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- ItemDesign, synthesis and evaluation of the activity of 4-aminoquinoline derivatives as potential cruzain and rhodesin inhibitors(Kampala International University, 2023-10) Rahamah IdreesIn this research work a series of aminoquinolines, potential inhibitors of cruzain was designed, studied in silico by molecular modeling docking methods, synthesized and evaluated in vitro assays. Chagas disease is a neglected disease called America Trypanosomiasis caused by Trypanosoma cruzi and about 8 million people are estimated to be infected worldwide. Trypanosoma cruzi is 70 percent related to Trypanosoma brucei responsible for Human Africa Trypanosomiasis, is a major health problem worldwide. Current drugs used in treatment of both diseases shows high toxicity and low efficacy at chronic stage of the disease. Cruzain (or cruzipain) and TbrCATL is a cathepsin L-like cysteine protease considered the dominant protease of the protozoan Trypanosoma cruzi and Trypanosoma brucei, respectively. These proteases are believed to be involved in the acquisition of nutrients, degradation of host proteins and evasion of the immune system, representing a promising target for developing trypanocidal drugs. A series of potential inhibitors of cruzain was planned based on 7-chloro-4-aminoquinolines 2 and 3 (IC50 = 13.2 μM and 25μM) respectively. The molecular modeling docking results of the studies suggest that designed compounds are possible to be potent. The synthesized series contains a 7-chloro-4-aminoquinolines motif and different side chain lengths were explored. QFF (3) inhibited more than 85% of the activity of both cruzain and TbrCATL, with IC50 value of 23 and 29 μM, respectively. The results of the enzymatic assays without pre-incubation suggest that the compounds are not time dependent inhibitors. However, additional assay is required to exclude the possibility of QFF acting as a promiscuous inhibitor through aggregation. The overall results showed that aminoquinolines is a promising class in further investigation of cruzain and rhodesain inhibition.
- ItemEvaluation of the safety and hypoglycemic activity of aqueous extract of Albizia chinensis (Osbeck) Merr stem bark in streptozotocin-induced diabetic Wistar rats(Kampala International University, 2021-11) Wilberforce MfitundindaBackground: WHO estimates show global diabetes prevalence as 463 million adults as of 2021. Due to shortcomings of conventional antidiabetic drugs especially with regard to adverse effects and high cost, use of extracts from medicinal plants, like Albizia chinensis, has come up as one of the alternative ways of managing diabetes. but with claims of safety and efficacy requiring scientific validation. Therefore, this study was undertaken to validate the safety and hypoglycemic activity of the aqueous extract of the stem bark of Albizia chinensis. Methods: The aqueous stem bark of extract of Albizia chinensis obtained by cold maceration was tested for acute toxicity in Wistar rats using Lorke‟s method followed by sub-acute toxicity assessment. The hypoglycaemic activity was assessed using Wistar rats with streptozotocin-induced Type II diabetes mellitus and using with metformin as the positive control. Results: The LD50 was found to be above 5000mg/kg although the extract showed signs of sedation and reduced activity but no significant effect on serum biochemical parameters though with a statistically significant effect on hematological levels width RDW-SD (p=0.0016), mean platelet volume MPV (p=0.0022) and procalcitonin (p-value = 0.0056). The plant extract also showed significant reduction of blood glucose levels comparable to those of metformin. Conclusion: The aqueous extract of the stem bark of Albizia chinensis has hypoglycemic activity against streptozotocin induced type II DM and is relatively safe for use at acute and subacute levels although more research needs to done to establish the chronic effects of the plant extract.
- ItemIsolation, characterisation and in vivo efficacy of lytic bacteriophages from sewage-treatment plants against ciprofloxacin-resistant Salmonella Typhi in Mbarara District, Uganda(Kampala International University, 2023-10) Bindyo Phoebe NzulaThe emergency of ciprofloxacin-resistant Salmonella Typhi infection among majority of the developing countries has elevated morbidity and mortality rate. The present study aimed at determining the in vivo efficacy against ciprofloxacin-resistant Salmonella Typhi of lytic bacteriophages from sewage treatment plants in Mbarara district, Southwestern Uganda. A laboratory based experimental study was conducted. Twelve samples obtained from two sewage treatment plants within Mbarara district, Southwestern Uganda; Kakoba and Taso were used for isolation of bacteriophages using the double agar overlay plaque assay. The isolated phages were assayed for both biological and physico-chemical characteristics. A mice infection model that included; bacteria + phage, bacteria + SM buffer, bacteria + ciprofloxacin antibiotic groups and phage only were used to assess the in vivo efficacy of bacteriophage cocktail against ciprofloxacin resistant Salmonella Typhi after intraperitoneal administration. The bacterial loads and phage titres from the lungs, intestines, liver, and kidney were determined using surface spreading and double agar overlay plaque assay. Data was analyzed using SPSS-26 to compute descriptive statistics and statistical significance was considered at P ≤ 0.05. The four isolated phages exhibited lytic activity against the ciprofloxacin-resistant S. Typhi with an average host range limited to S. Typhi species with exception of phage TA001 with activity against Shigella species. The adsorption time of phages ranged from 5-15 minutes, with latent period of 10 – 20 minutes and burst sizes ranged from 286 to 163 PFU/ml. The phages exhibited high stability at temperatures up to 60 oC and pH 4 -12. The phage had an average host range of 8.3% to 50.0%. The phage cocktail rapidly decreased the S. Typhi counts in blood, liver, spleen intestines and kidney to 0 CFU/mL within 48 h as compared to ciprofloxacin treated mice. The phages were completely cleared at a rapid rate in the spleen, kidney, and blood within 60h, 96 h and 120 h respectively. Treatment with phage cocktail caused a significant reduction in the weights of liver and intestines as compared to ciprofloxacin treated mice. Sewage harbored virulent lytic phages against ciprofloxacin resistant S. Typhi and the cocktail exhibited potent in vivo therapeutic efficacy in mice model. The study recommends molecular characterization, pharmacokinetic, histological effects and immunological responses in order to establish their safety for therapeutic usage in humans.
