A content analysis of two african medical schools' antibiotic stewardship curricula.

Background: Antibiotics are precious substances that have saved millions of lives since their discovery, resulting in significant advances in modern medicine. However, antibiotic resistance and a slowdown in the discovery of new antibiotics with novel mechanisms of action are affecting the sustainability of antibiotics. The objective of this study was to describe the content of South African and Nigerian medical students' curricula with respect to prudent antimicrobial prescribing. Methods: A content analysis framework was used to identify, describe, and count the keywords, key phrases, and sentences relevant to the teaching of prudent antimicrobial prescribing in the complete curricula content of two African countries' medical schools. The courses are taught in the Graduate Entry Medical Programme (GEMP) curriculum (years 3-6) of the South African medical school and years 4-6 of the Nigerian medical school. The frequency of keywords/key phrases relevant to prudent antibiotic prescribing such as antimicrobial stewardship, mechanisms of bacterial resistance, and principles of antibiotic therapy was determined. Results: The two curricula reviewed were found to be different. While the South African medical school uses an integrated curriculum in the GEMP (a stream where candidates with undergraduate degrees are enrolled into the 3rd year of medical school and spend 4 years), the Nigerian medical school operates a traditional (discipline based) curriculum from MBBS 1-6. A greater number of keywords and key phrases were found in the South African curriculum compared to the Nigerian curriculum in relation to prudent antibiotic prescribing and antimicrobial stewardship. The key phrase "antimicrobial stewardship" or "antibiotic stewardship" was absent in the Nigerian curriculum but appeared four times in the South African curriculum. Discussion: The findings of this curriculum review suggest a need for revision of the medical curricula of the two countries, to one that will better prepare learners for antimicrobial stewardship.

Bioactivity of select essential oil constituents against life stages of Anopheles arabiensis (Diptera: Culicidae).

Malaria is transmitted by infected female Anopheles mosquitoes, and An. arabiensis is a main malaria vector in arid African countries. Like other anophelines, its life cycle comprises of three aquatic stages; egg, larva, and pupa, followed by a free flying adult stage. Current vector control interventions using synthetic insecticides target these stages using adulticides or less commonly, larvicides. With escalating insecticide resistance against almost all conventional insecticides, identification of agents that simultaneously act at multiple stages of Anopheles life cycle presents a cost-effective opportunity. A further cost-effective approach would be the discovery of such insecticides from natural origin. Interestingly, essential oils present as potential sources of cost-effective and eco-friendly bioinsecticides. This study aimed to identify essential oil constituents (EOCs) with potential toxic effects against multiple stages of An. arabiensis life cycle. Five EOCs were assessed for inhibition of Anopheles egg hatching and ability to kill larvae, pupae and adult mosquitoes of An. arabiensis species. One of these EOCs, namely methyleugenol, exhibited potent Anopheles egg hatchability inhibition with an IC50 value of 0.51 ± 0.03 µM compared to propoxur (IC50: 5.13 ± 0.62 µM). Structure-activity relationship study revealed that methyleugenol and propoxur share a 1,2-dimethoxybenze moiety that may be responsible for the observed egg-hatchability inhibition. On the other hand, all five EOCs exhibited potent larvicidal activity with LC50 values less than 5 µM, with four of them; cis-nerolidol, trans-nerolidol, (-)-α-bisabolol, and farnesol, also possessing potent pupicidal effects (LC50 < 5 µM). Finally, all EOCs showed only moderate lethality against adult mosquitoes. This study reports for the first time, methyleugenol, (-)-α-bisabolol and farnesol as potent bioinsecticides against early life stages of An. arabiensis. This synchronized activity against Anopheles aquatic stages shows a prospect to integrate EOCs into existing adulticide-based vector control interventions.

The insecticidal activity of essential oil constituents against pyrethroid-resistant Anopheles funestus (Diptera: Culicidae).

