Development of a protocol for extracting and quantifying the concentration of thiafentanil in blesbok (Damaliscus pygargus phillipsi) matrices 72-74 hours post administration
- Authors: Webber, Judith Tracy
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/164738 , vital:41159
- Description: Thesis (MSc)--Rhodes University, Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
- Authors: Webber, Judith Tracy
- Date: 2020
- Subjects: Uncatalogued
- Language: English
- Type: thesis , text , Masters , MSc
- Identifier: http://hdl.handle.net/10962/164738 , vital:41159
- Description: Thesis (MSc)--Rhodes University, Faculty of Science, Chemistry, 2020
- Full Text:
- Date Issued: 2020
Formulation and evaluation of liposomal films for buccal delivery of antiretroviral drug
- Authors: Okafor, Nnamdi Ikemefuna
- Date: 2020
- Subjects: Liposomes , Highly active antiretroviral therapy , Antiretroviral agents , HIV infections -- Prevention
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117161 , vital:34485
- Description: The human immune deficiency virus (HIV) infection has been ranked as one of the most devastating microbial infections in the world. This status is a result of the HIV rapid genetic variation, which limits discovery of a vaccine. Use application of antiretroviral therapy (ARVT) in treatment of the disease caused by the HIV infection (known as acquired immunodeficiency syndrome, HIV-AIDS) is frequently compromised by several factors such as the low bioavailability and severe adverse effects associated with the existing antiretroviral drugs (ARVDs). This underlines the need for controlling the pharmacokinetics profiles of ARVD using effective vehicles that can modify drug biodistribution. The same is true for many other conditions, where delivery systems can determine the success or failure of treatment by controlling pharmacokinetic and dynamic properties. The mucosal linings of the oral cavities in addition offer adorable route of administration for systematic drug delivery, improving drug therapeutic performance and often preferred by clinicians and patients. Liposomes are tiny spherical sacs of phospholipid molecules enclosing water droplets, formed (artificially) to carry drugs or other substances into the tissues by crossing and targeting to specific organelles. This work therefore focused on preparation of liposomes and liposomal buccal films (BFs) for potential buccal delivery of efavirenz, an ARVD model endowed with poor solubility and several side effects. The liposomes were prepared by thin film hydration method using crude soybean lecithin (CL) and cholesterol. Efavirenz loaded liposomes were evaluated for particle size, Zeta potential (ZP), morphology, encapsulation efficiency (EE%) and release kinetics studies. The physiochemical properties of the liposomes were also evaluated using Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), energy dispersity spectroscopy (EDS), and Fourier transform infrared (FTIR), while the formulation with the best encapsulation efficiency was used as the solvent medium for the buccal film formation. The buccal films were prepared using solvent casting method, where the liposomal suspension was used as the dispersing medium. The films were optimized for physical properties (thickness, weight variation and folding endurance) using digital Vernier calliper and digital weighing balance. The physiochemical properties of the selected BFs films made of Carbopol (CP) and its combination with Pluronic F127 (PF127) were further characterized using XRD, DSC, FTIR, Transmission Electron Microscopy (TEM), EDS and Scanning Electron Microscopy (SEM). The permeation study of the selected BFs was investigated using Franz diffusion cell. The BFs composed of CP alone or its combination with PF127 demonstrated much better bio-adhesive properties than the films made of other polymers (like Hydroxyl propyl methyl cellulose, HPMC) alone or in combination with PF127. The developed liposome formulation showed high encapsulation 98.8 ± 0.01 % in CL to cholesterol mass ratio of 1:1 and total lipid to drug mass ratio of 2:1. The average particle size 104.82 ± 2.29 nm and Zeta potential -50.33 ± 0.95 mV of these liposomes were found to be attractive for targeted delivery to the HIV infected cells. The CP based BFs (without and with PF127) exhibited good film thickness 0.88 ± 0.10 and 0.76 ± 0.14 mm, with weight uniformity 68.22 ± 1.04 and 86.28 ± 2. 16 mg, satisfactory flexibility values 258 and 321, and slightly acidic pH 6.43 ± 0.76 and 6.32 ± 0.01. The swelling percentage was found to be 50 % for CP film alone and 78 % for CP film with PF127. The cumulative amount of drug that permeated through the buccal epithelium over 24 hours was about 66 % from CP film alone and 75 % from CP film with PF127. Since no evidence of the liposomal encapsulation of EFV have been reported to our knowledge, we find the insights from the present study valuable as a set of preliminary data to encourage further investigations of the encapsulation and delivery of EFV like antiretrovirals for enhanced solubility, site targeting and prolonged release using crude soybean lecithin and mucoadhesive polymers, which holds some added economical values as naturally occurring lipid and polymeric mixtures as a promising delivery systems for buccal delivery of ARVDs.
- Full Text:
- Date Issued: 2020
- Authors: Okafor, Nnamdi Ikemefuna
- Date: 2020
- Subjects: Liposomes , Highly active antiretroviral therapy , Antiretroviral agents , HIV infections -- Prevention
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/117161 , vital:34485
- Description: The human immune deficiency virus (HIV) infection has been ranked as one of the most devastating microbial infections in the world. This status is a result of the HIV rapid genetic variation, which limits discovery of a vaccine. Use application of antiretroviral therapy (ARVT) in treatment of the disease caused by the HIV infection (known as acquired immunodeficiency syndrome, HIV-AIDS) is frequently compromised by several factors such as the low bioavailability and severe adverse effects associated with the existing antiretroviral drugs (ARVDs). This underlines the need for controlling the pharmacokinetics profiles of ARVD using effective vehicles that can modify drug biodistribution. The same is true for many other conditions, where delivery systems can determine the success or failure of treatment by controlling pharmacokinetic and dynamic properties. The mucosal linings of the oral cavities in addition offer adorable route of administration for systematic drug delivery, improving drug therapeutic performance and often preferred by clinicians and patients. Liposomes are tiny spherical sacs of phospholipid molecules enclosing water droplets, formed (artificially) to carry drugs or other substances into the tissues by crossing and targeting to specific organelles. This work therefore focused on preparation of liposomes and liposomal buccal films (BFs) for potential buccal delivery of efavirenz, an ARVD model endowed with poor solubility and several side effects. The liposomes were prepared by thin film hydration method using crude soybean lecithin (CL) and cholesterol. Efavirenz loaded liposomes were evaluated for particle size, Zeta potential (ZP), morphology, encapsulation efficiency (EE%) and release kinetics studies. The physiochemical properties of the liposomes were also evaluated using Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), energy dispersity spectroscopy (EDS), and Fourier transform infrared (FTIR), while the formulation with the best encapsulation efficiency was used as the solvent medium for the buccal film formation. The buccal films were prepared using solvent casting method, where the liposomal suspension was used as the dispersing medium. The films were optimized for physical properties (thickness, weight variation and folding endurance) using digital Vernier calliper and digital weighing balance. The physiochemical properties of the selected BFs films made of Carbopol (CP) and its combination with Pluronic F127 (PF127) were further characterized using XRD, DSC, FTIR, Transmission Electron Microscopy (TEM), EDS and Scanning Electron Microscopy (SEM). The permeation study of the selected BFs was investigated using Franz diffusion cell. The BFs composed of CP alone or its combination with PF127 demonstrated much better bio-adhesive properties than the films made of other polymers (like Hydroxyl propyl methyl cellulose, HPMC) alone or in combination with PF127. The developed liposome formulation showed high encapsulation 98.8 ± 0.01 % in CL to cholesterol mass ratio of 1:1 and total lipid to drug mass ratio of 2:1. The average particle size 104.82 ± 2.29 nm and Zeta potential -50.33 ± 0.95 mV of these liposomes were found to be attractive for targeted delivery to the HIV infected cells. The CP based BFs (without and with PF127) exhibited good film thickness 0.88 ± 0.10 and 0.76 ± 0.14 mm, with weight uniformity 68.22 ± 1.04 and 86.28 ± 2. 16 mg, satisfactory flexibility values 258 and 321, and slightly acidic pH 6.43 ± 0.76 and 6.32 ± 0.01. The swelling percentage was found to be 50 % for CP film alone and 78 % for CP film with PF127. The cumulative amount of drug that permeated through the buccal epithelium over 24 hours was about 66 % from CP film alone and 75 % from CP film with PF127. Since no evidence of the liposomal encapsulation of EFV have been reported to our knowledge, we find the insights from the present study valuable as a set of preliminary data to encourage further investigations of the encapsulation and delivery of EFV like antiretrovirals for enhanced solubility, site targeting and prolonged release using crude soybean lecithin and mucoadhesive polymers, which holds some added economical values as naturally occurring lipid and polymeric mixtures as a promising delivery systems for buccal delivery of ARVDs.
- Full Text:
- Date Issued: 2020
Development of a computational chemistry scheme for testing the utility of synthetic bacteriochlorin in dye-sensitized solar cells
- Authors: Kota, Ntsika
- Date: 2018
- Subjects: Dye-sensitized solar cells , Computational chemistry , Density functionals , Electronic excitation , Molecular orbitals , Oscillator strengths , Bacteriochlorin
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62327 , vital:28155
- Description: A computational chemistry scheme, based on density functional theory, was developed for in silico testing of a few bacteriochlorin properties relevant to dye-sensitized solar cells. These properties included electronic excitation wavelengths, molecular orbital energy levels, and oscillator strengths among others. Comparisons were made among four species, using computational proxies for electron injection quantum yield and photo-induced current production. The proxy measures for current production (frontier orbital energy level and short circuit current) made consistent, though qualitative, predictions about the ranking of the four dyes. The proxy measures for electron injection quantum yield (change in planar dipole moment and density of states) made less categorical predictions about the ranking. Overall, the scheme singled out one dye as the worst, but made no conclusive predictions about the relative ranking of the other three. There was insufficient data for comparison of the ranking predictions with experiment.
