Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 649
Filtrar
Mais filtros


Intervalo de ano de publicação
1.
Cien Saude Colet ; 26(9): 4233-4242, 2021 Sep.
Artigo em Português, Inglês | MEDLINE | ID: mdl-34586274

RESUMO

Drug utilization research to describe the control of thalidomide in Brazil and its use in Minas Gerais state. An online questionnaire was sent to the Brazilian federative units to collect data concerning distribution, dispensation, user registration, and thalidomide adverse events. Distribution (2011-2018) and dispensing (2015-2018) data in Minas Gerais were obtained through the pharmaceutical care management system. Analysis of variance and Tukey test were used for data comparisons. Of the 16 participating federative units, 100% and 50% used electronic distribution and dispensing systems, respectively, and about 43% registered users. Adverse event reporting systems were scarce. A 44% reduction was observed in the distribution in Minas Gerais for the period. Dispensing remained constant (mean 0.0004 DDD/1,000 inhabitants/day) and occurred mainly for erythema nodosum leprosum and multiple myeloma. Off-label use (2.2%) was increasing. Most users were male (mean age 56 years) and thirty percent of women were of childbearing age. Thalidomide surveillance is a public health challenge. Despite the increased use and mandatory control, there is no national standardization, and adverse event reporting is incipient.


Assuntos
Uso de Medicamentos , Talidomida , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Talidomida/efeitos adversos
3.
Biochem Pharmacol ; 192: 114727, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390739

RESUMO

Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED50 values of 44.9 and 23.5 mg/kg, and Emax values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1ß and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and ß-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and ß-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of ß-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum, and preferred or selective µ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/ß-endorphin expression, rather than downregulation of TNFα expression.


Assuntos
Interleucina-10/biossíntese , Microglia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Talidomida/uso terapêutico , beta-Endorfina/biossíntese , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interleucina-10/agonistas , Masculino , Microglia/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Talidomida/farmacologia , beta-Endorfina/agonistas
4.
PLoS Negl Trop Dis ; 15(7): e0009635, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34319982

RESUMO

BACKGROUND: Protective effects of Bacillus Calmette-Guérin (BCG) vaccination and clofazimine and dapsone treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. Patients at risk for leprosy represent an interesting model for assessing the effects of these therapies on the occurrence and severity of coronavirus disease 2019 (COVID-19). We assessed the influence of leprosy-related variables in the occurrence and severity of COVID-19. METHODOLOGY/PRINCIPAL FINDINGS: We performed a 14-month prospective real-world cohort study in which the main risk factor was 2 previous vaccinations with BCG and the main outcome was COVID-19 detection by reverse transcription polymerase chain reaction (RT-PCR). A Cox proportional hazards model was used. Among the 406 included patients, 113 were diagnosed with leprosy. During follow-up, 69 (16.99%) patients contracted COVID-19. Survival analysis showed that leprosy was associated with COVID-19 (p<0.001), but multivariate analysis showed that only COVID-19-positive household contacts (hazard ratio (HR) = 8.04; 95% CI = 4.93-13.11) and diabetes mellitus (HR = 2.06; 95% CI = 1.04-4.06) were significant risk factors for COVID-19. CONCLUSIONS/SIGNIFICANCE: Leprosy patients are vulnerable to COVID-19 because they have more frequent contact with SARS-CoV-2-infected patients, possibly due to social and economic limitations. Our model showed that the use of corticosteroids, thalidomide, pentoxifylline, clofazimine, or dapsone or BCG vaccination did not affect the occurrence or severity of COVID-19.


Assuntos
COVID-19/epidemiologia , COVID-19/terapia , Hanseníase/tratamento farmacológico , Hanseníase/epidemiologia , Corticosteroides/uso terapêutico , Vacina BCG/administração & dosagem , Brasil/epidemiologia , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , Teste para COVID-19 , Clofazimina/uso terapêutico , Estudos de Coortes , Dapsona/uso terapêutico , Humanos , Pentoxifilina/uso terapêutico , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2/isolamento & purificação , Análise de Sobrevida , Talidomida/uso terapêutico
5.
Ther Innov Regul Sci ; 55(6): 1155-1164, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34331266

