RESUMO
Pharmacogenetics aims to maximize the beneficial effects of a medical therapy by identifying genetic finger prints from responders and non-responders and, thereby improving safety and efficacy profile of the drug. Most subjects who are deficient in growth hormone (GHD) are candidates for recombinant human GH (rhGH) therapy. To date, it is well established that even after adjustments for several clinical variables, such as age, gender, body composition and the age at onset of the GHD, response to rhGH treatment is highly variable among individuals, part of which is believed to be due to genetic factors within the GH system. As the first genetic variant to potentially influence the individual response to rhGH therapy in children with growth disorders, polymorphism in the GH receptor (GHR) has attracted a great interest as a target for pharmacogenetics. Studies have been conducted to compare the functional and molecular effects of the full-length GHR (fl-GHR) isoform with the exon 3 deleted (d3-GHR) isoform in children and adults treated with rhGH therapy. Additionally, the impact of the GHR polymorphism has been investigated in relation to the clinical status and response to medical treatment in acromegaly, especially to the GHR antagonist drug pegvisomant. We have performed a narrative review of the studies performed to date on the association of GHR polymorphism with rhGH response in children and adults, and its potential influence in the medical management of acromegaly. In addition, data from studies on the general population and in other chronic diseases examining a role of this genetic variant in the regulation of growth and metabolism are summarized.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo Genético , Receptores da Somatotropina/genética , Acromegalia/induzido quimicamente , Acromegalia/genética , Acromegalia/metabolismo , Acromegalia/terapia , Adulto , Criança , Resistência a Medicamentos , Éxons , Deleção de Genes , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Hormônio do Crescimento Humano/efeitos adversos , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/genética , Humanos , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Isoformas de Proteínas/efeitos adversos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapêutico , Receptores da Somatotropina/agonistas , Receptores da Somatotropina/antagonistas & inibidores , Receptores da Somatotropina/metabolismo , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêuticoRESUMO
Mo-CBP3 is an antifungal protein produced by Moringa oleifera which has been investigated as potential candidate for developing transgenic crops. Before the use of novel proteins, food safety tests must be conducted. This work represents an early food safety assessment of Mo-CBP3, using the two-tiered approach proposed by ILSI. The history of safe use, mode of action and results for amino acid sequence homology using the full-length and short contiguous amino acids sequences indicate low risk associated to this protein. Mo-CBP3 isoforms presented a reasonable number of alignments (>35% identity) with allergens in a window of 80 amino acids. This protein was resistant to pepsin degradation up to 2 h, but it was susceptible to digestion using pancreatin. Many positive attributes were presented for Mo-CBP3. However, this protein showed high sequence homology with allergens and resistance to pepsin digestion that indicates that further hypothesis-based testing on its potential allergenicity must be done. Additionally, animal toxicity evaluations (e.g. acute and repeated dose oral exposure assays) must be performed to meet the mandatory requirements of several regulatory agencies. Finally, the approach adopted here exemplified the importance of performing an early risk assessment of candidate proteins for use in plant transformation programs.