CYP2C19 and CYP2J2 genotypes predict praziquantel plasma exposure among Ethiopian school-aged children.

Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.

Evaluation of Statin Indication and Dose Intensification Among Type 2 Diabetic Patients at a Tertiary Hospital.

Background: Diabetes mellitus (DM) increases cardiovascular disease (CVD) incidence and mortality. While guidelines endorse statin use in type 2 DM (T2DM) to mitigate cardiovascular risks and mortality, challenges like statin initiation and prompt treatment adjustments affect patient outcomes. This study aimed to assess the appropriateness of indications for and dose intensification of statin therapy among T2DM patients at Tikur Anbessa Specialized Hospital (TASH). Methodology: A hospital-based cross-sectional study was conducted from April 1 to June 30 2020. In total, 405 T2DM patients were selected using a systematic random sampling technique. The data were analyzed using SPSS version 26.0. An adjusted odds ratio (OR) was used and a 95% confidence interval (CI) and p-values of <0.05 were utilized to determine statistical significance. Results: Of the total 405 participants, 346 (85.4%) started taking statins for primary or secondary prevention purposes. Indication for statin use was appropriate in 96.2% patients, while for 216 (62.4%) patients their doses were appropriately intensified. Predictors of the inappropriateness of statin use were an atherosclerotic cardiovascular disease (ASCVD) score of ≥7.5% (AOR=0.28; 95% CI: 0.102-0.738, p=0.01), the presence of dyslipidemia (AOR=4.48; 95% CI: 1.85-10.84; p=0.001), initiation of aspirin therapy (AOR=3.7; 95% CI: 1.522-9.144; p=0.004), and an LDL-cholesterol level of 70-189 mg/dL (AOR=0.124; 95% CI: 0.042-0.365; p=0.001). DM duration of ≥10 years (AOR=2.51; 95% CI: 1.35-4.66, p=0.004), male gender (AOR=2.04; 95% CI: 1.16-3.58, p=0.013), age ≥65 years (AOR=2.15; 95% CI: 1.23-3.75, p=0.007) and uncontrolled blood pressure (AOR=2.09; 95% CI: 1.07-4.08, p=0.031) were associated with inappropriate statin intensification. Conclusion: The study found that indication of statins was optimal and about two-thirds of patients had their doses appropriately intensified. Monitoring is needed to avoid inappropriate intensification of statin therapy, particularly in patients with longer diabetes duration, those of male gender and advanced age, and those with uncontrolled blood pressure.

Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis.

BACKGROUND: Rifampicin, a key drug against tuberculosis (TB), displays wide between-patient pharmacokinetics variability and concentration-dependent antimicrobial effect. We investigated variability in plasma rifampicin concentrations and the role of SLCO1B1, ABCB1, arylacetamide deacetylase (AADAC) and carboxylesterase 2 (CES-2) genotypes in Ethiopian patients with TB. METHODS: We enrolled adult patients with newly diagnosed TB (n = 119) who had received 2 weeks of rifampicin-based anti-TB therapy. Venous blood samples were obtained at three time points post-dose. Genotypes for SLCO1B1 (c.388A > G, c.521T > C), ABCB1 (c.3435C > T, c.4036A > G), AADACc.841G > A and CES-2 (c.269-965A > G) were determined. Rifampicin plasma concentration was quantified using LC-MS/MS. Predictors of rifampicin Cmax and AUC0-7 h were analysed. RESULTS: The median rifampicin Cmax and AUC0-7 were 6.76 µg/mL (IQR 5.37-8.48) and 17.05 µg·h/mL (IQR 13.87-22.26), respectively. Only 30.3% of patients achieved the therapeutic efficacy threshold (Cmax>8 µg/mL). The allele frequency for SLCO1B1*1B (c.388A > G), SLCO1B1*5 (c.521T > C), ABCB1 c.3435C > T, ABCB1c.4036A > G, AADAC c.841G > A and CES-2 c.269-965A > G were 2.2%, 20.2%, 24.4%, 14.6%, 86.1% and 30.6%, respectively. Sex, rifampicin dose and ABCB1c.4036A > G, genotypes were significant predictors of rifampicin Cmax and AUC0-7. AADACc.841G > A genotypes were significant predictors of rifampicin Cmax. There was no significant influence of SLCO1B1 (c.388A > G, c.521T > C), ABCB1c.3435C > T and CES-2 c.269-965A > G on rifampicin plasma exposure variability. CONCLUSIONS: Subtherapeutic rifampicin plasma concentrations occurred in two-thirds of Ethiopian TB patients. Rifampicin exposure varied with sex, dose and genotypes. AADACc.841G/G and ABCB1c.4036A/A genotypes and male patients are at higher risk of lower rifampicin plasma exposure. The impact on TB treatment outcomes and whether high-dose rifampicin is required to improve therapeutic efficacy requires further investigation.