Malaria vector control relies on the use of insecticides for indoor residual spraying and long-lasting bed nets. However, insecticide resistance to pyrethroids among others, has escalated. Anopheles funestus, one of the major African malaria vectors, has attained significant levels of resistance to pyrethroids. Overexpressed P450 monooxygenases have been previously identified in pyrethroid resistant An. funestus. The escalating resistance against conventional insecticides signals an urgent need for identification of novel insecticides. Essential oils have gained recognition as promising sources of alternative natural insecticides. This study investigated six essential oil constituents, farnesol, (-)-α-bisabolol, cis-nerolidol, trans-nerolidol, methyleugenol, santalol (α and ß isomers) and essential oil of sandalwood, for the adulticidal effects against pyrethroid-resistant An. funestus strain. The susceptibility against these terpenoids were evaluated on both pyrethroid-susceptible and resistant An. funestus. Furthermore, the presence of overexpressed monooxygenases in resistant An. funestus was confirmed. Results showed that both the pyrethroid-susceptible and resistant An. funestus were susceptible to three EOCs; cis-nerolidol, trans-nerolidol and methyleugenol. On the other hand, the pyrethroid-resistant An. funestus survived exposure to both farnesol and (-)-α-bisabolol. This study however does not show any direct association of the overexpressed Anopheles monooxygenases and the efficacy of farnesol and (-)-α-bisabolol. The enhanced activity of these terpenoids against resistant An. funestus that has been pre-exposed to a synergist, piperonyl butoxide, suggests their potential effectiveness in combination with monooxygenase inhibitors. This study proposes that cis-nerolidol, trans-nerolidol and methyleugenol are potential agents for further investigation as novel bioinsecticides against pyrethroid-resistant An. funestus strain.

In vitro and in silico analysis of the Anopheles anticholinesterase activity of terpenoids.

Anopheles gambiae, An. coluzzii, An. arabiensis, and An. funestus are major vectors in high malaria endemic African regions. Various terpenoid classes form the main chemical constituent repository of essential oils, many of which have been shown to possess insecticidal effects against Anopheles species. The current study aimed to assess the bioactivity of terpenoids including four sesquiterpene alcohols, farnesol, (-)-α-bisabolol, cis-nerolidol, and trans-nerolidol; a phenylpropanoid, methyleugenol, and a monoterpene, (R)-(+)-limonene, using the larvicidal screening assay against the four Anopheles species. The mechanism of action was investigated through in vitro acetylcholinesterase inhibition assay and in silico molecular modelling. All six terpenoids showed potent larvicidal activity against the four Anopheles species. Insights into the mechanism of action revealed that the six terpenoids are strong AChE inhibitors against An. funestus and An. arabiensis, while there was a moderate inhibitory activity against An. gambiae AChE, but very weak activity against An. coluzzii. Interestingly, in the in silico study, farnesol established a favourable hydrogen bonding interaction with a conserved amino acid residue, Cys447, at the entrance to the active site gorge. While (-)-α-bisabolol and methyleugenol displayed a strong interaction with the catalytic Ser360 and adjacent amino acid residues; but sparing the mutable Gly280 residue that confers resistance to the current anticholinesterase insecticides. As a result, this study identified farnesol, (-)-α-bisabolol, and methyleugenol as selective bioinsecticidal agents with potent Anopheles AChE inhibition. These terpenoids present as natural compounds for further development as anticholinesterase bioinsecticides.

The in silico and in vitro analysis of donepezil derivatives for Anopheles acetylcholinesterase inhibition.