RESUMO

Thalidomide (α-phthalimidoglutaride) was marketed in the 1950s and early 1960s; it was promoted as a sedative-hypnotic agent with minimal hangover. It was available in some countries as an over-the-counter medicine. Publications reporting profound teratogenic effects with thalidomide brought about major revisions to the monitoring of the safety of medicines. As a consequence of previously unrecognised teratogenic effects, it has been estimated that over 12,000 children were born with a range of defects and disabilities, including severe congenital anomalies. Notably, it has been hypothesised that around 40% of babies with thalidomide-induced malformations born during the 1950s and 1960s died in the neonatal period. The commonest causes of death were atresia of the small bowel, cardiac or renal malformations. Nevertheless, phocomelia (as a typical manifestation of thalidomide´s teratogenic effects) has been reported once again after thalidomide was approved for use in areas where leprosy is endemic. As a result, thalidomide embryopathy remains an important topic in countries such as Brazil. Nowadays thalidomide is approved around the world for the treatment of a wide range of conditions, including leprosy, Crohn's disease, multiple myeloma, and certain malignant solid tumours. Second-generation immunmodulatory drugs including lenalidomide and pomalidomide have received approval for use in the management of various forms of neoplastic disease. Based on clinical experience with thalidomide and its derivatives, learnings have been transferred to further research on a subset of substituted phthalimides each of which has a high risk of causing teratogenic effects. This group of phthalimides is classified within regulatory science as human teratogens. In order to gain approval, a Pregnancy Prevention Programme (PPP), along with a Controlled Distribution System (CDS) is required. The challenges of PPPs in particular for a generic manufacturer have been described, including Raising of awareness, and education; Special aspects of data collection and evaluation; Ethically and socially relevant aspects, and Utilising existing information technology and infrastructure. This paper highlights the risks of unplanned pregnancies, provides information on the regulatory background, and regulatory expectations. Our aim is to provide insights and practical learnings that have impacted operational risk management with the teratogenic phthalimides. Opportunities are presented that may support the implementation of harmonised approaches for PPP and CDS using existing IT-systems across countries and companies.


Assuntos
Teratógenos , Talidomida , Criança , Feminino , Humanos , Recém-Nascido , Lenalidomida , Ftalimidas , Gravidez , Teratógenos/toxicidade , Talidomida/análogos & derivados
6.
J Oncol Pharm Pract ; 27(3): 673-678, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33249990

RESUMO

BACKGROUND: Thalidomide is the most teratogenic human medicine ever marketed and was associated with birth defects in approximately 10,000 children in the 1960s. The pharmacological effects of thalidomide are attributed to its anti-angiogenic, anti-inflammatory and modulatory effect on cytokines principally tumor necrosis factor-α, while the teratogenic effects are linked to two molecular targets, namely cereblon and tubulin. Teratogenicity is the gravest adverse effect of thalidomide depending on the dose and time of exposure. Nonetheless, with System for Thalidomide Education and Prescribing Safety program, the possibility of teratogenicity can be completely avoided. The sensitive period during pregnancy for thalidomide teratogenicity in humans is approximately 20-34 days after fertilization. METHODS: Relevant articles were identified from Google scholar and PubMed (MEDLINE) using different search strategies. CONCLUSION: Clinical trials showed that thalidomide has been found effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy refractory endometrial cancer and pancreatic cancer, which can suggest its future therapeutic potential in cancer treatment. Thalidomide is also used in the treatment of inflammatory skin disorders and has shown promising effect in the treatment of autoimmune disorders and inflammatory bowel disease. Despite thalidomide being a renowned teratogen and neurotoxin, it has been successfully repositioned and FDA approved for the treatment of erythema nodosum leprosum and multiple myeloma under strict control.