Reduced efficacy of single-dose albendazole against Ascaris lumbricoides, and Trichuris trichiura, and high reinfection rate after cure among school children in southern Ethiopia: a prospective cohort study.

BACKGROUND: Mass drug administration (MDA) program of albendazole to at-risk populations as preventive chemotherapy is the core public health intervention to control soil-transmitted helminths (STHs). Achieving this goal relies on drug effectiveness in reducing the parasite reservoirs in the community and preventing reinfection. We assessed the efficacy of albendazole against STH parasite infection and reinfection status after cure. METHODS: A total of 984 schoolchildren infected with at least one type of STH parasite (hookworm, Ascaris lumbricoides, Trichuris trichiura) in southern Ethiopia were enrolled and received albendazole and praziquantel in MDA campaign conducted from January to March 2019. Stool exams at week-4 and at week-8 of post-MDA were done using Kato Katz technique. The primary outcome was efficacy assessed by cure rate (CR) and fecal egg reduction rates (ERRs) at four weeks of post-MDA. The secondary outcome was reinfection status defined as parasite egg positivity at eight weeks among those who were cured at 4 weeks of post-MDA. Group comparisons in CR and related factors were assessed with chi-square or Fisher's exact tests. Predictors of CR were examined through univariate and multivariate regression analyses. RESULTS: The overall CR and ERR for hookworm infection were 97.2% (95% CI 94.6-99.4) and 97.02%, respectively. The overall CR and ERR for A. lumbricoides were 71.5% (95% CI 68.3-74.6) and 84.5% respectively. The overall CR and ERR and for T. trichiura were 49.5% (95% CI 44.8-54.2) and 68.3%, respectively. The CR among moderate T. trichiura infection intensity was 28.6%. Among children cured of hookworm, A. lumbricoides and T. trichiura at week 4 post-MDA, 4.6%, 18.3% and 52.4% became reinfected at week-8 post-MDA, respectively. Significantly lower CR (36.6%) and higher reinfection after cure (60.6%) among A. lumbricoides and T. trichiura coinfected children than A. lumbricoides only (CR = 69.6%, reinfection rate = 15.1%) or T. trichiura only infected children (CR = 55.6%, reinfection rate = 47.1%) was observed. Pre-treatment coinfection with ≥ two types of STH parasites was significantly associated with re-infection after cure. CONCLUSION: Albendazole MDA is efficacious against hookworm but has reduced efficacy against A. lumbricoides and is not effective against T. trichiura. The low drug efficacy and high reinfection rate after cure underscore the need for alternative treatment and integration of other preventive measures to achieve the target of eliminating STHs as a public health problem by 2030.

Efficacy and safety of praziquantel treatment against Schistosoma mansoni infection among pre-school age children in southern Ethiopia.

BACKGROUND: Preventive chemotherapy with a single dose of praziquantel given to an all-at-risk population through mass drug administration is the cornerstone intervention to control and eliminate schistosomiasis as a public health problem. This intervention mainly targets school age children, and pre-school age children (pre-SAC) are excluded from receiving preventive chemotherapy, partly due to scarcity of data on praziquantel treatment outcomes. METHODS: We conducted active efficacy and safety surveillance of praziquantel treatment among 240 Schistosoma mansoni-infected pre-SAC who received a single dose of praziquantel (40 mg/kg) in southern Ethiopia. The study outcomes were egg reduction rates (ERR) and cure rates (CRs) four weeks after treatment using the Kato-Katz technique and treatment-associated adverse events (AEs) that occurred within 8 days post-treatment. RESULTS: The overall ERR was 93.3% (WHO reference threshold ≥ 90%), while the CR was 85.2% (95% CI = 80.0-89.5%). Baseline S. mansoni infection intensity was significantly associated with CRs, 100% among light infected than moderate (83.4%) or heavy (29.4%) infected children. An increase of 100 in baseline S. mansoni egg count per gram of stool resulted in a 26% (95% CI: 17%, 34%) reduction in the odds of cure. The incidence of experiencing at least one type of AE was 23.1% (95% CI: 18.0%, 29.0%). Stomachache, diarrhea, and nausea were the most common AEs. AEs were mild-to-moderate grade and transient. Pre-treatment moderate (ARR = 3.2, 95% CI: 1.69, 6.14) or heavy infection intensity (ARR = 6.5, 95% CI: 3.62, 11.52) was a significant predictor of AEs (p < 0.001). Sex, age, or soil-transmitted helminth coinfections were not significant predictors of CR or AEs. CONCLUSIONS: Single-dose praziquantel is tolerable and effective against S. mansoni infection among pre-SAC, and associated AEs are mostly mild-to-moderate and transient. However, the reduced CR in heavily infected and AEs in one-fourth of S. mansoni-infected pre-SAC underscores the need for safety and efficacy monitoring, especially in moderate-to-high infection settings. Integrating pre-SACs in the national deworming programs is recommended to accelerate the elimination of schistosomiasis as a public health problem.

