers to the development of existing drugs for new indications. These drugs may have (I) failed to show efficacy in late stage clinical trials without safety issues; (II) stalled in the development for commercial reasons; (III) passed the point of patent expiry; or (IV) are being explored in new geographic markets. Over the past decade, pressure on the pharmaceutical industry caused by the 'innovation gap' owing to rising development costs and stagnant product output have become major reasons for the growing interest in drug repositioning. Companies that offer a variety of broad platforms for identifying new indications have emerged; some have been successful in building their own pipelines of candidates with reduced risks and timelines associated with further clinical development. The business models and platforms offered by these companies will be validated if they are able to generate positive proof-of-concept clinical data for their repositioned compounds. This review describes the strategy of biomarker-guided repositioning of chemotherapeutic drugs for inflammation therapy, considering the repositioning of methylthiouracil (MTU), an antithyroid drug, as a potential anti-inflammatory reagent.


Assuntos
Reposicionamento de Medicamentos/métodos , Metiltiouracila/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antitireóideos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/análise , Doxiciclina/farmacologia , Descoberta de Drogas , Reposicionamento de Medicamentos/tendências , Eritema Nodoso/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana , Humanos , Propriedade Intelectual , Hanseníase Virchowiana/tratamento farmacológico , Periodontite/tratamento farmacológico , Fosfolipases A2 Secretórias/antagonistas & inibidores , Talidomida/farmacologia , Vasculite/tratamento farmacológico
7.
Bioorg Med Chem Lett ; 24(14): 3084-7, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24907144

RESUMO

We synthesized a series of novel dapsone-thalidomide hybrids (3a-i) by molecular hybridization and evaluated their potential for the treatment of type 2 leprosy reactions. All of the compounds had analgesic properties. Compounds 3c and 3h were the most active antinociceptive compounds and reduced acetic acid-induced abdominal constrictions by 49.8% and 39.1%, respectively. The hybrid compounds also reduced tumor necrosis factor-α levels in lipopolysaccharide-stimulated L929 cells. Compound 3i was the most active compound; at concentrations of 15.62 and 125 µM, compound 3i decreased tumor necrosis factor-α levels by 86.33% and 87.80%, respectively. In nude mice infected with Mycobacterium leprae in vivo, compound 3i did not reduce the number of bacilli compared with controls. Compound 3i did not have mutagenic effects in Salmonella typhimurium strains TA100 and TA102, with or without metabolic activation (S9 mixture). Our results indicate that compound 3i is a novel lead compound for the treatment of type 2 leprosy reactions.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Dapsona/farmacologia , Hanseníase/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Talidomida/farmacologia , Animais , Antibacterianos/química , Linhagem Celular , Dapsona/química , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Nus , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Talidomida/química
8.
Med Clin (Barc) ; 142(8): 360-4, 2014 Apr 22.
Artigo em Espanhol | MEDLINE | ID: mdl-23830554

RESUMO

Thalidomide is a synthetic glutamic acid derivative first introduced in 1956 in Germany as an over the counter medications. It was thought to be one of the safest sedatives ever produced as it was effective in small doses, was not addictive, and did not have acute side-effects such as motor impairment, but was quickly removed from market after it was linked to cases of severe birth defects. The Food and Drug Administration approved use in the treatment of erythema nodosum leprosum. Further, it was shown its effectiveness in unresponsive dermatological conditions such as actinic prurigo, adult Langerhans cell hystiocytosis, aphthous stomatitis, Behçet syndrome, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, Kaposi sarcoma, lichen planus, lupus erythematosus, melanoma, prurigo nodularis, pyoderma gangrenosum and others. In May 2006, it was approved for the treating multiple myeloma. New thalidomide analogues have been developed but lack clinical experience. This paper is a review of the history, pharmacology, mechanism of action, clinical applications and side effects of thalidomide and its analogues.