Assuntos
Reposicionamento de Medicamentos/métodos , Imunossupressores/administração & dosagem , Teratógenos , Talidomida/administração & dosagem , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Reposicionamento de Medicamentos/tendências , Feminino , Humanos , Recém-Nascido , Neoplasias Renais/diagnóstico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Gravidez , Talidomida/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
8.
PLoS Negl Trop Dis ; 14(10): e0008678, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33035210

RESUMO

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, is a multi-system immune-mediated complication in patients with multibacillary leprosy, frequently associated with chronicity and recurrences. Management of ENL requires high doses of oral corticosteroids, which may not be universally effective and pose serious adverse effects. Thalidomide has proven to be a steroid-sparing agent and is useful in controlling the reactions. However, many centres do not employ it in outpatient settings due to adverse effects and teratogenicity risk. Hence, we studied the feasibility of treating ENLs and reported the therapeutic outcome.This is a five-year record-based analysis of ENL leprosy patients treated with thalidomide, includingdescriptive statistics of demographic variables. Clinical characteristics were stratified by treatment compliance status (yes/no). Incidence rates and rate ratios for recovery stratified by bacillary index, type of ENL presentation and MDT treatment status were calculated.Out of 102 ENL patients treated with thalidomide, 68 (66.7%) were compliant and improved. Among them, ENL recurrence was noted in 11(16.2%) patients. The commonest thalidomide side effect was pedal oedema (73.5%). Patients with bacillary index (BI) less than or equal to 4.0 had a 37% increase in the incidence of recovery. Patients with acute ENL were almost twice as likely to recover as those with chronic ENL. Also, the improvement was two and a half times greater among those who completed MDT as compared to those on MDT. The study showed that thalidomide treatment for patients with ENL is possible in outpatientclinics. We also successfully prevented pregnancies to a larger extent through counselling for contraception.We observed that early institution of thalidomide induces faster remission and prevents ENL recurrence.


Assuntos
Eritema Nodoso/tratamento farmacológico , Hansenostáticos/efeitos adversos , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Adulto , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
9.
Rev Soc Bras Med Trop ; 53: e20190454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32935774

RESUMO

INTRODUCTION: Thalidomide is an anti- tumor necrosis factor alpha (TNF-a) drug used mainly in the management of moderate to severe form of Erythema Nodosum Leprosum (ENL). Because of its teratogenic potential it has to be used under proper supervision. Our critical analysis tries to look into the rationale with which it has been used by means of case reports on lepra reaction. METHODS: We looked for the case reports between December 2005 to June 2019 in databases like Pubmed, Embase and other relevant resources. We used search words like "erythema nodosum leprosum(ENL)", "thalidomide", "case report" in different combinations to get relevant reports that focus on thalidomide usage atleast once at any time point during management. The information extracted were indication of thalidomide use, dose, response, outcome, complication if any, along with all the demographic details and geographical distribution. RESULTS: We found 41 case reports eligible for analysis.The information was critically evaluated. From the analysis it was found that 7 of the case report mentioned the exact indication, 4 case report showed irrational use of thalidomide in the case of neuritis without use of steroids, 7 showed proper use of Clofazimine prior to thalidomide initiation, 26 case report showed case report of rationale dose range and in 4 case reports clofazimine was used prior to thalidomide along with the rational dose of thalidomide. CONCLUSIONS: This analysis helps to guide the rationale use of thalidomide focussing on few important points that anyone should keep in mind while managing a case of ENL.


Assuntos
Eritema Nodoso , Hanseníase Virchowiana , Hanseníase Multibacilar , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Hansenostáticos , Masculino , Pessoa de Meia-Idade , Talidomida , Adulto Jovem
10.
PLoS Negl Trop Dis ; 14(8): e0008329, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760161

RESUMO

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


Assuntos
Hanseníase/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Anormalidades Induzidas por Medicamentos/epidemiologia , Brasil/epidemiologia , Eritema Nodoso/tratamento farmacológico , Feminino , Humanos , Hansenostáticos/efeitos adversos , Hansenostáticos/uso terapêutico , Hanseníase/epidemiologia , Hanseníase Virchowiana/tratamento farmacológico , Masculino , Gravidez
11.
Front Immunol ; 11: 1248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574274

RESUMO

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


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Talidomida/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Progressão da Doença , Humanos , Inflamação/tratamento farmacológico , Inflamação/etiologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia
12.
Biomed Pharmacother ; 127: 110114, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32304852

RESUMO

Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the pleiotropic properties of this class of drugs, including their anti-inflammatory, antiangiogenic and immunomodulatory activities. Based on their notable activities, thalidomide and its analogues, lenalidomide and pomalidomide, have been repurposed to treat erythema nodosum leprosum, multiple myeloma and other haematological malignancies. Thalidomide analogues were recently found to hijack CRL4CRBN ubiquitin ligase to target a number of cellular proteins for ubiquitination and proteasomal degradation. Thalidomide-mediated degradation of SALL4 and p63, transcription factors essential for embryonic development, very likely plays a critical role in thalidomide embryopathy. In this review, we provide a brief retrospective summary of thalidomide-induced teratogenesis, the mechanism of thalidomide activity, and the latest advances in the molecular mechanism of thalidomide-induced birth malformations.