Prevalence and Determinants of Schistosoma mansoni Infection among Pre-School Age Children in Southern Ethiopia.

School-based deworming program is implemented to control and eliminate Schistosoma mansoni infection in many endemic countries, including Ethiopia. However, pre-school-age children (pre-SAC) are not targeted to receive preventive chemotherapy against S. mansoni infection, partly due to a lack of information on the disease burden. We assessed the prevalence and correlates of S. mansoni infection among pre-SAC in Southern Ethiopia. A total of 1683 pre-SAC aged 4 to 7 years were screened for S. mansoni infection. A multilevel binary logistic regression was fitted to detect the significant determinants of S. mansoni infection. Adjusted odds ratios (AORs) with a 95% confidence interval (CI) were used to identify determinants of S. mansoni infection. The overall prevalence of S. mansoni infection was 14.3% (95% CI: 12.6, 16.0%). S. mansoni infection was significantly higher among 6-year-old (AOR = 2.58, 95% CI: 1.55, 4.27) and 7-year-old children (AOR = 4.63, 95% CI: 2.82, 7.62). Accompanying others to water sources sometimes (AOR = 2.60, 95% CI: 1.12, 6.01) and all the time (AOR = 5.91, 95% CI: 2.51, 13.90), and residing in less than one kilometer from the infested water source (AOR = 3.17, 95% CI: 1.47, 6.83) increased the odds of S. mansoni infection. In conclusion, the prevalence of S. mansoni infection among pre-SAC in the study area was moderate. The study highlights the urgent need to include pre-SAC aged 4 to 7 years in annual preventive chemotherapy campaigns to reduce the risk of possible sources of infection and enhance the achievement of the elimination target.

Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients.

Unfavorable treatment outcomes for tuberculosis (TB) treatment might result from altered plasma exposure to antitubercular drugs in TB patients. The present study investigated the distribution of the N-Acetyltransferase 2 (NAT2) genotype, isoniazid acetylation status, genotype-phenotype concordance of NAT2, and isoniazid plasma exposure among Ethiopian tuberculosis patients. Blood samples were collected from newly diagnosed TB patients receiving a fixed dose combination of first-line antitubercular drugs daily. Genotyping of NAT2 was done using TaqMan drug metabolism assay. Isoniazid and its metabolite concentration were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 120 patients (63 male and 57 female) were enrolled in this study. The mean daily dose of isoniazid was 4.71 mg/kg. The frequency of slow, intermediate, and fast NAT2 acetylators genotypes were 74.2%, 22.4%, and 3.3% respectively. The overall median isoniazid maximum plasma concentration (Cmax) was 4.77 µg/mL and the AUC0-7 h was 11.21 µg.h/mL. The median Cmax in slow, intermediate, and fast acetylators were 5.65, 3.44, and 2.47 µg/mL, respectively. The median AUC0-7 h hour in slow, intermediate, and fast acetylators were 13.1, 6.086, and 3.73 mg•h/L, respectively. The majority (87.5%) of the study participants achieved isoniazid Cmax of above 3 µg/mL, which is considered a lower limit for a favorable treatment outcome. There is 85% concordance between the NAT2 genotype and acetylation phenotypes. NAT2 genotype, female sex, and dose were independent predictors of Cmax and AUC0-7 h (p < 0.001). Our finding revealed that there is a high frequency of slow NAT2 genotypes. The plasma Cmax of isoniazid was higher in the female and slow acetylators genotype group. The overall target plasma isoniazid concentrations in Ethiopian tuberculosis patients were achieved in the majority of the patients. Therefore, it is important to monitor adverse drug reactions and the use of a higher dose of isoniazid should be closely monitored.

Anti-Hyperglycemic and Hypoglycemic Activities of 80% Methanol Extract and Solvent Fractions of Ocimum lamiifolium Hochst Ex Benth. (Lamiaceae) Leaves in Mice.