Current studies on Anopheles anticholinesterase insecticides are focusing on identifying agents with high selectivity towards Anopheles over mammalian targets. Acetylcholinesterase (AChE) from electric eel is often used as the bioequivalent enzyme to study ligands designed for activity and inhibition in human. In this study, previously identified derivatives of a potent AChE, donepezil, that have exhibited low activity on electric eel AChE were assessed for potential AChE-based larvicidal effects on four African malaria vectors; An. funestus, An. arabiensis, An. gambiae and An. coluzzii. This led to the identification of four larvicidal agents with a lead molecule, 1-benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2 showing selectivity for An. arabiensis as a larvicidal AChE agent. Differential activities of this molecule on An. arabiensis and electric eel AChE targets were studied through molecular modelling. Homology modelling was used to generate a three-dimensional structure of the An. arabiensis AChE for this binding assay. The conformation of this molecule and corresponding interactions with the AChE catalytic site was markedly different between the two targets. Assessment of the differences between the AChE binding sites from electric eel, human and Anopheles revealed that the electric eel and human AChE proteins were very similar. In contrast, Anopheles AChE had a smaller cysteine residue in place of bulky phenylalanine group at the entrance to the catalytic site, and a smaller aspartic acid residue at the base of the active site gorge, in place of the bulky tyrosine residues. Results from this study suggest that this difference affects the ligand orientation and corresponding interactions at the catalytic site. The lead molecule 2 also formed more favourable interactions with An. arabiensis AChE model than other Anopheles AChE targets, possibly explaining the observed selectivity among other assessed Anopheles species. This study suggests that 1-benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2 may be a lead compound for designing novel insecticides against Anopheles vectors with reduced toxic potential on humans.

Potential of Essential Oil-Based Anticholinesterase Insecticides against Anopheles Vectors: A Review.

The insect nervous system is critical for its functional integrity. The cholinergic system, of which acetylcholinesterase (AChE) is a key enzyme, is essential to the Anopheles (consisting of major malaria vector species) nervous system. Furthermore, the nervous system is also the primary target site for insecticides used in malaria vector control programs. Insecticides, incorporated in insecticide-treated nets and used for indoor residual spraying, are a core intervention employed in malaria vector control. However, Anopheles resistance against these insecticides has grown rapidly. Due to this major setback, novel agents with potential activity against resistant Anopheles and/or capacity to overcome resistance against current WHO-approved insecticides are urgently needed. The essential oils have the potential to be natural sources of novel insecticides with potential to inhibit the Anopheles AChE target. In the current review, the scientific evidence highlights the ability of essential oils and specific essential oil constituents to serve as anticholinesterase insecticides. For this reason, the published data from scientific databases on the essential oils and essential oil constituents on anticholinesterase, ovicidal, larvicidal, pupicidal and adulticidal activities were analyzed. The identification of major constituents in active essential oils and their possible influence on the biological activity have also been critically evaluated. Furthermore, the toxicity to mammals as well as potential activity against the mammalian AChE target has also been reviewed. The importance of identifying novel potent insecticides from essential oils has been discussed, in relation to human safety and cost-effectiveness. Finally, the critical insights from this review can be used to inform future researchers towards potent and safe anticholinesterase insecticides for the management of Anopheles malaria vectors.

Optimization of covalent docking for organophosphates interaction with Anopheles acetylcholinesterase.

Organophosphates (OPs) used as potent insecticides for malaria vector control, covalently phosphorylate the catalytic serine residue of Anopheles gambiae AChE (AgAChE) in a reaction that liberates their leaving groups. In the recent 10-year insecticide use assessment, OPs were the most frequently used World Health Organization prequalified insecticides. Molecular modelling programs are best suited to display molecular interactions between ligands and the target proteins. The docking modes that generate ligand poses closer to the binding site show high accuracy in predicting the ligand binding mode. The implicit solvation approach such as molecular mechanics-generalized born surface area (MM-GBSA) is a more reliable method to predict ligand onformations and binding affinities. Apart from covalent docking studies being scarce, current molecular docking programs do not adequately possess the covalent docking reaction algorithm to display the molecular mechanism of OPs at the AgAChE catalytic site. This results into OP docking studies commonly being conducted through noncovalent pannels. The aim of this study was to establish the optimim covalent docking system for OPs through manual customization of Schrödinger's Glide covalent docking reaction algorithm. To achieve this, a newly customized covalent reaction algorithm was assessed on a set of ligands covering aromatic, non-aromatic and hydrophobic OPs and compared to the noncovalent docking results in terms of reliability based on the reported X-ray diffraction molecular interactions and crystal poses. The study established that by virtue of omitting the well-known OP hydrolysis, noncovalent mode suggested molecular interactions that were further from the catalytic triad and could not otherwise occur when the molecule is hydrolyzed as in the customized covalent docking mode. Moreover, the MM-GBSA concurred with the optimized covalent docking in eliminating such inaccurate molecular interactions. Additionally, the covalent docking mode confined the interactions and ligand poses to the catalytic site indicating relatively high accuracy and reliability. This study reports the optimized covalent docking panel that effectively confirmed the molecular mechanisms of OPs, as well as indentifying the corresponding amino acid residues required to stabilize the aromatic, non-aromatic and hydrophobic OPs at the AgAChE catalytic site in line with the reported X-ray diffraction studies. As such, the proposed manual customization of the Schrödinger's Glide covalent docking platform can be used to reliably predict molecular interactions between OPs and AgAChE target.

