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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
2.
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
3.
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
4.
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
5.
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
6.
Sci Rep ; 9(1): 11413, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31388035

RESUMO

Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.


Assuntos
Acetiltransferases/genética , Proteínas Cromossômicas não Histona/genética , Predisposição Genética para Doença , Proteínas com Domínio T/genética , Teratogênese/genética , Talidomida/efeitos adversos , Fatores de Transcrição/genética , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/genética , Brasil , Linhagem Celular , Anormalidades Craniofaciais/induzido quimicamente , Anormalidades Craniofaciais/genética , Conjuntos de Dados como Assunto , Síndrome da Retração Ocular/induzido quimicamente , Síndrome da Retração Ocular/genética , Ectromelia/induzido quimicamente , Ectromelia/genética , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/genética , Comunicação Interatrial/induzido quimicamente , Comunicação Interatrial/genética , Humanos , Hipertelorismo/induzido quimicamente , Hipertelorismo/genética , Hanseníase/tratamento farmacológico , Deformidades Congênitas das Extremidades Inferiores/induzido quimicamente , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Mutação , Células-Tronco Pluripotentes , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações na Gravidez/tratamento farmacológico , Mapas de Interação de Proteínas/genética , Teratogênese/efeitos dos fármacos , Deformidades Congênitas das Extremidades Superiores/induzido quimicamente , Deformidades Congênitas das Extremidades Superiores/genética
7.
Pharmacogenomics ; 20(7): 503-516, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31124417

RESUMO

Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.


Assuntos
Citocromo P-450 CYP2C19/genética , Eritema Nodoso/tratamento farmacológico , Fator de Necrose Tumoral alfa/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Brasil/epidemiologia , Relação Dose-Resposta a Droga , Eritema Nodoso/genética , Eritema Nodoso/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Masculino , Polimorfismo Genético , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Receptores de Glucocorticoides/genética , Talidomida/administração & dosagem , Talidomida/efeitos adversos
8.
Indian J Pharmacol ; 51(1): 72-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031470

RESUMO

The distressing consequences of immunology in leprosy is the lepra reaction. Erythema nodosum leprosum(ENL) in special cases need to be managed with capsule thalidomide in varying doses. We report such a case of bradycardia in thalidomide dose dependent manner in a young ENL male.


Assuntos
Bradicardia/induzido quimicamente , Eritema Nodoso/tratamento farmacológico , Hansenostáticos/efeitos adversos , Hanseníase Virchowiana/tratamento farmacológico , Talidomida/efeitos adversos , Adulto , Relação Dose-Resposta a Droga , Humanos , Hansenostáticos/administração & dosagem , Masculino , Talidomida/administração & dosagem , Adulto Jovem
9.
Rev Soc Bras Med Trop ; 52: e20180385, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30994805

RESUMO

INTRODUCTION: Thalidomide, used to treat erythema nodosum leprosum (ENL), is associated with severe adverse events (AEs) and is highly teratogenic. METHODS: A cross-sectional study was conducted on thalidomide-treated patients with ENL. AEs and selected variables were investigated through interviews and assessment of medical records. Odds ratios with 95% confidence intervals were estimated via logistic regression. RESULTS: Peripheral neuropathy symptoms and deep vein thrombosis (DVT) were the most common AEs reported. Although women of reproductive age used contraceptives, <50% of patients reported using condoms. Polypharmacy was associated with all endpoints, except DVT. CONCLUSIONS: Pharmacovigilance is crucial to prevent harmful thalidomide-associated AEs.


Assuntos
Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Talidomida/efeitos adversos , Estudos Transversais , Escolaridade , Feminino , Humanos , Hansenostáticos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Talidomida/uso terapêutico
10.
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
11.
Rev. Soc. Bras. Med. Trop ; 52: e20180385, 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1041594

RESUMO

Abstract INTRODUCTION: Thalidomide, used to treat erythema nodosum leprosum (ENL), is associated with severe adverse events (AEs) and is highly teratogenic. METHODS: A cross-sectional study was conducted on thalidomide-treated patients with ENL. AEs and selected variables were investigated through interviews and assessment of medical records. Odds ratios with 95% confidence intervals were estimated via logistic regression. RESULTS: Peripheral neuropathy symptoms and deep vein thrombosis (DVT) were the most common AEs reported. Although women of reproductive age used contraceptives, <50% of patients reported using condoms. Polypharmacy was associated with all endpoints, except DVT. CONCLUSIONS: Pharmacovigilance is crucial to prevent harmful thalidomide-associated AEs.