Background: Globally, the prevalence of diabetes mellitus is rising. Due to the scarcity, high cost, and many adverse effects of modern treatments, traditional medicine is commonly used in rural areas to treat a variety of illnesses, including diabetes mellitus. The aim of this study was to assess the antihyperglycemic and hypoglycemic effects of Ocimum lamiifolium Hochst ex Benth leaves. Methods: A crude methanol 80% extract's and its solvent fractions' effects on healthy, oral glucose-given, and STZ-induced diabetic mice were examined. Swiss albino mice of either sex were assigned into sixteen groups, each containing six mice, for the OGTT and hypoglycemia tests. Male mice were used in the study, and they were divided into groups for the negative control (citrate buffer for diabetic mice), the normal control (Tween 2%), the test groups, and a positive control (glibenclamide) for the antihyperglycemic test in STZ (200 mg/kg body weight)-induced diabetic mice. Results: A crude 80% methanol extract of 200 mg/kg effectively lowered blood glucose levels (p <0.05) and none of the fractions extracts caused hypoglycemia shock in norma mice. The aqueous residue at 100, 200, and 400 mg/kg, the n-butanol fraction at 100 and 200 mg/kg, and the chloroform fraction at 200 mg/kg demonstrated higher glucose tolerance in orally glucose-loaded mice (p <0.05). The crude 400 mg/kg of an 80% methanol extract, 100 and 200 mg/kg of the n-butanol fraction, 200 and 400 mg/kg of the chloroform fraction, and 5 mg/kg of glibenclamide significantly reduced blood glucose levels in STZ-induced diabetic mice (p <0.05). Conclusion: The current research demonstrates that a crude 80% methanol extract of Ocimum lamiifolium Hochst ex Benth leaves, as well as its solvent fractions, significantly reduce blood sugar levels in mice that are healthy, loaded with glucose, and streptozotocin induced diabetic mice.

Safety of equine tetanus antitoxin for prophylactic use in Ethiopia: a retrospective multi-center study.

BACKGROUND: Tetanus remains a severe life-threatening infectious disease and neurological disorder in many parts of the world, where immunization programs are suboptimal. Any human injury or trauma has the possibility of getting infected with Clostridium tetani which is the sole causative bacterium of tetanus. Evidence is available that TAT may cause anaphylaxis and late serum sickness, while there has been no study conducted in Ethiopia. The Ethiopian Ministry of Health standard treatment guideline recommends tetanus prophylaxis for all tetanus-prone wounds. This study aimed to evaluate the safety of TAT administration in adults exposed to tetanus-prone wounds in Ethiopia. METHODS: The target product of this study was the equine tetanus antitoxin developed and manufactured by the ViNS Bioproducts Limited, India (Code: 130202084, A.W.No: 15/AAW/PI/02.00, DT: 25.04.2016). The product is delivered with the dose of 1000/1500 IU intramuscularly or subcutaneously to individuals at risk of tetanus infection for prophylactic purposes. The study was carried out in 11 healthcare facilities in Addis Ababa, Ethiopia, that had a relatively high clients load for tetanus-prone wounds. Medical records of patients with tetanus-prone wounds who received the equine TAT were reviewed retrospectively for any adverse events following immunization according to the World Health Organization (WHO) definition for adverse events following immunization (AEFI). RESULTS: There were more than 20,000 patients treated for trauma in the facilities from 2015 to 2019. Upon revision of available registration books, we identified 6000 charts to be eligible for the study, of which 1213 charts that had complete and reliable data on the AEFI profile of the TAT were included in the final analysis. The median age of the study participants was 26 years (IQR = 11 years, age range: 18-91 years) and 78% (949) were male. The tetanus-prone wounds resulted mainly from stab (44%, 535) and blunt force (30%, 362), and the most common sites of wounds were hand (22%, 270) and head (21%, 253). The most and least frequently occurring types of wounds were open wounds (77%, 930) and organ system injury (0.003%, 4), respectively. The mean time of presenting at health facilities from the onset of trauma was 2.96 h. Of the total 1231 participants, one male participant who presented within 3 h after experiencing a wound on his nose at the workplace had a severe local reaction immediately after injection of the TAT. No AEFI was recorded for the other participants. CONCLUSIONS: The adverse event following immunization of the equine tetanus antitoxin produced by the ViNS Bioproducts Limited was very rare. A regular review of the product's safety performance and systematic collection and analysis of adverse event reports are important to ensure the safety of the product.

In vitro Anti-Leishmanial Activities of Methanol Extract of Brucea antidysenterica J.F. Mill Seeds and Its Solvent Fractions.