Impact of an antibiotic stewardship programme in a surgical setting.

BACKGROUND: Antibiotics are miracles of science and critical for many surgical procedures. However, the emergence of multidrug resistant pathogens resulting from inappropriate antibiotic use is a threat to modern medicine. This study aimed to determine the appropriateness of antibiotic use, cost, consumption and impact of an antibiotic stewardship intervention round in a surgical ward setting. METHODS: Baseline antibiotic utilisation was determined with a retrospective cross-sectional study in two surgical wards in a tertiary academic hospital in South Africa where medical records of 264 patients who received antibiotics were reviewed. In the second stage of the study, records of 212 patients who received antibiotics were reviewed during a weekly antibiotic stewardship intervention round. The volume of antibiotics consumed was determined using defined daily doses (DDDs)/1000 patients' days, and the appropriateness of the antibiotic prescription for treatment was also determined using a quality-of-use algorithm. RESULTS: There was a reduction in the volume of antibiotic consumption from a total 739.30 DDDs/1000 to 564.93 DDDs/1000 patient days, with reduction in inappropriate antibiotic use from 35% to 26% from baseline to antibiotic stewardship programme stages, respectively. There was an overall increase in culture targeted therapy in both wards in the antibiotic stewardship programme stage. CONCLUSION: The implementation of an antibiotic stewardship programme led to a reduction in antibiotic consumption and improvement in appropriate use of antibiotics.

Educational antimicrobial stewardship programs in medical schools: a scoping review.

OBJECTIVE: The objective of this scoping review was to identify the available evidence on antimicrobial stewardship programs for teaching medical students about rational antimicrobial use, including the content taught and the method of instruction used. INTRODUCTION: Antibiotics are a precious resource whose discovery have saved millions of lives. They are used extensively in surgical procedures, cancer chemotherapy, and in the treatment of infectious diseases. However, the development of antimicrobial resistance and the slow rate of discovery of new agents with novel mechanisms of actions represent a threat to modern medicine. INCLUSION CRITERIA: This scoping review considered papers that described medical school curricula that focused on the teaching and learning of the prescription of antimicrobial medication. Studies that described this concept in the curricula of other health profession students, such as nursing, pharmacy, or dentistry students, were excluded. METHODS: The JBI three-step process was followed and conducted by two reviewers. The scoping review followed an a priori published protocol. Eight databases were searched for both published and unpublished literature and gray literature. Only studies published in English from 1996 onwards were included. Full texts of selected citations were assessed against the inclusion criteria by two independent reviewers. Data were independently extracted by two reviewers. Disagreements were resolved through discussion, and the need for a third reviewer was not required. Data extraction was undertaken using a modified charting table developed for the review objectives. The findings are presented using the narrative synthesis. RESULTS: Thirteen studies were included in the review, with most of the papers originating from the United States of America and Europe, with one from developing countries. Didactic lectures and web-based distance learning were the most common modes of instruction used in the included papers. Six of the included papers presented the outcomes of their interventions; different methods of assessment were used to evaluate students, which included baseline and post-instruction assessment or a series of short exams. Some of the concepts in the teaching material included the use of antimicrobial agents, prevention of antimicrobial resistance, antimicrobial stewardship, and infection prevention control. The programs (ranging from 75 minutes to 100 hours) were implemented from second to fourth year of study. CONCLUSIONS: A wide range of interventions were used to teach the principles of antimicrobial stewardship to medical students. There is a need to further evaluate these programs through follow-up of students after graduation to determine whether the skills learned are retained.

