Tamoxifen displays wide inter-individual variability (IIV) in its pharmacokinetics and treatment outcome. Data on tamoxifen pharmacokinetics and pharmacogenetics from black African breast cancer patient populations is lacking. We investigated the pharmacokinetic and pharmacogenetic profile of tamoxifen and its major active metabolite, endoxifen, in Ethiopian breast cancer patients. A total of 81 female breast cancer patients on adjuvant tamoxifen therapy were enrolled. Tamoxifen (Tam) and its major metabolites, N-desmethyltamoxifen (NDM), 4-hydroxy-tamoxifen (4-HT), and (Z)-endoxifen (E) were quantified using LC-MS/MS. Genotyping for CYP2D6, CYP2C9, CYP2C19, CYP3A5, POR, and ABCB1 and UGT2B15 and copy number variation for CYP2D6 were done. The proportion of patients with low endoxifen level (<5.9 ng/mL) was 35.8% (median concentration 7.94 ng/mL). The allele frequency of CYP2D6 gene deletion (*5) and duplication (*1×N or *2×N) was 4.3% and 14.8%, respectively. Twenty-six percent of the patients carried duplicated or multiplicated CYP2D6 gene. An increase in CYP2D6 activity score was associated with increased endoxifen concentration and MRE/NDM (p < 0.001). The IIV in endoxifen concentration and MRE/NDM was 74.6% and 59%, respectively. CYP2D6 diplotype explained 28.2% and 44% of the variability in absolute endoxifen concentration and MRE/NDM, respectively. The explanatory power of CYP2D6 diplotype was improved among ABCB1c.4036G carriers (43% and 65.2%, respectively for endoxifen concentration and MRE/NDM) compared to A/A genotype. CYP2C9, CYP2C19, and CYP3A5 genotypes had no significant influence on endoxifen concentration or MRE/NDM. In conclusion, we report a high rate of low endoxifen level as well as large IIV in tamoxifen and its metabolite concentrations. CYP2D6 is significant predictor of plasma endoxifen level in a gene-dose dependent manner.

Abstract:The combination of cross-section and controlled field trail were carried out from December 2015 to June 2016 at Haramaya District, Eastern Hararhge, Ethiopia to evaluate the prevalence ofgastrointestinal nematodes and anthelmintic efficacy test in naturally infected small ruminants using faecal egg count reduction (FECR) test. From a total of 372 faecal samples examined using fecal flotation technique about 57% (212/372) samples were positive to gastrointestinal nematodes. Coprological investigation revealed that sheep and goats in district were infested with varieties of nematode parasites. The strongyles species were highly prevalent nematode parasites identified at about 22.3% (83/372) followed by trichuris 9.1% (34/372) and strongyloides 5.6% (21/372); whereas mixed infections of strongyles and strongyloides were recovered at lowest rate which accounted for about 5.1% (19/372). From considered risk factors age and kebele showed significant association (p<0.05) with prevalence of nematodes parasites. The study revealed that 53.29% (97/182) of goats and 60.53% (115/190) sheep were found positive, while 58% (115/198) in female and 55.74% (97/174) in male and showed no significant difference (p>0.05) between these factors. Mc Master egg counting in sheep harbored nematode parasites showed relatively similar percentage with no significant difference; but more of examined animals were classified in the range of moderate to heavy infections. The faecal egg count reduction test against albendazole, Tetraclozash and ivermectin indicated that 97.59%, 98.79% and 99.56% respectively which indicated an overall of very good state of efficacy against gastrointestinal nematodes of sheep. Therefore this study revealed that small ruminants of the study area harbored considerable level of gastrointestinal nematodes parasites which need further studies on species identification, larval ecology and strategic deworming with proper practice of available anthelmintics in small ruminants of the study area.

BackgroundH1/IC31® is a tuberculosis (TB) subunit vaccine candidate consisting of the fusion protein of Ag85B and ESAT-6 (H1) formulated with the IC31® adjuvant. Previous trials have reported on the H1/IC31® vaccine in M. tuberculosis (Mtb)-naïve, BCG-vaccinated and previously Mtb-infected individuals. In this trial, conducted between December 2008 and April 2010, the safety and immunogenicity of H1/IC31® was assessed in participants living in Ethiopia – a highly TB-endemic area.MethodsHealthy male participants aged 18–25 years were recruited into four groups. Participants in group 1 (N = 12) and group 2 (N = 12) were Tuberculin Skin Test (TST) negative and QuantiFERON-TB Gold in-tube test (QFT) negative (Mtb-naïve groups), participants in group 3 (N = 3) were TST positive and QFT negative (BCG group), and participants in group 4 (N = 12) were both TST and QFT positive (Mtb-infected group). H1 vaccine alone (group 1) or H1 formulated with the adjuvant IC31® (groups 2, 3 and 4) was administered intramuscularly on day 0 and day 56. Safety and immunogenicity parameters were evaluated for up to 32 weeks after day 0.ResultsThe H1/IC31®vaccine was safe and generally well tolerated. There was little difference among the four groups, with a tendency towards a higher incidence of adverse events in Mtb-infected compared to Mtb-naïve participants. Two serious adverse events were reported in the Mtb-infected group where a relationship to the vaccine could not be excluded. In both cases the participants recovered without sequelae within 72 h. Immunogenicity assays, evaluated in the 29 participants who received both vaccinations, showed a stronger response to TB antigens in the Mtb-naïve group vaccinated with the adjuvant.ConclusionThe trial confirmed the need for an adjuvant for the vaccine to be immunogenic and highlighted the importance of early phase testing of a novel TB vaccine candidate in TB-endemic areas.Trial registrationClinicalTrials.gov, ID: NCT01049282. Retrospectively registered on 14 January 2010.Electronic supplementary materialThe online version of this article (10.1186/s13063-017-2354-0) contains supplementary material, which is available to authorized users.