Assuntos
Talidomida/análogos & derivados , Talidomida/uso terapêutico , Anormalidades Induzidas por Medicamentos/etiologia , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Doenças do Colágeno/tratamento farmacológico , Doenças do Sistema Endócrino/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doenças Hematológicas/induzido quimicamente , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Lenalidomida , Neoplasias/tratamento farmacológico , Segunda Neoplasia Primária/induzido quimicamente , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Retirada de Medicamento Baseada em Segurança , Dermatopatias/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/farmacologia , Trombofilia/induzido quimicamente , Vasculite/tratamento farmacológico
9.
Curr Med Chem ; 20(33): 4102-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23931282

RESUMO

In the past 50 years, thalidomide has undergone a remarkable metamorphosis from a notorious drug inducing birth defects into a highly effective therapy for treating leprosy and multiple myeloma. Today, most notably, thalidomide and its analogs have shown efficacy against a wide variety of diseases, including inflammation and cancer. The mechanism underlying its teratogenicity as well as its anticancer activities has been intensively studied. This review summarizes the biological effects and therapeutic uses of thalidomide and its analogs, and the underlying mechanisms of thalidomide's action with a focus on its suppression of tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Talidomida/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia
10.
Proc Natl Acad Sci U S A ; 110(31): 12703-8, 2013 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-23858438

RESUMO

Thalidomide and its analog, Lenalidomide, are in current use clinically for treatment of multiple myeloma, complications of leprosy and cancers. An additional analog, Pomalidomide, has recently been licensed for treatment of multiple myeloma, and is purported to be clinically more potent than either Thalidomide or Lenalidomide. Using a combination of zebrafish and chicken embryos together with in vitro assays we have determined the relative anti-inflammatory activity of each compound. We demonstrate that in vivo embryonic assays Pomalidomide is a significantly more potent anti-inflammatory agent than either Thalidomide or Lenalidomide. We tested the effect of Pomalidomide and Lenalidomide on angiogenesis, teratogenesis, and neurite outgrowth, known detrimental effects of Thalidomide. We found that Pomalidomide, displays a high degree of cell specificity, and has no detectable teratogenic, antiangiogenic or neurotoxic effects at potent anti-inflammatory concentrations. This is in marked contrast to Thalidomide and Lenalidomide, which had detrimental effects on blood vessels, nerves, and embryonic development at anti-inflammatory concentrations. This work has implications for Pomalidomide as a treatment for conditions Thalidomide and Lenalidomide treat currently.


Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Neuritos/metabolismo , Neurotoxinas , Teratógenos , Talidomida/análogos & derivados , Peixe-Zebra/embriologia , Animais , Embrião de Galinha , Galinhas , Lenalidomida , Especificidade da Espécie , Talidomida/farmacologia
11.
Biomed Pharmacother ; 66(5): 323-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22770990

RESUMO

Thalidomide is used to treat a variety of diseases including erythema nodosum leprosum, an inflammatory complication of leprosy. However, this drug has severe teratogenic activity and novel thalidomide analogues might be used to treat diseases without this severe side effect. A series of diamine compounds containing two hydrolyzed phthalimide units were chosen as analogues of thalidomide and evaluated regarding their capacity to regulate the production of molecules involved in inflammatory responses. TNF-α, IL-12 and IL-10 production, and the expression of CD80 and CD86 were investigated in LPS plus IFN-γ-stimulated J774A.1 cells by ELISA and flow cytometry, respectively. The expression of TNF-α and IL-10 mRNA was analyzed by real time RT-PCR. TNF-α, IL-6, IFN-γ, CXCL9 and CXCL10 production by human peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry. Compounds 3, 6 and 9 greatly inhibited TNF-α and IL-12 production while enhancing IL-10. In addition, CD80 expression was inhibited, but not CD86. The compounds inhibited TNF-α production by PBMC more than thalidomide and also had an inhibitory effect on the production of IL-6, IFN-γ, CXCL9 and CXCL10. Levels of mRNA for TNF-α were reduced after treatment with the compounds, suggesting post- transcriptional effects. The compounds had no effect on cell viability. Our results indicate that the novel diamine compounds 3, 6 and 9 inhibit critical pro-inflammatory cytokines and stimulate IL-10, which make them attractive candidate drugs for the treatment of certain inflammatory conditions and cancer.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Talidomida/farmacologia , Animais , Antígeno B7-1/genética , Linhagem Celular , Citocinas/biossíntese , Diaminas/química , Citometria de Fluxo , Humanos , Inflamação/patologia , Interleucina-10/genética , Interleucina-10/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Talidomida/análogos & derivados
12.
BMC Res Notes ; 5: 292, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22695124

