FACULTY OF PHARMACY
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Item MOLECULAR CHARACTERISATION OF METALLO-BETA LACTAMASE AND OTHER RESISTANCE GENES IN PSEUDOMONAS AERUGINOSA FROM SEVEN TERTIARY HOSPITALS IN SOUTHWESTERN NIGERIA(2019-06) OLANIRAN, O.BThe emergence of resistance to carbapenems, a last resort antibiotic, among Pseudomonas aeruginosa is of great health concern. Detailed studies on the molecular basis of carbapenem resistance in clinical P. aeruginosa isolates are scanty in Nigeria. Therefore, this study was aimed at determining the incidence of Metallo-Beta Lactamase (MBL) and other mechanisms mediating carbapenem resistance, and evaluating clonal spread among carbapenem-resistant P. aeruginosa isolates. Four hundred and forty-seven presumptive P. aeruginosa isolates collected from seven tertiary hospitals laboratories in southwestern Nigeria were identified using biochemical tests and amplification of oprI and oprL genes. Antibiogram of the isolates and Minimum Inhibitory Concentrations (MIC) were determined by Kirby-Bauer disk diffusion and broth microdilution, respectively. Phenotypic detection of carbapenemases was carried out using Modified-Hodge and combined disc tests. Carbapenem-resistant P. aeruginosa isolates were screened for class A, B and D carbapenemases, integrons and type III secretion effectors by Polymerase Chain Reaction (PCR) followed by sequencing of amplified carbapenemase genes. Transferability of MBL genes was determined by transformation experiments. Quantitative reverse transcription PCR (RT-qPCR) was used to quantify expression levels of eight efflux pump genes, ampC cephalosporinase and outer membrane porin oprD. The isolates were further genotyped using three PCR-based fingerprinting techniques. Fisher’s exact test was used to determine the association between MBL and integrons at p ≤ 0.05. Four hundred and thirty isolates were identified as P. aeruginosa of which 185(43.0%) were multidrug resistant and 50(11.6%) were extensively drug resistant. All the isolates were resistant to ampicillin, cephalothin and cefuroxime, while sensitivity to polymyxin B was most common (96.3%). The MICs ranged from 0.125 to >64 µg/mL and 0.0625 to >64 µg/mL against imipenem and meropenem, respectively. All the isolates were negative for Modified-Hodge test, while combined disc test revealed the presence of MBL. Two class B carbapenemases were detected in 86.3% of the carbapenem resistant isolates: blaVIM and blaNDM in 35.6% and 38.4% isolates, respectively, co-existing in 12.3% isolates. Fifty-one (57.5%) carbapenem-resistant P. aeruginosa strains carried class 1 integrons while class 1 and 2 integrons were present concomitantly in 12.3%. Type III effector genes, exoY and exoT were found in all isolates, while exoU and exoS were present in 49.3% and 53.4%, respectively. Two isolates possessed both exoU and exoS. Sequence analysis of blaVIM and blaNDM revealed maximum identity with blaVIM-5 and blaNDM-1, respectively. MBL genes were successfully transferred into Escherichia coli DH5α. MexXY-OprM was the most overexpressed pump (5.0 - 996.3 fold increase) occurring in 58.3% of the isolates. The ampC was overexpressed in 27.1% isolates, while oprD porin down-regulation was observed in 77.1% of the isolates. Nine disseminated clones were identified across southwestern states. There was positive association between integrons and MBL (p = 0.0064). There is a high incidence of transmissible metallo-beta lactamase genes in Pseudomonas aeruginosa from tertiary hospitals in southwestern Nigeria with different mechanisms mediating carbapenem resistance. blaVIM-5 and blaNDM-1 were found co-occurring for the first time. There is a need for surveillance of resistance to carbapenems and associated resistance genes.Item PRESCRIBING ERRORS AND INTERVENTION OUTCOMES IN SELECTED TERTIARY HOSPITALS IN NIGERIA(2014-11) AJEMIGBITSE, ADETUTU ADEBAMBOPrescribing errors, particularly in the medical and paediatric specialties have been reported globally to affect up to 52.0% of hospitalized patients with potential to cause harm. Prescribing errors have however not been adequately investigated in Nigeria. This study was designed to carry out an in-depth evaluation of the nature, severity and causes of prescribing errors in three purposively selected tertiary hospitals in Nigeria