Healthy African Volunteers Research Articles

Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers.

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n=12), CYP2D6*17*17 (n=12), and CYP2D6*29*29 (n=4). Each subject received a single oral dose of dextromethorphan 30mg syrup on day1 and desipramine 50mg tablet on day8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast), and extrapolated to infinity (AUCinf), and the maximum plasma concentration (Cmax) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUCinf, Cmax, and the elimination half-life, followed a similar trend: CYP2D6*17*17>CYP2D6*29*29>CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings.

Frequent Anti-V1V2 Responses Induced by HIV-DNA Followed by HIV-MVA with or without CN54rgp140/GLA-AF in Healthy African Volunteers.

Antibody responses that correlated with reduced risk of HIV acquisition in the RV144 efficacy trial were assessed in healthy African volunteers who had been primed three times with HIV-DNA (subtype A, B, C) and then randomized into two groups; group 1 was boosted twice with HIV-MVA (CRF01_AE) and group 2 with the same HIV-MVA coadministered with subtype C envelope (Env) protein (CN54rgp140/GLA-AF). The fine specificity of plasma Env-specific antibody responses was mapped after the final vaccination using linear peptide microarray technology. Binding IgG antibodies to the V1V2 loop in CRF01_AE and subtype C Env and Env-specific IgA antibodies were determined using enzyme-linked immunosorbent assay. Functional antibody-dependent cellular cytotoxicity (ADCC)-mediating antibody responses were measured using luciferase assay. Mapping of linear epitopes within HIV-1 Env demonstrated strong targeting of the V1V2, V3, and the immunodominant region in gp41 in both groups, with additional recognition of two epitopes located in the C2 and C4 regions in group 2. A high frequency of V1V2-specific binding IgG antibody responses was detected to CRF01_AE (77%) and subtype C antigens (65%). In conclusion, coadministration of CN54rgp140/GLA-AF with HIV-MVA did not increase the frequency, breadth, or magnitude of anti-V1V2 responses or ADCC-mediating antibodies induced by boosting with HIV-MVA alone.

Sleep patterns in villagers and urban African volunteers in a humid tropical climate: Influence of accessibility to electric light?

Recent publications focusing on sleep–wake alternation, using actigraphic recordings in hunter-gatherers, stressed the existence of a potential effect of electricity availability on sleep habits. These reports prompted us to achieve a new analysis of the polysomnographic data already obtained in healthy African volunteers in equatorial Africa during two different investigations. Comparison of the 24-h polysomnographic sleep patterns were done between 9 volunteers sleeping in a laboratory in Abidjan (Abidjan cohort) and 11 villagers living in electricity-free bush villages (Sinfra cohort). Sleep was lighter in the villagers, with more stage 1 and less slow wave sleep (SWS). Latency to SWS was also shorter. Total sleep time, however, was not different between the two groups. There were no indications as to whether the observed differences were attributable to the availability of electrical power. Reactivity of human sleep structure to the environment was discussed in terms of multifactorial influences such as daylight length, temperature, humidity, electromagnetic field, time of sleep onset, thermoregulatory mechanisms, stress or anxiety.

Association of alcohol consumption with specific biomarkers: a cross-sectional study in South Africa.