Assuntos
Humanos , Masculino , Feminino , Talidomida/efeitos adversos , Hansenostáticos/efeitos adversos , Hanseníase/tratamento farmacológico , Talidomida/uso terapêutico , Estudos Transversais , Escolaridade , Hansenostáticos/uso terapêutico , Pessoa de Meia-Idade
12.
Indian J Dermatol Venereol Leprol ; 84(5): 539-546, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29998864

RESUMO

Paternally transmitted damage to offspring is recognized as a complex issue. Each parent contributes 23 chromosomes to a child; hence, it is necessary to know the effects of both maternal and paternal pre-and peri-conceptional exposure to drugs on pregnancy outcome. While there are many studies on the effects of maternal drug exposure on pregnancy outcome, literature on paternal exposure is scarce. Of late however, paternal exposure has been receiving increasing attention. We present a brief review on the safety of commonly used drugs in dermatology, focused on retinoids, immune suppressants, anti androgens and thalidomide.


Assuntos
Antagonistas de Androgênios/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Imunossupressores/administração & dosagem , Resultado da Gravidez , Reprodução/efeitos dos fármacos , Retinoides/administração & dosagem , Talidomida/administração & dosagem , Antagonistas de Androgênios/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Pai , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Gravidez , Resultado da Gravidez/epidemiologia , Reprodução/fisiologia , Retinoides/efeitos adversos , Talidomida/efeitos adversos
13.
Rev Soc Bras Med Trop ; 51(1): 99-104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29513853

RESUMO

INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.


Assuntos
Corticosteroides/administração & dosagem , Síndrome Antifosfolipídica , Hanseníase Multibacilar/imunologia , Talidomida/administração & dosagem , Corticosteroides/efeitos adversos , Adulto , Idoso , Anticorpos Antifosfolipídeos/sangue , Anticorpos Antifosfolipídeos/efeitos dos fármacos , Anticorpos Antifosfolipídeos/genética , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/genética , Ensaio de Imunoadsorção Enzimática , Fator V/análise , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Hanseníase Multibacilar/tratamento farmacológico , Hanseníase Multibacilar/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Genético , Protrombina/análise , Talidomida/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , beta 2-Glicoproteína I/sangue
14.
Rev. Soc. Bras. Med. Trop ; 51(1): 99-104, Jan.-Feb. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1041441

RESUMO

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Idoso , Talidomida/administração & dosagem , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/sangue , Corticosteroides/administração & dosagem , Hanseníase Multibacilar/imunologia , Polimorfismo Genético , Talidomida/efeitos adversos , Fator V/análise , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Protrombina/análise , Ensaio de Imunoadsorção Enzimática , Anticorpos Antifosfolipídeos/efeitos dos fármacos , Anticorpos Antifosfolipídeos/genética , Anticorpos Antifosfolipídeos/sangue , Corticosteroides/efeitos adversos , beta 2-Glicoproteína I/sangue , Tromboembolia Venosa/tratamento farmacológico , Hanseníase Multibacilar/genética , Hanseníase Multibacilar/tratamento farmacológico , Pessoa de Meia-Idade , Mutação
16.
Birth Defects Res ; 109(4): 296-299, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28398668

