BackgroundCYP1A2 and CYP2A6 are polymorphic drug-metabolising enzymes that are also implicated in the activation of procarcinogens in humans. Some of their alleles and haplotypes, often varied in prevalence across populations, are thought to influence activity despite the known contribution of environmental factors. This study assessed the potential influence of some genetic variants of CYP1A2 and CYP2A6 on metabolic phenotypes in Nigerians.MethodsGenomic DNA was extracted from blood samples of 100 healthy, unrelated subjects for whom CYP1A2 and CYP2A6 phenotypes had previously been determined, alongside an additional 80 other individuals for whom phenotype data were unavailable. The samples were screened for CYP1A2 (*1C,*1D,*1E,*1F, *3,*4,*6,*7) and CYP2A6 (*9,*11,*17) alleles using the Sequenom MassARRAY platform for some alleles and direct Sanger sequencing for others. The genetic data acquired were subsequently analysed for haplotypes and assessed for concordance with phenotypes.ResultsAll five CYP1A2 haplotypes (CYP1A2*1F, 1J, 1N, 1L, 1W) identified in the Nigerian population were not significantly predictive of metabolic phenotypes. Heterozygous CYP1A2*1J carriers and homozygous CYP1A2*1W carriers showed statistically insignificant decrease in CYP1A2 activity. The CYP2A6*9/*17 genotype was, however, significantly associated with the CYP2A6-poor metabolic phenotype, whereas CYP2A6*9 or CYP2A6*17 alone did not show any such association. CYP2A6*11 was not detected in the population.ConclusionsOur findings suggest that CYP1A2 alleles or haplotypes were not predictive of metabolic phenotypes in the Nigerian population. Carriers of CYP2A6*9/*17 genotype are likely to be poor metabolisers of CYP2A6 substrates and may experience adverse reactions or poor efficacy while using drugs metabolised mainly by CYP2A6.
\n \n\n \n \nBACKGROUND AND OBJECTIVE:MAMA decoction (MD) is an antimalarial product prepared from the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae). A previous report showed that MD enhanced the efficacy of amodiaquine (AQ) in malaria-infected mice, thus suggesting a herb-drug interaction. The present study hence evaluated the effect of MD on the disposition of AQ in mice with a view to investigating a possible pharmacokinetic interaction. METHODS:In a 3-period study design, three groups of mice (n\u2009=\u200972) were administered oral doses of AQ (10\u00a0mg/kg/day) alone, concurrently with MD (120\u00a0mg/kg/day), and in the 3rd period, mice were given AQ after a 3-day pre-treatment with MD. Blood samples were collected between 0 and 96\u00a0h for quantification of AQ and its major metabolite, desethylamodiaquine, by a validated high-performance liquid chromatography method. RESULTS:Maximum concentrations of AQ increased by 12% with the concurrent dosing of MD and by 85% in the group of mice pre-treated with MD. The exposure and half-life of desethylamodiaquine increased by approximately 11% and 21%, respectively, with concurrent administration. Corresponding increases of approximately 20% and 33% of desethylamodiaquine were also observed in mice pre-treated with MD. CONCLUSION:MD influenced the pharmacokinetics of AQ and desethylamodiaquine, its major metabolite. The increase in the half-life and systemic exposure of AQ following its co-administration with MD may provide a basis for the enhanced pharmacological effect of the combination in an earlier study in Plasmodium-infected mice.
\n \n\n \n \nObjectivesThis study assessed the activity of thiopurine S-methyltransferase (TPMT) in Nigerians with a view to providing data on susceptibility to thiopurine toxicity, and as well generate reference activity values for clinical use.ResultsTPMT activity, expressed as the amount of 6MMP in ng/mL after 1\u00a0h incubation at 37\u00a0\u00b0C per haemoglobin (U/g Hb), varied between 2.34 and 63.50 U/g Hb in the study population. Poor metabolic phenotypes, characterised by an activity values below 8.41 U/g Hb, were observed in 20% of the study subjects. Intermediate metabolizers had activity values between 8.41 and 16.13 U/g Hb. Fast and very fast metabolizers were characterised by activity values of 16.20-56.22 and >\u00a056.22 U/g Hb, respectively. These findings suggest that a potentially huge discordance between TPMT phenotype and genotype exist in Nigerians, and emphasizes the superiority of a prior determination of TPMT metabolic phenotype in ensuring the safety of thiopurine drug administration in the population.
