Doctor Pharmaceuticae - DPharm

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An investigation of the production of non-coated sustained release beads by extrusion and Spheronization
(University of the Western Cape, 1995) Pather, Sathasivan Indiran; Russell, Irina
The popularity and increasing complexity of sustained release dosage forms has resulted in increased costs to the patient. One approach to achieve cheaper, yet effective, sustained release medication is through the simplification of production processes. Matrix tablets have been used to sustain the release of numerous drugs and are cheap to prepare. Since they are single-unit dosage forms, however, they display less predictable transit through the gastrointestinal tract. Hence, they provide less reliable blood levels of the drug in comparison with multi particulate dosage forms. Of the various types of multiparticulates available, pellets are popular for oral administration. A fairly recent innovation, in pelletization technology, is extrusion and spheronization. With this technique it is possible to produce pellets with a high degree of drug loading directly and rapidly. The drug loaded beads are usually coated for a sustained release effect. If one could omit the coating step, it would avoid many problems (thus reducing the number of quality control procedures required) and save chemicals, labour and capital for the purchase of additional equipment. The primary aim of this project was to investigate the preparation of non-coated, spheronized sustained release pellets, while a secondary aim was to prepare beads that can be compressed into sustained release tablets. A tablet can accommodate a larger mass and the compaction forces involved may enhance the sustained release effect. Several techniques were used in an attempt to sustain the release of drugs of different solubilities. In one series of formulations, a novel method was used to incorporate a binder consisting of ethylcellulose in ethanol. Using this technique, the release of Theophylline was sustained for approximately 8 hours. In other formulations, several materials were added to beads with the aim of forming sustained release matrixes. Only magnesium stearate was able to prolong the release of Acetaminophen and Theophylline for a reasonable time. In an attempt to explain why materials that were successfully used in sustained release matrix tablets were of very limited value in beads, an equation was developed to calculate the approximate distance between the retardant particles. Calculations using this equation revealed that the retardant particles were too far apart, within each bead, to expect consolidation to occur. The discrete retardant particles do not retard drug release effectively. Eudragit?-containing beads, which sustained the release of the drug to a small extent, were successfully compressed into tablets, both on their own and in combination with non pareil seeds. In each case, the sustained release effect was improved by compaction. In the case of the products manufactured with non pareil seeds, the tablets disintegrated rapidly to release the beads, thus ensuring that the advantages of multiparticulates were maintained. Because it was realised that a large amount of the matrix material could not be incorporated within the beads if a high dose drug was formulated with Avicel? PH 101, the idea of forming the matrix outside the beads was developed. Several materials were tried in an attempt to form a sustained release external matrix. Eudragit? RSPO prolonged the dissolution of Theophylline for more than four hours. Magnesium stearate was able to sustain the release of Acetaminophen and Theophylline appreciably. In the latter case, the dissolution, in water, of a standard adult dose of the drug was prolonged for more than 12 hours. However, the dissolution in an acidic medium was much faster. The described technique represents an advance in extrusion and spheronization technology. While beads containing Cutina? HR did not show promise as sustained release units, they compacted to form sustained release tablets of good appearance and acceptable strength. These tablets were considered to have been efficiently prepared because the constituent beads were easily manufactured and showed good flowability, and because a glidant and a lubricant were not required. The production of sustained release Indomethacin beads with a more steady release profile than the innovator's product has also been described in other experiments. The research described in this thesis represents progress towards the widespread commercial production of effective non-coated sustained release beads and may encourage further work towards this goal.
The formulation and evaluation of indomethacin tablets
(University of the Western Cape, 1998) van Niekerk, Johan
The overall objective of this research is to attempt to produce, by direct compression, indomethacin tablets which have good dissolution characteristics and an improved bioavailability profile, when compared to the capsule formulations currently available. In order to use the direct compression method, the solubilized form of indomethacin should have good flow properties, as well as a small bulk volume for incorporation into reasonably sized tablets.
