Association of the Reduced Function Met420del Polymorphism of SLC22A1 with Metformin-Induced Gastrointestinal Intolerance in Ethiopian Patients with Type 2 Diabetes Mellitus.

Background: Despite its widespread use and favored profile, there are extensive variations in the treatment outcome of metformin therapy. Furthermore, studies reported that the inter-individual variability in the occurrence of metformin treatment associated side effects were related to the differences in individual genetic profiles. Thus, this study aimed to evaluate whether the reduced function methionine deletion at codon 420 (Met420del) variant of SLC22A1 (rs72552763) is associated with metformin induced gastrointestinal intolerance in Ethiopian patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A retrospective observational study was conducted on 47 T2DM patients on metformin treatment for <3 years to assess the association of SLC22A1 (rs72552763) polymorphism with metformin induced gastrointestinal intolerance. Accordingly, 24 metformin tolerant and 23 metformin intolerant individuals with T2DM were recruited. Genotyping of rs72552763 was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association to metformin induced gastrointestinal intolerance was assessed based on switching to a new class of glucose lowering agents or failure to up titrate dose due to metformin induced gastrointestinal intolerance. Chi-square, logistic regression and Mann-Whitney statistical tests were used as appropriate. Statistical significance was set at p < 0.05. Results: In our study, no significant association was observed between rs72552763 and metformin induced gastrointestinal intolerance. We found that the female gender and physical inactivity were risk factors for metformin gastrointestinal intolerance. Conclusion: Our study found that the Met420del variant of SLC22A1 (rs72552763) was not associated with metformin induced gastrointestinal intolerance in Ethiopian patients with T2DM. This is the study first to investigate the association of rs72552763 with metformin intolerance in the Ethiopian population with T2DM. However, the findings need to be cautiously interpreted given the relatively small sample size. In addition, a more complete investigation of SLC22A1 variants would be required to fully assess the effect of the gene on metformin induced gastrointestinal intolerance as several variants with a more severe loss of function have been described.

Liver Cirrhosis of Unknown Etiology and Its Predictors in Eastern Ethiopia.

Background: The global burden of liver cirrhosis is increasing, with 2.1 million incident cases and nearly 1.5 million deaths in 2019. Despite the enormous progress in our understanding of the etiology of liver cirrhosis, significant cases of the disease have been reported in Eastern Ethiopia due to unidentified causes. Hence, this study aimed to identify predictors of liver cirrhosis of unknown etiology in Eastern Ethiopia. Methods: A score of 7 out of 11 possible points on the ultrasound-based cirrhosis scale was used as a diagnostic criterion to include 127 liver cirrhosis patients. The study participants' demographic, dietary, lifestyle, and clinical data were gathered using a structured questionnaire and standardized reporting forms. The associations between the outcome (known and unknown etiology) and independent variables were modeled using binary logistic regression analysis. Results: The etiology of liver cirrhosis was known in only 23% of patients and attributed to hepatitis B virus (21%), hepatitis C virus (0.8%), and alcohol abuse (0.8%). Sorghum consumption as a staple food (adjusted odds ratio (AOR) =3.8; 95% CI: 1.2, 12.5), splenomegaly (AOR = 4.0; 95% CI: 1.1, 14.4), and a family history of liver disease (AOR = 0.24; 95% CI: 0.06, 0.91) were significantly associated with liver cirrhosis of unknown etiology. Conclusion: Sorghum consumption was found to be the determinant factor of liver cirrhosis of unknown etiology, suggesting it as a possible source of exposure to aflatoxin B1.

Characterization of potential probiotic starter cultures of lactic acid bacteria isolated from Ethiopian fermented cereal beverages, Naaqe, and Cheka.

