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.

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.

Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis.

BACKGROUND: Malaria is a major cause of morbidity and mortality in pediatrics in malaria endemic areas. Artemisinin-based combination therapies (ACTs) are the drugs of choice for malaria management particularly across malaria-endemic countries. This systematic review and meta-analysis was performed to assess efficacy and safety of ACTs for uncomplicated malaria in pediatric populations. METHODS: A body of evidence was searched for published ACT trials until March 06, 2020. The search was focused on efficacy and safety studies of ACTs for uncomplicated malaria in pediatrics. PubMed library was searched using best adapted search terms after multiple trials. References were exported to the endnote library and then to Covidence for screening. Data was extracted using the Covidence platform. The per-protocol analysis report for the efficacy and the intention-to-treat analysis for the safety were synthesized. Met-analysis was carried using Open Meta-Analyst software. Random effects model was applied and the heterogeneity of studies was evaluated using I2 statistic. RESULTS: Nineteen studies were included in the final analysis. Overall, crude, PCR-corrected P. falciparum malaria treatment success rate was 96.3 and 93.9% for day 28 and 42, respectively. In the subgroup analysis, PCR-corrected adequate clinical and parasitological response (ACPR) of dihydroartemisinin-piperaquine (DP) was 99.6% (95% CI: 99.1 to 100%, I2 = 0%; 4 studies) at day 28 and 99.6% (95% CI of 99 to 100%, I2 = 0%; 3 studies) at day 42. Nine studies reported ACT related adverse drug reactions (ADR) (8.3%, 356/4304). The reported drug related adverse reactions ranged from 1.8% in DP (two studies) to 23.3% in artesunate-pyronaridine (AP). Gastrointestinal symptoms were the most common ACT related adverse effects, and all ADRs were reported to resolve spontaneously. CONCLUSION: ACTs demonstrated a high crude efficacy and tolerability against P. falciparum. The high treatment success and tolerability with low heterogeneity conferred by DP has implication for policy makers who plan the use of ACTs for uncomplicated falciparum malaria treatment in pediatrics.

Reproducibility of malaria sporozoite challenge model in humans for evaluating efficacy of vaccines and drugs: a systematic review.

BACKGROUND: The development of novel malaria vaccines and antimalarial drugs is limited partly by emerging challenges to conduct field trials in malaria endemic areas, including unknown effects of existing immunity and a reported fall in malaria incidence. As a result, Controlled Human Malaria Infection (CHMI) has become an important approach for accelerated development of malarial vaccines and drugs. We conducted a systematic review of the literature to establish aggregate evidence on the reproducibility of a malaria sporozoite challenge model. METHODS: A systematic review of research articles published between 1990 and 2018 on efficacy testing of malaria vaccines and drugs using sporozoite challenge and sporozoite infectivity studies was conducted using Pubmed, Scopus, Embase and Cochrane Library, ClinicalTrials.gov and Trialtrove. The inclusion criteria were randomized and non-randomized, controlled or open-label trials using P. falciparum or P. vivax sporozoite challenges. The data were extracted from articles using standardized data extraction forms and descriptive analysis was performed for evidence synthesis. The endpoints considered were infectivity, prepatent period, parasitemia and safety of sporozoite challenge. RESULTS: Seventy CHMI trials conducted with a total of 2329 adult healthy volunteers were used for analysis. CHMI was induced by bites of mosquitoes infected with P. falciparum or P. vivax in 52 trials and by direct venous inoculation of P. falciparum sporozoites (PfSPZ challenge) in 18 trials. Inoculation with P. falciparum-infected mosquitoes produced 100% infectivity in 40 studies and the mean/median prepatent period assessed by thick blood smear (TBS) microscopy was ≤ 12 days in 24 studies. On the other hand, out of 12 infectivity studies conducted using PfSPZ challenge, 100% infection rate was reproduced in 9 studies with a mean or median prepatent period of 11 to 15.3 days as assessed by TBS and 6.8 to 12.6 days by PCR. The safety profile of P. falciparum and P.vivax CHMI was characterized by consistent features of malaria infection. CONCLUSION: There is ample evidence on consistency of P. falciparum CHMI models in terms of infectivity and safety endpoints, which supports applicability of CHMI in vaccine and drug development. PfSPZ challenge appears more feasible for African trials based on current evidence of safety and efficacy.

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer; Part 3: Selective Cytotoxic Activity of 22 Plants against Human Cancer Cell Lines.

Medicinal plants have been traditionally used to treat cancer in Ethiopia. However, very few studies have reported the in vitro anticancer activities of medicinal plants that are collected from different agro-ecological zones of Ethiopia. Hence, the main aim of this study was to screen the cytotoxic activities of 80% methanol extracts of 22 plants against human peripheral blood mononuclear cells (PBMCs), as well as human breast (MCF-7), lung (A427), bladder (RT-4), and cervical (SiSo) cancer cell lines. Active extracts were further screened against human large cell lung carcinoma (LCLC-103H), pancreatic cancer (DAN-G), ovarian cancer (A2780), and squamous cell carcinoma of the esophagus (KYSE-70) by using the crystal violet cell proliferation assay, while the vitality of the acute myeloid leukemia (HL-60) and histiocytic lymphoma (U-937) cell lines was monitored in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) microtiter assay. Euphorbia schimperiana, Acokanthera schimperi, Kniphofia foliosa, and Kalanchoe petitiana exhibited potent antiproliferative activity against A427, RT-4, MCF-7, and SiSo cell lines, with IC50 values ranging from 1.85 ± 0.44 to 17.8 ± 2.31 µg/mL. Furthermore, these four extracts also showed potent antiproliferative activities against LCLC-103H, DAN-G, A2780, KYSE-70, HL-60, and U-937 cell lines, with IC50 values ranging from 0.086 to 27.06 ± 10.8 µg/mL. Hence, further studies focusing on bio-assay-guided isolation and structural elucidation of active cytotoxic compounds from these plants are warranted.

Evaluation of the anti-malarial activity of crude extract and solvent fractions of the leaves of Olea europaea (Oleaceae) in mice.

BACKGROUND: Drug resistance poses a challenge to malaria control measures. This calls for discovery & development of new chemotherapeutic agents. This study therefore was initiated to investigate the antimalarial activity of Olea europaea against Plasmodium berghei infected mice and to further ascertain in which fraction (s) the constituents responsible for anti-malarial activity are concentrated. METHODS: The leaves of Olea europaea were extracted by maceration using 80% methanol and the crude extract was then successively fractionated with solvents of differing polarity (chloroform, n-butanol and water). The anti-malarial activity of various doses of the extract and fractions (200, 400 and 600 mg/kg) was evaluated using chemo-suppressive, curative, and repository tests. Parameters, including parasitemia, rectal temperature, body weight, and packed cell volume were determined to establish the activity. RESULTS: The acute oral toxicity test result revealed that the LD50 values of the extract and fractions were greater than 2000 mg/kg in mice. The crude extract significantly reduced parasitemia (p < 0.001) and prolonged survival time (p < 0.001), in a dose-dependent manner, in all tests, as compared to the negative control group. Higher parasitemia suppression (58%) was achieved with the larger dose (600 mg/kg) in the 4-day suppressive test, suggesting that the crude extract has largely a chemo-suppressive activity. Parasitemia was significantly reduced (p < 0.001) by all fractions in all doses used when compared to the negative controls, with the rank order of n-butanol (51%) > chloroform>aqueous (21%) fractions. Larger (600 mg/kg) and middle (400 mg/kg) doses of the crude extract as well as the fractions ameliorated all the other parameters in a consistent manner, with the crude being more active than the fractions. Preliminary phytochemical analysis revealed the presence of secondary metabolites that were differentially distributed in the fractions. CONCLUSION: The findings collectively indicate that the plant is endowed with antimalarial activity, the activity being more in the crude extract than the fractions, owing to the presence of secondary metabolites that act independently or in synergy. The varying degree of antimalarial activity in the fractions suggests that non-polar and medium polar principles could be responsible for the observed activity.

Involvement of CB2 Receptors in the Neurobehavioral Effects of Catha Edulis (Vahl) Endl. (Khat) in Mice.

There is behavioral evidence for the interaction between crude khat extract and the endocannabinoid system, whereby the endocannabinoid system alters khat extract-mediated behavioral effects through modulation of the monoaminergic system. The objective of this study was to investigate the role of the endocannabinoid system on the neurobehavioral effect of khat extract in mice following concomitant administration of khat extract and the CB2R agonist, JWH133. Locomotor activity test, immunohistochemistry, and reverse transcriptase polymerase chain reaction technique were utilized to assess locomotor activity, tyrosine hydroxylase immunoreactivity, and expression of dopamine transporter mRNA gene. The results show sub-acute administration of khat extract alone increased locomotor activity in mice and co-administration of the CB2R agonist, JWH133, reduced khat extract induced hyperlocomotor activity. The data revealed that cell type specific deletion of CB2Rs on dopaminergic neurons increased the hyperlocomotor behavior of khat extract. Furthermore, the results revealed that khat extract attenuated MPTP induced motor deficits, which is enhanced by JWH133. Khat extract also increased expression of tyrosine hydroxylase positive cells and expression of dopamine transporter mRNA gene in wild type mice. Nevertheless, JWH133 did not alter the effect of khat extract on tyrosine hydroxylase immunoreactivity and dopamine transporter mRNA expression when given together with khat extract. Taken together, the results suggest that the CB2Rs selectively interact with khat extract-mediated locomotor effects and could be utilized as therapeutic target in central nervous system movement disorders associated with dopamine dysregulation.

Multiple challenges of antibiotic use in a large hospital in Ethiopia - a ward-specific study showing high rates of hospital-acquired infections and ineffective prophylaxis.

BACKGROUND: This project aims to study the use of antibiotics in three clinical wards in the largest tertiary teaching hospital in Ethiopia for a period of 1 year. The specific aims were to assess the prevalence of patients on antibiotics, quantify the antibiotic consumption and identify the main indications of use. METHOD: The material was all the medical charts (n = 2231) retrieved from three clinical wards (internal medicine, gynecology/obstetrics and surgery) in Tikur Anbessa Specialized Hospital (TASH) in Addis Ababa between September 2013 and September 2014. Data collection was performed manually by four pharmacists. RESULTS: Each medical chart represented one patient. About 60% of the patients were admitted to internal medicine, 20% to each of the other two wards. The number of bed days (BD) was on average 16.5. Antibiotics for systemic use were prescribed to 73.7% of the patients (on average: 2.1 antibiotics/patient) of whom 86.6% got a third or fourth generation cephalosporin (mainly ceftriaxone). The average consumption of antibiotics was 81.6 DDD/100BD, varying from 91.8 in internal medicine and 71.6 in surgery to 47.6 in gynecology/obstetrics. The five most frequently occurring infections were pneumonia (26.6%), surgical site infections (21.5%), neutropenic fever (6.9%), sepsis (6.4%) and urinary tract infections (4.7%). About one fourth of the prescriptions were for prophylactic purposes. Hospital acquired infections occurred in 23.5% of the patients (353 cases of surgical site infection). The prescribing was based on empirical treatment and sensitivity testing was reported in only 3.8% of the cases. CONCLUSIONS: In the present study from three wards in the largest tertiary teaching hospital in Ethiopia, three out of four patients were prescribed antibiotics, primarily empirically. The mean antibiotic consumption was 81.6 DDD/100BD. Surgical site infections constituted a large burden of the infections treated in the hospital, despite extensive prescribing of prophylaxis. The findings show the need to implement antibiotic stewardship programs in Ethiopian hospitals with focus on rational prescribing, increased sensitivity testing and better procedures to prevent hospital acquired infections.

Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells.

BACKGROUND: Most of herbal medicines are used without any standard safety and toxicological trials although common assumption is that these products are nontoxic. However, this assumption is incorrect and dangerous, so toxicological studies should be done for herbal drugs. Although Pterolobium stellatum, Otostegia integrifolia and Vernonia amygdalina root extracts are frequently used in Ethiopian traditional medicine, there are no evidences of their active toxic compounds. Therefore, we made an effort to assess probable genotoxic effect of these plant extracts on DNA of human hematoma (HepG2) cells using alkaline comet assay. METHODS: Genotoxic effects of extracts were evaluated using single cell gel electrophoresis (SCGE) method on HepG2 cell. Regarding comet data, the average mean tail intensities (TI) from each individual experiment and treatment (usually at least 3 cultures/treatment) were pooled and the average mean TI was used as an indicator of DNA damage and the standard error of mean (SEM) as the measure of variance. RESULTS: DNA damage in the form of comet tail has been observed for 1 and 0.5 mg/ml P. stellatum chloroform and 80% methanol extracts on HepG2 cells, respectively. The chloroform extract of P. stellatum showed increased tail DNA percentage in a concentration dependent manner. Comet tail length in the chloroform P. stellatum extract treated cells (1 mg/ml) was significantly higher by 89% (p < 0.05) compared to vehicle treated controls. The rest of test extracts seemed to be without genotoxic effect up to a concentration of 0.5 mg/ml. CONCLUSIONS: Our findings show that two extracts from one plant evaluated have a genotoxic potential in vitro which calls for a more thorough safety evaluation. Such evaluation should include other end-points of genotoxicity apart from DNA damage, and possibly also pure compounds.

Current status, challenges and the way forward for clinical pharmacy service in Ethiopian public hospitals.

BACKGROUND: Clinical pharmacy service has evolved steadily over the past few decades and is now contributing to the 'patient care journey' at all stages. It is improving the safety and effectiveness of medicines and has made a significant contribution to the avoidance of medication errors. In Ethiopia, clinical pharmacy service is in its initial phase, being started in July 2013. This study therefore aimed at assessing the status, challenges and way forward of clinical pharmacy service in the country. METHODS: A cross-sectional survey was conducted in six regional states and one city- administration in September 2014. A total of 51 hospitals were included in the study. Both qualitative and quantitative methods were employed for data collection. RESULTS: A total of 160 pharmacy graduates, and 51 pharmacy heads participated in the study. Internal Medicine and Pediatric wards were the major wards where the graduates provide clinical pharmacy service. Almost 94% of the new graduates were found to be involved in clinical pharmacy service, but 47% of them rated their service as poor. The overall satisfaction of the graduates was close to 36%. Thirteen hospitals discontinued and two hospitals not even initiated the service largely due to shortage of pharmacists and lack of management support. About 44% of the surveyed hospitals documented the clinical pharmacy service provided using either developed or adopted formats. Lack of awareness by the medical fraternity, high attrition rate, lack of support from the management as well as from the health care team, readiness of the graduates to deliver the service, and shortage of pharmacists were identified by the key informants as the major stumbling block to deliver clinical pharmacy service. CONCLUSION: Clinical pharmacy service is initiated in most of the surveyed hospitals and a large proportion of the graduates were involved in the service. Although there is a great enthusiasm to promote clinical pharmacy service in the surveyed hospitals, efforts made to institutionalize the service is minimal. Thus, concerted efforts need to be exerted to promote the service through organizing awareness forums as well as revisiting the curriculum.

Evaluation of the antidiarrheal activity of the leaf extracts of Myrtus communis Linn (Myrtaceae) in mice model.

BACKGROUND: Myrtus communis L. has a folkloric repute for the management of diarrhea and dysentery in different parts of the world. However, the safety and efficacy of the leaf extract have not been scientifically validated in animal model. This study was, therefore, aimed to investigate the antidiarrheal effect of 80% methanol extract (80ME) and solvent fractions of the leaves of Myrtus communis L. in mice. METHODS: The antidiarrheal activity of the 80ME and solvent fractions was evaluated against castor oil induced diarrheal model, charcoal meal and enteropooling tests. For the 80%ME, the test groups received 100, 200 and 400 mg/kg of the extract. In case of fractions, the test groups received various doses of fractions (200, 300, 400 mg/kg and an additional dose of 800 mg/kg for the aqueous fraction (AF)), where as negative controls received the vehicle (10 ml/kg) and positive controls received loperamide (3 mg/kg). RESULTS: The 80ME at 200 mg/kg (p < 0.05) & 400 mg/kg (p < 0.01) as well as the chloroform fraction (CF) and methanol fraction (MF) at 400 mg/kg (p < 0.05) significantly delayed the onset of diarrhea. Besides, the 80ME (at all tested doses) and both of these fractions (at 300 & 400 mg/kg) significantly decreased the frequency and weight of fecal outputs. Results from the charcoal meal test revealed that the 80ME, at all doses, (p < 0.001) as well as the CF and MF at 300 mg/kg (p < 0.05) & 400 mg/kg (p < 0.001) produced a significant anti-motility effect. Similarly, in the entero-pooling test, the 80ME (at all tested doses) (p < 0.01) as well as the CF and MF (at 300 & 400 mg/kg, p < 0.05) produced a significant decline in the weight and volume of intestinal contents, whereas the AF revealed significant effect (p < 0.05) at dose of 800 mg/kg only. CONCLUSION: The study demonstrated that the 80ME and solvent fractions contain bioactive constituents that have antidiarrheal activity. Therefore, this study provides a scientific support for the acclaimed traditional use of Myrtus communis L for the treatment of diarrheal diseases.

Evaluation of the anti-diarrheal activity of the aqueous stem extract of Lantana camara Linn (Verbenaceae) in mice.

BACKGROUND: Diarrheal disease remains a public health problem in developing countries, including Ethiopia. In order to alleviate this disease, Ethiopian traditional healers use a wide range of medicinal plants from which Lantana camara is one of them. The stem of this plant is traditionally used for the treatment of diarrhoea. In addition, this plant is scientifically evaluated to have an antispasmodic effect on in vitro study. The aim of this study was to evaluate the antidiarrheal activity of the aqueous stem extract of L. camara Linn in mice. METHODS: The antidiarrheal activity of the extract was investigated using castor oil induced diarrhoea, enteropooling and small intestine transit models. The test groups received various doses (100, 200, and 400 mg/kg) of the extract, whereas positive controls received Loperamide (3 mg/kg) and negative controls received distilled water (10 ml/kg). RESULTS: In castor oil induced diarrhoea model, the extract, at all test doses, significantly (p < 0.001) prolonged diarrhoea onset, decreased the frequency of defecation, and weight of faeces. Similarly, the extract produced a significant (p < 0.001) decline in the weight and volume of intestinal contents at all tested doses. In addition, a significant (P < 0.001) reduction in the gastrointestinal motility in charcoal meal test was also observed in all doses of the extract. Phytochemical screening of the extract revealed the presence of flavonoids, alkaloids, tannins, and phytosterols that may play a key role in its antidiarrheal activity. CONCLUSION: The obtained results of the present study confirm antidiarrheal activity of the stem of L. camara, thus provide the scientific basis for the traditional uses of this plant as a treatment for diarrhoea.

Evaluation of the antimycobacterial activity of crude extracts and solvent fractions of selected Ethiopian medicinal plants.

BACKGROUND: Tuberculosis (TB) is a global health problem complicated by drug resistance and human immunodeficiency virus that has dramatically increased active TB. Several medicinal plants are used traditionally to treat TB in Ethiopia and investigating these plants is required as plants are an alternative source for development of new anti-TB drugs. The purpose of this study was to investigate antimycobacterial activity of crude extract of Carissa edulis, Otostegia integrifolia, Persea americana, Pterolobium stellatum and Vernonia amygdalina as well as fractions of the most active crude extract. METHODS: The effect of various doses of the crude extracts as well as solvent fractions on M. tuberculosis H37Rv and/or MDR-TB clinical isolate was determined using broth microdilution and microtiter resazurin assay methods. Minimum inhibitory concentration was determined by CFU count and resazurin color change observation. RESULTS: Chloroform and 80% methanol extracts of P. stellatum and O. integrifolia as well as 80% methanol and acetone extracts of P. americana had significant antimycobacterial activity (p < 0.001) against M. tuberculosis H37Rv. Chloroform extract of V. amygdalina and C. edulis didn't, however, show any significant activity compared to negative controls. P. stellatum chloroform extract was the most active on M. tuberculosis H37Rv (MIC 0.039 mg/ml) and AOZ8W-4 (MDR-TB clinical isolate) (MIC = 0.078 mg/ml). Ethyl acetate fraction of P. stellatum chloroform extract was the most active fraction. CONCLUSION: P. stellatum, O. integrifolia and P. americana were found to be endowed with antimycobacterial activity. However, P. stellatum appears to be the most promising plant based on criteria set by different studies. Ethyl acetate fraction of P. stellatum was found to be the most active and future studies should involve this fraction.

Pharmacological and Toxicological Effects of Catha edulis F. (Khat).

Khat chewing is deeply rooted in the culture and tradition of communities in khat belt countries, and its consumption is spread to other countries through the suitcase trade. The aim of this article is to review current knowledge on the chemistry, social, pharmacology and toxicology of khat and its use. Khat produces effect invariably in every system, which is harmful or beneficial in some instances. Harmful effects are observed in heavy users, although firm evidence is lacking. Chewing khat acutely elicits states of euphoria, which is followed by low mood. Khat contains alkaloids with psychostimulant properties, but the effect cannot be totally explained by these alkaloids. It is also not clear whether the effect produced in some organs like liver could be attributed to khat or pesticides sprayed during farming. Although the evidence indicates that khat has adverse effects in most organs, our understanding of the complex interaction between use and effect is incomplete, and causal relationships have not yet been described. Moreover, khat has positioned itself well in the social, economic and political arena. Thus, a multidisciplinary research is required to understand the different dimensions and come up with ways that maximize the benefit while minimizing the risk. Copyright © 2017 John Wiley & Sons, Ltd.

Validation of the Amharic Version of the Brief Pain Inventory for Utility in Ethiopian Cancer Patients.

BACKGROUND: Pain is a highly prevalent and distressing symptom in patients with cancer but at the same time inadequately treated in many of these patients. The major reason for such imbalance is inappropriate pain assessment. To overcome such a barrier, the use of a valid and reliable pain assessment tool in the language the patient understands is invaluable. Unfortunately, until now, no such standardized tool has been utilized in Ethiopian patients with cancer for both clinical and research purposes. OBJECTIVES: This study tried to validate the Amharic language version of the Brief Pain Inventory (BPI-Am) and evaluate the adequacy of cancer pain management using the Pain Management Index (PMI). METHODS: A standard forward/backward translation technique was used for translating the BPI from its original English version into Amharic (BPI-Am). The BPI-Am was administered to 291 Ethiopian patients with cancer who fulfilled the inclusion criteria. Factor analysis was used to identify the underlying constructs of the tool. Mean comparison was used to confirm the sensitivity of the BPI-Am to known patient groups that differed based on their performance status. Cronbach's α and intraclass correlation coefficients, respectively, were used to assure internal consistency and test-retest reliability of the BPI-Am. The PMI was calculated to identify the level of inadequate pain management in the current sample. Stepwise logistic regression was used to identify potential predictors of inadequate pain management. RESULTS: Factor analysis yielded 3 factors-pain severity, physical activity interference, and psychosocial interference-with Cronbach's α coefficients of 0.85, 0.87, and 0.77, respectively. The BPI-Am showed the capacity to detect higher mean pain severity and mean pain interference scores in patients with poor performance status as compared with those having a good performance status (P < 0.001). Intraclass correlation coefficients for test-retest reliability were 0.75 and 0.78 for the pain severity and pain interference composite scores, respectively. Sixty-seven percent of patients in the current sample were inadequately treated for their pain according to the PMI. Good performance status (odds ratio [OR] = 2.9, P < 0.01), absence of cancer-related complications (OR = 2.1, P < 0.05), and being unemployed (OR = 2.6, P < 0.01) were identified as predictors of inadequate pain management. CONCLUSION: The BPI-Am is a valid and reliable tool for use in Ethiopian patients with cancer. The inadequacy of cancer pain management in these groups of patients is high, which calls for needed attention.

Fecal prevalence, serotype distribution and antimicrobial resistance of Salmonellae in dairy cattle in central Ethiopia.

BACKGROUND: Salmonellae are major worldwide zoonotic pathogens infecting a wide range of vertebrate species including humans. Consumption of contaminated dairy products and contact with dairy cattle represent a common source of non-typhoidal Salmonella infection in humans. Despite a large number of small-scale dairy farms in Addis Ababa and its surrounding districts, little is known about the status of Salmonella in these farms. RESULTS: Salmonella was recovered from the feces of at least one animal in 7.6% (10/132) of the dairy farms. Out of 1203 fecal samples examined, 30 were positive for Salmonella resulting in a weighted animal level prevalence of 2.3%. Detection of diarrhea in an animal and in a farm was significantly associated with animal level (p = 0.012) and herd level (p < 0.001) prevalence of Salmonella. Animal level prevalence of Salmonella was significantly associated with age (p = 0.023) and study location; it was highest among those under 6 months of age and in farms from Adaa district and Addis Ababa (p < 0.001). Nine different serotypes were identified using standard serological agglutination tests. The most frequently recovered serotypes were Salmonella Typhimurium (23.3%), S. Saintpaul (20%), S. Kentucky (16.7%) and S. Virchow (16.7%). All isolates were resistant or intermediately resistant to at least one of the 18 drugs tested. Twenty-six (86.7%), 19 (63.3 %), 18 (60%), 16 (53.3%) of the isolates were resistant to streptomycin, nitrofurantoin, sulfisoxazole and tetracycline , respectively. Resistance to 2 drugs was detected in 27 (90%) of the isolates. Resistance to 3 or more drugs was detected in 21 (70%) of the isolates, while resistance to 7 or more drugs was detected in 11 (36.7%) of the isolates. The rate of occurrence of multi-drug resistance (MDR) in Salmonella strains isolated from dairy farms in Addis Ababa was significantly higher than those isolated from farms outside of Addis Ababa (p = 0.009). MDR was more common in S. Kentucky, S. Virchow and S. Saintpaul. CONCLUSION: Isolation of Salmonella serotypes commonly known for causing human salmonellosis that are associated with an MDR phenotype in dairy farms in close proximity with human population is a major public health concern. These findings imply the need for a strict pathogen reduction strategy.

Evaluation of the anti-diarrheal activity of the leaf extract of Croton macrostachyus Hocsht. ex Del. (Euphorbiaceae) in mice model.

BACKGROUND: Traditional healers in Ethiopia use a wide range of medicinal plants with antidiarrheal properties. Among these, Croton macrostachyus is one such plant claimed to have an antidiarrheal activity in Ethiopian folklore medicine. Previous studies showed that the crude extract is endowed with the claimed property. The present study was undertaken to further the claim by screening different fractions for the said activity so that it could serve as a basis for subsequent studies. METHODS: The fractions were obtained by successive extraction in soxhlet apparatus with solvents of different polarity (chloroform & methanol) followed by cold maceration of the deposit of the methanol fraction with distilled water. The antidiarrheal activity was evaluated using castor oil induced diarrheal model, charcoal meal test and anti-enteropooling test in mice. The test groups received various doses (300, 400, 500 mg/kg and an additional dose of 1000 mg/kg for the aqueous fraction) of the fractions, whereas positive controls received either Loperamide (3 mg/kg) or Atropine (5 mg/kg) and negative controls received vehicle (10 ml/kg). RESULTS: In the castor oil induced model, the chloroform (at all test doses) and methanol (at 400 & 500 mg/kg) fractions significantly delayed diarrheal onset, decreased stool frequency and weight of feces. The aqueous fraction was however devoid of significant effect at all the tested doses. Chloroform and methanol fractions produced a significant dose dependent decline in the weight and volume of intestinal contents while the aqueous fraction did not have a significant effect. All the fractions produced a significant anti-motility effect either at all doses (chloroform fraction) or at middle and higher doses (methanol and aqueous fractions). CONCLUSION: The present study demonstrated that the chloroform and methanol fractions possessed significant anti-diarrheal activity. Nevertheless, the aqueous fraction showed only significant anti-motility effect at the higher dose (1000 mg/kg) employed in the study.

The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans.

The use of khat (Catha edulis) while on medication may alter treatment outcome. In particular, the influence of khat on the metabolic activities of drug-metabolizing enzymes is not known. We performed a comparative 1-way crossover study to evaluate the effect of khat on cytochrome P450 (CYP)2D6 and CYP3A4 enzyme activity. After 1 week of khat abstinence, baseline CYP2D6 and CYP3A4 metabolic activities were determined in 40 Ethiopian male volunteers using 30 mg dextromethorphan (DM) as a probe drug and then repeated after 1 week of daily use of 400 g fresh khat leaves. Urinary concentrations of cathinone and cathine were determined to monitor the subjects' compliance to the study protocol. Genotyping for CYP2D6*3 and CYP2D6*4 was done. Plasma DM, dextrorphan and 3-methoxymorphinan concentrations were quantified. CYP2D6 and CYP3A4 enzyme activities were assessed by comparing plasma log DM/dextrorphan and log DM/methoxymorphinan metabolic ratio (MR) respectively in the presence and absence of khat. Cytochrome 2D6 MR was significantly increased from baseline by concurrent khat use (paired t test, P = 0.003; geometric mean ratio, 1.38; 95% confidence interval [95% CI], 1.12-1.53). Moreover, the inhibition of CYP2D6 activity by khat was more pronounced in CYP2D6*1/*1 compared with CYP2D6*1/*4 genotypes (P = 0.01). A marginal inhibition of CYP3A4 activity in the presence of khat was observed (P = 0.24). The mean percentage increase of CYP2D6 and CYP3A4 MR from baseline by khat use was 46% (95% CI, 20-72) and 31% (95% CI, 8-54), respectively. This is the first report linking khat use with significant inhibition of CYP2D6 metabolic activity in humans.

Non-typhoidal Salmonella serotypes, antimicrobial resistance and co-infection with parasites among patients with diarrhea and other gastrointestinal complaints in Addis Ababa, Ethiopia.