with a view to providing pharmacist-led evidence-based recommendations for their prevention. A retrospective review of 8270 out-patient prescriptions and 1200 in-patient records from medical and paediatric units between January and December 2010 in National Hospital, Abuja (NHA) with University of Abuja Teaching Hospital, Gwagwalada (UATH) and University College Hospital, Ibadan (UCH) as controls. Baseline prescribing pattern was measured using the British National Formulary and Nigeria Standard Prescribing Guidelines. Causes of prescribing errors were investigated using a prospective qualitative approach involving semi-structured face-to-face interviews and questionnaires guided by the Reason’s accident causation model. Error rates were studied in the three tertiary hospitals while intervention was carried out at NHA. Interventions involved educational outreaches consisting of structured teaching and training. Data collected compared error rates pre- and post- intervention, to determine impact of the intervention. Data were analysed using descriptive and Chi-square statistics. Prescribing error rates were 24.6 ± 1.4 (UATH), 5.7 ± 1.2 (NHA) and 6.7 ± 2.3 (UCH) for out-patient prescriptions and 28.7 ± 2.3 (UATH), 26.3 ± 2.1 (NHA) and 41.0 ± 3.1 (UCH) for in-patient prescriptions. Non-inclusion of direction of use (38.1%, UATH); missing signature and/or name of prescriber (66.6%, NHA) and omitting end date of therapy (54.4%, UCH) were the commonest errors in out-patient prescriptions. The most common in-patient prescribing error was missing end date of therapy: 71.3% (UATH), 65.9% (NHA) and 86.0% (UCH). The highest proportion of medications was ordered at admission: 57.3% (UATH), 44.3% (NHA) and 44.7% (UCH) while time of discharge was associated with the highest error rates of 37.8% (UATH), 58.6% (NHA) and 80.8% (UCH). Severity of prescribing error rates for in-patients was 4.9% (UATH), 2.8% (NHA) and 1.3% (UCH). Prescriptions involving antimicrobials contained the highest prescribing UNIVERSITY OF IBADAN LIBRARY iii errors 53.8% (UATH), 37.9% (NHA), and 36.3% (UCH). Risk factors identified in error causation included organisational (91.0%), environment (50.0%), individual (45.0%), task (45.0%) and team (36.0%) factors. Absence of self-awareness of errors and organisational factors identified included inadequate training and experience and absence of reference materials. Defences against errors, particularly pharmacists’ involvement, were deficient. There was no change in overall error rates 5.8%, pre- and post- intervention (p = 0.98). However, there were reductions in drug-drug interactions 1.2% to 0.4% (p<0.001), omission of drug route 0.3% to 0.1% (p<0.001) and ambiguous orders 0.2% to 0.0% (p<0.001) at the NHA. Prescribing errors were common in the 3 facilities resulting from writing prescriptions that lacked details and slips in attention. Majority of the errors, though of minor severity, had potential of causing harm. Continuing prescriber education and training will likely result in error reduction. Pharmacists’ involvement in prescribing error prevention should be an on-going process. Key words: Prescribing errors, Reason’s accident causation model, In- and out-patients. Word count: 500Item Evaluation of freeze-dried pregelatinized Chinese yam (Dioscorea oppositifolia) starch as a polymer in floating gastroretenive metformin microbeads.(2010) Okunlola, A.; Patel, R. P.; Odeku, O. A.Pregelatinized Chinese yam (Dioscorea oppositifolia) starch has been evaluated as a polymer for the formulation of floating gastroretentive beads for the controlled delivery of metformin hydrochloride. Floating microbeads were prepared by the ionotropic gelation method using a blend of modified Chinese yam starch and sodium alginate at different ratios. Sodium bicarbonate was added as a gas-generating agent. The floating microbeads were characterized by SEM, DSC, FTIR analyses and the drug entrapment efficiency and floating ability was evaluated. Drug release was investigated using in vitro dissolution test and the results were fitted to various kinetic models to determine the mechanism(s) of release. Spherical, discrete and free flowing microbeads were obtained from the modified starch-alginate blends. Minimum lag time (< 20 s) was observed for the floating microbeads containing starch and buoyancy was