AIMS: To test the in vitro probiotic potential and starter culture capacity of lactic acid bacteria (LAB) isolated from Naaqe and Cheka, cereal-based Ethiopian traditional fermented beverages. METHODS AND RESULTS: A total of 44 strains were isolated from spontaneously fermented Ethiopian cereal-based beverages, Naaqe and Cheka with 24 putatively identified as LAB and 14 identified up to the species level. The species Limosilactobacillus fermentum (6/12; 50%) and Weissella confusa (5/12, 41.67%) were the predominant species identified from Naaqe, while the two Cheka isolates were L. fermentum and Pediococcus pentosaceus. Six LAB strains inhibited eight of the nine gastrointestinal indicator key pathogens in Ethiopia, including Escherichia coli, Salmonella enterica subsp. enterica var. Typhimurium, Staphylococcus aureus, Shigella flexneri, and Listeria monocytogenes. Three of the LAB isolates exhibited strain-specific immunostimulation in human monocytes. Based on these probiotic properties and growth, six strains were selected for in situ evaluation in a mock fermentation of Naaqe and Cheka. During primary fermentations, L. fermentum 73B, P. pentosaceus 74D, L. fermentum 44B, W. confusa 44D, L. fermentum 82C, and Weissella cibaria 83E and their combinations demonstrated higher pH-lowering properties and colony-forming unit counts compared to the control spontaneous fermentation. The same pattern was also observed in the secondary mock fermentation by the Naaqe LAB isolates. CONCLUSIONS: In this study, we selected six LAB strains with antipathogenic, immunostimulatory, and starter culture potentials that can be used as autochthonous probiotic starters for Naaqe and Cheka fermentations once their health benefit is ascertained in a clinical trial as a next step.

Copy Number Variation in the GSTM1 and GSTT1 Genes and the Risk of Liver Cirrhosis in Eastern Ethiopia.

Background: Polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) can cause an entire gene deletion. The current methodology can accurately identify GSTM1 and GSTT1 copy number variants (CNVs), which may shed light on the true contribution of each gene copy to the cellular detoxification process and disease risk. Because liver cirrhosis is becoming a critical worldwide health issue, this study determined the CNVs of GSTM1 and GSTT1 and their relationship to the risk of liver cirrhosis. Methods: In this study, we compared 106 patients with liver cirrhosis to 104 healthy controls. Real-time PCR was used to identify the CNVs of GSTM1 and GSTT1. Logistic and linear regression models were used to estimate the relationship between liver cirrhosis and clinical chemistry variables with the CNVs, respectively. Results: In 3.3% of the study participants, >2 copies of the GSTM1 or GSTT1 genes were detected. GSTT1 carriers had a significantly lower risk of liver cirrhosis (p<0.05) compared with individuals who had homozygous deletion (adjusted odds ratio (AOR) = 0.47; 95% CI: 0.25, 0.86). This risk reduction was significant (p<0.05) in patients with a single copy of the GSTT1 gene (AOR = 0.48; 95% CI: 0.25, 0.91). Those with ≥2 copies of combined GSTM1 and GSTT1 also had a significantly (p<0.05) lower risk of developing liver cirrhosis compared with double null genotypes (AOR = 0.38; 95% CI: 0.16, 0.91, p trend <0.001). Moreover, ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a substantial decrease in alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels, respectively. Conclusion: A single copy number of GSTT1, and ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a reduced risk of liver cirrhosis in Ethiopians. These findings underscore the importance of gene-environment interactions in the multifactorial development of liver cirrhosis.

Chemopreventive Activity of 80% Methanol Leaf Extract of Vernonia auriculifera Hiern (Asteraceae) Against Dimethylhydrazine-Induced Colorectal Carcinogenesis in Rats.

Background: Vernonia auriculifera Hiern (Asteraceae) is among Ethiopian herbal medicines that are traditionally used to treat skin and gastrointestinal cancers. In this study, the chemopreventive potential of Vernonia auriculifera leaf extract in dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats was investigated. Methods: Rats were assigned to nine groups (normal, positive, and negative control groups, and three pre- and three post-initiation groups). Except for the normal control group (administered with 1 mL/100 g distilled water), the remaining eight groups were given DMH (20 mg/kg) intraperitoneally (ip) for 15 consecutive weeks to induce colorectal tumours. The extract was given orally to the pre-initiation and post-initiation groups at doses of 100, 200, and 400 mg/kg before and after the induction of cancer, respectively. The positive control group was treated with aspirin (60 mg/kg/day) orally for the whole experimental period. Parameters including body weight, average tumour number, size, progression, incidence, total cholesterol, serum total protein, and triglyceride levels were determined. The cytotoxic activity of the extract in Caco-2 cells was evaluated using the MTT assay, and the antioxidant activity of the extract was also assessed using 2.2-diphenyl-1-picrylhydrazine (DPPH) and reducing power methods. Moreover, total phenol and flavonoid contents were determined using appropriate methods. Results: Rats treated with the extract showed a lower incidence of up to 50% in the pre-initiation higher dose, average number (p<0.05),and size (p<0.05) of tumours compared to untreated rats. It also inhibited colorectal cancer-associated increases in serum total cholesterol and triglycerides. The extract's IC50 value in the MTT assay was found to be higher than 200 µg/mL. The extract had an IC50 of 74.88 ± 0.86 µg/mL and 84.69 ± 2.02 µg/mL in the reducing power and DPPH assays, respectively. Total flavonoid and phenol contents were 14.51 ± 0.41 mg quercetin acid equivalent/gm and 47.37 ± 0.72 mg gallic acid equivalent/gm of the crude extract, respectively. Conclusion: The findings collectively indicated that the leaves of V. auriculifera possess chemopreventive activity, probably mediated through antioxidant mechanisms, which supports the traditional claim.

Contribution of Aflatoxin B1 Exposure to Liver Cirrhosis in Eastern Ethiopia: A Case-Control Study.

Background: Liver cirrhosis is a global health problem due to a large number of disability-associated life years and mortality. However, evidence is scarce on its causes in Eastern-Ethiopia, a place where there is a high prevalence of liver cirrhosis of unknown etiology. This study attempted to identify the risk factors related to liver cirrhosis in the area. Methods: A case-control study was conducted at a tertiary care hospital from January 2020 to July 2021. Following diagnoses using an ultrasound-based cirrhosis scale, a total of 127 cases were identified and compared with 253 control patients. A structured questionnaire and data abstraction form were used to collect demographic, lifestyle, and clinical information. A blood sample was also taken from each participant for clinical chemistry, hepatitis B virus (HBV), and hepatitis C virus tests as well as for an aflatoxin B1 (AFB1) albumin adduct (AF-alb) assay. Binary logistic regression analysis was used to determine predictors of liver cirrhosis. Results: AF-alb levels were detected in 75% of the cases and 64% of the controls, with a median (IQR) level of 11 pg/mg (5.5-25) and 7.0 pg/mg (4.3-20.5), respectively (p<0.05). Moreover, the number of subjects with high AF-alb levels (≥8.6 pg/mg) was greater in cases (45%, p<0.05)) than controls (28%). Age ≥55 years (adjusted odds ratio (AOR)=0.4; 95% CI: 0.2, 0.8), being a farmer (AOR= 3.0; 95% CI: 1.5, 6.0), family history of liver disease (AOR= 2.9; 95% CI: 1.1, 7.9), HBV seropositivity (AOR=4.0; 95% CI: 1.9, 8.8), and exposure to high levels of AF-alb (AOR=2.0; 95% CI: 1.1, 3.7) were significantly associated with liver cirrhosis. Conclusion: This study found a strong link between AFB1 exposure and liver cirrhosis. Mitigation of aflatoxin exposure and a better understanding of additional environmental risk factors like pesticides may be necessary to reduce the disease burden in Ethiopia.

Association of Met420del Variant of Metformin Transporter Gene SLC22A1 with Metformin Treatment Response in Ethiopian Patients with Type 2 Diabetes.

Objective: This study aimed to evaluate whether the M420del variants of SLC22A1 (rs72552763) is associated with metformin treatment response in Ethiopian patients with type 2 diabetes mellitus (T2DM). Patients and Methods: A prospective observational cohort study was conducted on 86 patients with T2DM who had been receiving metformin monotherapy for <1 year. Patients showing ≥0.5% reduction in HbA1c levels from baseline within 3 months and remained low for at least another 3 months were defined as responders while those patients with <0.5% reduction in HbA1c levels and/or those whom started a new class of glucose-lowering drug(s) because of unsatisfactory reduction were defined as non-responders. In addition, good glycemic control was observed when HbA1c ≤7.0%, and the above values were regarded as poor. Genotyping of rs72552763 SNP was performed using TaqMan® Drug Metabolism Enzyme Genotyping Assay and its association with metformin response and glycemic control were assessed by measuring the change in HbA1c and fasting blood glucose levels using Chi-square, logistic regression and Mann-Whitney U-test. Statistical significance was set at p <0.05. Results: The minor allele frequency of the rs72552763 SNP of SLC22A1 was 9.3%. Metformin response was significantly higher in deletion_GAT (del_G) genotypes as compared to the wild-type GAT_GAT (G_G) genotypes. Furthermore, a significantly lower median treatment HbA1 level was found in del_G genotypes as compared to G_G genotypes. However, the association of rs72552763 with metformin response was not replicated at the allele level. In contrast, the minor del_allele was significantly associated with good glycemic control compared to the G_allele, though not replicated at del_G genotypes level. Conclusion: This study demonstrated that metformin response was significantly higher in study participants with a heterozygous carrier of M420del variants of SLC22A1 as compared to the wild-type G_G genotypes after 3 months of treatment.

Anti-Convulsant Activity of Soxhlet Leaf Extracts of Ajuga Integrifolia Buch.-Ham. Ex D.Don (Lamiaceae) in Mice.

Background: The leaves of Ajuga integrifolia Buch.-Ham. ex D.Don (Lamiaceae) have long been used as an anti-convulsant remedy in Ethiopian traditional medicine. However, the evidence supporting their use is sparse in the literature. This study was conducted to add to the existing body of knowledge about the anti-convulsant activity of the plant. Methods: The anti-convulsant activity of the extract was investigated in both acute (pentylenetetrazol [PTZ], 80 mg/kg; and maximal electroshock [MES]) and chronic (PTZ, 35 mg/kg) kindling seizure models. For the experimental paradigms, various doses of the extract (100, 200, and 400 mg/kg) were administered. Positive controls received sodium valproate (200 mg/kg) for the PTZ model and phenytoin (25 mg/kg) for the MES model. Parameters including the onset of clonus and duration of hindlimb tonic extension were recorded and compared with controls. Moreover, the total alkaloid, flavonoid, and phenol contents of the extracts were determined. Results: Ethyl acetate extract produced a superior effect among all solvent extracts in both the PTZ and MES models. At all doses, it significantly delayed the mean onset of clonus (p<0.01) in the PTZ test compared to controls. It also significantly reduced (p<0.001) the mean duration of hindlimb tonic extension in the MES model. Treatment of mice with 200 mg/kg (p<0.01) and 400 mg/kg (p<0.001) of ethyl acetate extract significantly protected against PTZ-induced kindling compared to controls. The leaf was found to contain 10.002±0.119 mg atropine equivalent per gram of dry extract of alkaloids, 9.045±0.8445 mg quercetin equivalent per gram of dry extract of flavonoids, and 21.928±1.118 mg gallic acid equivalent per gram of dry extract of phenols. Conclusion: This study indicated that the plant A. integrifolia has anti-convulsant activity in both acute and chronic models of seizure. This plant represents a potential source for the development of a new anti-epileptic drug for pharmacoresistant epilepsy.

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Crosstalk between the endocannabinoid and mid-brain dopaminergic systems: Implication in dopamine dysregulation.

Endocannabinoids (eCBs) and the expanded endocannabinoid system (ECS)-"endocannabinoidome", consists of the endogenous ligands, eCBs, their canonical and non-canonical receptor subtypes, and their synthesizing and metabolizing enzymes. This system modulates a wide range of body functions and acts as a retrograde signaling system within the central nervous system (CNS) by inhibition of classical transmitters, and plays a vital modulatory function on dopamine, a major neurotransmitter in the CNS. Dopamine is involved in different behavioral processes and contributes to different brain disorders-including Parkinson's disease, schizophrenia, and drug addiction. After synthesis in the neuronal cytosol, dopamine is packaged into synaptic vesicles until released by extracellular signals. Calcium dependent neuronal activation results in the vesicular release of dopamine and interacts with different neurotransmitter systems. The ECS, among others, is involved in the regulation of dopamine release and the interaction occurs either through direct or indirect mechanisms. The cross-talk between the ECS and the dopaminergic system has important influence in various dopamine-related neurobiological and pathologic conditions and investigating this interaction might help identify therapeutic targets and options in disorders of the CNS associated with dopamine dysregulation.

Cardiometabolic syndrome in HIV-positive and HIV-negative patients at Zewditu Memorial Hospital, Addis Ababa, Ethiopia: a comparative cohort study.

Cardiometabolic syndrome (CMetS) has recently emerged as a serious public health concern, particularly for individuals living with chronic conditions. This study aimed to determine the incidence and prevalence of CMetS, as well as the risk factors linked with it, in HIV-positive and HIV-negative adult patients. Methods: A comparative cohort study was designed. The National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) tools were used to determine the outcome variables. Association studies were done using logistic regression. Result: CMetS was found to have a greater point and period prevalence, and incidence estimation in HIV-negative than HIV+ patients using both the NCEP and the IDF tools. Using the NCEP tool, the risk of obesity was 44.1% [odds ratio (OR) = 0.559, 95% confidence interval (CI), (0.380-0.824); P = 0.003] lower in HIV+ than in HIV-negative participants. By contrast, no apparent difference was noted using the IDF tool. Similarly, hyperglycemia [OR = 0.651, 95% CI (0.457-0.926); P = 0.017], and hypertension [OR = 0.391, 95% CI (0.271-0.563); P < 0.001] were shown to be lower in HIV+ patients than HIV-negative patients by 34.9% and 60.9%, respectively. The study revealed significant variation in all biomarkers across the follow-up period in both HIV+ and HIV-negative participants, except for SBP. Conclusions: CMetS caused more overall disruption in HIV-negative people with chronic diseases than in HIV-positive people. All of the indicators used to assess the increased risk of CMetS were equally meaningful in HIV+ and HIV-negative subjects.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Antidepressant-Like Activity of Solvent Fractions of the Root Bark of Carissa spinarum Linn. (Apocynaceae) in Rodents Involves Multiple Signaling Pathways.

Background: The root bark of Carissa spinarum Linn. (Apocynaceae) is claimed to be used for the management of depression in Ethiopian folkloric medicine, and the crude extract has been reported to possess antidepressant-like activity in rodents. Objective: This study aimed to evaluate the antidepressant-like effect of different fractions of the root bark in rodents and the possible underlying mechanisms in rats. Methods: A 70% ethanol extract of the root bark was successively fractionated with n-butanol, ethyl acetate, and water. Animals of both sexes received 2% Tween 80, imipramine (30 mg/kg), or various doses (50, 100, 200 mg/kg) of the fractions. Duration of immobility was determined using the tail suspension test and the forced swim test. Locomotor activity was evaluated in the open field test. Serum corticosterone levels, total phenols, flavonoids, and alkaloids were determined. Preliminary mechanistic studies were also performed to explore possible mechanisms of action of the active fraction. Results: All fractions but the aqueous fraction significantly (p<0.001) decreased the duration of immobility in both tests, with the ethyl acetate fraction being the most active. The locomotor test revealed that the activity was not due to non-specific psycho-stimulant effects. Serum corticosterone levels were reduced by both fractions, with the ethyl acetate fraction again being the most effective. Mechanistic studies showed the involvement of multiple neurotransmission systems, including adrenergic, dopaminergic and cholinergic as well as L-Arginine-NO-cGMP pathway. Higher contents of phenols (42.42 vs 29.8 mgGAE/g), flavonoids (12.43 vs 2.07 mgQE/g), and alkaloids (0.17 vs 0.07 mgATE/g) were found in the ethyl acetate than in the n-butanol fraction. Conclusion: The present findings collectively indicate that the ethyl acetate and n-butanol fractions are endowed with antidepressant-like activity due to the presence of phenols, flavonoids, and alkaloids, which are medium polar in nature.

Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis.

Objective: This study aimed to explore the population pharmacokinetic modeling (PopPK) of levofloxacin (LFX) and moxifloxacin (MXF), as well as the percent probability of target attainment (PTA) as defined by the ratio of the area under the plasma concentration-time curve over 24 h and the in vitro minimum inhibitory concentration (AUC0-24/MIC) in Ethiopian multidrug resistant tuberculosis (MDR-TB) patients. Methods: Steady state-plasma concentration of the drugs in MDR-TB patients were determined using optimized liquid chromatography-tandem mass spectrometry. PopPK and simulations were run at various doses, and pharmacokinetic parameters were estimated. The effect of covariates on the PK parameters and PTA for maximum mycobacterial kill and resistance prevention was also investigated. Results: LFX and MXF both fit in a one-compartment model with adjustments. Serum-creatinine (Cr) influenced (p = 0.01) the clearance of LFX, whereas body mass index (BMI) influenced (p = 0.01) the apparent volume of distribution (V) of MXF. The PTA for LFX maximal mycobacterial kill at the critical MIC of 0.5 mg/L with the simulated 750 mg, 1000 mg, and 1500 mg doses were 29%, 62%, and 95%, respectively, whereas the PTA for resistance prevention at 1500 mg was only 4.8%, with none of the lower doses achieving this target. At the critical MIC of 0.25 mg/L, there was no change in the PTA for maximum bacterial kill when the MXF dose was increased (600 mg, 800 mg, and 1000 mg), but the PTA for resistance prevention was improved. Conclusion: The standard doses of LFX and MXF may not provide adequate drug exposure. PopPK of LFX is more predictable for maximum mycobacterial kill, whereas MXF's resistance prevention target increases with dose. Cr and BMI are likely important covariates for dose optimization in Ethiopian patients.

Antidiarrheal and Antibacterial Activities of Calpurnia aurea: Benth Seed Different Extracts.

Background: Calpurnia aurea is believed to have antidiarrheal potential but with limited scientific evidence. This study aimed investigating antidiarrheal and antibacterial activity of aqueous and 80% methanol seed extracts of the plant in mice and selected diarrhea-causing bacterial strains, respectively. Methods: Castor oil-induced diarrhea, prostaglandin-induced enteropooling, and castor oil-induced charcoal meal test models in mice of either sex using three dose levels (60, 120, and 240 mg/kg) were applied to evaluate antidiarrheal activity. Parameters, including onset, number, wet stool weight, weight and volume of secretion, and intestinal motility, were taken into consideration. The antibacterial activity was assessed on Shigella soni, Salmonella typhimurium, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa using disk diffusion and microdilution techniques. Results: Compared to controls, pretreatment of mice at the graded dose (60, 120, and 240 mg/kg) resulted in a significant (p < 0.05) drop in frequency of wet stools and watery content of diarrhea as well as in delaying onset of diarrhea. Both extracts exhibited inhibition of diarrhea in a dose-dependent manner in all models used. The extracts also showed significant (p < 0.05) reduction in intestinal motility in castor oil-induced models. Both extracts showed a marginal activity against the selected bacterial strains; a better effect was seen with 80% methanol seed extract. Conclusion: Both extracts of the plant have beneficial effect in controlling diarrhea. This finding supports the use of the plant as a traditional antidiarrheal remedy.

In Vivo Anti-Malarial Activity of the Aqueous Root Extract of Euclea divinorum Hiern (Ebenaceae) against Plasmodium berghei ANKA.

Background: Drug resistance is a universal challenge to malaria control measures. As a result, the development and discovery of new chemotherapeutic agents from medicinal plants having anti-malarial traditional claims are very important. This work, therefore, attempted to evaluate the anti-malarial activity of the aqueous root extract of E. divinorum using a rodent model of malaria. Methods: The roots of E. divinorum were extracted by hot decoction using distilled water. Anti-malarial activity of various doses (100 mg/kg, 200 mg/kg, and 600 mg/kg) of the root aqueous extract was evaluated using the 4-day suppressive test as well as curative and repository tests. Parasitemia, rectal temperature, body weight, PCV, and MST were also determined. Results: The finding showed that there were a dose-related significant parasitemia chemo-suppression and increment in survival time as compared to the negative control (p < 0.001) in all tests. The chemo-suppression effect was higher at 400 mg/kg extract-treated groups in the 4-day suppressive test followed by the curative test. The lowest chemo-prophylaxis effect was observed in 100 mg/kg extract-treated groups in the repository test. Regarding the other parameters, the extract prevented weight loss, temperature drop, and hemolysis in all models but not in a consistent manner. Conclusion: The current study showed that the aqueous root extract of E. divinorum possessed a varying degree of anti-malarial activity in all three tests, with greater parasitemia suppression observed in the 4-day suppressive test. The extract produced higher parasitemia chemo-suppression and longer survival time in early infections followed by established and then residual infection.

CYP3A and CYP2B6 Genotype Predicts Glucose Metabolism Disorder among HIV Patients on Long-Term Efavirenz-Based ART: A Case-Control Study.

Long-term antiretroviral treatment (cART) increases the risk of glucose metabolism disorders (GMDs). Genetic variation in drug-metabolizing enzymes and transporters may influence susceptibility to cART-associated GMDs. We conducted a case-control study to investigate the association of pharmacogenetic variations with cART-induced GMDs. A total of 240 HIV patients on long-term efavirenz-based cART (75 GMD cases and 165 controls without GMDs) were genotyped for CYP3A4*1B, CYP3A5 (*3,*6), CYP2B6*6, UGT2B7*2, ABCB1 (c.3435C>T, c.4036A>G), and SLCO1B1 (*1b, *5). GMD cases were defined as the presence of impaired fasting glucose, insulin resistance, or diabetes mellitus (DM). Case-control genotype/haplotype association and logistic regression analysis were performed by adjusting for age, sex, and BMI. The major CYP3A haplotype were CYP3A5*3 (53.8%), CYP3A4*1B (17.3%), combinations of CYP3A4*1B, and CYP3A5*6 (10.9%), and CYP3A wild type (7%). CYP3A5*6 allele (p = 0.005) and CYP3A5*6 genotype (p = 0.01) were significantly associated with GMD cases. Multivariate analysis indicated CYP3A haplotype as a significant predictor of GMD (p = 0.02) and IFG (p = 0.004). CYP2B6*6 significantly predicted DM (p = 0.03). CYP3A haplotype and CYP2B6*6 genotype are independent significant predictors of GMD and DM, respectively, among HIV patients on long-term EFV-based cART.

Dyslipidemia and associated cardiovascular risk factors in HIV-positive and HIV-negative patients visiting ambulatory clinics: A hospital-based study.

Background: Dyslipidemia is a well-known risk factor for cardiovascular disease (CVD), accounting for more than half of all instances of coronary artery disease globally (CAD). Purpose: The purpose of this study was to determine lipid-related cardiovascular risks in HIV-positive and HIV-negative individuals by evaluating lipid profiles, ratios, and other related parameters. Methods: A hospital-based study was carried out from January 2019 to February 2021 in both HIV + and HIV- ambulatory patients. Results: High TG (p = .003), high TC (p = .025), and low HDL (p < .001) were all associated with a two-fold increased risk of CVD in people aged 45 and up. Due to higher TG (p < .001) and lower HDL (p < .001), males were found to have a higher risk of atherogenic dyslipidemia. A twofold increase in the likelihood of higher TG levels has been associated with smoking (p = .032) and alcohol intake (p = .022). A twofold increase in a high TC/HDL ratio and an elevated TG/HDL ratio was observed with an increase in waist-to-height ratio (p = .030) and a high level of FBS (126 mg/dl) and/or validated diabetes (p = .017), respectively. In HIV + participants, central obesity (p < .001), diabetes (p < .001), and high blood pressure (p < .001) were all less common than in HIV- participants. Conclusions: Dyslipidemia is linked to advanced age, male gender, diabetes, smoking, alcohol consumption, and increased waist circumference, all of which could lead to an increased risk of CVD, according to the study. The study also revealed that the risks are less common in HIV + people than in HIV-negative ambulatory patients.