Introduction: Leishmaniasis is one of the neglected tropical diseases, threatening lives of about 350 million people globally. Brucea antidysenterica seeds are used for the treatment of cutaneous leishmaniasis in the traditional medicine in Ethiopia. Objective: This study aimed to evaluate Brucea antidysenterica seeds' anti-leishmanial activity in vitro. Methods: The crude (80% methanol) extract of Brucea antidysenterica seeds and its fractions were evaluated for their anti-leishmanial activities against promastigotes and intracellular amastigotes of Leishmania donovani and Leishmania aethiopica, and for their cytotoxic effects against mammalian cells. The quantitative estimations of total phenolic compounds (TPCs), flavonoids (TFCs) and alkaloids (TACs) were determined, spectrophotometrically. Median inhibitory concentration (IC50) and median cytotoxic concentration (CC50) of the extract and its solvent fractions were calculated using GraphPad Prism 9.1.0 computer software. Data was presented as mean ± standard error of the mean (SEM). Results: The crude extract and its hexane, ethyl acetate and butanol fractions showed anti-leishmanial activities, with IC50 values of 4.14-60.12 µg/mL against promastigotes, and 6.16-40.12 µg/mL against amastigotes of both Leishmania species. They showed moderate cytotoxicity against Vero cell lines and peritoneal mice macrophages, with CC50 values of 100-500 µg/mL, but >1600 µg/mL against red blood cells. Selectivity indices ranged from 7.97 to 30.97. The crude extract, and its ethyl acetate and hexane fractions possessed 54.78-127.72 mg of gallic acid equivalent TPC, 18.30-79.21 mg of quercetin equivalent TFC, and 27.62-97.22 mg of atropine equivalent TAC per gram of extracts. Conclusion: The seeds of the plant possessed anti-leishmanial activities against L. aethiopica and L. donovani that might provide a scientific justification for its use in the treatment of leishmaniasis by traditional healers. Future works are recommended to isolate, purify and identify the possible secondary metabolites attributed to the anti-leishmanial activity.

Efficacy and safety of praziquantel preventive chemotherapy in Schistosoma mansoni infected school children in Southern Ethiopia: A prospective cohort study.

Background: The World Health Organization recommends efficacy and safety surveillance of anti-helminths used in mass drug administration campaigns. We evaluated the effectiveness of single-dose praziquantel against Schistosoma mansoni infection, and the safety of praziquantel plus albendazole preventive chemotherapy (PC) in Schistosoma mansoni infected school children (n = 512) in Southern Ethiopia. Method: Stool examinations were done using thick smear Kato-Katz at baseline, week-4, and week-8 of post-Mass drug administration (MDA) to assess praziquantel efficacy. Participants were followed for MDA-associated adverse events up to day 7 of post-MDA. The primary and secondary study outcomes were praziquantel efficacy (parasitological cure and egg reduction rates) and MDA-associated adverse events (AEs), respectively. Result: The overall cure rates at week-4 and week-8 were 89.1% (95%CI = 86.1-91.7) and 87.5% (95%CI = 83.6-90.8), respectively. Cure rates among moderate-to-heavily infected children were significantly lower (p = 0.001) compared to those with light infection at week-4 (84.4% vs. 91.1%, p = 0.03) and week-8 (78.6% vs. 91.9%, respectively). Older children had a higher cure rate than younger ones at week-8 (90.1% vs. 79.5%, p = 0.01). Among those who were Schistosoma egg-free (cured) at week 4, 7.8% became egg-positive at week 8. The overall egg reduction rate (ERR) at week-4 and week-8 were 93.5% and 91.3%, respectively, being lower among the 5-9 years old age groups (p = 0.01) at week-8. The proportion of children who remained schistosoma egg-positive throughout the study follow-up period was 4.6%, and their ERR at week-4 and week-8 was 50% and 51%, respectively, which is below the 90% World Health Organization threshold for efficacy. The incidence of experiencing at least one type of MDA-associated AEs were 17.0% (95%CI = 13.8%-20.5%); abdominal pain, headache, and vomiting were the most common. The proportion of mild, moderate, and severe AEs was 63.2%, 26.3%, and 10.5%, respectively. Females experienced more AEs than males (p = 0.03). Conclusion: Single-dose praziquantel is still effective for the treatment of intestinal schistosomiasis. Praziquantel and albendazole preventive chemotherapy is safe and tolerable, and associated AEs are mostly mild-to-moderate and transient. However, the reduced PZQ effectiveness in moderate-to-heavy infection and observed AEs in about one-fifth of infected children underscores the need for better treatment strategies and surveillance for early detection of parasite resistance and management of AEs.

Genetic and non-genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus-1-infected children in Ethiopia.

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A one-compartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 µg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.

Antimicrobial prescription patterns in East Africa: a systematic review.

