INTRODUCTION AND OBJECTIVE: Cytochrome P450 enzymes are the major drug-metabolizing enzymes in humans and the importance of drug transport proteins, in particular P-glycoprotein, in the variability of drug response has also been highlighted. Activity of cytochrome P450 enzymes and P-glycoprotein can vary widely between individuals and genotyping and/or phenotyping can help assess their activity. Several phenotyping cocktails have been developed. The Geneva cocktail is composed of a specific probe for six different cytochrome P450 enzymes and one for P-glycoprotein and was used in the context of a research aiming at exploring genotypes and phenotypes in distinct human populations (NCT02789527). The aim of the present study is to solely report the safety results of the Geneva cocktail in the healthy volunteers of these populations.MATERIALS AND METHODS: The Geneva cocktail is composed of caffeine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, and fexofenadine. The volunteers fasted and avoided drinking caffeine-containing beverages or food and grapefruit juice overnight before receiving the cocktail orally. They provided blood spots for the probes' concentrations at 2, 3, and 6 h after ingestion and were asked about adverse events. RESULTS: A total of 265 healthy adult volunteers were included from Ethiopia, Oman, and the Czech Republic. The mean plasma concentrations at the 2-h sampling time of each probe drug in the total sample were: 1663 ng/mL for caffeine, 8 ng/mL for bupropion, 789 ng/mL for flurbiprofen, 6 ng/mL for dextromethorphan, 2 ng/mL for midazolam, 35 ng/mL for fexofenadine, and 103 ng/mL for omeprazole. Four adverse events were observed representing an occurrence of 1.5%. All these events were categorized as mild to moderate, non-serious, and resolved spontaneously. A causal link with the cocktail cannot be excluded because of the temporal relationship but is at most evaluated as possible according to the World Health Organization-Uppsala Monitoring Centre causal assessment system. CONCLUSIONS: In this research, healthy volunteers from three different human populations were phenotyped with the Geneva cocktail. Four adverse events were observed, confirming the safety of this cocktail that is given at lower than clinically relevant doses and therefore results in concentrations lower than those reported to cause adverse events.
- MeSH
- dospělí MeSH
- fixní kombinace léků MeSH
- genotyp MeSH
- inhibitory cytochromu P450 MeSH
- léčivé přípravky metabolismus MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- P-glykoprotein genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- substrátová specifita MeSH
- systém (enzymů) cytochromů P-450 genetika metabolismus MeSH
- zdraví dobrovolníci pro lékařské studie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Etiopie MeSH
- Omán MeSH
BACKGROUND: Today, African pastoralists are found mainly in the Sahel/Savannah belt spanning 6,000 km from west to east, flanked by the Sahara to the north and tropical rainforests to the south. The most significant group among them are the Fulani who not only keep cattle breeds of possible West Eurasian ancestry, but form themselves a gene pool containing some paternally and maternally-transmitted West Eurasian haplogroups. MATERIALS AND METHODS: We generated complete sequences for 33 mitogenomes belonging to haplogroups H1 and U5 (23 and 10, respectively), and genotyped 16 STRs in 65 Y chromosomes belonging to haplogroup R1b-V88. RESULTS: We show that age estimates of the maternal lineage H1cb1, occurring almost exclusively in the Fulani, point to the time when the first cattle herders settled the Sahel/Savannah belt. Similar age estimates were obtained for paternal lineage R1b-V88, which occurs today in the Fulani but also in other, mostly pastoral populations. Maternal clade U5b1b1b, reported earlier in the Berbers, shows a shallower age, suggesting another possibly independent input into the Sahelian pastoralist gene pool. CONCLUSIONS: Despite the fact that animal domestication originated in the Near East ∼ 10 ka, and that it was from there that animals such as sheep, goats as well as cattle were introduced into Northeast Africa soon thereafter, contemporary cattle keepers in the Sahel/Savannah belt show uniparental genetic affinities that suggest the possibility of an ancient contact with an additional ancestral population of western Mediterranean ancestry.
- MeSH
- antropologie fyzická MeSH
- černoši genetika MeSH
- dějiny starověku MeSH
- fylogeneze MeSH
- haplotypy genetika MeSH
- lidé MeSH
- lidský chromozom Y genetika MeSH
- migrace lidstva dějiny MeSH
- mitochondriální DNA genetika MeSH
- populační genetika MeSH
- zemědělství dějiny MeSH
- Check Tag
- dějiny starověku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- subsaharská Afrika MeSH
The objective of this study was to provide deeper knowledge of the maternal genetic structure and demographic history of the human populations of the Sahel/Savannah belt, the extensive region lying between the Sahara and tropical rainforests, spanning from the Atlantic Ocean to the Red Sea coast. The study aimed to confirm or disconfirm archaeological and linguistic data indicating that the region's populations underwent diversification as a result of the spread of agropastoral food-producing subsistence lifestyles, over time dividing the region into separate areas of nomadic pastoralism, on the one hand, and sedentary farming, on the other. To perform both descriptive and coalescence analyses from the Sahel/Savannah belt's entire region, including western and eastern rather than just central populations studied previously, we generated a new mitochondrial DNA (mtDNA) data set not only having almost 2,000 samples (875 of which were newly collected) but also encompassing whole mtDNA D-loop segment rather than only the previously studied hypervariable segment 1. While comparing our analyses with previous results from the Lake Chad Basin (central Sahel/Savannah Belt), we found similar intrapopulation diversity measures (i.e., lower values in pastoralists than in farmers). However, the new data set pointed to significant differences in mating strategies between western and eastern pastoralists: our results suggest higher gene flow between the Arabic pastoralists and neighboring farmers in the eastern part than between the Fulani pastoralists and their sedentary neighbors in the western part of the Sahel/Savannah belt. The findings are discussed in light of archaeological and linguistic data, allowing us to postulate that the genetic differentiation of Fulani pastoralists from the common western African agropastoral gene pool occurred at around the same time as the arrival of the Arabic pastoralists to eastern Africa. However, it seems that while the process of divergence of the Fulani pastoralists in the west was accompanied by a loss of Fulani females to other populations, the Arab pastoralists' immigration to the Sahel/Savannah belt conversely resulted in some gain of local females into this Arab population.
- MeSH
- Arabové genetika MeSH
- archeologie metody MeSH
- černoši genetika dějiny MeSH
- dějiny starověku MeSH
- dějiny středověku MeSH
- emigrace a imigrace MeSH
- genetické struktury MeSH
- jazyk (prostředek komunikace) MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- mitochondriální DNA genetika MeSH
- osoby s přechodným pobytem a migranti MeSH
- populační genetika MeSH
- tok genů genetika MeSH
- zemědělství trendy MeSH
- Check Tag
- dějiny starověku MeSH
- dějiny středověku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- historické články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Geografické názvy
- severní Afrika MeSH