RESUMO

BACKGROUND: Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy. In this research, we use DNA microarray analysis to identify the impact of thalidomide on gene expression responses in human cells after lipopolysaccharide (LPS) stimulation. We employed a two-stage framework. Initially, we identified 1584 altered genes in response to LPS. Modulation of this set of genes was then analyzed in the LPS stimulated cells treated with thalidomide. RESULTS: We identified 64 genes with altered expression induced by thalidomide using the rank product method. In addition, the lists of up-regulated and down-regulated genes were investigated by means of bioinformatics functional analysis, which allowed for the identification of biological processes affected by thalidomide. Confirmatory analysis was done in five of the identified genes using real time PCR. CONCLUSIONS: The results showed some genes that can further our understanding of the biological mechanisms in the action of thalidomide. Of the five genes evaluated with real time PCR, three were down regulated and two were up regulated confirming the initial results of the microarray analysis.


Assuntos
Anti-Inflamatórios/farmacologia , Biologia Computacional , Perfilação da Expressão Gênica/métodos , Inflamação/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Talidomida/farmacologia , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
13.
J Drugs Dermatol ; 11(5): 626-30, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22527432

RESUMO

BACKGROUND: Leprosy was the first disease classified according to the thymus derived T-cell in the 1960s and the first disease classified by the cytokine profile as intact interferon-γ (IFN-γ) and interleukin-2 (IL2) or TH1 (tuberculoid) and deficient IFN-γ and IL2 or TH2 (lepromatous), in the 1980s. OBJECTIVE: In the present study, we set out to explore the T helper 17 (TH17) lymphocyte subset, the hallmark of T-cell plasticity, in skin biopsies from patients with erythema nodosum leprosum (ENL) who were treated with thalidomide. METHOD: RNA was extracted from paraffin embedded tissue before and after thalidomide treatment of ENL and RT-PCR was performed. RESULTS: IL17A, the hallmark of TH17, was consistently seen before and after thalidomide treatment, confirming the TH17 subset to be involved in ENL and potentially up-regulated by thalidomide. CONCLUSION: A reduction in CD70, GARP, IDO, IL17B (IL-20), and IL17E (IL-25), coupled with increases in RORγT, ARNT, FoxP3, and IL17C (IL-21) following thalidomide treatment, opens the door to understanding the complexity of the immunomodulatory drug thalidomide, which can operate as an anti-inflammatory while simultaneously stimulating cell-mediated immunity (CMI). We conclude that TH17 is involved in the immunopathogenesis of ENL and that thalidomide suppresses inflammatory components of TH17, while enhancing other components of TH17 that are potentially involved in CMI.


Assuntos
Eritema Nodoso/imunologia , Hanseníase Virchowiana/imunologia , Células Th17/imunologia , Talidomida/uso terapêutico , Adolescente , Adulto , Biópsia , Citocinas/imunologia , Eritema Nodoso/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Hansenostáticos/farmacologia , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Talidomida/farmacologia , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
14.
Eur J Pharmacol ; 670(1): 272-9, 2011 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-21925494

RESUMO

It is widely accepted that tumor necrosis factor alpha (TNF-α) plays a critical role in the development of tissue and nerve damage in leprosy and during the reactional episodes of acute inflammation. Thalidomide (N-α-phthalimidoglutarimide), a drug used to treat leprosy reaction, modulates immune response, inhibits inflammation and NF-κB activity. Here we investigated whether thalidomide inhibits NF-κB activation induced by Mycobacterium leprae, p38 and ERK1/2 MAPK activation. EMSA and supershift assays were performed to investigate NF-κB activation in response to M. leprae and its modulation following in vitro treatment with thalidomide. Luciferase assay was assayed in transfected THP-1 cells to determine NF-κB transcriptional activity. Flow cytometry and immunofluorescence were used to investigate p65 accumulation in the nucleus. Immunoblotting was used to investigate p38 and ERK1/2 phosphorylation. Following activation of PBMC and monocytes with M. leprae, the formation and nuclear localization of NF-κB complexes composed mainly of p65/p50 and p50/p50 dimers was observed. Induction of NF-κB activation and DNA binding activity was inhibited by thalidomide. The drug also reduced M. leprae-induced TNF-α production and inhibited p38 and ERK1/2 activation. Definition of the activation mechanisms in cells stimulated with M. leprae can lead to the development of new therapy applications to modulate NF-κB activation and to control the inflammatory manifestations due to enhanced TNF-α response as observed in leprosy and in leprosy reactions.