- ItemEfficacy evaluation of a lytic bacteriophage cocktail against carbapenem–resistant pseudomonas aeruginosa - infected wounds in mice(Kampala International University, 2021-11) Ivan IbandaBackground: Pseudomonas aeruginosa is an opportunistic infectious agent associated with burns/surgical infections. With the global emergence of resistance to carbapenems and last-resort drugs such as colistin, carbapenem-resistant Pseudomonas aeruginosa (CRPA) has been placed in the critical category of microorganisms for which alternatives to antibiotics are urgently needed. With bacteriophage application being one of the most promising alternatives to conventional antibiotics being pursued, the purpose of this study was to assess the efficacy of a locally formulated lytic bacteriophage cocktail against CRPA clinical isolates in a wound-infection mouse model. Materials and methods: The study involved isolation of phages from hospital effluent followed by evaluation of the lytic effects and in vitro activity of a phage cocktail against CRPA. The phage enrichment and isolation of bacteriophages were conducted according to the method described by Clokie et al., (2018), with modifications. The purification of the phage isolates was done according to the modified procedure of Bhensdadia et al., (2014) while the spot assay technique by Clokie et al., (2018) was employed for the quantification of the bacteriophages. In vivo efficacy of the bacteriophage cocktail on the healing of wounds infected with CPRPA was then evaluated using a mouse model. Results: Four phages were isolated from the hospital effluents and the cocktail, coded C12, from three of the isolates in a 2:1:1 ratio had the highest efficacy after 48 hours. The mean wound diameters at the end of the experiment showed that the phage cocktail-treated wounds registered satisfactory closures of at least 67.7% and the results were statistically significant from those of the meropenem-treated wounds (p < 0.0001). Conclusion:The locally formulated and optimized three-phage cocktail demonstrated satisfactory efficacy (p < 0.0001) in the treatment of wounds infected with carbapenem – resistant Pseudomonas aeruginosa clinical isolate when topically administered in sufficient doses and at optimal frequencies.
- ItemHypoglycaemic evaluation of the aqueous seed extract of Persea americana (Mill.) on dolutegravir-induced hyperglycaemia in wistar rats(Kampala International University, 2023-10) Vian NamanyaBackground: It has been increasingly reported world over that hyperglycaemia is common in HIV sero-positive and enrolled clients taking dolutegravir, a new second generation integrase strand inhibitor. Considering the fact that there is a possibility of HIV/AIDS and Diabetes mellitus co-morbidity, this poses a rather critical health care concern to low-income nations like Uganda, since it might demand for change to more expensive regimens or resorting to herbal concoctions to alleviate the adverse effects of HIV drugs. This research assessed the efficacy of aqueous extract of Persea americana seed against dolutegravir-induced hyperglycemia in Wistar rats. Methodology: Acute toxicity of aqueous extract Persea americana seed was determined using Lorke’s method while the efficacy against dolutegravir-induced hyperglycemia was determined by administering varying dosage concentrations to 6 groups of Wistar rats and determining sugar levels using a glucometer. On day 30, tests were done to determine of changes in haematological and biochemical parameters. Results: The median lethal dose of Persea americana was found to be 1264mg/kg, which is in the slightly toxic range while different extract percentages and dolutegravir were found to have no significant effects on haematological parameters, though there was significant derangement observed with creatinine, sodium and potassium electrolytes as well as alanine transaminase and aspartate transaminase liver enzymes. Animals that received dolutegravir with 240mg/kg of the extract and positive controls experienced significant blood sugar reductions demonstrating a protective effect if the extract was to be co-administered with dolutegravir. Conclusion: The results demonstrated that dolutegravir induces hyperglycaemia in Wistar rats and that the Persea americana seed extract has potential to ameliorate this effect.