Assuntos
Teratogênese/fisiologia , Talidomida/efeitos adversos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia , Humanos
13.
Immunohorizons ; 4(2): 47-56, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034084

RESUMO

Erythema nodosum leprosum (ENL) is an inflammatory complication in leprosy. Yet, the involvement of ENL neutrophils in the inflammatory response against Mycobacterium leprae remains poorly explored. Our primary aim was to investigate the utility of the surface expression of neutrophil IL-10R1 as an ENL biomarker and, secondarily, to evaluate whether leprosy or healthy M. leprae-stimulated neutrophils produce cytokines and are able to respond to IL-10. We, in this study, describe a subpopulation of circulating neutrophils of ENL patients that exclusively expressed IL-10R1, providing evidence that IL-10R1+ neutrophils are present in ENL lesions. It was also found that ENL neutrophils, but not those of nonreactional leprosy controls, were able to secret detectable levels of TNF ex vivo and the addition of IL-10 blocked TNF release. It was likewise observed that M. leprae-stimulated, healthy neutrophils expressed IL-10R1 in vitro, and ENL-linked cytokines were released by M. leprae-cultured neutrophils in vitro. Moreover, consistent with the presence of a fully functional IL-10R, the addition of IL-10 prevented the release of M. leprae-induced cytokines. Most importantly, dead M. leprae revealed its superior capacity to induce CCL4 and IL-8 in primary neutrophils over live Mycobacterium, suggesting that M. leprae may hamper the inflammatory machinery as an immune escape mechanism.


Assuntos
Eritema Nodoso/imunologia , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Interleucina-10/farmacologia , Hanseníase Virchowiana/imunologia , Neutrófilos/metabolismo , Pele/imunologia , Adulto , Células Cultivadas , Citocinas/metabolismo , Eritema Nodoso/tratamento farmacológico , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Hanseníase Virchowiana/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/microbiologia , Talidomida/uso terapêutico , Adulto Jovem
14.
Australas J Dermatol ; 61(2): e234-e237, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31984474

RESUMO

A leprosy reaction resembling Sweet syndrome was first described in 1987. This cutaneous manifestation can be classified as the type 2 reaction which arises from antigen-antibody interaction. It can occur in patients with diagnosed or undiagnosed leprosy, and men with borderline leprosy tend to exhibit this type of reaction. Triggering factors may include WHO multibacillary treatment or prescription antibiotics. Several reports of this clinical phenomenon have been published, making physicians consider it as part of this spectrum of the disease. Treatment regime can include systemic steroids and thalidomide.


Assuntos
Hansenostáticos/uso terapêutico , Hanseníase/diagnóstico , Síndrome de Sweet/diagnóstico , Antibacterianos/uso terapêutico , Humanos , Hanseníase/complicações , Hanseníase/tratamento farmacológico , Masculino , Síndrome de Sweet/complicações , Síndrome de Sweet/tratamento farmacológico , Talidomida/uso terapêutico
15.
Br J Dermatol ; 182(4): 837-838, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31621065
16.
J Clin Pharmacol ; 60(1): 67-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31392755

RESUMO

A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination. Inclusion of MM as a covariate on apparent clearance (CL/F) accounted for 4.4% of the interindividual variability (IIV) of CL/F. Body weight as a covariate on CL/F and apparent volume of distribution (V/F) also improved model fitting slightly, accounting for 7.2% and 20% of IIV, respectively. Although inclusion of body weight and MM as covariates of CL/F and body weight on V/F improved the goodness of fit of the model in a statistically significant manner, the impact of this difference in CL/F is not considered clinically relevant. Other factors such as age, sex, race, creatinine clearance, and alanine transaminase had no effect on thalidomide pharmacokinetics. MM, HIV, and Hansen's disease have no clinically relevant effect on thalidomide disposition relative to healthy volunteers.