Pharmacist educational outreach for improved primary care of asthma in children
(University of the Western Cape, 2001) Bheekie, Angeni; Zwarenstein, M F
Underdiagnosis and undertreatment of asthma in children are barriers to optimal health care delivery and health, incurring substantial costs to both the families and health services. A tailored multifaceted educational outreach intervention ("academic detailing") was designed and implemented among private sector general practitioners (GPs) serving a poor working class urban community in Cape Town, South Africa. The intervention aimed to improve primary care childhood asthma by promoting the adoption of guideline-based key messages. The effectiveness of the intervention was tested in a randomised controlled trial, Chestiness and Asthma in Mitchell's Plain (CHAMP) (Zwarenstein 1999). This thesis describes the design, implementation and qualitative evaluation of the outreach intervention. Methods Qualitative interviews and quantitative sample surveys were conducted among GPs to identify and measure the prevalence of perceived barriers to optimal asthma care in children. A trained pharmacist visited GPs twice, promoting eight evidence-based primary care messages to overcome barriers to optimal care for asthma in children. The messages focused on key diagnostic indicators, a treatment algorithm based on severity, cost of drug therapies, inhaler and spacer use, and preventive treatment. These messages were formatted into attractive promotional material. The first visit promoted use of the messages, the second reinforced adoption in routine practice and assessed GPs' responses using unobtrusive qualitative data collection methods. The dialogue was tailored to each GP's needs. Results Thirty-two GPs received the intervention. All but one consented to both visits. At the first visit responses were varied. A few GPs were confused or suspicious; most were in agreement with the messages but seemed passive towards implementation; a few were keen to adopt the messages into their routine practice. Response at first visit was not predictive of use as assessed at the second. At the second visit, most GPs claimed that they personally agreed with and used the messages, with a large minority less enthusiastic. Conclusion The intervention appears to have been broadly accepted as evident from GPs' acceptance of the outreach pharmacist, but reports of complete adoption of the messages and use of the kit were less prevalent. This finding is consistent with and helps to explain the improved health outcomes of children with asthma in the CHAMP trial. The combination of qualitative and quantitative research methods was effective in identifying and assessing GPs' barriers. Further, the combination helped to confirm the determinants for the intervention. Unobtrusive qualitative methods provided valuable insight into GP behaviour in routine setting. Additional studies conducted in public sector pnmary care settings and for other diseases are needed to confirm the wider acceptability and effectiveness of multifaceted outreach interventions aimed at improving professional practice. Such an intervention in our study setting seemed successful for childhood asthma.
Effects of Leonotis leonurus aqueous extract on the isolated perfused rat heart
(University of the Western Cape, 2007) Khan, Fatima; Mugabo, P.; Burger, A. P.
An aqueous extract prepared from the leaves and smaller stems of Leonotis leonurus was used to investigate the potential effects on certain cardiovascular parameters, such as left ventricular systolic pressure, end-diastolic pressure, developed pressure, heart rate, cardiac work and coronary perfusion pressure in isolated rat hearts. Hearts were perfused at constant flow for 3min using the modified Langendorf! perfused model of the heart. Effects of adrenaline and digoxin solutions on the isolated heart were compared to that of the plant extract. Adrenaline produced both positive inotropic and chronotropic effects. Adrenaline increased (p
Expanding presumptive male partner management of sexually transmitted infections (STIs) to Western Cape, South African community retail pharmacies
(University of the Western Cape, 2007) Ward, Kim Lana; Butler, Nadine; Mugabo, Pierre; School of Pharmacy; Faculty of Science
The effect of industrialisation has thrust the pharmaceutical profession into a clinical paradigm where the approcah to pharmaceutical decisions is more disease and patient orientated. Consequently, South African community pharmacies are inundated with requests from the public for advice and treatment on a wide range of medical conditions, including sexually transmitted infections (STI's). Although community pharmacies are often the first port of call for undiagnosed STI, limited diagnostic skills and legally-imposed prescribing restrictions preclude pharmacists from providing the necessary clinical management. The overarching goal of this dissertation was to present objective arguments and evidences (new and existing) around an expanded role for pharmacists in STI partner management.
An investigation into the medicinal properties of Tulbaghia alliacea phytotherapy
(University of the Western Cape, 2009) Thamburan, Samantha; Johnson, Quinton
The reproductive health of individuals is severely compromised by HIV infection, with candidiasis being the most prevalent oral complication in patients. Although not usually associated with severe morbidity, oropharyngeal candidiasis can be clinically significant, as it can interfere with the administration of medications and adequate nutritional intake, and may spread to the esophagus. Azole antifungal agents are commonly prescribed for the treatment and prophylaxis of candidal infections. However, the emergence of drug resistant strains and dose limiting toxic effects have complicated the treatment of candidiasis. Consequently, safe and effective and affordable medicine is required to combat this fungus. Commercial garlic (Allium sativum) has been used time since immemorial as a natural antibiotic, however very little is known about the antifungal properties of two indigenous South African species of garlic, namely Tulbaghia alliacea and Tulbaghia violacea, that are used as folk medicines for a variety of infections. This study compares the in vitro anti-candidal activity of Tulbaghia alliacea, Tulbaghia violacea and Allium sativum extracts. It was found that the greatest concentrations of inhibitory components were extracted by chloroform or water. The IC50 concentrations of Tulbaghia alliacea were between 0.007 – 0.038% (w/v). Assays using S. cerevisiae revealed that the T. alliacea extract was fungicidal, with a killing half-life of approximately 2 hours. This inhibitory effect of the T. alliacea extracts was observed via TLC, and may be due to an active compound called Marasmicin, that was identified using NMR. This investigation confirms that extracts of T.alliacea exhibit anti-infective activity against candida species in vitro.