Alcohol consumption plays an important role in the health transition associated with urbanization in developing countries. Thus, reliable tools for assessing alcohol intake levels are necessary. We compared two biological markers of alcohol consumption and self-reported alcohol intakes in participants from urban and rural South African communities. This cross-sectional epidemiological survey was part of the North West Province, South African leg of the 12-year International Prospective Urban and Rural Epidemiology (PURE) study which investigates the health transition in urban and rural subjects. A total of 2,010 apparently healthy African volunteers (35 years and older) were recruited from a sample of 6,000 randomly-selected households. Alcohol consumption was assessed through self-reports (24-hour recalls and quantitative food frequency questionnaire) and by two biological markers: percentage carbohydrate-deficient transferrin (%CDT) and gamma-glutamyl transferase (GGT). Of the 716 men and 1,192 women volunteers, 64% and 33% respectively reported regular alcohol consumption. Reported mean habitual intakes of drinker men and women were 29.9 (± 30.0) and 23.3 (± 29.1) g of pure alcohol per day. Reported habitual intake of the whole group correlated positively and significantly with both %CDT (R=0.32; p ≤ 0.01) and GGT (R=0.43; p ≤ 0.01). The correlation between the two biomarkers was low (0.211; p ≤ 0.01). GGT and %CDT values should be interpreted with care in Africans as self-reported non-drinker men and women had elevated levels of GGT (19% and 26%) and %CDT (48% and 38%). A need exists for a more specific biological marker for alcohol consumption in black Africans.

CYP3A4 and CYP3A5genotyping by Pyrosequencing

BackgroundHuman cytochrome P450 3A enzymes, particularly CYP3A4 and CYP3A5, play an important role in drug metabolism. CYP3A expression exhibits substantial interindividual variation, much of which may result from genetic variation. This study describes Pyrosequencing assays for key SNPs in CYP3A4 (CYP3A4*1B, CYP3A4*2, and CYP3A4*3) and CYP3A5 (CYP3A5*3C and CYP3A5*6).MethodsGenotyping of 95 healthy European and 95 healthy African volunteers was performed using Pyrosequencing. Linkage disequilibrium, haplotype inference, Hardy-Weinberg equilibrium, and tag SNPs were also determined for these samples.ResultsCYP3A4*1B allele frequencies were 4% in Europeans and 82% in Africans. The CYP3A4*2 allele was found in neither population sample. CYP3A4*3 had an allele frequency of 2% in Europeans and 0% in Africans. The frequency of CYP3A5*3C was 94% in Europeans and 12% in Africans. No CYP3A5*6 variants were found in the European samples, but this allele had a frequency of 16% in the African samples. Allele frequencies and haplotypes show interethnic variation, highlighting the need to analyze clinically relevant SNPs and haplotypes in a variety of ethnic groups.ConclusionPyrosequencing is a versatile technique that could improve the efficiency of SNP analysis for pharmacogenomic research with the ultimate goal of pre-screening patients for individual therapy selection.

Twenty-four-hour time course of intraocular pressure in healthy and glaucomatous africans: relation to sleep patterns

Objective The study was performed in early middle-aged African natives with primary open-angle glaucoma to compare the 24-hour intraocular pressure (IOP) variations in healthy versus young glaucoma patients, because IOP follows a circadian (24-hour) oscillation in healthy Caucasians. Design Case-control study. Participants Sixteen healthy African volunteers (age 24.5 ± 1 years, mean ± standard error of the mean) and 11 open-angle glaucoma African patients (age 36.2 ± 3.3 years). Methods IOP was measured hourly during 24 hours with a Modular One pneumatonometer (Modular One, Digilab, Cambridge, MA), which allows measures in supine subjects. To allow the IOP measurement at night, subjects were awakened under polysomnography (electroencephalogram, electromyogram, electro-oculogram) recorded at night and during a 90-minute afternoon nap. Main outcome measures Hourly IOP values were analyzed for circadian rhythmicity with the Cosinor technique and in relation to the state of wakefulness, light sleep (stages 1 and 2), slow-wave sleep (stages 3 and 4), and rapid eye movement (REM) sleep upon awakening. Results Sleep patterns did not differ between patients and healthy volunteers. As expected, in the healthy subjects, IOP followed a 24-hour rhythm with a nocturnal peak value (acrophase), and the variations in IOP during sleep were related to sleep structure, being lowest during REM sleep and highest during slow-wave sleep. In the glaucoma patients, however, the 24-hour rhythm of IOP was reversed, with an afternoon acrophase and an early morning trough. Conclusions These data suggest a circadian phase shift in IOP in glaucoma patients, with maintained relation to sleep structure.