Assuntos
Infecções por HIV/metabolismo , Imunossupressores/farmacocinética , Hanseníase/metabolismo , Mieloma Múltiplo/metabolismo , Talidomida/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Infecções por HIV/tratamento farmacológico , Voluntários Saudáveis , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Hanseníase/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Mieloma Múltiplo/tratamento farmacológico , Talidomida/administração & dosagem , Talidomida/sangue , Talidomida/uso terapêutico , Adulto Jovem
17.
Br J Dermatol ; 182(4): 1034-1037, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31218666

RESUMO

Erythema nodosum leprosum (ENL) is a severe immune reaction commonly encountered as a complication in patients with multibacillary leprosy. Management of chronic ENL in leprosy is challenging and necessitates the use of systemic immunosuppressants, including corticosteroids and thalidomide. No single drug is universally effective and most current therapeutic agents carry a significant risk of systemic toxicity. Apremilast is an orally effective phosphodiesterase-4 inhibitor with a potent immunomodulatory action and is clinically effective in inflammatory conditions like chronic plaque psoriasis. We report two patients with poorly controlled chronic ENL, despite the use of multiple therapeutic agents. Both patients demonstrated significant clinical improvement with apremilast, without any adverse effects, thereby suggesting its potential as a novel therapeutic option in chronic ENL. What's already known about this topic? Erythema nodosum leprosum (ENL) is an immune-mediated reaction in patients with multibacillary leprosy, with chronicity and recurrences frequently reported. Management of chronic ENL requires systemic immunosuppressants like corticosteroids, which may not be universally effective and carry a risk of serious toxicity. Apremilast is an oral immunomodulator with good efficacy in inflammatory conditions like chronic plaque psoriasis. What does this study? Apremilast may be an effective therapeutic agent in patients with chronic ENL.


Assuntos
Eritema Nodoso , Hanseníase Virchowiana , Hanseníase Multibacilar , Eritema Nodoso/tratamento farmacológico , Humanos , Hanseníase Virchowiana/tratamento farmacológico , Talidomida/análogos & derivados
18.
Rev. Soc. Bras. Med. Trop ; 53: e20190454, 2020. tab, graf
Artigo em Inglês | LILACS, ColecionaSUS, SES-SP | ID: biblio-1136901

RESUMO

Abstract INTRODUCTION: Thalidomide is an anti- tumor necrosis factor alpha (TNF-a) drug used mainly in the management of moderate to severe form of Erythema Nodosum Leprosum (ENL). Because of its teratogenic potential it has to be used under proper supervision. Our critical analysis tries to look into the rationale with which it has been used by means of case reports on lepra reaction. METHODS: We looked for the case reports between December 2005 to June 2019 in databases like Pubmed, Embase and other relevant resources. We used search words like "erythema nodosum leprosum(ENL)", "thalidomide", "case report" in different combinations to get relevant reports that focus on thalidomide usage atleast once at any time point during management. The information extracted were indication of thalidomide use, dose, response, outcome, complication if any, along with all the demographic details and geographical distribution. RESULTS: We found 41 case reports eligible for analysis.The information was critically evaluated. From the analysis it was found that 7 of the case report mentioned the exact indication, 4 case report showed irrational use of thalidomide in the case of neuritis without use of steroids, 7 showed proper use of Clofazimine prior to thalidomide initiation, 26 case report showed case report of rationale dose range and in 4 case reports clofazimine was used prior to thalidomide along with the rational dose of thalidomide. CONCLUSIONS: This analysis helps to guide the rationale use of thalidomide focussing on few important points that anyone should keep in mind while managing a case of ENL.


