The pharmacologenetics of lopinavir in a cohort of black African HIV/AIDS patients

The Sub-Saharan African region remains the most severely affected by the HIV/AIDS epidemic. At the end of 2011, The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that about 5% of adults were living with the HIV in this region, accounting for 69% of the global HIV prevalence. Efforts to curb the epidemic are focused on managing HIV through prevention strategies, such as advocating the use of condoms or pre-exposure or post-exposure prophylactic treatment, and prolonging life through the use of antiretroviral (ARV) therapy. Drugs used in ARV therapy target different major steps of the HIV reproductive cycle. These are nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs/NNRTIs); fusion/entry inhibitors; integrase inhibitors; and protease inhibitors (PIs). In South Africa PIs, specifically lopinavir (LPV) boosted with another PI, ritonavir (RTV) are used in second-line ARV regimens along with a backbone of 2 NRTIs. The use of ARVs is not without issues - patients often experience side-effects to the drugs such as nausea, diarrhoea, and lipodystrophy with LPV use, which may influence their adherence to treatment and eventually lead to treatment failure. Inter-individual variability exists in patients' response to treatment despite the standard dose of 400 mg/100 mg (LPV/RTV) that is given and this may be due to differences in transport or metabolism of the drug in the liver. High plasma drug levels (associated with side-effects or toxicity) may be a result of poor metabolism or conversely, low plasma drug levels (associated with failure to suppress the virus) may be a result of extensive metabolism of the drug. Proteins involved in the disposition of LPV include the drug metabolising enzymes, CYP3A4 and CYP3A5; the hepatic uptake transporter, OATP1B1; and the efflux transporter, MRP2. Variation in the genes encoding these proteins may influence their functioning and hence LPV disposition. The aim of the study was to identify significant single nucleotide polymorphisms (SNPs) in each gene; to genotype a cohort of HIV-infected patients from Malawi and South Africa to identify the frequency of those variants; and to correlate genotypes with LPV plasma levels and other clinical parameters

Developmental stress elicits preference for methamphetamine in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder

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 attentiondeficit/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