An investigation into the medicinal properties of Tulbaghia alliacea phytotherapy
(University of the Western Cape, 2009) Thamburan, Samantha; Johnson, Quinton; School of Pharmacy; Faculty of Science
The reproductive health of individuals is severely compromised by HIV infection, with candidiasis being the most prevalent oral complication in patients. Although not usually associated with severe morbidity, oropharyngeal candidiasis can be clinically significant, as it can interfere with the administration of medications and adequate nutritional intake, and may spread to the esophagus. Azole antifungal agents are commonly prescribed for the treatment and prophylaxis of candidal infections. However, the emergence of drug resistant strains and dose limiting toxic effects have complicated the treatment of candidiasis. Consequently, safe and effective and affordable medicine is required to combat this fungus. Commercial garlic (Allium sativum) has been used time since immemorial as a natural antibiotic, however very little is known about the antifungal properties of two indigenous South African species of garlic, namely Tulbaghia alliacea and Tulbaghia violacea, that are used as folk medicines for a variety of infections. This study compares the in vitro anti-candidal activity of Tulbaghia alliacea, Tulbaghia violacea and Allium sativum extracts. It was found that the greatest concentrations of inhibitory components were extracted by chloroform or water. The IC50 concentrations of Tulbaghia alliacea were between 0.007 - 0.038% (w/v). Assays using S. cerevisiae revealed that the T. alliacea extract was fungicidal, with a killing half-life of approximately 2 hours. This inhibitory effect of the T. alliacea extracts was observed via TLC, and may be due to an active compound called Marasmicin, that was identified using NMR. This investigation confirms that extracts of T.alliacea exhibit anti-infective activity against candida species in vitro.
Cardiovascular effects of (13S)-9_, 13_- epoxylabda-6_(19), 15(14)diol dilactone, a diterpenoid isolated from the organic extract of leonotis leonurus leaves, in anaesthetized normotensive rats
(2009) Chibuzo, Obikeze Kenechukwu; Mugabo, Pierre; Green, Ivan
Plants used in traditional medicines have served as sources of some of the drug compounds used in medicines today, and could still serve as leads for then development of new drugs to treat existing chronic diseases such as hypertension. This study was aimed at the isolation and identification of a cardio-active compound from L. leonurus, a plant commonly used in traditional medicines in South Africa for the treatment of hypertension and other cardiac problems. The possible mechanisms by which the isolated compound produced its effect on the cardiovascular system were explored using the anaesthetized normotensive rat model.Fractionation of the organic extracts of the leaves led to the isolation of a novel diterpene,(13S)-9 , 13 -epoxylabda-6 (19),15(14)diol dilactone (EDD) whose structure was elucidated using infra red (IR), nuclear magnetic resonance (NMR), mass spectroscopy(MS), and X-ray diffraction analysis. In anaesthetized normotensive male Wistar rats, EDD(0.5 mg/kg – 5.0 mg/kg; IV) produced slight non-significant decreases in systolic pressure(SP), diastolic pressure (DP), and mean arterial pressure (MAP) with the lower (0.5 mg/kg– 2.0 mg/kg) doses, while significant increases in SP, DP and MAP occurred with the higher (3.0 mg/kg – 5.0 mg/kg) doses. All doses of EDD administered also produced significant decreases in heart rate (HR).Prazosin and reserpine pre-treatment abolished the vasoconstrictive effect of EDD,suggesting an indirect vasoconstrictive effect for EDD via the release of catecholamines.Atenolol pre-treatment led to increases in the negative chronotropic effect of EDD, while the positive chronotropic effect of dobutamine was significantly decreased by EDD,suggesting the involvement of the 1 adrenoceptor in the negative chronotropic effect of EDD. In animals pre-treated with verapamil, a cardio-selective Ca2+ channel blocker, no significant changes in HR occurred with all EDD doses, but HR values were significantly lower than those obtained with EDD in non pre-treated animals.The results of this study indicate that (13S)-9 , 13 -epoxylabda-6 (19),15(14)diol dilactone, a novel dilactone diterpene isolated from the leaves of L. leonurus has an effect on the cardiovascular system. EDD exhibits a dual effect on the cardiovascular system by producing a vasoconstrictive effect accompanied by bradycardia. The vasoconstrictive effect of EDD is probably due to the release of catecholamines, while the negative chronotropic effect is probably due to 1 adrenoceptor antagonism. Further studies are however required to fully determine the mechanism by which EDD produces its cardiovascular effects.
Aspects of the gastrointestinal uptake and metabolism of luteolin derivatives from Artemisia afra aqueous extract (preclinical)
(University of the Western Cape, 2011) Mukinda, James Tshikosa; School of Pharmacy; Faculty of Community and Health Sciences
The aim of this study was to investigate the effect the plant matrix and the structure of the flavonoid (i.e. whether aglycone or glycoside) may have on the gastrointestinal uptake and metabolism of luteolin derivatives from Artemisia afra traditional plant medicine. Specifically, how these two factors influenced the intestinal uptake and disposition of luteolin derivatives in pure and in Artemisia afra plant extract forms were to be assessed by investigating the uptake and metabolism of the luteolin derivatives in human intestinal epithelial Caco-2 cells and the perfused rat intestinal loop. To realize this aim, the following were determined: (1) identification and characterization of major luteolin derivatives found in Artemisia afra, (2) the effect of the plant matrix on the uptake of luteolin derivatives in Artemisia afra aqueous-extract forms across the Caco-2 cell monolayer, (3) the effect of the plant matrix on the absorption and metabolism of luteolin derivatives in Artemisia afra aqueous-extract forms in the perfused rat small intestine, (4) the effect of gut contents on the uptake and metabolism of luteolin derivatives in intestinal loop and (5) the metabolic profiles of luteolin derivatives obtained for the pure solutions versus plant aqueous extract solutions in Caco-2 cells and the rat intestine.