BACKGROUND: Non-typhoidal Salmonella (NTS) is an important public health problem worldwide. Consumption of animal-derived food products and direct and/or indirect contact with animals are the major routes of acquiring infection with NTS. Published information, particularly on the serotype distribution of NTS among human patients with gastroenteritis and associated risk factors, is scarce in Ethiopia. This study investigated the prevalence, risk factors, serotype distribution and antimicrobial susceptibility of Salmonella species among diarrheic out-patients attending health centers in Addis Ababa and patients with various gastrointestinal complaints at Tikur Anbessa Specialized Hospital (TASH). METHODS: Stool samples were cultured for Salmonella species according to the WHO Global Foodborne Infections Network laboratory protocol. Salmonella serotyping was conducted using slide agglutination and microplate agglutination techniques. Antibiotic susceptibility testing was performed using the disk diffusion method according to Clinical and Laboratory Standards Institute guidelines. RESULTS: A total of 59 (6.2 %) stool samples, out of 957 were culture positive for Salmonella species. Fifty-five (7.2 %) of 765 diarrheic patients from health centers and 4 (2.1 %) of 192 patients from TASH were culture positive for Salmonella species. Multivariable logistic regression analysis after adjusting for all other variables revealed statistically significant association of Salmonella infection with consumption of raw vegetables (OR = 1.91, 95 % CI = 1.29-2.83, χ(2) = 4.74, p = 0.025) and symptom of watery diarrhea (OR = 3.3, 95 % CI = 1.23-8.88, χ(2) = 10.54, p = 0.005). Eleven serotypes were detected, and the most prominent were S. Typhimurium (37.3 %), S. Virchow (34 %), and S. Kottbus (10.2 %). Other serotypes were S. Miami, S. Kentucky, S. Newport, S. Enteritidis, S. Braenderup, S. Saintpaul, S. Concord and S. V:ROUGH-O. Resistance to three or more antimicrobials was detected in 27 (40.3 %) of the isolates. Resistance to five or more antimicrobials was detected in 17 (25.4 %). Resistance to individual antimicrobials was found at varying proportions: streptomycin (50; 74.6 %), nitrofurantoin (27; 40.3 %), sulfisoxazole (26; 38.8 %), kanamycin (23; 34.3 %), cephalothin (12; 17.9 %), and ampicillin (11; 16.4 %) respectively. Two S. Kentucky, one S. Typhimurium and one S. Concord isolates were multi-drug resistant to more than 10 antimicrobials. CONCLUSIONS: The study demonstrated significant association of Salmonella infection with consumption of raw vegetables. There was no significant association of Salmonella infection with co-occurring parasites. The study also showed the dominance of S. Typhimurium and S. Virchow in primary health care units. Overall, prevalence of MDR was low compared to previous studies. Although their proportion was low, S. Kentucky and S. Concord demonstrated wider spectrum of MDR. Continuous monitoring of circulating serotypes, antimicrobial resistance profile and characterization on molecular resistance determinants is essential for proper treatment of patients and for identifying potential environmental origins of antimicrobial resistance.

Evaluation of wound healing and anti-inflammatory activity of the rhizomes of Rumex abyssinicus J. (Polygonaceae) in mice.

BACKGROUND: Rumex abyssinicus Jacq (Polygonaceae) is widely used in Ethiopia for treatment of wound and other diseases. Although reports are available in the literature on some of the claimed activities, nothing has so far been reported about the wound healing activity of R. abyssinicus. Thus, this work was initiated to investigate the wound healing and anti-inflammatory activities of 80% methanol extract of the rhizomes of R. abyssinicus in mice. METHODS: Following extraction of the rhizomes of the plant with 80% methanol, the extract was formulated as ointment (5% & 10% w/w) with simple ointment base B.P. The ointment was then evaluated for wound healing activity using excision and incision wound models. Parameters, including wound contraction, epithelization time and hydroxyproline content were determined using the excision model, whereas tensile strength was measured from the incision model. In parallel, anti-inflammatory activity of the rhizome was evaluated with carrageenan induced hind paw edema model by dissolving the 80% methanol extract in 1% carboxyl methyl cellulose and administering orally in various doses (250, 500 and 750 mg/kg). RESULTS: Wound treated with 5% and 10% (w/w) hydroalcoholic extract ointment exhibited significant wound healing activity in both models, as evidenced by increased wound contraction, shorter epithelization time, higher tissue breaking strength and increased hydroxyproline content. The hydroalcoholic extract also produced dose-related significant reduction (p < 0.05-0.001) of inflammation. CONCLUSIONS: The results of this study demonstrated that the hydroalcoholic extract of the rhizomes of R. abyssinicus facilitated wound healing at least in part via its anti-inflammatory activity, supporting its traditional claim as a wound healing agent.