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Idoso , Adulto Jovem , Hanseníase Virchowiana , Eritema Nodoso , Hanseníase Multibacilar , Talidomida , Hansenostáticos , Pessoa de Meia-Idade
19.
Adv Rheumatol ; 59(1): 52, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779703

RESUMO

INTRODUCTION: Antiphospholipid antibodies (aPL) are described in individuals with leprosy without the clinical features of antiphospholipid antibody syndrome (APS), a condition involving thromboembolic phenomena. We have described the persistence of these antibodies for over 5 years in patients with leprosy after specific treatment. OBJECTIVES: To determine whether epidemiological, clinical and immunological factors played a role in the long-term persistence of aPL antibodies in leprosy patients after multidrug therapy (MDT) had finished. METHODS: The study sample consisted of 38 patients with a diagnosis of leprosy being followed up at the Dermatology and Venereology Outpatient Department at the Alfredo da Matta Foundation (FUAM) in Manaus, AM. ELISA was used to detect anticardiolipin (aCL) and anti-ß2 glycoprotein I (anti-ß2GPI) antibodies. Patients were reassessed on average of 5 years after specific treatment for the disease (MDT) had been completed. RESULTS: Persistence of aPL antibodies among the 38 leprosy patients was 84% (32/38), and all had the IgM isotype. Mean age was 48.1 ± 15.9 years, and 23 (72.0%) were male. The lepromatous form (LL) of leprosy was the most common (n = 16, 50%). Reactional episodes were observed in three patients (9.4%). Eighteen (47.37%) were still taking medication (prednisone and/or thalidomide). Mean IgM levels were 64 U/mL for aCL and 62 U/mL for anti-ß2GPI. In the multivariate binary logistic regression the following variables showed a significant association: age (p = 0.045, OR = 0.91 and CI 95% 0.82-0.98), LL clinical presention (p = 0.034; OR = 0.02 and CI 95% = 0.0-0.76) and bacterial index (p = 0.044; OR = 2.74 and CI 95% = 1.03-7.33). We did not find association between prednisone or thalidomide doses and positivity for aPL (p = 0.504 and p = 0.670, respectively). No differences in the variables vascular thrombosis, pregnancy morbidity, diabetes, smoking and alcoholism were found between aPL-positive and aPL-negative patients. CONCLUSION: Persistence of positivity for aPL antibodies was influenced by age, clinical presentation and bacterial index. However, further studies are needed to elucidate the reason for this persistence, the role played by aPL antibodies in the disease and the B cell lineages responsible for generation of these antibodies.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Hanseníase/imunologia , beta 2-Glicoproteína I/imunologia , Adulto , Anticorpos Anticardiolipina/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Hansenostáticos/uso terapêutico , Hanseníase/sangue , Hanseníase/tratamento farmacológico , Hanseníase Multibacilar/sangue , Hanseníase Multibacilar/tratamento farmacológico , Hanseníase Multibacilar/imunologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Talidomida/uso terapêutico
20.
PLoS Negl Trop Dis ; 13(9): e0007368, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504035

RESUMO

Up to 50% of patients with the multibacillary form of leprosy are expected to develop acute systemic inflammatory episodes known as type 2 reactions (T2R), thus aggravating their clinical status. Thalidomide rapidly improves T2R symptoms. But, due to its restricted use worldwide, novel alternative therapies are urgently needed. The T2R triggering mechanisms and immune-inflammatory pathways involved in its pathology remain ill defined. In a recent report, we defined the recognition of nucleic acids by TLR9 as a major innate immunity pathway that is activated during T2R. DNA recognition has been described as a major inflammatory pathway in several autoimmune diseases, and neutrophil DNA extracellular traps (NETs) have been shown to be a prime source of endogenous DNA. Considering that neutrophil abundance is a marked characteristic of T2R lesions, the objective of this study was to investigate NETs production in T2R patients based on the hypothesis that the excessive NETs formation would play a major role in T2R pathogenesis. Abundant NETs were found in T2R skin lesions, and increased spontaneous NETs formation was observed in T2R peripheral neutrophils. Both the M. leprae whole-cell sonicate and the CpG-Hlp complex, mimicking a mycobacterial TLR9 ligand, were able to induce NETs production in vitro. Moreover, TLR9 expression was shown to be higher in T2R neutrophils, suggesting that DNA recognition via TLR9 may be one of the pathways triggering this process during T2R. Finally, treatment of T2R patients with thalidomide for 7 consecutive days resulted in a decrease in all of the evaluated in vivo and ex vivo NETosis parameters. Altogether, our findings shed light on the pathogenesis of T2R, which, it is hoped, will contribute to the emergence of novel alternative therapies and the identification of prognostic reactional markers in the near future.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata , Hanseníase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Mycobacterium leprae/patogenicidade , Neutrófilos/patologia , Talidomida/administração & dosagem , Talidomida/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA