RESUMEN
BACKGROUND: Developmental stress has been hypothesised to interact with genetic predisposition to increase the risk of developing substance use disorders. Here we have investigated the effects of maternal separation-induced developmental stress using a behavioural proxy of methamphetamine preference in an animal model of attention-deficit/hyperactivity disorder, the spontaneously hypertensive rat, versus Wistar Kyoto and Sprague-Dawley comparator strains. RESULTS: Analysis of results obtained using a conditioned place preference paradigm revealed a significant strain × stress interaction with maternal separation inducing preference for the methamphetamine-associated compartment in spontaneously hypertensive rats. Maternal separation increased behavioural sensitization to the locomotor-stimulatory effects of methamphetamine in both spontaneously hypertensive and Sprague-Dawley strains but not in Wistar Kyoto rats. CONCLUSIONS: Our findings indicate that developmental stress in a genetic rat model of attention-deficit/hyperactivity disorder may foster a vulnerability to the development of substance use disorders.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/psicología , Metanfetamina/metabolismo , Animales , Atención/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Hipertensión , Aprendizaje/efectos de los fármacos , Masculino , Privación Materna , Metanfetamina/farmacología , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Ratas Wistar , Estrés Psicológico/metabolismoRESUMEN
INTRODUCTION: Variability in lopinavir (LPV) plasma concentration among patients could be due to genetic polymorphisms. This study set to evaluate significance of variants in CYP3A4/5, SLCO1B1 and ABCC2 on LPV plasma concentration among African HIV-positive patients. MATERIALS & METHODS: Eighty-six HIV-positive participants on ritonavir (LPV/r) were genetically characterized and LPV plasma concentration determined. RESULTS & DISCUSSION: LPV plasma concentrations differed >188-fold (range 0.0206-38.6 µg/ml). Both CYP3A4*22 and SLCO1B1 rs4149056G (c.521C) were not observed in this cohort. CYP3A4*1B, CYP3A5*3, CYP3A5*6 and ABCC2 c.1249G>A which have been associated with LPV plasma concentration, showed no significant association. CONCLUSION: These findings highlight the need to include African groups in genomics research to identify variants of pharmacogenomics significance.
Asunto(s)
Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Lopinavir/sangre , Variantes Farmacogenómicas , Adulto , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Población Negra/genética , Estudios Transversales , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Etnicidad/genética , Femenino , Infecciones por VIH/metabolismo , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
INTRODUCTION: Africa harbors a disproportionate burden of disease when taking into account the triple challenge caused by HIV/AIDS, tuberculosis (TB) and malaria, against a backdrop of an increasing burden of noncommunicable diseases. More than 80% of therapeutic drugs used in the management of these diseases/conditions are metabolized by CYP enzymes that exhibit genetic polymorphisms. AREAS COVERED: There is variability in the expression and activities of CYPs resulting in interindividual differences in the response to standard doses of therapeutic drugs, due to genetic polymorphisms, which exhibit both quantitative and qualitative differences between racial and between ethnic groups. The review aims to evaluate the implications of the genetic variation in CYPs on the public health of Africans. The CYPs reviewed here metabolize most of the commonly used therapeutic drugs and include CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 and 3A5. Allele frequencies are compared between African ethnic groups and among populations of African, Asian and European origin. Data are obtained from our own studies and literature. EXPERT OPINION: The variability in the pattern of genetic variation between populations translates into differences in drug response. Understanding CYP variability improves rational drug use and has public health significance.