\n \n\n \n \nEstrogen-receptor positivity in tumour, often requiring long-term tamoxifen therapy, is thought to characterise between 43% and 65% of breast cancer cases in Nigeria. The patient population is further marked by late-stage diagnosis which significantly heightens the tendency for tumour relapse in the course of tamoxifen therapy. Despite tamoxifen being considered a reliable chemopreventive in high-risk individuals and an effective adjuvant therapy for hormone-sensitive tumours, mortality has remained high among breast cancer patients in the West African region where Nigeria belongs. The Nigerian breast cancer population, like other similar patient-populations in the West African region, provides a mix of intrinsic genome-diversity and perhaps unique tumour biology and evolution. These peculiarities suggest the need for a rational approach to tumour management and a personalised delivery of therapy in Nigeria's dominant estrogen-receptor-positive patient population. Herein, critical indices of tamoxifen-therapy success are discussed in the context of the Nigerian breast cancer population with emphasis on salient aspects of tamoxifen-biotransformation, host- and tumour-genomics, and epigenetics.
\n \n\n \n \nImatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively. Statistical analysis of the influence of genetic polymorphisms on standardized trough level detected no significant relationship. However, higher trough levels were observed in two homozygous carriers of CYP2C8*2 while diminished imatinib levels were seen in two homozygous carriers of CYP3A5*7. The study findings suggest that polymorphisms in drug metabolizing enzymes may be significant for imatinib therapy only in instances where all copies of the relevant studied genes are functionally impaired.
\n \n\n \n \nBackgroundIsosteviol is a synthetic derivative of steviol glycosides with promising pharmacological properties and might find future use as a cardioprotective agent.ObjectiveA simple LC-MS/MS technique was developed and validated for the bioanalysis of isosteviol in plasma and erythrocytes. This method was subsequently utilized for the in vitro assessment of isosteviol's partitioning into blood compartments of humans and rats.MethodsFresh blood samples from healthy humans and Wistar rats were equilibrated with 1, 10, and 30 \u00b5M isosteviol at 37\u202f\u00b0C in a shaking dry-bath. The levels of isosteviol in plasma and erythrocytes partitions were determined in these samples, after separation, at intervals over a 60-minute period. The data derived was used to estimate erythrocyte-to-plasma and blood-to-plasma coefficients.ResultsMean erythrocyte-to-plasma partition coefficients (SD) after 60 minutes of equilibration were observed to be 0.039 (0.002) and 0.040 (0.003) in humans and rats, respectively. Derived values for the blood-to-plasma ratio (SD) were 0.576 (0.001) in humans and 0.543 (0.007) in rats, whereas plasma component binding was estimated to be more than 96%.ConclusionsThe findings suggest that isosteviol preferentially partitions into plasma compartments in humans and rats. The significance of this profile for the efficacy, tissue uptake, and retention of isosteviol will have to be further studied.
\n \n\n \n \nBackgroundThe varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans.ObjectiveUsing a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes.MethodsConcentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm.ResultsAll datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h-1, 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients.ConclusionsThe study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients.
\n \n\n \n \nIntroduction Thiopurine S-methyltransferase (TPMT) methylates clinically relevant thiopurine drugs most of which are noted for adverse reactions in certain users, largely due to polymorphisms in the TPMT gene. Aim This study investigated the prevalence of functionally relevant TPMT alleles in the Nigerian population. Material and methods One hundred eighty unrelated subjects consisting of 123 males and 57 females from the main Nigerian ethnicities (44 Igbo, 101 Yoruba, 23 Hausa and 12 from other minor ethnic groups) were genotyped for TPMT*2, *3B, *3C and *4 alleles using the iPLEX genotyping assay technique. The genotype calls were validated with Sanger sequencing in a random set of samples and the acquired data were assessed for Hardy\u2013Weinberg equilibrium using the Fisher's exact test. Results and discussion Defective TMPT alleles were found in individuals representing 10% of the study population. TPMT*3C constituted 9.4% (95% CI, 5.6\u201314.7) of all alleles detected, with one homozygote and 17 heterozygotes recorded. The prevalence of the TPMT*3C allele in the population conformed with Hardy\u2013Weinberg equilibrium. TPMT*2, 3B and *4 were, however, not detected in the population. Conclusions TPMT*3C was the only defective allele identified in Nigerians and may hence be the major underlying genetic contributor to adverse reactions due to thiopurine drugs in the population.