Effect of Tulbaghia violacea on the blood pressure and heart rate in male spontaneously hypertensive wistar rats
(University of the Western Cape, 2011) Raji, Ismaila; Mugabo, Pierre; School of Pharmacy
Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family, Alliaceae, most commonly associated with onions and garlic. In South Africa (SA), this herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension (HTN) and stomach problems. The aim of this study was to evaluate the effect of methanol leaf extracts (MLE) of T. violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats and to find out the mechanism(s) by which it acts. The MLE of T. violacea (5 - 150 mg/kg), angiotensin I (ang I, 3.1 - 100 mg/kg), captopril (10 mg/kg), angiotensin II (ang II, 3.1 - 50 g/kg), losartan (30 mg/kg), phenylephrine (0.01 ; 0.16 mg/kg), prazosin (1 mg/kg), dobutamine (0.2 ; 10.0mg/kg), propranolol (0.1 - 12.8 mg/kg), muscarine (0.16 -10 mg/kg), and atropine (0.02 - 20.48 mg/kg) were administered intravenously into male spontaneously hypertensive rats (SHR) weighing between 300 g and 350 g and aged less than 5; months. The MLE of T. violacea and/or the standard drugs were infused alone, simultaneously, or separately into each animal. The BP and HR were measured via a pressure transducer connecting the femoral artery and the Powerlab. The vehicle (0.2 mls of a mixture of dimethylsulfoxide and normal saline), T. violacea (60 mg/kg) and captopril (10 mg/kg) were injected intraperitoneally into some SHR for 21 days to investigate the chronic effect of these agents on plasma levels of aldosterone. The mean change, the mean of the individual percentage changes and the percentage difference (in mean) observed with each intervention was calculated and statistically analyzed using the Student t test for significant difference (p < 0.05). The Microsoft Excel software was used for statistical analysis. T. violacea significantly (p < 0.05) reduced the systolic, diastolic, and mean arterial BP; and HR dose-dependently. In a dose-dependent manner, ang I, ang II, phenylephrine significantly (p < 0.05) increased the BP, while propranolol, muscarine and atropine reduced the BP. The increases in BP due to dobutamine were not dose-dependent. In a dose dependent manner, phenylephrine and propranolol reduced the HR, while dobutamine increased the HR. The effect of ang I, ang II, muscarine and atropine on HR were not dose-dependent; with both increases as well as decreases observed with ang I, and II and atropine, while decreases were seen with muscarine. Captopril produced significant (p < 0.05) reduction in BP which were not associated with any change in HR. The co-infusion of ang I with the MLE produced significant (p < 0.05) reduction in BP, which were not associated with significant changes in HR. The co-infusion of ang II with the MLE did not produce any significant changes in BP or HR when compared to the infusion of the standard drug alone. The co-infusion of phenylephrine with the MLE did not produce any significant change in BP or HR when compared to the values obtained with the infusion of the standard drug alone, in both the absence and presence of prazosin. The co-infusion of dobutamine with T. violacea produced siginificant (p < 0.05) increases in DBP which were associated with significant (p < 0.05) reductions in HR, when compared to the values obtained with the infusion of the standard drug alone. Theco-infusion of atropine with the MLE did not produce any significant change in BP or HR when compared to the values obtained with the infusion of atropine alone. However, the infusion of T. violacea, 20 minutes after pre-treating animals with atropine (5.12 mg/kg) lead to dose dependent significant (p< 0.05) increases in BP, which were associated with dose-dependent increases in HR. The chronic treatment of animals with T. violacea or captropril produced (a) signicant (p < 0.05) reductions in the plasma levels of aldosterone when compared to the values obtained in the vehicle-treated group, (b) produced signifiant (p< 0.05) reduction in BP in the captopril treated group when compared to the vehicle-treated, (c) did not produce any signficant change in BP in the T. violacea-treated group when compared to the vehicle-treated group and (d) did not produce any signifiant change in HR or body weight in any of the groups. The result obtained in this study suggests that T. violacea reduced BP and HR in the SHR. Secondly, the BP and HR reducing effect of the MLE may involve a) the inhibition of the ACE, b) the inhibition of the beta; adrenoceptors, c) the stimulation of the muscarinic receptors and d) the reduction of the levels of aldosternone in plasma. The results also suggest that the MLE may not act through the angiotensin II receptors or the alpha adrenergic receptors.
Pharmacy perspectives in the design and implementation of a mobile cellular phone application as a communication aid for dispensing medicines to deaf people in the South African context
(University of the Western Cape, 2015) Parker, Mariam B.; Bheekie, Angeni; Tucker, William D.