- Full Text:
- Date Issued: 2018
- Authors: Kota, Ntsika
- Date: 2018
- Subjects: Dye-sensitized solar cells , Computational chemistry , Density functionals , Electronic excitation , Molecular orbitals , Oscillator strengths , Bacteriochlorin
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/62327 , vital:28155
- Description: A computational chemistry scheme, based on density functional theory, was developed for in silico testing of a few bacteriochlorin properties relevant to dye-sensitized solar cells. These properties included electronic excitation wavelengths, molecular orbital energy levels, and oscillator strengths among others. Comparisons were made among four species, using computational proxies for electron injection quantum yield and photo-induced current production. The proxy measures for current production (frontier orbital energy level and short circuit current) made consistent, though qualitative, predictions about the ranking of the four dyes. The proxy measures for electron injection quantum yield (change in planar dipole moment and density of states) made less categorical predictions about the ranking. Overall, the scheme singled out one dye as the worst, but made no conclusive predictions about the relative ranking of the other three. There was insufficient data for comparison of the ranking predictions with experiment.
- Full Text:
- Date Issued: 2018
Antimalarial secondary metabolites from Morinda lucida
- Authors: Chithambo, Bertha
- Date: 2017
- Subjects: Botanical chemistry , Anthraquinones , Antimalarials , Rubiaceae -- Therapeutic use , Malaria -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/45730 , vital:25535
- Description: Antimalarial activities of secondary metabolites from Morinda lucida (Rubiaceae), were investigated. Even though M. lucida is traditionally used to treat malaria, diabetes, jaundice, hypertension, dysentery and many other diseases, the compounds in this plant have not yet been fully investigated and characterised. Most of the studies that have been done on this plant focused on the medicinal properties of the crude extracts but have not gone further to isolate and characterise the compounds. In this study, the methanol - dichloromethane crude extract from the bark of M. lucida was fractionated into fractions 1-8. Fractions 2-5 were purified in order to isolate active secondary metabolites. The isolated pure compounds were characterised and identified. An in vitro antimalarial assay was carried out on the crude extract, fractions, pure compounds and solutions made from different combinations of pure compounds using the parasite lactate dehydrogenase (pLDH) assay. An IC50 done on the methanolic crude extract gave a value of 25 µg/mL. The % cell viability for the crude extract in cell toxicity assay remained at 100%. Each of the pure compounds tested had very little activity. Their activities were increased when samples from the different compounds were mixed. One of these mixtures reduced malaria viability to about 22 % at 20 µM and gave an IC50 value of 17 µM. Antibacterial assays were also carried out on the crude extract and fractions. Fractions 2 and 3 were relatively active (MIC values ranging between 125-1000 µg/mL) against M. cattarhalis and E. faecalis. Fraction 2 was also the most active on S. typhimurium and S. aureus (MIC value of 1000 µg/mL) compared with the other fractions. This same fraction also showed some activity against M. tuberculosis with MIC90 and MIC99 values of 40.9 and 46.3 µg/mL respectively in an anti-tuberculosis assay.The following compounds, comprising of iridoids (asperuloside and asperulosidic acid), terpenoids (stigmasterol, P-sitosterol, campesterol, lanosterol and cycloartenol) and anthraquinones [5,15-O-dimethylmorindol, 1,7-dihydroxy-2-methoxy-5-(methoxymethyl) anthraquinone and 1,6-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone], were isolated. All these compounds have been isolated from different plants before with the exception of 1,7-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone and 1,6-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone which were tentatively assigned the structures due to insufficient data. To the best of our knowledge, this is the first report on the identification of all of the mentioned compounds, with the exception of ß-sitosterol and stigmasterol, from M. lucida. Molecular docking was performed on one of the isolated anthraquinones (5,15-O- dimethylmorindol) to check if it can bind to cytochrome bci, a known target for atovaquone. This compound interacted with the same amino acids that atovaquone, a well known antimalarial agent, interacted with on cytochrome bc1 indicating a possible similar mode of action.
- Full Text:
- Date Issued: 2017
- Authors: Chithambo, Bertha
- Date: 2017
- Subjects: Botanical chemistry , Anthraquinones , Antimalarials , Rubiaceae -- Therapeutic use , Malaria -- Treatment
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/45730 , vital:25535
- Description: Antimalarial activities of secondary metabolites from Morinda lucida (Rubiaceae), were investigated. Even though M. lucida is traditionally used to treat malaria, diabetes, jaundice, hypertension, dysentery and many other diseases, the compounds in this plant have not yet been fully investigated and characterised. Most of the studies that have been done on this plant focused on the medicinal properties of the crude extracts but have not gone further to isolate and characterise the compounds. In this study, the methanol - dichloromethane crude extract from the bark of M. lucida was fractionated into fractions 1-8. Fractions 2-5 were purified in order to isolate active secondary metabolites. The isolated pure compounds were characterised and identified. An in vitro antimalarial assay was carried out on the crude extract, fractions, pure compounds and solutions made from different combinations of pure compounds using the parasite lactate dehydrogenase (pLDH) assay. An IC50 done on the methanolic crude extract gave a value of 25 µg/mL. The % cell viability for the crude extract in cell toxicity assay remained at 100%. Each of the pure compounds tested had very little activity. Their activities were increased when samples from the different compounds were mixed. One of these mixtures reduced malaria viability to about 22 % at 20 µM and gave an IC50 value of 17 µM. Antibacterial assays were also carried out on the crude extract and fractions. Fractions 2 and 3 were relatively active (MIC values ranging between 125-1000 µg/mL) against M. cattarhalis and E. faecalis. Fraction 2 was also the most active on S. typhimurium and S. aureus (MIC value of 1000 µg/mL) compared with the other fractions. This same fraction also showed some activity against M. tuberculosis with MIC90 and MIC99 values of 40.9 and 46.3 µg/mL respectively in an anti-tuberculosis assay.The following compounds, comprising of iridoids (asperuloside and asperulosidic acid), terpenoids (stigmasterol, P-sitosterol, campesterol, lanosterol and cycloartenol) and anthraquinones [5,15-O-dimethylmorindol, 1,7-dihydroxy-2-methoxy-5-(methoxymethyl) anthraquinone and 1,6-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone], were isolated. All these compounds have been isolated from different plants before with the exception of 1,7-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone and 1,6-dihydroxy-2-methoxy-5-(methoxymethyl)anthraquinone which were tentatively assigned the structures due to insufficient data. To the best of our knowledge, this is the first report on the identification of all of the mentioned compounds, with the exception of ß-sitosterol and stigmasterol, from M. lucida. Molecular docking was performed on one of the isolated anthraquinones (5,15-O- dimethylmorindol) to check if it can bind to cytochrome bci, a known target for atovaquone. This compound interacted with the same amino acids that atovaquone, a well known antimalarial agent, interacted with on cytochrome bc1 indicating a possible similar mode of action.
- Full Text:
- Date Issued: 2017
Studies towards the development of novel antimalarial agents
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Date Issued: 2015
- Authors: Adeyemi, Christiana Modupe
- Date: 2015
- Subjects: Antimalarials , Malaria , Drug resistance , Drug development , Enzyme inhibitors , Plasmodium
- Language: English
- Type: text , Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10962/54645 , vital:26596
- Description: Considerable efforts have been made in the modification of existing antimalarial drugs, and the support of incentive programmes have led to a drastic decrease in malaria cases reported by WHO during the past 6 years. However, the development of drug resistance threatens the eradication of this deadly disease and has prompted research on the synthesis of novel antimalarial drugs. Our research has involved the design and synthesis of novel benzylated phosphonate esters as potential 1-deoxy-D-xylose-5-phosphate reductoisomerase (DXR) inhibitors. A series of amidoalkylphosphonate esters were obtained by reacting various 3-subsituted anilines and heterocyclic amines with chloroalkanoyl chlorides and reacting the resulting chloroalkanamides with triethyl phosphite using Michaelis-Arbuzov methodology. Benzylation of the phosphonate esters afforded a series of novel N-benzylated derivatives in good yields and these compounds were fully characterised by NMR and HRMS methods. Several approaches to the introduction of a benzyl group at the C-2 position of the phosphonate ester derivatives have been explored, leading unexpectedly to the isolation of unprecedented tetrahydrofuranyl derivatives. Studies towards the preparation of potential bi-functional PfDXR / HIV-1 RT inhibitors have also been initiated. Preliminary in silico docking studies of selected non-benzylated and benzylated phosphonated derivatives into the Pf-DXR active-site has provided useful insight into the binding potential of these ligands. Bioassays have revealed a very low toxicity for all the synthesised phosphonated compounds and a number of these ligands also exhibit a promising inhibitory activity against the Plasmodium parasite.
- Full Text:
- Date Issued: 2015
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