Knowledge and perceptions about antibiotic resistance and prudent antibiotic prescribing among final year medical students in two African countries.

OBJECTIVES: The objectives of this study were to assess the knowledge and perceptions of final year medical students about antibiotic resistance and antibiotic use to assist in the development of an antibiotic stewardship curriculum for teaching medical students in South Africa and Nigeria and the principles of prudent antibiotic prescribing. METHODS: A cross-sectional study was conducted to determine the knowledge and perceptions of final year medical students in one South African and three Nigerian universities about prudent antibiotic use, antibiotic resistance and antibiotic stewardship. A 26-item questionnaire was administered electronically to students in three medical schools and a paper-based copy in the fourth. KEY FINDINGS: A difference in the gap in knowledge between the two countries was identified; however, respondents from both countries had a similar understanding of antibiotic use and antibiotic resistance. Most respondents in South Africa (94.8%) and Nigeria (91.4%) agreed that antibiotics are overused in their countries. There was a significant difference between the number of respondents in the two countries who thought that there are new antibiotics available to treat resistant pathogens; 45.4% of Nigerian respondents agreed with the statement as compared to 9.6% of the South African respondents. Of the 10 vignettes answered correctly, South African respondents scored an average of 62.4% in the knowledge segment compared to 31.9% scored by the Nigerian respondents (P = 0.001). All of the South African (100%) and 98.3% of the Nigerian respondents indicated their desire for more education on appropriate antibiotic use. CONCLUSIONS: Although students from both countries had the same perception of antibiotic resistance, there was, however, a difference in their level of knowledge, which could have been improved in both countries. This should be addressed at an undergraduate curriculum level; as well as with continued education to reinforce antibiotic knowledge.

Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors.

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N'-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds. The antiplasmodial screening revealed that seven analogues showed promising to good activity with half-maximal inhibitory concentration (IC50) = 0.32 µM-4.30 µM. Compound 7a with 1,4-diamine butyl linker and 4-hydroxyl phenyl on fourth and sixth position of pyrimidine core showed the most prominent activity with an IC50 value of 0.32 ± 0.06 µM, with a favourable safety profile of 9.79 to human kidney epithelial (HEK293) cells. The remaining six analogues showed moderate activity with IC50 values ranging from 7.50 µM to 83.01 µM. We further investigated the binding affinities of the molecules to two essential cytosolic P. falciparum heat shock protein 70 homologues; PfHsp70-1 and PfHsp70-z. Compound 7a exhibited the highest binding affinity for both PfHsp70s with KD in a lower nanomolar range (4.4-11.4 nM). Furthermore, molecular docking revealed that compounds 6, 6k, 7b and 7a exhibited better fitness in PfHsp70-1 with compound 7a showing the highest and lowest binding scores of -9.8 kcal/mol. Therefore, we speculate that PfHsp70-1 is one of the targets of these inhibitors. The bioisoteric replacement of the groups at phenyl ring at the fourth and sixth position of the pyrimidine core had a constructive association with antiplasmodial activity. The promising antiplasmodial activity of the synthesised analogues illustrates how crucial molecular hybridisation is as a strategy in the development of quinoline-pyrimidine hybrids as prospective antiprotozoal agents.

Educational antimicrobial stewardship programs in medical schools: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify the available evidence on antimicrobial stewardship programs for teaching medical students about rational antimicrobial use, including the content taught and the method of instruction used. INTRODUCTION: Antibiotics are life-saving drugs and their discovery is one of the most important advances of the 20th century. They have transformed modern medicine by playing a critical role in the management of infectious diseases. However, the rapid development of resistance of pathogens to antibiotics is gradually affecting this initial success. Antimicrobial stewardship programs have been shown to reduce the burden of antimicrobial resistance in hospitals. INCLUSION CRITERIA: This scoping review will consider papers conducted in medical school curricula to improve the prescribing of antimicrobial medication. Studies that include other health profession students, such as nursing, pharmacy, or dentistry students, will be excluded. Studies published in English from 1996 onwards will be included. METHODS: Databases to be searched are PubMed, Wiley Online library, CINAHL Complete, Web of Knowledge, Scopus and Education Resources Information Center. Unpublished studies and gray literature will be included. Searching will follow a three-step process and will be conducted by two reviewers. Data will be extracted by two independent reviewers. Any disagreements that arise between the reviewers during the study selection process or data extraction will be resolved through discussion, or with a third reviewer. Results will be presented in tabular or diagrammatic form, together with a narrative summary.

