Design and evaluation of illustrated information leaflets as an educational tool for low-literate asthma patients
- Authors: Wrench, Wendy Merle
- Date: 2012 , 2012-10-08
- Subjects: Asthma -- South Africa -- Study and teaching , Asthmatics -- South Africa -- Education
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3867 , http://hdl.handle.net/10962/d1016236
- Description: Asthma is a chronic non-communicable disease associated with an increase in morbidity, mortality and economic burden. Globally 300 million people have asthma and it is estimated that one in every 250 deaths worldwide are due to asthma. South Africa has the highest asthma prevalence (8.1%) in Africa and the disease is 18th in the top 20 causes of death. Inadequate home management, poor availability of health care, and poor transport and emergency services are recognised as important contributing factors. Patients with a low level of education and limited literacy skills may be unable to understand instructions on frequency and use of asthma medicines, which could result in unintentional non-adherence leading to serious complications and increased health care costs. The aim of this study was to investigate the impact of a tailored educational intervention on low-literate patients with asthma. Objectives to achieve this aim included designing patient information leaflets (PILs) containing information on asthma, management of asthma and asthma therapy, and using the PILs to educate low-literate asthma patients. A before-andafter intervention type design evaluated self-reported selected health-related quality of life measures, self-reported self-efficacy, knowledge of asthma and asthma management, knowledge of the use of metered dose inhalers (MDIs) and MDI technique. The acceptability and understanding of the tailored PILs was also investigated. Two simple, readable PILs containing pictograms were developed in English and then translated into isiXhosa, the home language of the majority of the target population. Various guidelines on the design of health-related information for people with low-literacy were consulted and input on the design was received from health care providers, patients and graphic artists. A pilot study was conducted at a local primary health care (PHC) clinic to evaluate the PILs and final modifications to the PILs were made based on feedback received. For the main study, patients were recruited from the KwaNonqubela PHC clinic in Alexandria in the Eastern Cape, South Africa. Patients were 18 years or older, dependent on public sector health care facilities, diagnosed with asthma, prescribed a MDI (beclomethasone and/or salbutamol) for at least one month and English or isiXhosa-speaking. The exclusion criterion for patients in this study was involvement in any other asthma educational intervention during the period of study. Interviewer-led structured questionnaires were administered to 55 patients at the baseline and follow-up. Data collected include demographics, brief medical history and current asthma medications. Self-efficacy and iii health-related quality of life were assessed. Knowledge of asthma and asthma management was evaluated, and the use of beclomethasone and/or salbutamol metered dose inhalers was assessed. The PIL ‘Understanding asthma and trigger factors of asthma’ formed part of the educational intervention to explain asthma and aspects related to its management. Inhaler technique was evaluated and corrected using the PIL ‘How to use your pump’ together with a demonstration of correct technique by the investigator. Follow-up interviews were conducted approximately four weeks after baseline. PIL acceptability, readability and understanding of each pictogram were investigated at follow-up only. The educational intervention resulted in a significant increase in mean knowledge of asthma from 52.7% at baseline to 75.5% at follow-up. Gender was not associated with knowledge, but there was a significant age effect at baseline only, with the younger patients achieving better knowledge results. In both phases, patients with higher education had improved scores. A significant increase (2.4% to 38.6%) in the number of patients taking the minimum recommended adult dose of beclomethasone was noted but it is a matter of concern that the majority of patients were taking less than this. Patient self-reports suggested a significant increase in adherence, with the number of patients taking beclomethasone daily increasing from 33.3% to 61.3%. Self-reported management and control of asthma improved and this was reflected by the enhanced HRQOL results. MDI technique also improved significantly with an increase in the mean number of correct steps from 4.6 ± 2.2 to 7.9 ± 2.7. Education had a significant effect on MDI technique with more errors associated with lower educational status. There were no significant age or gender effects on the total number of correct steps in either phase. The illustrated PILs were received favourably with the majority of literate patients reporting that they were easy to read. Patients commented positively on the inclusion of pictograms and stated that the pictograms had served as aids in the understanding of asthma, trigger factors of asthma and correct MDI technique. The results of this study show that specially designed illustrated PILs can be an effective tool in educating low-literate patients with asthma. , Adobe Acrobat Pro 11.0.0 Paper Capture Plug-in
- Full Text:
- Date Issued: 2012
- Authors: Wrench, Wendy Merle
- Date: 2012 , 2012-10-08
- Subjects: Asthma -- South Africa -- Study and teaching , Asthmatics -- South Africa -- Education