maintained for 12 h. The release of MET from the floating microbeads appeared to be controlled by varying the starch to alginate polymer ratio. In general, the formulations followed diffusion and erosion mechanisms of drug release. The results suggest that modified Chinese yam starch-sodium alginate blend can be useful for the formulation of floating gastroretentive system for metformin hydrochlorideItem Flow, compaction and tabletting properties of co-processed excipients using pregelatinized ofada rice starch and HPMC(IPEC-Americas Inc., 2018) Okunlola, A.The growing popularity of direct-compression process necessitates an ideal filler–binder that can substitute two or more excipients. Pregelatinization of starches significantly improves swelling and flow properties but produces tablets with low mechanical strength. When used as a binder in many tablet formulations, hydroxyl propyl methyl cellulose (HPMC) imparts mechanical strength but because of its poor flow during high speed tablet manufacturing, granulation of HPMC-based formulations is required prior to compaction. Directly-compressible co-processed excipients were developed utilizing pregelatinized starch of the indigenous Ofada rice starch (Oryza glaberrima Steud Family Poaceae) and HPMC. Co-processed excipients of various combinations of pregelatinized Ofada rice starch and HPMC K15M (15cps) were prepared using a co-fusion method (97.5:2.5; 95:5; 92.5:7.5; 90:10; 85:15; 80:20). The flow and compaction properties of the co-processed excipients, as well as, individual excipients were evaluated using density, Hausner ratio, Carr’s index, angle of repose, angle of internal friction, the Kawakita model, consolidation index and rate. Aceclofenac tablets were formulated using direct compression with starch, HPMC and specific co-processed excipients as filler-binders. Pregelatinization produced starch with larger granules and improved flow characteristics. FTIR spectra of the co-processed excipients confirmed absence of any chemical interaction. The angle of repose, Hausner ratio, Carr’s index, angle of internal friction indicated that flow properties improved with increasing starch content of the co-processed excipients. Kawakita plots, consolidation index and consolidation rate demonstrated cohesiveness while compressibility and rate of packing were enhanced. Aceclofenac tablets containing co-processed excipients exhibited a crushing strength ≥ 66.03 ± 1.58 MNm-2; friability ≤ 1%; disintegration time ≤ 10.75 ±3.10 minutes and dissolution time (t80) ≤ 30.00 ± 3.07 minutes. The co-processed excipients of pregelatinized Ofada rice starch and HPMC could be cheaper alternatives to other synthetic excipients used in direct compression of tablets assuming the starch would meet all compendial specifications.Item Formulation of metronidazole tablets using hydroxypropylated white yam (dioscorea rotundata) starch as the binding agent(IPEC-Americas Inc, 2017) Okunlola, A.; Alade, O. O.; Odeku, O. A.White yam starch obtained from the tubers of Dioscorea rotundata Poir was modified by hydroxypropylation and used as a binding agent in a metronidazole tablet formulation and compared with corn starch BP. The quantitative effects of the novel starch binder on the mechanical (tensile strength and friability) and release properties (disintegration and dissolution times) of the metronidazole tablet was analyzed using a full 23 factorial experimental design. The individual and interaction effects of type of starch binder (X1), concentration of binder (X2) and relative density (X3) on tensile strength, friability, disintegration time and dissolution time (t90) were determined. The ranking of the coefficients was X3 > X2 > X1 on T, X1 > X3 > X2 on F and X3 > X1 > X2 on DT and t90 (time for 90% drug release) indicating that the formulation variables influence the properties of metronidazole tablets to varying degrees. This indicates that the type and concentration of starch binder as well as the compression pressure employed in table formulation need to be carefully selected to obtain tablets with the desired mechanical and drug release properties. Hydroxypropyl white yam starch could be more useful as a binder especially when tablets require high mechanical strength and faster drug release are desired.Item Development of ibuprofen microspheres using