RESUMO
New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients' quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.
Assuntos
Toxidermias/etiologia , Drogas em Investigação/efeitos adversos , Imunoterapia/efeitos adversos , Melanoma/terapia , Terapia de Alvo Molecular/efeitos adversos , Neoplasias Cutâneas/terapia , Terapias em Estudo/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Toxidermias/patologia , Humanos , Melanoma/patologia , Terapia de Alvo Molecular/métodos , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Neoplasias Cutâneas/patologiaAssuntos
Anticoncepcionais Orais Hormonais/uso terapêutico , Drogas em Investigação/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Anticoncepcionais Orais Hormonais/efeitos adversos , Suplementos Nutricionais , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Drogas em Investigação/efeitos adversos , Feminino , Previsões , Humanos , Síndrome do Ovário Policístico/genéticaAssuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Animais , Pesquisa Biomédica/métodos , Desenho Assistido por Computador , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Desenho de Fármacos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/química , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/químicaRESUMO
The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis. This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet medical needs. Several compounds are in the pipeline of pharmaceutical industries and are being studied in phase II trials, but only a few (obeticholic acid, elafibranor) have started phase III trials. This concise review is intended to offer a systematic analysis of the most promising therapeutic intervention in NASH. In conclusion, there is reasonable expectation that drug may help curb the burden of NASH, and we look forward to obtaining solid data on their long-term safety and effectiveness. However, we should not forget that behavioral interventions remain a mandatory background treatment, able to stop disease progression in compliant overweight/ obese patients, with results that compare favorably with - and add to - the beneficial effects of drug treatment.
Assuntos
Drogas em Investigação/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Drogas em Investigação/efeitos adversos , Humanos , Estilo de Vida , Fígado/metabolismo , Fígado/patologia , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fatores de Risco , Comportamento de Redução do Risco , Resultado do TratamentoRESUMO
Atrial fibrillation (AF) is associated with an increased risk of stroke. AF-related strokes cause greater disability and mortality than those in patients without AF, and are associated with a significant clinical and economic burden in Mexico. Antithrombotic therapy reduces stroke risk in patients with AF and is recommended for all patients except those classified as having a low stroke risk. However, its use is suboptimal all around the world; one study showed that only 4 % of Mexican patients with AF who presented with ischemic stroke were in the therapeutic range for anticoagulation. Vitamin K antagonists (VKAs) such as warfarin or acenocoumarin have long been the only oral anticoagulants for stroke prevention in AF. Although effective, VKAs have disadvantages, including the need for regular coagulation monitoring and dose adjustment. Interactions with numerous common medications and foods contribute to the risk of serious bleeding and thrombotic events in VKA-treated patients. Thus novel oral anticoagulants (NOACs), more properly called direct oral anticoagulants (DOACs), such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban (not available in Mexico), have been developed. These offer the convenience of fixed-dose treatment without the need for monitoring, and have few drug or food interactions. Pivotal phase III trials have demonstrated that these agents are at least as effective as warfarin in preventing stroke and are associated with a reduced risk of intracranial hemorrhage. With apixaban approved in Mexico in April 2013, clinicians now have the choice of three novel DOACs as alternatives to warfarin. However, it is yet to be established which of these agents should be the first choice, and treatment decisions are likely to depend on the individual patient's characteristics.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Medicina Baseada em Evidências , Medicina de Precisão , Acidente Vascular Cerebral/prevenção & controle , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antitrombinas/uso terapêutico , Fibrilação Atrial/fisiopatologia , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Dabigatrana/uso terapêutico , Esquema de Medicação , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/uso terapêutico , Humanos , México , Guias de Prática Clínica como Assunto , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Fatores de Risco , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Vitamina K/antagonistas & inibidores , Vitamina K/metabolismoAssuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Potenciais de Ação , Animais , Antiarrítmicos/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Drogas em Investigação/efeitos adversos , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Terapia de Alvo Molecular , Resultado do TratamentoRESUMO
This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with ≥68% of subjects achieving hSBA titers ≥5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever (≥38.0°C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885].