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3867 , http://hdl.handle.net/10962/d1016236
- Description: Asthma is a chronic non-communicable disease associated with an increase in morbidity, mortality and economic burden. Globally 300 million people have asthma and it is estimated that one in every 250 deaths worldwide are due to asthma. South Africa has the highest asthma prevalence (8.1%) in Africa and the disease is 18th in the top 20 causes of death. Inadequate home management, poor availability of health care, and poor transport and emergency services are recognised as important contributing factors. Patients with a low level of education and limited literacy skills may be unable to understand instructions on frequency and use of asthma medicines, which could result in unintentional non-adherence leading to serious complications and increased health care costs. The aim of this study was to investigate the impact of a tailored educational intervention on low-literate patients with asthma. Objectives to achieve this aim included designing patient information leaflets (PILs) containing information on asthma, management of asthma and asthma therapy, and using the PILs to educate low-literate asthma patients. A before-andafter intervention type design evaluated self-reported selected health-related quality of life measures, self-reported self-efficacy, knowledge of asthma and asthma management, knowledge of the use of metered dose inhalers (MDIs) and MDI technique. The acceptability and understanding of the tailored PILs was also investigated. Two simple, readable PILs containing pictograms were developed in English and then translated into isiXhosa, the home language of the majority of the target population. Various guidelines on the design of health-related information for people with low-literacy were consulted and input on the design was received from health care providers, patients and graphic artists. A pilot study was conducted at a local primary health care (PHC) clinic to evaluate the PILs and final modifications to the PILs were made based on feedback received. For the main study, patients were recruited from the KwaNonqubela PHC clinic in Alexandria in the Eastern Cape, South Africa. Patients were 18 years or older, dependent on public sector health care facilities, diagnosed with asthma, prescribed a MDI (beclomethasone and/or salbutamol) for at least one month and English or isiXhosa-speaking. The exclusion criterion for patients in this study was involvement in any other asthma educational intervention during the period of study. Interviewer-led structured questionnaires were administered to 55 patients at the baseline and follow-up. Data collected include demographics, brief medical history and current asthma medications. Self-efficacy and iii health-related quality of life were assessed. Knowledge of asthma and asthma management was evaluated, and the use of beclomethasone and/or salbutamol metered dose inhalers was assessed. The PIL ‘Understanding asthma and trigger factors of asthma’ formed part of the educational intervention to explain asthma and aspects related to its management. Inhaler technique was evaluated and corrected using the PIL ‘How to use your pump’ together with a demonstration of correct technique by the investigator. Follow-up interviews were conducted approximately four weeks after baseline. PIL acceptability, readability and understanding of each pictogram were investigated at follow-up only. The educational intervention resulted in a significant increase in mean knowledge of asthma from 52.7% at baseline to 75.5% at follow-up. Gender was not associated with knowledge, but there was a significant age effect at baseline only, with the younger patients achieving better knowledge results. In both phases, patients with higher education had improved scores. A significant increase (2.4% to 38.6%) in the number of patients taking the minimum recommended adult dose of beclomethasone was noted but it is a matter of concern that the majority of patients were taking less than this. Patient self-reports suggested a significant increase in adherence, with the number of patients taking beclomethasone daily increasing from 33.3% to 61.3%. Self-reported management and control of asthma improved and this was reflected by the enhanced HRQOL results. MDI technique also improved significantly with an increase in the mean number of correct steps from 4.6 ± 2.2 to 7.9 ± 2.7. Education had a significant effect on MDI technique with more errors associated with lower educational status. There were no significant age or gender effects on the total number of correct steps in either phase. The illustrated PILs were received favourably with the majority of literate patients reporting that they were easy to read. Patients commented positively on the inclusion of pictograms and stated that the pictograms had served as aids in the understanding of asthma, trigger factors of asthma and correct MDI technique. The results of this study show that specially designed illustrated PILs can be an effective tool in educating low-literate patients with asthma. , Adobe Acrobat Pro 11.0.0 Paper Capture Plug-in
- Full Text:
- Date Issued: 2012
Development, assessment and optimisation of oral famciclovir formulations for paediatric use
- Authors: Magnus, Laura
- Date: 2012
- Subjects: Drugs -- Dosage forms , Drugs -- Analysis , Capsules (Pharmacy) , Antiviral agents , Pediatrics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3870 , http://hdl.handle.net/10962/d1018244
- Description: Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.
- Full Text:
- Date Issued: 2012
- Authors: Magnus, Laura
- Date: 2012
- Subjects: Drugs -- Dosage forms , Drugs -- Analysis , Capsules (Pharmacy) , Antiviral agents , Pediatrics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3870 , http://hdl.handle.net/10962/d1018244
- Description: Many Active Pharmaceutical Ingredients (API) such as the antiviral agent famciclovir (FCV) are required for paediatric treatment but are not commercially available in age-appropriate dosage forms. It is common practice to prepare oral liquid dosage forms using commercially available tablets, capsules or powdered API and then dispersing or dissolving the crushed and/or powdered materials in a vehicle that the patient can swallow. Vehicles that are commonly used for this purpose include methylcellulose, syrup or combinations of these carriers where possible or commercially available suspending agents such as Ora-Sweet®, if available, can be used. However, several critical factors are overlooked when manufacturing extemporaneous formulations including, but not limited to, physical and chemical properties of the API, excipients, compatibility, stability and bioavailability issues. A stability-indicating High Performance Liquid Chromatography (HPLC) method for the analysis of FCV was developed and validated according to the International Conference on Harmonization (ICH) guidelines. The method is sensitive, selective, precise, accurate and linear over the concentration range 2-120 μg/ml. The stability of 25 mg/ml FCV formulations was assessed in vehicles manufactured from syrup simplex, hydroxypropyl methylcellulose (HPMC), Ora-Sweet® and an aqueous buffer (pH 6) following storage at 25 °C/60% RH and 40 °C/75% RH over six (6) to eight (8) weeks. The shelf life of the products was calculated as the longest period of storage for approximately 90% of the added FCV to be recovered. Formulations were manufactured using syrup simplex or HPMC with methylparaben and propylparaben individually or in combination and with sodium metabisulphite, ascorbic acid or citric acid as antioxidants. The resultant products were subject to quality control analysis for API content, viscosity, pH and appearance and the resultant data were subject to statistical analysis. The degradation rates were calculated for each product and a degradation profile plotted. The degradation rates of FCV in extemporaneous formulations were compared to those of FCV manufactured using a commercially available suspending agent and a buffered vehicle. FCV undergoes major degradation in the presence of sucrose, as observed for formulations in which the vehicle was syrup and Ora-Sweet®. FCV was found to be most stable when dissolved/dispersed in an HPMC vehicle incorporating sodium metabisulphite and a combination of parabens. The formulation that exhibited the maximum stability was manufactured using an aqueous solution buffered to pH 6. Due to the enhanced stability of FCV when added to a buffered vehicle a formulation in which an HPMC vehicle buffered to pH 6 with sodium metabisulphite, methylparaben and propylparaben was selected for optimisation using a Central Composite Design approach (CCD). In this way it was possible to establish a relationship between input variables such as pH, % w/v HPMC, % w/v antioxidant and % w/v preservative and the responses selected for monitoring by means of response surface modelling. A quadratic model was found to be the most appropriate to describe the relationship between input and output variables. Thirty batches of product were randomly manufactured according to the CCD and analysed to establish the stability in respect of viscosity, pH and the amount of FCV remaining following storage and the data were fitted to models using Design-Expert® software. A correlation between input variables and the responses was best described by a quadratic polynomial model. Analysis of Variance indicated that the response surface models were significant (P-value < 0.0001). The pH to which a FCV formulation was buffered was the most significant factor to effect the % drug content and the ultimate pH of the formulation, while the % w/v HPMC had the most significant effect on the viscosity of the product. The optimum composition for the manufacture of an oral liquid FCV formulation was predicted using the optimisation function of the Design-Expert® software. A low % error of prediction was established, indicating that the model is robust and that RSM is an appropriate formulation optimisation tool as it has a high prognostic ability. A liquid FCV formulation was developed, optimised and found to be suitable for its intended purpose. However further optimisation is required in respect of colourants, sweeteners and/or flavourants. The approach followed is useful in ensuring the development of quality products and can be applied in future.
- Full Text:
- Date Issued: 2012
The development of an orodispersible sildenafil citrate tablet intended for paediatric use
- Authors: Dagnolo, Bianca
- Date: 2012
- Subjects: Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3751 , http://hdl.handle.net/10962/d1003229 , Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Description: Sildenafil citrate (SC) is a phosphodiesterase-5 inhibitor that is used to treat pulmonary hypertension (PH) in paediatric patients. The purpose of these studies was to develop a formulation and manufacture an orodispersible tablet (ODT) that can be easily administered to neonates and children with PH. The advantages of ODT dosage forms include ease of administration, rapid dissolution of the API, SC. Furthermore the dosage form can be taken without water which is beneficial to patients without immediate access to potable fluids. A simple, rapid, accurate, precise and selective reversed-phase HPLC method was developed and validated in accordance with International Conference on Harmonization (ICH) guidelines and was successfully used for the analysis of SC as raw material and in SC containing pharmaceutical dosage forms. Preformulation studies were performed on SC, alone and in combination with potential excipients that could be used to make tablets. Investigations into potential interactions between SC and the excipients were performed using Differential Scanning Calorimetry (DSC) and Infrared Spectroscopy (IR). DSC results revealed that SC was compatible with all potential excipients except mannitol and magnesium stearate. However these interactions were not observed with IR and therefore it was concluded that the interactions were induced by the high temperatures that DSC operates at. Particle size and shape was also established by use of Scanning Electron Microscopy (SEM) and flow properties were monitored by calculating Carr’s Index (CI) and the Hausner Ratio (HR). Direct compression was used as the method of manufacture for SC tablets as this approach is simple and the most economic production approach. The powder blends were assessed for bulk and tapped density and the CI and HR were used to determine the flowability of the blends. The quality attributes of the resultant tablets that were monitored included uniformity of weight, friability, crushing strength, tensile strength, disintegration, wetting and in vitro dispersion times. Design of Experiments is an efficient statistical approach that has become a popular tool used in the pharmaceutical industry to optimize formulation compositions, as it allows for the investigation of several input factors at the same time whilst not using the tedious and traditional “ modification of one variable at a time” approach. A Central composite experimental design was chosen as the most appropriate means to optimize the formulation as it produces more accurate results as opposed to other experimental designs approaches as input factors are investigated at five different levels. Through the use of mathematical modelling, optimum concentrations of disintegrant(s) and an appropriate blending time were established. Analysis of the data from the experimental design and mathematical modelling studies reveal that no changes in disintegrant concentration or blending time altered the disintegration time of the formulation to any significant extent. This result is most likely due to the fact that the critical disintegrant concentration has been reached and increasing the disintegrant concentration further has no effect on disintegration time. It was also established that a change in the concentration of CMS and CRP altered the wetting time of the tablet significantly. Finally it was noted that there was a linear relationship between blending time and the uniformity of content of the tablets produced in these studies. The optimized product was a white tablet with a diameter of 7.31 mm with a thickness of 2.80mm.The dosage form had no visible cracks or evidence of picking or sticking. The tablet exhibits suitable friability and tensile strength while exhibiting a disintegration time of only 8s. Therefore an orodispersible tablet containing SC intended for paediatric use has been successfully developed, manufactured and optimized through the use of preformulation studies, appropriate quality control monitoring and mathematical modelling. These formulations require further optimization in respect of addition of flavours and or additional sweetening agents.
- Full Text:
- Date Issued: 2012
- Authors: Dagnolo, Bianca
- Date: 2012
- Subjects: Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3751 , http://hdl.handle.net/10962/d1003229 , Drug development -- Children -- Research -- South Africa , Pulmonary hypertension -- Children -- Research , Tablets (Medicine) -- Development , Pharmaceutical chemistry -- Research
- Description: Sildenafil citrate (SC) is a phosphodiesterase-5 inhibitor that is used to treat pulmonary hypertension (PH) in paediatric patients. The purpose of these studies was to develop a formulation and manufacture an orodispersible tablet (ODT) that can be easily administered to neonates and children with PH. The advantages of ODT dosage forms include ease of administration, rapid dissolution of the API, SC. Furthermore the dosage form can be taken without water which is beneficial to patients without immediate access to potable fluids. A simple, rapid, accurate, precise and selective reversed-phase HPLC method was developed and validated in accordance with International Conference on Harmonization (ICH) guidelines and was successfully used for the analysis of SC as raw material and in SC containing pharmaceutical dosage forms. Preformulation studies were performed on SC, alone and in combination with potential excipients that could be used to make tablets. Investigations into potential interactions between SC and the excipients were performed using Differential Scanning Calorimetry (DSC) and Infrared Spectroscopy (IR). DSC results revealed that SC was compatible with all potential excipients except mannitol and magnesium stearate. However these interactions were not observed with IR and therefore it was concluded that the interactions were induced by the high temperatures that DSC operates at. Particle size and shape was also established by use of Scanning Electron Microscopy (SEM) and flow properties were monitored by calculating Carr’s Index (CI) and the Hausner Ratio (HR). Direct compression was used as the method of manufacture for SC tablets as this approach is simple and the most economic production approach. The powder blends were assessed for bulk and tapped density and the CI and HR were used to determine the flowability of the blends. The quality attributes of the resultant tablets that were monitored included uniformity of weight, friability, crushing strength, tensile strength, disintegration, wetting and in vitro dispersion times. Design of Experiments is an efficient statistical approach that has become a popular tool used in the pharmaceutical industry to optimize formulation compositions, as it allows for the investigation of several input factors at the same time whilst not using the tedious and traditional “ modification of one variable at a time” approach. A Central composite experimental design was chosen as the most appropriate means to optimize the formulation as it produces more accurate results as opposed to other experimental designs approaches as input factors are investigated at five different levels. Through the use of mathematical modelling, optimum concentrations of disintegrant(s) and an appropriate blending time were established. Analysis of the data from the experimental design and mathematical modelling studies reveal that no changes in disintegrant concentration or blending time altered the disintegration time of the formulation to any significant extent. This result is most likely due to the fact that the critical disintegrant concentration has been reached and increasing the disintegrant concentration further has no effect on disintegration time. It was also established that a change in the concentration of CMS and CRP altered the wetting time of the tablet significantly. Finally it was noted that there was a linear relationship between blending time and the uniformity of content of the tablets produced in these studies. The optimized product was a white tablet with a diameter of 7.31 mm with a thickness of 2.80mm.The dosage form had no visible cracks or evidence of picking or sticking. The tablet exhibits suitable friability and tensile strength while exhibiting a disintegration time of only 8s. Therefore an orodispersible tablet containing SC intended for paediatric use has been successfully developed, manufactured and optimized through the use of preformulation studies, appropriate quality control monitoring and mathematical modelling. These formulations require further optimization in respect of addition of flavours and or additional sweetening agents.
- Full Text:
- Date Issued: 2012
The isolation, quantification and synthetic modification of antiplasmodial natural products from sargassum heterophyllum
- Authors: Munedzimwe, Tatenda Carol
- Date: 2012
- Subjects: Malaria -- Developing countries -- Prevention , Antimalarials
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3871 , http://hdl.handle.net/10962/d1018252
- Description: Malaria is one of the most deadly parasitic diseases known to man. Although the number of malaria cases reported each year is decreasing, this disease continues to pose health and economic problems mainly in developing countries. Significant progress has been made in the fight against this disease. This includes the discovery and development of potent antimalarial agents. However, the development of resistance to most of these potent antimalarials has made the development of new antiplasmodial agents of paramount importance. Several promising antiplasmodial agents have been found from the marine environment. Amongst these are the tetraprenylated toluquinols from the brown alga: Sargassum heterophyllum. These metabolites have been reported to exhibit a range of antiplasmodial activity; however, the mechanisms by which these compounds bring about their antiplasmodial activity and the pharmacophoric groups responsible for such activity are unknown. Two species of Sargassum algae were encountered during the course of this project. From the investigation of the geographical and seasonal variation of metabolites of S. heterophyllum and S. elegans we established that there were no significant intra and inter site variations amongst metabolite profiles of both species both within and between the sampled seasons. These results enabled us to establish that the collection of both species from three different sites on the eastern coast of South Africa namely; Kenton on Sea, Port Alfred and Noordhoek in autumn, winter or spring would qualitatively yield the same metabolites. A comparison of metabolite profiles of both species also revealed no qualitative differences between metabolites of S. heterophyllum and S. elegans. The quantities of selected prenylated metabolites extracted from S. heterophyllum using four different extraction techniques was also assessed using qNMR as the method of quantification. This led to the identification of optimal extraction techniques and conditions for the extraction of sargahydroquinoic acid (1.38), sargaquinoic aid (1.39) and sargachromenol (2.10) from S. heterophyllum. From this study, the extraction of algae by soxhlet extraction using EtOH as the extraction solvent led to the extraction of the highest quantities of sargahydroquinoic acid. The potential of other extraction techniques such as microwave assisted extraction, to yield high quantities of the selected metabolites were also identified. With gram quantities of sargahydroquinoic acid (1.38) in hand, this compound was modified by oxidation, reduction, acetylation, methylation and cyclization reactions to yield nine derivatives. The derivatives and four naturally occurring prenylated toluquinols were assessed for antiplasmodial and cytotoxic activity against the FCR-3 Gambian Chloroquine resistant strain of P. falciparum and the MDA-MB-231 breast carcinoma cell line respectively. Comparison of antiplasmodial data for all twelve compounds showed that the hydroquinone moeity of sargahydroquinoic acid (1.38) is important for antiplasmodial activity while esterification of the carboxylic acid group in 1.38 resulted in more potent antiplasmodial compounds. Of all twelve compounds, compound 5.2, the hydroquinone methyl ester of 1.38 was found to be the most potent antiplasmodial compound with an IC₅₀ value of 1.94 μM and a selectivity index of 22.68.
- Full Text:
- Date Issued: 2012
- Authors: Munedzimwe, Tatenda Carol
- Date: 2012
- Subjects: Malaria -- Developing countries -- Prevention , Antimalarials
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3871 , http://hdl.handle.net/10962/d1018252
- Description: Malaria is one of the most deadly parasitic diseases known to man. Although the number of malaria cases reported each year is decreasing, this disease continues to pose health and economic problems mainly in developing countries. Significant progress has been made in the fight against this disease. This includes the discovery and development of potent antimalarial agents. However, the development of resistance to most of these potent antimalarials has made the development of new antiplasmodial agents of paramount importance. Several promising antiplasmodial agents have been found from the marine environment. Amongst these are the tetraprenylated toluquinols from the brown alga: Sargassum heterophyllum. These metabolites have been reported to exhibit a range of antiplasmodial activity; however, the mechanisms by which these compounds bring about their antiplasmodial activity and the pharmacophoric groups responsible for such activity are unknown. Two species of Sargassum algae were encountered during the course of this project. From the investigation of the geographical and seasonal variation of metabolites of S. heterophyllum and S. elegans we established that there were no significant intra and inter site variations amongst metabolite profiles of both species both within and between the sampled seasons. These results enabled us to establish that the collection of both species from three different sites on the eastern coast of South Africa namely; Kenton on Sea, Port Alfred and Noordhoek in autumn, winter or spring would qualitatively yield the same metabolites. A comparison of metabolite profiles of both species also revealed no qualitative differences between metabolites of S. heterophyllum and S. elegans. The quantities of selected prenylated metabolites extracted from S. heterophyllum using four different extraction techniques was also assessed using qNMR as the method of quantification. This led to the identification of optimal extraction techniques and conditions for the extraction of sargahydroquinoic acid (1.38), sargaquinoic aid (1.39) and sargachromenol (2.10) from S. heterophyllum. From this study, the extraction of algae by soxhlet extraction using EtOH as the extraction solvent led to the extraction of the highest quantities of sargahydroquinoic acid. The potential of other extraction techniques such as microwave assisted extraction, to yield high quantities of the selected metabolites were also identified. With gram quantities of sargahydroquinoic acid (1.38) in hand, this compound was modified by oxidation, reduction, acetylation, methylation and cyclization reactions to yield nine derivatives. The derivatives and four naturally occurring prenylated toluquinols were assessed for antiplasmodial and cytotoxic activity against the FCR-3 Gambian Chloroquine resistant strain of P. falciparum and the MDA-MB-231 breast carcinoma cell line respectively. Comparison of antiplasmodial data for all twelve compounds showed that the hydroquinone moeity of sargahydroquinoic acid (1.38) is important for antiplasmodial activity while esterification of the carboxylic acid group in 1.38 resulted in more potent antiplasmodial compounds. Of all twelve compounds, compound 5.2, the hydroquinone methyl ester of 1.38 was found to be the most potent antiplasmodial compound with an IC₅₀ value of 1.94 μM and a selectivity index of 22.68.
- Full Text:
- Date Issued: 2012
The synthesis and breast cancer inhibitory activity of cinnamic acid analogues based on the halogenated monoterpene pharmacophore
- Authors: Chiwakata, Maynard Tendai
- Date: 2012
- Subjects: Halocarbons , Cancer -- Treatment , Breast -- Cancer -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3866 , http://hdl.handle.net/10962/d1016129
- Description: Breast cancer is one of the leading causes of death, with mortality rate estimates of 465 000 deaths per annum. It is estimated that 1.3 million women are diagnosed with the disease each year especially in the developing countries. Current chemotherapy relies on the use of high doses of non-specific toxic agents that possess adverse side effects and compromise patient’s compliance and adherence to treatment. Paclitaxel, one of the common drugs used in breast cancer chemotherapy results in sensory and motor neuropathy, whilst hormonal therapy e.g. Herceptin causes severe cardiovascular, gastrointestinal and cutaneous side effects. There has been a demand in developing newer cancer agents that demonstrate selective cytoxicity with minimal effect on normal body tissue. Numerous studies have shown that marine organisms produce a wide range of halogenated compounds that possess cytotoxic properties, and hence can be a source of new drug hits or leads for cancer therapy. Halomon, a polyhalogenated monoterpene from Portieria hornemannii, displayed interesting activity against brain, renal and lung cancer tumours with selective/differential cytotoxicity. This inspired us to focus our project on halogenated monoterpenes isolated from the same Rhodophyta class as P. hornemannii but with particular attention to Plocamium species. Several metabolites have been isolated from P. cornutum, P. corallorhiza and P. suhrii that possess interesting cytotoxicities against a breast cancer cell line (MCF7) and an oesophageal cancer line (WHCO1). The aim of the project was therefore centred at isolating target compounds for preliminary structure-activity studies against a breast cancer cell line, and use this information to synthesize a series of analogues that are more stable than the natural products and yet as active using a fragment-based type approach to map out pharmacophoric elements. Five metabolites were isolated from P. cornutum and five from P. corallorhiza. Cell-based assays were conducted using an MTT assay kit against MCF7 and MDA-MB-231 breast cancer cell lines and (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene, isolated from P. cornutum was the most active with IC50 values of 3.0 μM and 6.15 μM respectively. Introduction of a terminal aromatic ring to enhance stability, together with varying substituents (H, CH3, CF3, Br, CN, CHO, CHCl2) on position 7 of the molecule, gave rise to a series of cinnamate ester derivatives inspired by (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene. The analogues were synthesized from their benzaldehyde precursors via Aldol condensation, esterification and Wittig reactions. Their carboxylic acid counterparts were synthesized by hydrolysis of the parent esters in an attempt to promote water solubilities of the analogues. Biological activity assays were then conducted with the cinnamate analogues against the MDA-MB-231 breast cancer cell line using an MTT assay kit. Ester derivatives with -CHO and -CHCl2 functionalities had IC50 values of 43.45 μM and 100.01 μM respectively whilst the other ester derivatives were inactive. It was concluded that either an aldehyde (-CHO) or gem-dichlorides (-CHCl2) is specifically required for cytotoxic activity to be observed. None of the carboxylic acids were active which could have been due to failure of the compounds to enter the breast cancer cells and reach the target site because of their polar nature. Compounds with -CHO and -CHCl2 functionalities were therefore selected for future SARs studies.
- Full Text:
- Date Issued: 2012
- Authors: Chiwakata, Maynard Tendai
- Date: 2012
- Subjects: Halocarbons , Cancer -- Treatment , Breast -- Cancer -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3866 , http://hdl.handle.net/10962/d1016129
- Description: Breast cancer is one of the leading causes of death, with mortality rate estimates of 465 000 deaths per annum. It is estimated that 1.3 million women are diagnosed with the disease each year especially in the developing countries. Current chemotherapy relies on the use of high doses of non-specific toxic agents that possess adverse side effects and compromise patient’s compliance and adherence to treatment. Paclitaxel, one of the common drugs used in breast cancer chemotherapy results in sensory and motor neuropathy, whilst hormonal therapy e.g. Herceptin causes severe cardiovascular, gastrointestinal and cutaneous side effects. There has been a demand in developing newer cancer agents that demonstrate selective cytoxicity with minimal effect on normal body tissue. Numerous studies have shown that marine organisms produce a wide range of halogenated compounds that possess cytotoxic properties, and hence can be a source of new drug hits or leads for cancer therapy. Halomon, a polyhalogenated monoterpene from Portieria hornemannii, displayed interesting activity against brain, renal and lung cancer tumours with selective/differential cytotoxicity. This inspired us to focus our project on halogenated monoterpenes isolated from the same Rhodophyta class as P. hornemannii but with particular attention to Plocamium species. Several metabolites have been isolated from P. cornutum, P. corallorhiza and P. suhrii that possess interesting cytotoxicities against a breast cancer cell line (MCF7) and an oesophageal cancer line (WHCO1). The aim of the project was therefore centred at isolating target compounds for preliminary structure-activity studies against a breast cancer cell line, and use this information to synthesize a series of analogues that are more stable than the natural products and yet as active using a fragment-based type approach to map out pharmacophoric elements. Five metabolites were isolated from P. cornutum and five from P. corallorhiza. Cell-based assays were conducted using an MTT assay kit against MCF7 and MDA-MB-231 breast cancer cell lines and (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene, isolated from P. cornutum was the most active with IC50 values of 3.0 μM and 6.15 μM respectively. Introduction of a terminal aromatic ring to enhance stability, together with varying substituents (H, CH3, CF3, Br, CN, CHO, CHCl2) on position 7 of the molecule, gave rise to a series of cinnamate ester derivatives inspired by (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene. The analogues were synthesized from their benzaldehyde precursors via Aldol condensation, esterification and Wittig reactions. Their carboxylic acid counterparts were synthesized by hydrolysis of the parent esters in an attempt to promote water solubilities of the analogues. Biological activity assays were then conducted with the cinnamate analogues against the MDA-MB-231 breast cancer cell line using an MTT assay kit. Ester derivatives with -CHO and -CHCl2 functionalities had IC50 values of 43.45 μM and 100.01 μM respectively whilst the other ester derivatives were inactive. It was concluded that either an aldehyde (-CHO) or gem-dichlorides (-CHCl2) is specifically required for cytotoxic activity to be observed. None of the carboxylic acids were active which could have been due to failure of the compounds to enter the breast cancer cells and reach the target site because of their polar nature. Compounds with -CHO and -CHCl2 functionalities were therefore selected for future SARs studies.
- Full Text:
- Date Issued: 2012
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