Assuntos
Hansenostáticos/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/patogenicidade , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/microbiologia , DNA/metabolismo , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Hanseníase/metabolismo , Hanseníase/microbiologia , Hanseníase/patologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-21913886

RESUMO

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomide's immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokine's tumor necrosis factor-α (TNF-α), interleukins (IL) 1ß, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-α) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.


Assuntos
Imunomodulação/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Talidomida/análogos & derivados , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Lenalidomida , Patentes como Assunto , Talidomida/farmacologia , Talidomida/uso terapêutico
16.
Toxicol Sci ; 122(1): 1-6, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21507989

RESUMO

Thalidomide was a widely used drug in the late 1950s and early 1960s for the treatment of nausea in pregnant women. It became apparent in the 1960s that thalidomide treatment resulted in severe birth defects in thousands of children. Though the use of thalidomide was banned in most countries at that time, thalidomide proved to be a useful treatment for leprosy and later, multiple myeloma. In rural areas of the world that lack extensive medical surveillance initiatives, thalidomide treatment of pregnant women with leprosy has continued to cause malformations. Research on thalidomide mechanisms of action is leading to a better understanding of molecular targets. With an improved understanding of these molecular targets, safer drugs may be designed. The thalidomide tragedy marked a turning point in toxicity testing, as it prompted United States and international regulatory agencies to develop systematic toxicity testing protocols; the use of thalidomide as a tool in developmental biology led to important discoveries in the biochemical pathways of limb development. In celebration of the Society of Toxicology's 50th Anniversary, which coincides with the 50th anniversary of the withdrawal of thalidomide from the market, it is appropriate to revisit the lessons learned from the thalidomide tragedy of the 1960s.


Assuntos
Anormalidades Induzidas por Medicamentos , Inibidores da Angiogênese/efeitos adversos , Hanseníase/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Talidomida/efeitos adversos , Animais , Relação Dose-Resposta a Droga , Ectromelia/induzido quimicamente , Feminino , Humanos , Lenalidomida , Náusea/tratamento farmacológico , Estresse Oxidativo , Gravidez , Teratógenos/farmacologia , Talidomida/análogos & derivados , Talidomida/farmacologia , Resultado do Tratamento , Estados Unidos
17.
J Drugs Dermatol ; 10(3): 274-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21369644

RESUMO

Erythema nodosum leprosum (ENL) is an inflammatory reaction that may occur in multibacillary leprosy patients, and thalidomide is the treatment of choice. Its cause and the mechanism by which thalidomide suppresses ENL are not known. In the skin lesions, im- mune complexes and split products of complement are found. The activation of complement could precipitate ENL, and thalidomide could suppress the inflammation by inhibiting the activation of complement. To determine if thalidomide could suppress the activation of complement, we first incubated normal serum with thalidomide and with M. leprae or zymosan. The amount of residual functional complement was then assessed by determining the dilution of serum required to lyses sheep erythrocytes sensitized by rabbit antibodies (CH50 Assay). M. leprae and zymosan activated complement. The residual complement activity in the serum incubated with M. leprae or with zymosan was equivalent to that incubated with M. leprae or zymosan in the presence of thalidomide, hydrolyzed thalidomide and metabolites of thalidomide. Thalidomide did not inhibit the activation of complement by zymosan, a known initiator of complement activation by the alternative pathway, or by M. leprae.