BACKGROUND: Antimicrobial resistance is currently a recognized global health problem stemming from poor antibiotic stewardship by health workers and inappropriate antimicrobial use by patients. Data showing the extent of poor antimicrobial stewardship in low- and middle-income countries are scanty though high incidences of antimicrobial resistance are increasingly reported in many settings across the globe. The objective of the present study was, therefore, to evaluate prescriptions for antimicrobials in East Africa. METHODS: A comprehensive literature search strategy that includes text words and medical subject headings was developed and applied to predefined electronic databases. Two authors independently screened the titles and abstracts of the outputs of the literature search. Full texts were then independently reviewed by the first and the second authors. Eligible studies were formally assessed for quality and risk of bias using a scoring tool. Extracted data from included studies were combined in a meta-analysis where appropriate and presented using forest plots and tables or in a narrative text. Where data were available, subgroup analyses were performed. RESULTS: A total of 4284 articles were retrieved, but only 26 articles were included in the review. The majority of the included studies (30.8%) were retrieved from Ethiopia, followed by Sudan, Kenya, and Tanzania each contributing 19.2% of the included studies. The overall proportion of encounters with antimicrobials reported by the included studies was 57% CI [42-73%]. Ethiopia had an overall patient encounter with antimicrobials of 63% [50-76%] followed by Sudan with an overall encounter with antimicrobials of 62% CI [34-85%]. Included studies from Kenya reported an overall encounter with antimicrobials of 54% CI [15-90%], whereas included studies from Tanzania reported an overall patient encounter with antimicrobials of 40% CI [21-60%]. CONCLUSION: Prescription patterns demonstrated in this review significantly deviate from WHO recommendations suggesting inappropriate antimicrobial use in the East African countries. Further studies have to be pursued to generate more information on antimicrobial use in this region.

System and facility readiness assessment for conducting active surveillance of adverse events following immunization in Addis Ababa, Ethiopia.

BACKGROUND: To help distinguish vaccine-related adverse events following immunization (AEFI) from coincidental occurrences, active vaccine pharmacovigilance (VP) prospective surveillance programs are needed. From February to May 2021, we assessed the system and facility readiness for implementing active AEFI VP surveillance in Addis Ababa, Ethiopia. METHODS: Selected hospitals were assessed using a readiness assessment tool with scoring measures. The site assessment was conducted via in-person interviews within the specific departments in each hospital. We evaluated the system readiness with a desk review of AEFI guidelines, Expanded Program for Immunization Guidelines and Ethiopian Food and Drug Administration and Ethiopian Public Health Institute websites. RESULTS: Of the hospitals in Addis Ababa, 23.1% met the criteria for our site assessment. During the system readiness assessment, we found that essential components were in place. However, rules, regulations and proclamations pertaining to AEFI surveillance were absent. Based on the tool, the three hospitals (A, B and C) scored 60.6% (94/155), 48.3% (75/155) and 40% (62/155), respectively. CONCLUSIONS: Only one of three hospitals assessed in our evaluation scored >50% for readiness to implement active AEFI surveillance. We also identified the following areas for improvement to ensure successful implementation: training, making guidelines and reporting forms available and ensuring a system that accommodates paper-based and electronic-based recording systems.

Prenatal developmental toxicity study of herbal tea of Moringa stenopetala and Mentha spicata leaves formulation in Wistar rats.

Background: Moringa stenopetala and Mentha spicata have long been used to treat diabetes, hypertension, asthma, and other ailments. Herbal tea of M. stenopetala and Mentha spicata leaves formulation showed better antidiabetic and antihypertensive activities. This study investigated the prenatal developmental toxicity potential of the herbal tea of M. stenopetala and M. spicata leaves blend in rats. Methods: Wistar pregnant rats were randomly distributed into four groups (n = 8). Group I (control) dams received distilled water. Group II-IV dams were treated with 559.36, 1118.72, and 2237.44 mg/kg of herbal tea of M. stenopetala and Mentha spicata leaves formulations, respectively, during days 5-19 of gestation. Maternal mortality, clinical signs, body weight changes, and food consumption were recorded. On gestation day 20, cesarean sections were performed, and maternal parameters of systemic toxicity (e.g., body weight, serum biochemistry, organ weight, and macro-pathology) as well as reproductive toxicity (e.g., number of corpora lutea, implantations, resorptions (early/late), pre/postimplantation losses, number of fetuses (live/dead), and fetal body weights, length, and their sex ratio) were evaluated. Fetuses were further examined for external, soft tissue, and skeletal alterations. Results: No herbal tea-related maternal deaths or overt toxic symptoms were observed. The measured maternal systemic and reproductive toxicity parameters showed no herbal tea-associated significant alterations at any dosage levels. Moreover, there were no overt toxic effects of the herbal tea on the fetal external, visceral, or skeletal prenatal growth and development. Conclusion: The study findings demonstrated that the herbal tea of M. stenopetala and M. spicata leaves blend could be relatively safe/low toxic to pregnant rats and developing fetuses. The no-observed-adverse-effect level (NOAEL) of herbal tea for maternal toxicity, fetotoxicity, and teratogenicity in rats is estimated to be > 2237.44 mg/kg/day.