\n \n\n \n \nAfrican populations in sub-Saharan Africa and African migrants in Europe are facing a rapid upsurge in obesity. This trend has been related to urbanization, migration and associated shifts in lifestyle, including dietary habits. Whether changes in eating patterns contribute to the rising burden of obesity among African populations is currently unknown. Our aims in conducting this study were to characterize eating patterns among Ghanaian adults living in their country of origin and in Europe and to explore associations of meal patterns with body mass index (BMI). Within the cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study, data of single 24-h dietary recalls from Ghanaian adults in rural Ghana (n = 20), urban Ghana (n = 42), and Europe (n = 172) were recorded. Eating frequencies, energy intake, and macronutrient composition of eating occasions (EOs, i.e. meals or snacks) were compared between study sites based on descriptive statistics and \u03c72-/Kruskal-Wallis tests. A rising gradient of EO frequencies from rural Ghana through urban Ghana to Europe was observed, mainly reflecting the differences in snacking frequencies (\u22651 snack per day: 20 vs. 48 vs. 52%, P = 0.008). Meal frequencies were similar across study sites (\u22653 meals per day: 30 vs. 33 vs. 38%, P = 0.80). Meals were rich in carbohydrates (median 54.5, interquartile range (IQR): 43.2-64.0 energy%) and total fats (median: 27.0, IQR: 19.9-34.4 energy %); their protein content was lowest in rural Ghana, followed by urban Ghana and Europe (P = 0.0005). Snacks mainly contained carbohydrates (median: 75.7, IQR: 61.0-89.2 energy%). In linear regression analyses, there was a non-significant trend for an inverse association between snacking frequencies and BMI. The observed integration of carbohydrate-dense snacks into the diet supports the growing evidence for a nutrition transition among African populations undergoing socioeconomic development. This analysis constitutes a starting point to further investigate the nutritional implications of increased snacking frequencies on obesity and metabolic health in these African populations.
\n \n\n \n \nOutbreaks of trichinellosis caused by Trichinella papuae have been reported in South-East Asia. Mebendazole and thiabendazole are the treatments of choice for trichinellosis; however, both drugs result in significant side effects and are less effective for muscle-stage larvae (L1). An alternative therapeutic agent is needed to improve treatment. Information on lipid composition and metabolic pathways may bridge gaps in our knowledge and lead to new antiparasitics. The T. papuae L1 lipidome was analysed using a mass spectrometry-based approach, and 403 lipid components were identified. Eight lipid classes were found and glycerophospholipids were dominant, corresponding to 63% of total lipids, of which the glycerolipid DG (20:1[11Z]/22:4[7Z,10Z,13Z,16Z]/0:0) (iso2) was the most abundant. Overall, 57% of T. papuae lipids were absent in humans; therefore, lipid metabolism may be dissimilar in the two species. Proteins involved T. papuae lipid metabolism were explored using bioinformatics. We found that 4-hydroxybutyrate coenzyme A transferase, uncharacterized protein (A0A0V1MCB5) and ML-domain-containing protein are not present in humans. T. papuae glycerophospholipid metabolic and phosphatidylinositol dephosphorylation processes contain several proteins that are dissimilar to those in humans. These findings provide insights into T. papuae lipid composition and metabolism, which may facilitate the development of novel trichinellosis treatments.
\n \n\n \n \nMekong schistosomiasis is a parasitic disease caused by blood flukes in the Lao People\u2019s Democratic Republic and in Cambodia. The standard method for diagnosis of schistosomiasis is detection of parasite eggs from patient samples. However, this method is not sufficient to detect asymptomatic patients, low egg numbers, or early infection. Therefore, diagnostic methods with higher sensitivity at the early stage of the disease are needed to fill this gap. The aim of this study was to identify potential biomarkers of early schistosomiasis using an untargeted metabolomics approach. Serum of uninfected and S. mekongi-infected mice was collected at 2, 4, and 8 weeks post-infection. Samples were extracted for metabolites and analyzed with a liquid chromatography-tandem mass spectrometer. Metabolites were annotated with the MS-DIAL platform and analyzed with Metaboanalyst bioinformatic tools. Multivariate analysis distinguished between metabolites from the different experimental conditions. Biomarker screening was performed using three methods: correlation coefficient analysis; feature important detection with a random forest algorithm; and receiver operating characteristic (ROC) curve analysis. Three compounds were identified as potential biomarkers at the early stage of the disease: heptadecanoyl ethanolamide; picrotin; and theophylline. The levels of these three compounds changed significantly during early-stage infection, and therefore these molecules may be promising schistosomiasis markers. These findings may help to improve early diagnosis of schistosomiasis, thus reducing the burden on patients and limiting spread of the disease in endemic areas.
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