South Africa's White Paper for the transformation of the health care system in South Africa (DOH, 2007) acknowledges major disparities and inequalities as a result of an imprint by apartheid policies. In its transition to democracy, health promotion strategies have been initiated to address these disparities. However, such strategies have been narrowed and "favoured target audiences that are literate, urban-based and who have easy access to print and audio-visual media" (DOH, 1997). This implies that many vulnerable and marginalised groupings in South Africa, including the Deaf community are excluded from health promotion endeavours. Deaf people in South Africa communicate using South African Sign Language (SASL) and majority of the Deaf community exhibit poor literacy levels. Deafness is a significant communication barrier which limits a Deaf person's prospect to attain the best possible health care (Barnett, et al 2011). Various means of communication including spoken language, written instructions and the use of pictograms are used by healthcare workers to communicate health-related information. For many members of the Deaf community who communicate primarily in sign language, these methods are a sub-standard and prevent the attainment of optimum therapeutic outcomes. With regard to pharmaco-therapeutic services, Deaf people cannot hear the spoken language used by pharmacists during patient counselling, and their compromised functional literacy hinders the ability to read instructions on medicine labels. With both the spoken and written means of communication compromised, the Deaf patient's ability to comprehend instruction by pharmacists on how to use their medicines is inadequate and as a result, a Deaf patient may leave the pharmacy with medicine, but a poor understanding of how to use the medicine safely and effectively. Previous researchers have worked on building a technology base, including industrial design and computer science expertise to conceptualize the groundwork of a mobile phone application called SignSupport to facilitate communication between medical doctors and Deaf individuals. The particulars of the pharmacy scenario however, require a pharmacy-specific device to be of use in the dispensing of medicines to a Deaf patient in a pharmacy. The over-arching goal of this thesis is to design and evaluate a mobile phone application to facilitate the communication of medicine instructions between a Deaf patient and a pharmacist. Qualitative, participatory action research and community-based co-design strategies were directed toward Deaf participants, senior pharmacy students and pharmacists to create a prototype of the afore-mentioned mobile phone application. Preliminary results indicated that the application was suitable to pharmacists and Deaf community. Furthermore, both sets of users approved the overall design and were receptive to and keen on the practical uses of the application. Inadequacies pointed out by the Deaf community and pharmacists were addressed as an iterative modification to the prototype and culminated in version 2 which was deployed in an actual hospital pharmacy in 2015. Hospital usability studies generated largely positive results from both Deaf users and pharmacists, indicating that SignSupport is able to facilitate communication between pharmacists and Deaf patients. Next steps include advancing the application to a market–ready version that is downloadable and available as an application on the play stores of commercially available smart phones.
Content levels, in vitro dissolution and predicted bioavailability of flavonoids from Sutherlandia frutescens leaf powder and aqueous extracts
(University of the Western Cape, 2015) Mbamalu, Oluchi Nneka; Syce, James; Samsodien, Halima
Various formulations of the popular South African medicinal plant, Sutherlandia frutescens,are commercially available, with no documented specifications for quality assessment. With plans already underway for a clinical trial to assess its efficacy in HIV patients, there is a need for scientifically validated tests for the quality control of products of this plant. Chemical constituents of the plant are many and varied but it is still unclear which might be the most appropriate ones to monitor for activity or to describe the quality of the plant’s products. For quality control and regulatory purposes, the content and dissolution of flavonoids in the plant products can be assessed. However, these compounds are not monitored for regulation and there are as yet no HPLC or dissolution methods that can be employed for quality control of herbals like S. frutescens. Therefore, the objectives of this study were to assess the suitability of its flavonoid constituents as quality control (QC) marker compounds, and the suitability of content levels and dissolution tests of flavonoids as QC tools for S. frutescens products. To realise the afore-mentioned objectives, non-commercially available flavonoid compounds (sutherlandins) that could be used as marker compounds were isolated from S. frutescens. An HPLC assay was developed and validated for determination of flavonoid content in solution. Five S. frutescens materials viz leaf powder (LP), spray-dried aqueous extract (SDAE) and freeze-dried aqueous extracts (FDAE) were analysed for flavonoid content and dissolution. Dissolution tests were conducted for different S. frutescens materials and dissolution profiles of flavonoids in capsules containing these materials were compared using Q-release values, the similarity factor (f2) and mathematical models. To predict in vivo bioavailability of the flavonoids, in silico assessment of in vivo bioavailability of flavonoids (glycosides and aglycones) that may be contained in different S. frutescens materials was conducted. Sutherlandins A, B, C and D were successfully isolated (percentage purity approximately99 % for sutherlandins A, C and D, and 90 % for sutherlandin B) and identified, and used, along with other flavonoid compounds, for the development of a simple and robust HPLC method. Content of sutherlandins A, B, C and D, quercetin and kaempferol in different plant materials were 0.4 ± 0.3, 0.8 ± 0.2, 1.3 ± 0.2, 0.6 ± 0.1, 0.01 ± 0.02 and 0.08 ±0.1 %,respectively, and differed significantly (p < 0.001). In vitro dissolution showed faster dissolution of flavoniod glycosides compared to aglycones. The flavonoids from the LP and SDAE materials showed characteristics of immediate release with Q75 in ≤ 45 minutes, and delayed release from the FDAE material, i.e. Q75 > 45 minutes. The dissolution profiles of each flavonoid compared from different S. frutescens materials were different as signified by their f2 values which were all below 50. The mathematical models describing release were also different for each flavonoid from the different S. frutescens materials. For in vivo bioavailability modelling and prediction studies, the flavonoid aglycones met the conditions for oral bioavailability while the flavonoid glycosides did not. In conclusion, the sutherlandins isolated from S. frutescens proved to be good markers for HPLC assay and dissolution tests of S. frutescens materials. The HPLC method was suitable for assessing flavonoid levels in S. frutescens materials, and also showed differences in flavonoid content in these materials. The dissolution method was simple and reproducible, and Q-release values, the f2 and mathematical models proved to be good tools for differentiating between S. frutescens materials. In silico modelling showed that the flavonoid glycosides and aglycones differed in oral bioavailability. Although not presently required by the Medicines Control Council (MCC), quantification, release and dissolution studies and specifications may be employed as tools for routine analysis and for quality control of herbal drug formulations containing S. frutescens.