Assuntos
Ativação do Complemento/efeitos dos fármacos , Eritema Nodoso/tratamento farmacológico , Hansenostáticos/farmacologia , Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/imunologia , Talidomida/farmacologia , Animais , Proteínas do Sistema Complemento/análise , Eritema Nodoso/imunologia , Eritema Nodoso/fisiopatologia , Humanos , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/fisiopatologia , Fígado/enzimologia , Camundongos , Mycobacterium leprae/metabolismo , Coelhos , Ovinos
18.
Artigo em Japonês | MEDLINE | ID: mdl-21048383

RESUMO

Thalidomide was developed in the 1950s as a sedative drug and withdrawn in 1961 because of its teratogenic effects, but has been rediscovered as an immuno-modulatory drug. It has been administered successfully for the treatment of erythema nodosum leprosum, aphthous ulceration and cachexia in HIV disease, inflammatory bowel diseases, and several malignant diseases. The suppressive effect of thalidomide on the activation of the nuclear transcription factor NF-κB may explain these effects of thalidomide. NF-κB is retained in the cytoplasm with IκBα, and is activated by a wide variety of inflammatory stimuli including TNF, IL-1 and endotoxin followed by its translocation to the nucleus. Angiogenesis and organogenesis also require gene transcription and signal translocation. The findings shed new light on the anti-inflammatory properties of thalidomide and suggest pharmaceutical actions of thalidomide via interference of transcription mechanism. I reviewed the effects of thalidomide on auto-inflammatory diseases of childhood.


Assuntos
Fatores Imunológicos/farmacologia , Talidomida/farmacologia , Síndrome de Behçet/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , NF-kappa B/fisiologia , Sarcoidose/tratamento farmacológico , Talidomida/uso terapêutico
19.
J Drugs Dermatol ; 9(7): 814-26, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20677538

RESUMO

Thalidomide and analogues are a class of immunomodulatory drugs or IMiDS. Thalidomide was initially approved by the U.S. Food and Drug Administation for treatment of erythema nodosum in leprosy and is now approved for multiple myeloma as well. A second generation IMiD, lenalidomide, is also approved for multiple myeloma and refractory myelodysplastic syndrome. Discovery of this class of drugs has been serendipitous and empirical, as the drug targets have been unknown. In this review, the authors integrate recent identification of drug targets of IMiDS, which include the inducible form of nitric oxide synthase (iNOS), Rho GTPase and caspase-1, with the developments in the understanding of the molecular biology of human inflammatory, infectious and neoplastic skin disorders. Because thalidomide reemerged through leprosy, the original disease classified by the T cell, the authors have also emphasized advances in the understanding of T-cell subsets in human skin disorders.


Assuntos
Dermatite/tratamento farmacológico , Imunomodulação , Neoplasias Cutâneas/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Dermatite/imunologia , Eritema Nodoso/tratamento farmacológico , Eritema Nodoso/imunologia , Humanos , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/imunologia , Sarcoidose/tratamento farmacológico , Sarcoidose/imunologia , Neoplasias Cutâneas/imunologia , Talidomida/farmacologia
20.
Dermatol Clin ; 28(3): 577-86, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20510766

RESUMO

Thalidomide is approved for treating erythema nodosum leprosum and multiple myeloma, but it has also emerged as a useful treatment option for many refractory dermatologic disorders. Some of the innovative but off-label uses of thalidomide include aphthous stomatitis, Behçet's disease, lupus erythematosus, prurigo nodularis, sarcoidosis, actinic prurigo, graft-versus-host disease, Langerhans cell histiocytosis, erythema multiforme, lichen planus, Kaposi sarcoma, Jessner lymphocytic infiltrate, uremic pruritus, pyoderma gangrenosum, scleroderma, scleromyxedema, and necrobiosis lipoidica. This article reviews the background, pharmacology, and innovative uses of thalidomide in dermatology.


Assuntos
Hansenostáticos/uso terapêutico , Uso Off-Label , Dermatopatias/tratamento farmacológico , Talidomida/uso terapêutico , Terapias em Estudo , Contraindicações , Feminino , Humanos , Hansenostáticos/efeitos adversos , Hansenostáticos/farmacologia , Masculino , Talidomida/efeitos adversos , Talidomida/farmacologia
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