acetylated plantain starches as polymer for sustained release(Springer Publications, 2018) Okunlola, A.; Ghomorai, T.Ibuprofen has a short half-life (1–3 h) and istypically administered 3–4 times daily with subsequent adverse side effects. A good approach to reduce these effects is the preparation of sustained-release formulations of ibuprofen. Acetylated starches form water-insoluble, acid-resistant films that can substantially retard drug release. Ibuprofen microspheres were prepared using acetylated plantain starch as sustained-release polymer. Starch obtained from unripe plantain (Musa Paradisiaca normalis) were acetylated using acetic anhydride with pyridine (degrees of substitution, DS 1.5 ± 0.05 and 2.20 ± 0.10). The starches were characterized using morphology, crystallinity, swelling, density and flow properties. Ibuprofen microspheres were prepared by quasi-emulsion solvent diffusion method, using acetylated plantain starches DS 1.5 and 2.20 in comparison to Eudragit S100. Full 32 factorial experimental design was performed with polymer type (X1), polymer: drug ratio (X2) as independent factors; microsphere size, entrapment, and quantity of drug released in 12 h (Q12) were dependent variables. The data from in vitro drug release were fitted to various kinetic models. Acetylation resulted in larger starch aggregates with disruption in crystalline order. Ibuprofen microspheres were spherical with size 5.50 ± 4.00–129.90 ± 12.97μm. Drug entrapment was 43.92 ± 4.00–79.91 ± 6.15%. Values of Q12 ranged from 20.10 ± 0.55 to 54.00 ± 5.71%. Interaction between variables X1 and X2 had positive effects on size and entrapment. Drug release fitted zero order, first order and Baker-Lonsdale kinetic models. Acetylated starch of plantain with DS 2.20 was suitable as a polymer at polymer:drug ratio 4:1 for the formulation of ibuprofen microspheres with prolonged drug release.Item Development of repaglinide microspheres using novel acetylatedstarches of bitter and Chinese yams as polymers(Elsevier B.V., 2016) Okunlola, A.; Adebayo, A. S.; Adeyeye, M. C.Tropical starches from Dioscorea dumetorum (bitter) and Dioscorea oppositifolia (Chinese) yams were acetylated with acetic anhydride in pyridine medium and utilized as polymers for the delivery of repaglinide in microsphere formulations in comparison to ethyl cellulose. Acetylated starches of bitter and Chinese yams with degrees of substitution of 2.56 and 2.70 respectively were obtained. Acetylation was confirmed by FTIR, 1 H NMR spectroscopy. A 32 factorial experimental design was performed using polymer type and drug-polymer ratio as independent variables. Particle size, swelling, entrapment and time for 50% drug release (t50) were dependent variables. Contour plots showed the relationship between the independent factors and the response variables. All variables except swelling increased with drug: polymer ratio. Entrapment efficiency was generally in the rank of Bitter yam > Ethyl cellulose > Chinese yam. Repaglinide microspheres had size 50 ± 4.00 to 350 ± 18.10μm, entrapment efficiency 75.30 ± 3.03 to 93.10 ± 2.75% and t50 3.20 ± 0.42 to 7.20 ± 0.55h. Bitter yam starch gave longer dissolution times than Chinese yam starch at all drug-polymer ratios. Drug release fitted Korsmeyer-Peppas and Hopfenberg models. Acety-lated bitter and Chinese yam starches were found suitable as polymers to prolong release of repaglinidein microsphere formulations.Item Formulation of floating metronidazole microspheres using cassava starch (manihot esculenta) as polymer(Springer Publications, 2017) Odeku, O. A; Aderogba, A. A.; Ajala, T. O.; Akin-Ajani, O. D.; Okunlola, A" Floating gastroretentive microspheres have been used to prolong the gastric residence time after oral administration and improve the local effect of metronidazole in the stomach in the treatment of peptic ulcer caused by Helicobacter pylori. In the present study, cassava starch, obtained from the tubers of Manihot esculenta has been pregelatinized and used as polymer in combination with sodium alginate for the formulation of floating gastroretentive metronidazole microspheres. Metronidazole microspheres were prepared by ionic gelation method using pregelatinized cassava starch and sodium alginate at different concentrations as polymers and calcium chloride (2% w/v) as chelating agent. Sodium bicarbonate (2% w/w) was used as gas releasing agent. Microspheres were characterized using the particle size, swelling index, floating lag time (FLT), total floating time and drug release properties. Spherical discrete microspheres with size ranging from 1.52 to 2.23 mm were obtained with FLT of less than 5min and drug entrapment efficiency of 42–60% w/w. The microsphere maintained buoyancy for over 19h and the microspheres provided controlled release of metronidazolefor up to 18h. Drug release from the microspheres, swelling index and buoyancy depended on the concentration of cassava starch in the polymer blend. Formulations containing high concentration of cassava starch showing shorter floating lag time and faster drug release. Thus, buoyancy and rate of drug release appeared to be modulated by the concentration of cassava starch in the polymer blend. The results showed that pregelatinized cassava could be useful in the formulation of floating gastroretentive metronidazole microspheres "Item Optimization of formulations of metoprolol succinate tablets containing ofada rice starch acetate as tablet matrix for sustained release using response surface methodology(Pharmaceutical Society of Nigeria, 2016) Okunlola, A.Background: Release-retarding polymers in matrix tablets play a vital role in controlling drug release from tablets. Objectives: To prepare metoprolol succinate tablets by direct compression using Ofada rice (Oryza glaberrima Steud) starch acetate, degree of substitution (DS) 2.22, as a matrix for sustained release. Materials and methods: The central composite design and response surface methodology were applied to evaluate the interactive effects of three variables: percent content of starch acetate (X1), compression pressure (X2) and compression time (X3), on tablet crushing strength, friability and dissolution time (t80). Results: Crushing strength was 90.0 to 140.50 N; Friability 0.05 to 0.90% and t80 5.75 to 11.50 h. X1 and X2 had significant effects on crushing strength and dissolution time (p < 0.0001). The interactions between X1 and X2 and those between X1 and X3 were significant on crushing strength and dissolution time, and on friability respectively (p < 0.0001). The correlation coefficients indicated that the regression model represented the experimental data well (R2 = 0.9971 and R2 (Adj) = 0.9944 for crushing strength; R2 = 0.9976 and R2 (Adj) = 0.9954 for friability; R2 = 0.9979 and R2 (Adj) = 0.9961 for t80). Optimized conditions for formulation of metoprolol succinate tablets were 60 %w/w Ofada starch acetate; 150 MNm-2 compression pressure and 60s compression time. Conclusion: Optimized formulations of metoprolol tablets containing Ofada starch acetate with good mechanical strength and prolonged dissolution can be obtained when process conditions are adjusted within the reported values.Item Impact of degree of substitution of acetylated ofada rice starch polymer on the release properties of nimesulide microspheres(IPEC-Americas Inc, 2016) Okunlola, A.; Owojori, T.Nimesulide microspheres were prepared by the quasi-emulsion solvent diffusion method, using acetylated starches of the indigenous Ofada rice (Oryza glaberrima Steud) with degrees of substitution (DS) 1.42 and 2.62. A full 23 factorial experimental design was performed using DS (X1), drug:polymer ratio (X2) and polymer concentration (X3) as independent factors; size, entrapment, swelling and time taken for 80% drug release (t80) were the dependent variables. Contour plots were generated and data from the in vitro release studies were fitted to various kinetic models. Nimesulide microspheres were near spherical, sizes varying from 50.91±16.22 to 74.24±24.73μm for microspheres containing starch DS 1.42 and from 21.05±4.25 to 46.10±3.85μm for starch DS 2.62. Drug entrapment was 56.75±0.45 to 98.28±2.30%. DS had the greatest effect on the size, swelling and dissolution time (p = 0.01) which was confirmed by the contour plots. The interaction between factors DS and drug:polymer ratio (X1X2) had the greatest effect on the microsphere properties (p = 0.04). Drug release was fitted into the First Order, Higuchi and Korsmeyer models. Acetylated starch of Ofada rice DS 2.62 was found more suitable for the formulation of microspheres because of reduced size and swelling, higher entrapment and prolonged drug release.