Synthesis & biological evaluation of neuroprotective molecules with polycyclic scaffolds
(University of the Western Cape, 2017) Sharma, Rajan; Malan, Sarel F.; Joubert, Jacques
Among neurological disorders, many of the most devastating disorders are neurodegenerative. Modern research associates excitotoxicity to a variety of neuropathological conditions, suggesting that the neurodegenerative diseases with distinct etiologies may have excitotoxicity as a common pathway. Excitotoxicity occurs through over-stimulation of receptors for excitatory neurotransmitters like the N-methyl-D-aspartate (NMDA) receptors. Due to the relevance of NMDA receptors and excitotoxic processes, the antagonism or modulation of NMDA receptors is used as a therapeutic tool against neurodegenerative diseases. NMDA receptor activity can be modulated by S-nitrosylation and this modulation of NMDA receptor activity can be utilised in the development of neuroprotective drugs.
Adverse pregnancy outcomes among HIV-positive pregnant women treated with efavirenz-containing antiretroviral drugs: a retrospective cohort study in the Cape Flats
(University of the Western Cape, 2017) Mohammednur, Mohammedmekin Mohammedseid; Mugabo, Pierre
The use of efavirenz (EFV) in the first trimester of pregnancy remains controversial. In South Africa, the use of EFV-containing antiretroviral therapy (ART) as part of a Fixed Dose Combination (FDC) during the first trimester of pregnancy started in April, 2013. Literature to date has reported conflicting outcomes following the use of EFV-containing ART during the first trimester of pregnancy. The objectives of the study were to determine the prevalence of adverse pregnancy outcomes among HIV-positive pregnant women treated with EFV-containing ART and compare these results with those of pregnant women treated with NVP-containing ART and HIV-negative pregnant women in resource-limited settings. In addition, the study also aimed to determine the effect of the time of initiation of ART on the prevalence of adverse pregnancy outcomes.
A Reductionistic Epistemology utilizing Brain Laterality which Investigates Pharmacists' Ideal Interactive Environment
(University of the Western Cape, 2018) Symon, Bernard Dennis; Butler, Nadine
The brain laterality of pharmacists may influence where the pharmacists are best suited to work. Brain laterality refers to the asymmetry of the hemispheres of the brain with regard to specific cognitive functions, such as objectivity and emotion. The left hemisphere functions objectively and rationally, whereas the right hemisphere is subjective and non-rational. Animal behaviour in the literature demonstrated an influence of brain laterality, thus selecting an ideal work environment may also be driven by brain laterality bias. Further support for the research included: amblyopia; hemiplegia; the WADA test. The research question investigated the matching of the brain laterality groups of pharmacists to their ideal work environments. The aims investigated: ear, eye, hand and foot dominance in determining brain laterality; influence of brain laterality and reductionistic variables on job choice; location of emotion generation and job choice. Five objectives investigated these aims: influence of brain laterality alone; influence of brain laterality and reductionistic variables; influence of a new brain laterality determining continuum; Propinquity Principle in achieving data; correctness of the Right Hemisphere Theory (RHT) or the Valence Theory (VT). The RHT suggests that the right hemisphere is dominant in processing all emotion. The VT argues that the left hemisphere is specialised in processing the positive emotions while the right hemisphere is specialised in processing the negative emotions. The resulting Null Hypothesis posits that there is no statistical difference between the different brain laterality groups enabling pharmacists to work competently in any placement. The Alternative Hypothesis was that there is a statistical difference between the brain laterality groups, thus brain laterality can be used to best place pharmacists into ideal placements.
