RESUMO
Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.
Assuntos
Antipsicóticos/efeitos adversos , Doenças dos Gânglios da Base/genética , Discinesia Induzida por Medicamentos/genética , Estudo de Associação Genômica Ampla , Animais , Doenças dos Gânglios da Base/induzido quimicamente , Doenças dos Gânglios da Base/fisiopatologia , Mapeamento Cromossômico , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos A , Atividade Motora , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: The most common immediate hypersensitivity to macrogols is associated with polyethylene glycol (PEG) 3350; however, the epidemiology, mechanisms, and cross-reactivity are poorly understood. Thousands of medications contain either PEGs or structurally similar polysorbates. OBJECTIVE: Our objective was to better understand the mechanism, cross-reactivity, and scope of PEG hypersensitivity. METHODS: Two cases with a past history of immediate hypersensitivity to PEG-containing medications were used to study potential mechanisms and cross-reactivity of immediate reactions to PEG 3350. Skin testing and oral challenges with PEG and polysorbate-containing agents were employed to determine clinical reactivity and cross-reactivity between the 2 allergens. Enzyme-linked immunosorbent assay and electrochemiluminescent immunoassay were used to detect anti-PEG specific IgG and IgE, respectively, using PEGylated protein or PEG alone as antigens in 2 cases and 6 PEG 3350 tolerant controls. We searched US Food and Drug Administration (FDA) adverse event reports for immediate reactions to PEG 3350 to determine the potential scope of this problem in the United States. RESULTS: Skin and provocation testing demonstrated symptomatic reactivity in both cases to PEG 3350 and polysorbate 80. Plasma samples were positive for anti-PEG specific IgE and IgG antibodies only in cases and binding increased directly proportional to the molecular weight of PEG tested. FDA adverse event reports revealed 53 additional cases of possible PEG 3350 anaphylaxis. CONCLUSIONS: Immediate hypersensitivity to PEG 3350 with cross-reactive polysorbate 80 hypersensitivity may be underrecognized in clinical practice and can be detected with clinical skin testing. Our studies raise the possibility of an IgE-mediated type I hypersensitivity mechanism in some cases.