Impact of medication therapy management interventions on drug therapy problems, medication adherence and treatment satisfaction among ambulatory heart failure patients at Tikur Anbessa Specialised Hospital, Addis Ababa, Ethiopia: a one-group pre-post quasi-experimental study.

OBJECTIVE: To determine the impact of medication therapy management interventions on drug therapy problems (DTPs), medication adherence and treatment satisfaction among ambulatory heart failure (HF) patients. STUDY DESIGN, SETTING AND PARTICIPANTS: A one-group pre-post quasi-experimental study was conducted on 423 ambulatory HF patients at Tikur Anbessa Specialised Hospital (TASH), Addis Ababa, Ethiopia. All ambulatory HF patients ≥18 years old attending the adult cardiac clinic of TASH and having a complete medical record and fully met the inclusion criteria were taken as study participants. INTERVENTIONS: Educational interventions along with a brochure with information on the nature of HF disease and its treatment were provided to study participants. DTPs encountered were resolved by a team of pharmacists and physicians. RESULTS: In the preintervention phase, 288 DTPs were identified with a mean (SD) of 1.3±1.1. A significant reduction of DTPs (0.67±1.1, p<0.001) was observed in the postintervention phase compared with the preintervention phase. At the postintervention phase, 36.4%, 61.9% and 1.7% of HF patients were highly, medium and low adherent to their treatment regimens, respectively. The total composite score for treatment satisfaction of the study participants was 80.35%. CONCLUSIONS: The findings of this study demonstrated that by teaming up clinical pharmacists with cardiologists and cardiology fellows, it was possible to reduce the occurrence of DTPs, improve medication adherence and increase treatment satisfaction of HF patients attending at the outpatient cardiac clinic.

Biomarkers and Prevalence of Cardiometabolic Syndrome Among People Living With HIV/AIDS, Addis Ababa, Ethiopia: A Hospital-Based Study.

BACKGROUND: While the fast extension of combination antiretroviral therapy (cART) has resulted in significant increases in life expectancy, disorders such as cardiometabolic syndrome (CMetS), which have received less attention, are becoming a major concern in HIV/AIDS patients (PLWHA). OBJECTIVES: The purpose of this research was to identify biomarkers and determine the prevalence of CMetS in PLWHA using the National Cholesterol Education Program (NCEP) and the International Diabetes Federation (IDF) tools. METHODS: Between January 2019 and February 2021, a hospital-based study of HIV-infected patients (n = 288) was conducted. The data were analyzed using binary logistic regression. To control the effect of confounders, independent variables with a P-value of <.20 in the bivariate logistic regression were incorporated into multivariate logistic regression. Statistical significance was defined as a 95% confidence interval and a P-value of less than .05. RESULTS: The risk of CMetS increased twofold as age increased each year (P = .009), 1.2 times as the age at which cART began increased (P = .015), and 6 times with 1 or more co-morbidities (P = .028), according to the NCEP tool. Furthermore, significant NCEP-CMetS correlations were produced by a rise in diastolic blood pressure (P < .001) and cART duration (P = .006). Male gender was 99.9% less likely to be related to CMetS using the IDF tool, and the risk of CMetS increased fourfold with each unit increase in waist circumference (P < .001). Triglycerides and blood type "A" have been found to have substantial relationships with CMetS using both techniques. CONCLUSION: According to the study, CMetS was found to be common in PLWHA. Age, time on cART, age when cART started, gender, co-morbidities, waist circumference, and diastolic blood pressure were all revealed to be significant predictors of CMetS. Triglycerides and blood type "A" were the only biomarkers found to be significant with CMetS using both the NCEP and IDF tools.