Doctor Pharmaceuticae - DPharm

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Selected polyols as co-formers for pharmaceutical solid dispersions
(Universty of the Western Cape, 2024) Poka, Madan Sai; Aucamp, Marique
Poor aqueous solubility is a major concern for most new chemical entities (NCEs) developed for oral drug delivery as well as for almost 70% of registered and already marketed drugs. Solid-state alterations such as solid dispersions (SDs), co-amorphous and co-crystal systems have taken the lead over the past two decades, in an effort to address the challenge of poor drug solubility. One of the common factors amongst these techniques, that play a significant role in solubility enhancement, is the type of carrier or co-former used. Low molecular weight excipients such as amino acids, citric acid and a few sugars were studied as potential co-formers. However, the efforts made in identifying new low molecular weight excipients were modest. Given their low molecular weight, safety, hydrophilic nature and having high hydrogen bonding propensity makes polyols an interesting option to be explored as carriers.
The formulation of a microsphere based fixed dose combination for oral antiretroviral delivery
(University of the Western Cape, 2023) Omoteso, Omobolanle Ayoyinka; Aucamp, Marique Elizabeth
The cost of providing antiretroviral therapy (ART) remains a significant economic burden on African countries due to poverty and a lack of resources. To reduce the economic burden of HIV infection, a formulation scientist must use the limited resources available in Africa to develop drug dosage forms of antiretrovirals (ARVs) that are cost-effective, adaptable, and accessible, as well as result in successful therapeutic outcomes of HIV/AIDS treatment, raise the average life expectancies of HIV-positive adults, and increase the availability of the limited resources for other purposes. According to the literature, lamivudine (3TC) is still used in firstline HIV treatment regimens, and several 3TC-based fixed-dose combinations (FDCs) are on the market. These FDCs are typically relatively large and require patients to take medication daily. As a result, patients will accept a flexible dosage form that can be ingested once and provides adequate therapeutic efficacy for more than 24 hours, thereby increasing treatment adherence, decreasing drug resistance, and improving therapeutic efficacy. Formulation scientists must create dosage forms that provide better patient treatment and patient experience, focusing on patientcentred medicine development. Hence, this study focused on 3TC and tenofovir disoproxil fumarate (TDF), which are still among the cornerstones of many HIV treatment regimens.
Investigation of common deficiencies observed in scientific assessments and the implementation of a new robust review pathway, the risk-based assessment approach, by the South African Health Regulatory Authority, SAHPRA
(University of the Western Cape, 2022) Moeti, Lerato Petunia; Joubert, Jacques
The main objective of this study is to improve patient access to medicines. The research is two-fold, the first component promotes transparency between the South African Health Products Regulatory Authority (SAHPRA), pharmaceutical companies, manufacturers and clinical research organisations by investigating deficiencies in scientific assessments of medicines submitted for approval. The common deficiencies from the regional, Active Pharmaceutical Ingredient (API), Finished Pharmaceutical Product (FPP) and Bioequivalence study sections of dossiers submitted to SAHPRA were qualitatively and quantitatively investigated. The investigation was conducted retrospectively between 2011 to 2017 for non-sterile and sterile generic products finalised by the P&A pre-registration Unit. To strengthen the conclusions, up-to-date data was also collected between 2020-2021 to confirm the consistency of the findings.
Investigation of suitable microencapsulation techniques in the preformulation of selected antiretroviral drugs
(University of the Western Cape, 2022) Okafor, Nnamdi Ikemefuna; Aucamp, Marique
Background: The use of antiretroviral drugs (ARVDs) in the treatment of HIV/AIDS have been promising and effective especially amongst adults as it suppresses the viral load, thereby improving the life expectancy of HIV patients. However, the adoption of the treatment amongst children living with HIV have proved to be challenging. This is because of the poor drug adherence or non-compliance resulting from the lack of child-friendly formulations. The dosage forms are typically large tablets which have led to difficulty in swallowing or needs breaking of the tablets to obtain the correct dose and potentially some sort of dosage form manipulation by mixing it with milk or juice. The limited paediatric formulations that are available are mostly unpalatable, despite being formulated in a syrup or liquid, it still presents with a bitter taste. Therefore, all these factors combined have emphasized the need for child friendly dosage forms for children suffering from this debilitating disease.
Factors affecting the pharmacokinetics of vancomycin in children admitted to the intensive care unit (icu) of the Red Cross War Memorial Children's Hospital (RCWMCH).
(University of the Western Cape, 2023) Akunne, Onyinye Onyeka; Mugabo, Pierre
Vancomycin is a glycopeptide antibiotic that inhibits bacterial cell wall synthesis by binding to the D-alanyl-D-alanine terminal end of cell wall precursor units preventing the elongation and cross-linkage of the peptidoglycan. Vancomycin is used to treat infections with gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (S. aureus), coagulase-negative staphylococci and penicillin-resistant Streptococcus pneumoniae (S. pneumoniae). It is a time-dependent drug, and its efficacy depends on the duration of pathogen exposure to vancomycin. Low plasma concentration may lead to treatment failure and the re-emergence of bacterial resistance. Vancomycin is known to cause adverse effects at high concentrations. Therefore, it is necessary to monitor plasma concentrations to maintain vancomycin concentration within the therapeutic window. Vancomycin is mainly administered as an intravenous (IV) infusion as it is poorly absorbed from the gastrointestinal system.