Safety Surveillance of Mass Praziquantel and Albendazole Co-Administration in School Children from Southern Ethiopia: An Active Cohort Event Monitoring.

Preventive chemotherapy (PC) with praziquantel and albendazole co-administration to all at-risk populations is the global intervention strategy to eliminate schistosomiasis and soil-transmitted helminth (STH) from being public health problems. Due to weak pharmacovigilance systems, safety monitoring during a mass drug administration (MDA) is lacking, especially in sub-Saharan Africa. We conducted large-scale active safety surveillance to identify the incidence, types, severity, and associated risk factors of adverse events (AEs) following praziquantel and albendazole MDA in 5848 school children (5−15 years old). Before MDA, 1484 (25.4%) children were prescreened for S. mansoni and STH infections, of whom 71.8% were infected with at least one parasite; 34.5% (512/1484) had S. mansoni and 853 (57.5%) had an STH infection. After collecting the baseline socio-demographic, clinical, and medical data, including any pre-existing clinical symptoms, participants received single dose praziquantel and albendazole MDA. Treatment-associated AEs were actively monitored on days 1 and 7 of the MDA. The events reported before and after the MDA were cross-checked and verified to identify MDA-associated AEs. The cumulative incidence of experiencing at least one type of MDA-associated AE was 13.3% (95% CI = 12.5−14.2%); 85.5%, 12.4%, and 1.8% of reported AEs were mild, moderate, and severe, respectively. The proportion of experiencing one, two, or ≥ three types of AEs was 57.7%, 34.1%, and 8.2%, respectively. The cumulative incidence of AEs in S. mansoni- and (17.0%) and STH (14.1%)-infected children was significantly higher (p < 0.001, χ2 = 15.0) than in non-infected children (8.4%). Headache, abdominal pain, vomiting, dizziness, and nausea were the most common AEs. Being female, older age, having S. mansoni or STH infection were significant predictors of MDA-associated AEs. In summary, praziquantel and albendazole co-administration is generally safe and tolerable. MDA-associated AEs are mostly mild-to-moderately severe and transient. The finding of few severe AEs and significantly high rates of AEs in helminth-infected children underscores the need to integrate pharmacovigilance in MDA programs, especially in high schistosomiasis and STH endemic areas.

Joint Analysis of Phenotypic and Genomic Diversity Sheds Light on the Evolution of Xenobiotic Metabolism in Humans.

Variation in genes involved in the absorption, distribution, metabolism, and excretion of drugs (ADME) can influence individual response to a therapeutic treatment. The study of ADME genetic diversity in human populations has led to evolutionary hypotheses of adaptation to distinct chemical environments. Population differentiation in measured drug metabolism phenotypes is, however, scarcely documented, often indirectly estimated via genotype-predicted phenotypes. We administered seven probe compounds devised to target six cytochrome P450 enzymes and the P-glycoprotein (P-gp) activity to assess phenotypic variation in four populations along a latitudinal transect spanning over Africa, the Middle East, and Europe (349 healthy Ethiopian, Omani, Greek, and Czech volunteers). We demonstrate significant population differentiation for all phenotypes except the one measuring CYP2D6 activity. Genome-wide association studies (GWAS) evidenced that the variability of phenotypes measuring CYP2B6, CYP2C9, CYP2C19, and CYP2D6 activity was associated with genetic variants linked to the corresponding encoding genes, and additional genes for the latter three. Instead, GWAS did not indicate any association between genetic diversity and the phenotypes measuring CYP1A2, CYP3A4, and P-gp activity. Genome scans of selection highlighted multiple candidate regions, a few of which included ADME genes, but none overlapped with the GWAS candidates. Our results suggest that different mechanisms have been shaping the evolution of these phenotypes, including phenotypic plasticity, and possibly some form of balancing selection. We discuss how these contrasting results highlight the diverse evolutionary trajectories of ADME genes and proteins, consistent with the wide spectrum of both endogenous and exogenous molecules that are their substrates.