RESUMO

BACKGROUND: Between 1957 and 1962 thalidomide was used as a nonaddictive, nonbarbiturate sedative that also was successful in relieving the symptoms of morning sickness in early pregnancy. Infamously, thousands of babies were subsequently born with severe birth defects. The drug is used again, today, to successfully treat leprosy, and tragically, there is a new generation of thalidomide damaged children in Brazil. While the outward damage in babies has been documented, the effects of the damage upon the survivors as they grow up, the lifestyle changes and adaptations required to be made, as well as studies into ageing in survivors, has received little attention and remains understudied. METHODS: A unique multidisciplinary meeting was organized at the University of York bringing together thalidomide survivors, clinicians, scientists, historians, and social scientists to discuss the past, the current and the future implications of thalidomide. RESULTS: There is still much to learn from thalidomide, from its complex history and ongoing impact on peoples' lives today, to understanding its mechanism/s to aid future drug safety, to help identify new drugs retaining clinical benefit without the risk of causing embryopathy. CONCLUSION: For thalidomide survivors, the original impairments caused by the drug are compounded by the consequences of a lifetime of living with a rare disability, and early onset age-related health problems. This has profound implications for their quality of life and need for health and social care services. It is vital that these issues are addressed in research, and in clinical practice if thalidomide survivors are to "age well". Birth Defects Research 109:296-299, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Anormalidades Induzidas por Medicamentos/psicologia , Envelhecimento/efeitos dos fármacos , Hipnóticos e Sedativos/efeitos adversos , Imunossupressores/efeitos adversos , Hansenostáticos/efeitos adversos , Talidomida/efeitos adversos , Anormalidades Induzidas por Medicamentos/patologia , Anormalidades Induzidas por Medicamentos/fisiopatologia , Adulto , Envelhecimento/patologia , Criança , Pessoas com Deficiência/psicologia , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Imunossupressores/administração & dosagem , Estudos Interdisciplinares , Hansenostáticos/administração & dosagem , Pessoa de Meia-Idade , Farmacovigilância , Gravidez , Qualidade de Vida/psicologia , Talidomida/administração & dosagem , Reino Unido
18.
Curr Mol Med ; 17(2): 108-117, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28429672

RESUMO

Thalidomide is a teratogen that affects many organs but primarily induces limb truncations like phocomelia. Rodents are thalidomide resistant. In the 1950s, this has led to misinterpretations of animal tests and to the fatal assumption that the drug was safe for pregnant women to use against morning sickness. The result was one of the biggest scandals in medical history: 10.000 and more infants with birth defects in Europe. Nonetheless, thalidomide still has its place in modern medicine as it has strong therapeutic potential: it has been approved by the FDA for multiple myeloma and erythema nodosum leprosum, and its anti-inflammatory, immunomodulatory and antiangiogenic activities are considered in many other refractory diseases. The aim is to develop derivatives that are not teratogenic but maintain the therapeutic potential. This requires detailed knowledge about the underlying molecular mechanisms. Much progress has been made in deciphering the teratogenic mechanisms in the last decade. Here, we summarize these mechanisms, explain thalidomide resistance of rodents, and discuss possible mechanisms that could explain why the drug primarily targets the developing limb in the embryo. We also summarize the most important therapeutic mechanisms. Finally, we discuss which therapeutic and teratogenic mechanisms do and do not overlap, and if there is a chance for the development of non-teratogenic thalidomide derivatives with therapeutic potential.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/metabolismo , Medicina , Teratógenos/toxicidade , Talidomida/efeitos adversos , Anormalidades Induzidas por Medicamentos/diagnóstico , Animais , Biomarcadores , Feminino , Regulação da Expressão Gênica , Humanos , Deformidades Congênitas dos Membros , Medicina/tendências , Neovascularização Patológica/etiologia , Neovascularização Patológica/metabolismo , Estresse Oxidativo , Fenótipo , Gravidez , Transdução de Sinais
20.
Eur J Med Genet ; 60(1): 12-15, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27638330

RESUMO

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças Fetais/fisiopatologia , Hanseníase/fisiopatologia , Talidomida/efeitos adversos , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/epidemiologia , Brasil , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/fisiopatologia , Doenças Fetais/induzido quimicamente , Doenças Fetais/epidemiologia , Humanos , Hanseníase/complicações , Hanseníase/tratamento farmacológico , Teratogênese/efeitos dos fármacos , Teratógenos/toxicidade
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