Polycyclic propargylamine derivatives as multifunctional neuroprotective agents
(University of the Western Cape, 2018) Zindo, Frank T.; Joubert, Jacques; F. Malan, Sarel
The abnormal death of neurons in the central nervous system of individuals suffering from neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis, takes place by an intrinsic cell suicide programme known as apoptosis. This process is triggered by several stimuli, and consists of numerous pathways and cascades which lead to the death of neuronal cells. It is this multifactorial nature of neurodegenerative diseases that has over the years seen many researchers develop compounds that may serve as multi-target directed ligands (MTDLs) which could potentially confer neuroprotection by acting simultaneously on different receptors and target sites implicated in neurodegeneration. This study was aimed at developing MTDLs that may serve as neuroprotective agents by simultaneously (a) inhibiting N-methyl D-aspartate receptors (NMDAR) and blocking L-type voltage gated calcium channels (VGCC) thus regulating the Ca2+ influx mediated excitotoxic process; (b) inhibiting the monoamine oxidase enzymes A and -B (MAO-A/B) thus allowing increase in dopamine levels in the central nervous system and reducing the levels of the highly oxidative products produced by the activity of these enzymes; (c) possessing anti-apoptotic activity to halt the neuronal cell death process. In designing the compounds we focused on the structures of rasagiline and selegiline, two well-known MAO-B inhibitors and proposed neuroprotective agents, and of NGP1-01, a known VGCC blocker and NMDAR antagonist. The first series of compounds (reported in research article 1, Chapter 3), comprised polycyclic propargylamine and acetylene derivatives. Compounds 12, 15 and 16 from this series showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18 % to 59 % in micromolar concentrations, and compared favourably to the reference compounds. In the MAO-B assay, compound 10 exhibited weak MAO-B inhibition of 73.32 % at 300 μM. The rest of the series showed little to no activity on these target sites, despite showing significant anti-apoptotic activity. This suggested the compounds in this series to be exhibiting their neuroprotective action through some other mechanism(s) unexplored in this study.
Population pharmacokinetics of terizidone and cycloserine in patients with drugresistant tuberculosis
(University of the Western Cape, 2019) Mulubwa, Mwila; Mugabo, Pierre
Introduction: Drug-resistant tuberculosis remains a major world health problem and one of the leading cause of death worldwide. Despite adequate adherence to antituberculosis drugs by patients, the emergence of drug-resistance tuberculosis still occurs. This fact implies other factors leading to the emergence of resistant strains of Mycobacterium tuberculosis. A multidrug treatment regimen, which may consist of five to seven different drugs including terizidone, is used in the treatment of drugresistance tuberculosis. Terizidone is part of the multidrug regimen whose pharmacokinetics is scarce in literature and plasma concentration profile unknown. Two molecules of cycloserine joined by terephtalaldehyde moiety makes up a molecule of terizidone, which is thought to undergo complete metabolism into cycloserine in vivo. Additionally, the current literature report that terizidone and cycloserine can be used interchangeably as they are thought to be equivalent. The aim of this thesis was first to develop and validate bioanalytical methods for determination of terizidone and cycloserine in patients’ plasma samples. Secondly, to model population pharmacokinetics of terizidone and cycloserine. Thirdly, to determine the amount of cycloserine resulting from metabolism of terizidone.
Discovery of antibacterial lead compounds from marine organisms
(University of the Western Cape, 2020) Afolayan, Omolola; Beukes, Denzil R; Trindade, Marla
Marine organisms including algae and bacteria are known to produce chemically diverse secondary metabolites for survival purposes in the marine environment. Scientists have identified some of these natural products as therapeutic agents including some antibiotics. Given the increase in the resistance of pathogenic microorganisms especially methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis to commonly prescribed antibiotics, researchers have turned towards exploiting marine natural products for new antibacterial compounds. Due to the proven success of finding bioactive compounds in the marine environment this study therefore aims to discover lead compounds against MRSA and Mycobacterium tuberculosis from two marine sources, the marine algae and the bacteria associated with marine invertebrates referred to as bacterial isolates.
Design and synthesis of new scaffolds as antiproliferative agents and potential hsp90 inhibitors
(University of Western Cape, 2020) Adegoke, Yusuf Adeyemi; Beukes, Denzil R.
Natural products have been an important source of drugs and novel lead compounds in drug discovery. Their unique scaffolds have led to the synthesis of derivatives that continue to give rise to medicinally relevant agents. Thus, natural product-inspired drugs represent a significant proportion of drugs in the market and with several more in development. Cancer is among the leading public health problems and a prominent cause of death globally. Chemotherapy has been important in the management of this disease even though side effects that arise due to lack of selectivity is still an issue.