Effect of Genetic Variations in Drug-Metabolizing Enzymes and Drug Transporters on the Pharmacokinetics of Rifamycins: A Systematic Review.

Background: Rifamycins are a novel class of antibiotics clinically approved for tuberculosis chemotherapy. They are characterized by high inter-individual variation in pharmacokinetics. This systematic review aims to present the contribution of genetic variations in drug-metabolizing enzymes and transporter proteins to the inter-individual variation of rifamycin pharmacokinetics. Method: We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines. The search for relevant studies was done through PubMed, Embase, Web of Science, and Scopus databases. Studies reporting single nucleotide polymorphism in drug transporters and metabolizing enzymes' influence on rifamycin pharmacokinetics were solely included. Two reviewers independently performed data extraction. Results: The search identified 117 articles of which 15 fulfilled the eligibility criteria and were included in the final data synthesis. The single nucleotides polymorphism in the drug transporters SLCO1B1 rs4149032, rs2306283, rs11045819, and ABCB1 rs1045642 for rifampicin, drug metabolizing enzyme AADAC rs1803155 for rifapentine and CES2 c.-22263A>G (g.738A>G) for rifampicin partly contributes to the variability of pharmacokinetic parameters in tuberculosis patients. Conclusion: The pharmacokinetics of rifamycins is influenced by genetic variation of drug-metabolizing enzymes and transporters. Controlled clinical studies are, however, required to establish these relationships.

Constitutive androstane receptor and pregnane X receptor genotype influence efavirenz plasma concentration and CYP2B6 enzyme activity.

Efavirenz is metabolized by CYP2B6, an inducible enzyme whose expression is regulated by the constitutive androstane receptor and pregnane X receptor nuclear receptors. CAR and PXR are encoded by genetically polymorphic NR1I2 and NR1I3, respectively. We examined the impact of NR1I2 and NR1I3 genotype on plasma EFV concentration and CYP2B6 enzyme activity among TB-HIV co-infected patients in Ethiopia. Treatment-naïve HIV patients with TB co-infection (n = 80) were enrolled and received first-line EFV-based antiretroviral and rifampicin-based anti-TB therapy. Plasma EFV and 8-hydroxy-EFV concentrations at the 4th and 16th week of EFV treatment were determined using LC/MS/MS. EFV/8-hydroxy-EFVmetabolic ratio was used as CYP2B6 metabolic activity index. In multivariate regression analysis, NR1I3 rs3003596C or NR1I2 rs2472677T variant allele carriers had significantly lower plasma EFV concentrations than non-carriers. Patients with NR1I2 rs3814057C/C genotype or NR1I3 rs3003596C allele carriers had significantly lower mean log EFV MR. Among CYP2B6*6 allele carriers, patients with NR1I3 rs2502815T/T or NR1I2 rs3814057C/C genotype had significantly lower mean log EFV MR. In conclusion, genetic variants in NR1I2 and NR1I3 genes influence plasma EFV exposure and CYP2B6 enzyme activity in TB-HIV co-infected patients on drug treatment.

Evaluation of Wound Healing and Antibacterial Activities of Solvent Fractions of 80% Methanol Leaf Extract of Brucea antidysenterica J.F. Mill (Simaroubaceae).

Background: Brucea antidysenterica is a well-known medicinal plant that has traditionally been used to treat a variety of ailments, including wound healing. Supporting the traditional claims, wound healing, antibacterial, anti-inflammatory, and antioxidant activities of the crude extracts of different parts of the plant were reported. The aim of this study was to evaluate the wound healing and antibacterial activities of solvent fractions of the menthol leaf extract of Brucea antidysenterica. Methods: Methanol (80%) leaf extract of Brucea antidysenterica was fractionated using three solvents; water, n-butanol and chloroform. An ointment containing 2% and 4% of each fraction was formulated and applied to wounds inflicted on rats topically. The wound contraction rate, period of epithelialization, and breaking strength were analysed. In vitro antibacterial activities were tested using the agar diffusion method. The macro-tube dilution technique was used to determine the minimum inhibitory concentration (MIC), and the minimum bactericidal concentration (MBC) was determined by sub-culturing the MIC and concentrations below the MIC. Results: The 2% and 4% aqueous fractions (AF) significantly increased wound contraction (p 0.001) compared to the negative control and increased tensile strength compared to untreated (p 0.001). Among the three fractions, the n-butanol fraction showed the highest antibacterial growth inhibition, ranging from 8 mm (E. coli) to 16 mm (S. aureus). Conclusion: Data obtained from this study collectively indicated that the aqueous fraction of 80% methanol leaf extract of B. antidysenterica possesses wound healing and antibacterial activities.