Semi-Synthesis and Evaluation of Sargahydroquinoic Acid Derivatives as Potential Antimalarial Agents.

Background: Malaria continues to present a major health problem, especially in developing countries. The development of new antimalarial drugs to counter drug resistance and ensure a steady supply of new treatment options is therefore an important area of research. Meroditerpenes have previously been shown to exhibit antiplasmodial activity against a chloroquinone sensitive strain of Plasmodium falciparum (D10). In this study we explored the antiplasmodial activity of several semi-synthetic analogs of sargahydroquinoic acid. Methods: Sargahydroquinoic acid was isolated from the marine brown alga, Sargassum incisifolium and converted, semi-synthetically, to several analogs. The natural products, together with their synthetic derivatives were evaluated for their activity against the FCR-3 strain of Plasmodium falciparum as well as MDA-MB-231 breast cancer cells. Results: Sarganaphthoquinoic acid and sargaquinoic acid showed the most promising antiplasmodial activity and low cytotoxicity. Conclusions: Synthetic modification of the natural product, sargahydroquinoic acid, resulted in the discovery of a highly selective antiplasmodial compound, sarganaphthoquinoic acid.

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives.

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5-14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC50 values (0.14-1.26µM) lower than the standard drug metronidazole (IC50 1.80µM). All nine compounds exhibited antimalarial activity (IC50 range: 1.42-19.62µM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC50 range: 14.67-81.24µM) than quinine (IC50: 275.6±16.46µM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.

Design, synthesis and biological evaluation of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines as antiplasmodial antifolates.

The design, synthesis and biological evaluation of a series of 6-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines is described. These compounds exhibited in vitro antiplasmodial activity in the low nanomolar range against both drug sensitive and drug resistant strains of P. falciparum, with 1-(3-(2,4-dichlorophenoxy)propyl)-6-phenyl-1,6-dihydro-1,3,5-triazine-2,4-diamine hydrochloride identified as the most potent compound from this series against the drug resistant FCR-3 strain (IC50 2.66 nM). The compounds were not toxic to mammalian cells at therapeutic concentrations and were shown to be inhibitors of parasitic DHFR in a biochemical enzyme assay.

Impact of combination antiretroviral therapy initiation on adherence to antituberculosis treatment.

BACKGROUND: Healthcare workers are often reluctant to start combination antiretroviral therapy (ART) in patients receiving tuberculosis (TB) treatment because of the fear of high pill burden, immune reconstitution inflammatory syndrome, and side-effects. OBJECT: To quantify changes in adherence to tuberculosis treatment following ART initiation. DESIGN: A prospective observational cohort study of ART-naïve individuals with baseline CD4 count between 50 cells/mm3 and 350 cells/mm3 at start of TB treatment at a primary care clinic in Johannesburg, South Africa. Adherence to TB treatment was measured by pill count, self-report, and electronic Medication Event Monitoring System (eMEMS) before and after initiation of ART. RESULTS: ART tended to negatively affect adherence to TB treatment, with an 8% - 10% decrease in the proportion of patients adherent according to pill count and an 18% - 22% decrease in the proportion of patients adherent according to eMEMS in the first month following ART initiation, independent of the cut-off used to define adherence (90%, 95% or 100%). Reasons for non-adherence were multifactorial, and employment was the only predictor for optimal adherence (adjusted odds ratio 4.11, 95% confidence interval 1.06-16.0). CONCLUSION: Adherence support in the period immediately following ART initiation could optimise treatment outcomes for people living with TB and HIV.