Assuntos
Drogas em Investigação/efeitos adversos , Vacinas Meningocócicas/efeitos adversos , Vacinas Meningocócicas/imunologia , Adolescente , Atividade Bactericida do Sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Drogas em Investigação/administração & dosagem , Feminino , Voluntários Saudáveis , Humanos , Masculino , Vacinas Meningocócicas/administração & dosagem , Placebos/administração & dosagem , Vacinas Combinadas/administração & dosagem , Vacinas Combinadas/efeitos adversos , Vacinas Combinadas/imunologiaAssuntos
Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Drogas em Investigação/uso terapêutico , Acessibilidade aos Serviços de Saúde/legislação & jurisprudência , Direitos do Paciente/legislação & jurisprudência , Assistência Terminal/legislação & jurisprudência , Terapias em Estudo , Aprovação de Equipamentos/legislação & jurisprudência , Aprovação de Drogas/legislação & jurisprudência , Drogas em Investigação/efeitos adversos , Humanos , Medição de Risco , Assistência Terminal/métodos , Terapias em Estudo/efeitos adversos , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
INTRODUCTION: Drug toxicology is central to drug development. Despite improvements in our understanding of molecular and cell biology, high attrition rates in drug development continue, speaking to the difficulties of developing unequivocal methods to predict the efficacy and safety of drugs. AREAS COVERED: In this review, the authors provide a short overview of the 'omics' technologies that have been applied to drug toxicology, with an emphasis on a whole-genome DNA methylation analysis. Preliminary results from DNA methylation analysis technologies that may help in predicting response and efficacy of a drug are discussed. EXPERT OPINION: Currently, we cannot fully contextualize the application of epigenetics to the field of drug toxicology, as there are still many challenges to overcome before DNA methylation-based biomarkers can be effectively used in drug development. Comprehensive whole-genome DNA methylation methods for a unbiased analysis based on either microarray or next-generation sequencing need to be evaluated in drug toxicology in an intensive and systematic manner. Additionally, robust analysis systems need to be developed to decode the large amounts of data generated by whole-genome DNA methylation analyses as well as protocol standardization for reproducibility to develop meaningful databases that can be applied to drug toxicology.
Assuntos
Metilação de DNA/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Drogas em Investigação/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos/tendências , Epigenômica/métodos , Epigenômica/tendências , Humanos , Metabolômica/métodos , Metabolômica/tendências , Farmacologia Clínica/métodos , Farmacologia Clínica/tendências , Proteômica/métodos , Proteômica/tendênciasRESUMO
PURPOSE OF REVIEW: Improved understanding of the pathogenesis of lower urinary tract symptoms (LUTS) has led to the development of new drugs to treat male LUTS. The review aims to give an overview to the new drugs and to compounds in the pipeline. RECENT FINDINGS: Tadalafil, a phosphodiesterase type 5 inhibitor, is a drug newly approved for the treatment of male LUTS and a true new challenger for the current standard treatment with alpha1 blockers, particularly in men with concomitant erectile dysfunction. Botulinum toxin and mirabegron, a beta3 agonist, might be of value in treating persistent storage LUTS. Intraprostatic injections with botulinum toxin, NX-1207, and PRX302, need further evaluation but might be treatment alternatives in the future. Similarly, vitamin D3 receptor analogues (e.g., elocalcitol), gonadotropin-releasing hormone antagonists (e.g., cetorelix), and modulators of the cannabinoid system (e.g., fatty acid amide hydrolase inhibitors) need further evaluation in clinical studies. Other compounds, such as transient receptor potential vanilloid antagonists, Rho kinase inhibitors, purinergic receptor blockers, and endothelin targeting drugs, are still at experimental stages. SUMMARY: Novel drugs for the treatment of male LUTS have been introduced recently. Clinical practice along with further trials will have to prove their value, along with other compounds that are still in their early phase of development.