Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

The CYP2B6*6 allele occurs at a high frequency in people of African origin and is associated with high efavirenz concentrations. Simulations indicate that an a priori 35% dose reduction in homozygous CYP2B6*6 patients would maintain drug exposure within the therapeutic range in this group of patients. Our preliminary results suggest the conduct of a prospective clinical dose optimization study to evaluate the utility of genotype-driven dose adjustment in this population.

The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three-and four-dose regimens. Children had a lower body weightnormalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC day 0-63 ]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC day 3-20 ) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.

AimsThe study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artemisinin. Methods Microsomes from human B-lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated. The relative contribution of individual CYP450 isoenzymes to artemisinin metabolism in human liver microsomes was evaluated with a tree-based regression model of artemisinin disappearance rate and specific CYP450 activities. Results The involvement of CYP2B6 in artemisinin metabolism was demonstrated by metabolism of artemisinin by recombinant CYP2B6, inhibition of artemisinin disappearance in human liver microsomes by orphenadrine (76%) and primary inclusion of CYP2B6 in the tree-based regression model. Recombinant CYP3A4 was catalytically competent in metabolizing artemisinin, although the rate was 10% of that for recombinant CYP2B6. The tree-based regression model suggested CYP3A4 to be of importance in individuals with low CYP2B6 expression. Even though ketoconazole inhibited artemisinin metabolism in human liver microsomes by 46%, incubation with ketoconazole together with orphenadrine did not increase the inhibition of artemisinin metabolism compared to orphenadrine alone. Troleandomycin failed to inhibit artemisinin metabolism. The rate of artemisinin metabolism in recombinant CYP2A6 was 15% of that for recombinant CYP2B6. The inhibition of artemisinin metabolism in human liver microsomes by 8-methoxypsoralen (a CYP2A6 inhibitor) was 82% but CYP2A6 activity was not included in the regression tree. Conclusions Artemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6 with probable secondary contribution of CYP3A4 in individuals with low CYP2B6 expression. The contribution of CYP2A6 to artemisinin metabolism is likely of minor importance.Keywords: artemisinin, CYP2B6, CYP3A4, cytochrome P450, metabolism species. The fraction excreted unchanged in urine in Introduction humans is less than 1% of an oral administration [2]. In rats, the liver is the major organ of elimination [3]. Four Artemisinin is the parent compound of an emerging class of antimalarial drugs of importance in the treatment of metabolites, deoxy-artemisinin, deoxy-dihydroartemisinin, dihydroxyartemisinin and the so-called 'crystal-7' malaria in areas with multidrug resistant Plasmodium falciparum. Artemisinin is a sesquiterpene lactone with an were identified in urine following oral administration of artemisinin to humans, but plasma metabolites remain internal peroxide bridge (Figure 1) necessary for its antiparasitic effect [1]. Limited data are available on unknown [4]. Artemisinin is commonly used together with other artemisinin metabolism in both humans and animal antimalarial drugs and information on its enzymatic

AimsPrevious studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of ar temisinin in healthy subjects. MethodsTwenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/ 500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two-compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction. ResultsArtemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half-life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non-linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first-pass extraction. ConclusionArtemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the timecourse of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.