Development of rifampicin loaded in surface-modified 4.0 G PAMAM dendrimer as a novel antituberculosis pulmonary drug delivery system
(University of the Western Cape, 2020) Ahmed, Rami M. Y.; Samsodien, Halima
Introduction: Tuberculosis (TB) is a serious bacterial infections caused by the Mycobacterium Tuberculosis (MTB) organism affecting mainly the lungs. Occasionally, MTB bacilli may be transported out of the pulmonary region and infect peripheral organs causing extra-pulmonary tuberculosis. Many therapeutic agents were developed over the years to combat TB, however the rapid emergence of resistant strains hampered their use. Furthermore, most of the current anti-TB drugs experience many challenges, which can be summarized in treatment regimen factors, drug-drug interactions, and physicochemical characteristics factors (such as hydrophobicity and low permeability into alveolar macrophages). These challenges have a significant role in treatment failure and the emergence of resistant TB. Due to the lack of newly discovered anti-TB drugs, and the absence of effective vaccines, many scientists have suggested the use of novel modalities for the current anti-TB drugs to enhance their efficacy and overcome some of the drawbacks. One of these modalities is nanotechnology-based drug delivery systems. Most of the anti-TB drugs experience low drug distribution to the lung and particularly alveolar macrophages within which the MTB resides, leading to treatment failure. Employing nanoparticles as drug delivery systems can have a significant impact on improving the pharmacokinetic profile of anti-TB drugs, the feasibility of different routes of administration, enhancing drug permeability, controlled/sustained drug release, and targeting specific disease sites. Collectively, these impacts will aid in enhancing drug concentration at the site of infection and reduce dosing and regimen duration. Dendrimers, such as polyamidoamine (PAMAM) dendrimers, are synthetic polymeric nanoparticles that have unique features that afford a dendrimer-conjugate complex the possibility to overcome the most common hurdles associated with drug delivery and treatment of diseases. Obstacles associated with solubility, permeability, inadequate biodistribution associated side effects may be enhanced. Manipulating the outermost surface functional groups with various ligands and polymers, will enhance the dendrimer properties and targeting potential. Aim: This study aims to develop a novel pulmonary delivery system for the anti-TB drug rifampicin using surface-modified G4 PAMAM dendrimer nanoparticles (polyethylene glycol (PEG) or mannose moieties), to improve drug solubility, prolong-release, enhance permeability into the macrophages, and decrease the toxicity of the drug-dendrimer conjugates. Methods: PAMAM dendrimers having increasing concentrations of poly(ethylene glycol) (PEG) 2 kDa or mannose residues were synthesized. The 4-nitrophenyl chloroformate was used as an activator in the case of PEG functionalization, while for the mannose conjugation the 4-isothiocyanatophenyl alpha-D-mannopyranoside (4-ICPMP) directly interacted with the primary amines of the dendrimer. The conjugated PEG polymers and mannose moieties on the dendrimer periphery were confirmed using FTIR and 1H NMR analytical techniques. Thereafter, rifampicin was loaded into the native and surface-modified dendrimers via a simple dissolution solvent evaporation method. Rifampicin-loaded dendrimers were then characterized using several analytical techniques namely; FTIR, DSC, NMR, SEM, and DLS. The polymer encapsulation efficiency (EE%) and percentage of drug loading (DL%) were determined directly using a validated HPLC method. In vitro drug release was studied at pH 7.4 and pH 4.5. The MTT technique was used to assess the cytotoxicity of the dendrimer formulations against raw 264.7 cell lines. Finally, the uptake of dendrimer nanoparticles by raw macrophages was studied using a flow cytometer and fluorescence microscopy techniques. Results: The percentage coverage of 4.0 G PAMAM dendrimer peripheral with PEG was achieved in a range of 38% - 100%, while for mannose moieties was from 44% - 100%. The EE% of unmodified dendrimer was 7.5% (w/w). The EE% of PEGylated dendrimers ranged from 65.0% - 78.75% (w/w), whereas for mannosylated dendrimers was from 43.43% - 57.91% (w/w). The size of the unloaded dendrimer nanoparticles was less than 25 nm, a gradual increase in the size after drug conjugation followed. The zeta potential of dendrimers was positive with values greater than 12 mV, the nanoparticle's zeta potential decreased upon increasing the density of PEG/mannose and after drug loading. FTIR and NMR data showed that rifampicin molecules were conjugated to the dendrimer at three sites; at the surface amines via electrostatic linkages, within the PEG/mannose, and into the dendrimer interior. SEM images of dendrimer nanoparticles confirmed the spherical shape of particles, and DSC data verified drug entrapment. Drug release was found to be affected by the pH of the medium and the extent of dendrimer functionalization. At the physiologic pH, surface-modified dendrimers showed a slower release rate compared to the unmodified dendrimer and free drug. Among surface-modified dendrimers, the release rate was inversely associated with the density of PEG/mannose molecules. At pH 4.5, a relatively higher drug release from all formulations was observed which suggests a burst release inside the alveolar macrophages. Toxicity studies showed that the unmodified dendrimer experienced time-dependent and concentration-dependent cytotoxicity against raw 264.7 cells. The toxicity gradually decreased upon increasing the density of PEG/mannose, and negligible toxicity was detected for formulations with 100% functionalization. Dendrimer nanoparticles were successfully internalized into raw cells after 24 hrs of incubation. The order of nanoparticles permeability was PEG 100% < PEG 85% < PEG 70% < PEG 49% < PEG 38% < unmodified dendrimer < mannose 44% < mannose 69% < mannose 93% < mannose 100%. The significant increase in the uptake of mannosylated dendrimers was due to the interaction with lectin receptors at the surface of raw macrophages, whereas the lower internalization of PEGylated dendrimers was due to the shielding of the surface positive charges. Conclusion: The in-vitro and ex-vivo data studies suggested that the developed novel surface-modified G4 PAMAM dendrimers are suitable drug carriers in terms of biocompatibility, release behaviour, and site-specific delivery of the anti-TB drug rifampicin.

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