Synthesis and evaluation of 7-chloro-4-(piperazin-1-yl)quinoline-sulfonamide as hybrid antiprotozoal agents.

A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1-F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC50 <5 µM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC50 values of 2 µM. Compound F7, whose crystal structure was also determined, inhibited ß-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski 'rule of five' on all the compounds (F1-F11) suggested high drug likeness of F7 and F8, similar to quinine.

Antiprotozoal activity of chloroquinoline based chalcones.

A new series of chloroquinoline based chalcones were synthesized and evaluated for in vitro antiamoebic and antimalarial activities. The results showed that out of fifteen compounds, four were found to be more active against the Entamoeba histolytica; while one compound was moderatively active compared to the standard drug metronidazole (IC50=1.46 µM). In contrast, in vitro antimalarial activity against the chloroquine-sensitive (3D7) strain of P. falciparum indicated relatively low activity when compared to controls such as chloroquine and quinine (IC50=0.0065 µM and 0.14 µM, respectively). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were non-toxic at the concentration range of 1.56-50 µM.

Expeditious synthesis and biological evaluation of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as potential antimalarials.

A small set of novel 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines was prepared possessing a flexible tether between the exocyclic nitrogen bonded to C-6 of the 1,2-dihydro-1,3,5-triazine-4,6-diamine heterocycle and the distal aryl ring. Three zones were varied in this series of compounds, namely the nature of the substituent(s) on C-2; the nature of the substituent(s) on the distal aryl ring; as well as the nature and length of the flexible tether between the rings. The compound showing the best antimalarial activity (cycloguanil-resistant FCR-3 Plasmodium falciparum IC50=0.99 µM) was N6-(3-(4-chlorophenoxy)propyl)-2-(furan-2-yl)-1,2-dihydro-1,3,5-triazine-4,6-diamine hydrochloride.

The anti-diarrhoeal properties of Breonadia salicina, Syzygium cordatum and Ozoroa sphaerocarpa when used in combination in Swazi traditional medicine.

AIM OF THE STUDY: The aim of the study was to determine in vitro activity of the bark of Ozoroa sphaerocarpa R. Fern & A. Fern (Anacardiaceae), Breonadia salicina (Vahl) Hepper & J.I.R. Wood (Rubiaceae) and Syzygium cordatum Hochst ex C Krauss (Myrtaceae) against a diarrhoea-causing pathogen, Escherichia coli; as well as the pharmacological interactions present in their combination. MATERIALS AND METHODS: In consultation with traditional healers, the plants were collected from the wild, dried and extracted with dichloromethane:methanol (1:1). Thereafter, antimicrobial activity of the individual plants and their different combinations was tested using a common diarrhoea pathogen, Escherichia coli by employing the minimum inhibitory concentration assay. RESULTS: Ozoroa sphaerocarpa was the most potent inhibitor of antimicrobial growth (MIC value of 1.2 mg/ml), followed by Syzygium cordatum (MIC value of 1.44 mgl/ml) and lastly Breonadia salicina (MIC value of 10.89 mg/ml). The combination between Syzygium cordatum and Ozoroa sphaerocarpa gave the strongest synergistic interaction (MIC value of 0.33 mg/ml); whilst that between Syzygium cordatum and Breonadia salicina was mildly synergistic (MIC value of 1.00 mg/ml). The triple combination (1:1:1) was also very effective in inhibiting microbial growth (MIC value of 0.44 mg/ml). The combined effect of these plants on toxicity was predominantly synergistic except for the combination of Ozoroa sphaerocarpa and Syzygium cordatum which was predominantly antagonistic (ΣFIC value of 1.48 ± 0.25). The triple combination had a favourable toxicity profile with an IC(50) value of 155.76 ± 11.86 µg/ml. CONCLUSION: This study supports the rationale by traditional healers to use the bark of Syzygium cordatum, Breonadia salicina and Ozoroa sphaerocarpa in combination for the treatment of diarrhoea.