Evaluation of selected polycyclic compounds as resistance modulators in Mycobacterium tuberculosis
(University of the Western Cape, 2022) Kapp, Erika; Malan, Sarel
Progressive development of resistance to various chemotherapeutic agents used in the management of infectious diseases presents a serious problem in global public health. Increasing levels of antimicrobial resistance in Mycobacterium tuberculosis (Mtb) is particularly concerning in resource poor countries with a high incidence of tuberculosis (TB), as it is particularly difficult and very costly to treat. The Global Tuberculosis report released by the World health Organization (WHO) in 2022 (based on data from 2021) reports that South Africa is one of only 5 countries in the world with more than 500 cases per 100 000 people. It also falls in the WHO’s top 7 countries with the highest multidrug resistant (MDR) TB incidence.1 The same report released in 2021 states that global TB reporting rates dropped dramatically in 2020, and that TB death rates saw the first year-on-year increase since 2005.2 This is likely a direct consequence of COVID-19 and although improvements in reporting was seen in 2021, the trend has not yet been reversed.1 The pandemic had a negative impact on the progress made in the fight against TB and a renewed effort is needed to achieve the goals previously set out in the WHO End TB Strategy.
The development, implementation and evaluation of an integrated framework for undergraduate pharmacy education in maternal and child health at the University of the Western Cape
(University of the Western Cape, 2022) Egieyeh, Elizabeth Oyebola; Bheekie, Angeni
The high rate of maternal and child mortality is a global health concern. Nationally, it is one of South Africa’s quadruple disease burdens. The Sustainable Development Goal 3, 2030 targets related to maternal and child health (MCH) were implemented to reduce the rate of mortality. The interventions that led to reducing mortality rates during the Millennium Development Goals era, such as improved access to quality healthcare services and skilled healthcare workers, need to be scaled up and accelerated to achieve the SDG 3 targets. As easily accessible frontline healthcare workers, pharmacists play an essential role in the continuum of care for MCH as guided by international and local regulatory health bodies. However, studies have shown that pharmacists feel ill-prepared and uncomfortable rendering MCH services, attributed to most pharmacy schools’ curriculum content and teaching methods.
An exploratory study of the problem of training and skills development in the public health sector: The case of two district hospitals in the Limpopo province
(University of the Western Cape, 2022) Nefale, Mulalo; Esau, Michelle V.
Public health sectors across the globe are usually faced with challenges of adopting creative ways to improve performance and service delivery in the form of investing in employee skills development and training. During the apartheid era, employee training and skills development were reserved for the white minority group. The South African dawn of democracy in 1994 did not automatically result in a change in the status quo. In spite of various regulatory frameworks that emphasise skills development and training, skills development is still a problem, more than 25 years later. Amidst the high unemployment levels, there is also a short supply of critical skills or scarce skills in key sectors such as health.
Pharmacological characterization and chemo-informatics analysis of compounds from leonotis leonurus
(University of Western Cape, 2021) Oghenetega, Chioma O N; Obikeze, Kenechukwu
The central nervous system (CNS), consisting of the brain and the spinal cord, is responsible for integrating sensory information and influencing most bodily functions . The CNS is protected from toxic and pathogenic agents in the blood by permeability barrier mechanisms. These barrier mechanisms, specifically the blood brain barrier (BBB) presents a challenge for the discovery of CNS active drugs as it is requirement for these drugs to permeate the BBB to reach their target site in the CNS. The conventional processes of drug design and discovery from natural products are time consuming, tedious, expensive and have a high failure rate. It has been reported from various studies that the use of computational modelling and simulations in drug design and discovery is less costly and less time-consuming with a greater chance of success than the conventional processes. The process of drug discovery and design can, therefore, be easily carried out using proven computer models, software, and web-based tools .
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.
Pharmacological Characterization and Chemo-informatics analysis of Compounds from Leonotis leonurus.
(2021) Chioma O N, Oghenetega; Obikeze, Kene
The central nervous system (CNS), consisting of the brain and the spinal cord, is responsible for integrating sensory information and influencing most bodily functions . The CNS is protected from toxic and pathogenic agents in the blood by permeability barrier mechanisms. These barrier mechanisms, specifically the blood brain barrier (BBB) presents a challenge for the discovery of CNS active drugs as it is requirement for these drugs to permeate the BBB to reach their target site in the CNS. The conventional processes of drug design and discovery from natural products are time consuming, tedious, expensive and have a high failure rate. It has been reported from various studies that the use of computational modelling and simulations in drug design and discovery is less costly and less time-consuming with a greater chance of success than the conventional processes. The process of drug discovery and design can, therefore, be easily carried out using proven computer models, software, and web-based tools . As a result of the above stated facts, this study aims to utilize in silico as well as in vitro methods in identifying and characterizing promising druglike bioactive compounds from Leonotis leonurus with Central Nervous System (CNS) activity, more specifically in treating Alzheimer’s disease (AD).
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
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.
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.
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.
Selected antiretroviral and anti-tuberculosis drug combinations by non-covalent bonding
(University of Western Cape, 2021) Ngilirabanga, Jean Baptiste; Samsodien, Halima
Treatment of the human immunodeficiency virus (HIV) and tuberculosis (TB) infections have become very complicated due to the advent of drug resistance. Drug combinations offer an alternative approach to reducing the emergence of drug resistance. Pharmaceutical co-crystals have provided the pharmaceutical industry with the ability to optimise the physicochemical properties of active pharmaceutical ingredients (APIs) while preserving the biological activity. Pharmaceutical co-crystals are formed between APIs and suitable co-formers that are biologically safe or even a second or third API.
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.
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.
Novel norbornane derivatives as potential neuroprotective agents
(University of Western Cape, 2020) Egunlusi, Ayodeji Olatunde; Joubert, Jacques; Malan, Sarel
Neurodegenerative disorders are characterised by progressive loss of the brain’s physiological functions as a result of gradual degeneration of neurons in the central nervous system. Even though they are classified as diseases of the elderly, occurrence earlier in life is possible, but that would suggest the influence of genetic and/or environmental factors. Due to the continuous rise in modernisation and industrialisation over the years, there has been an increase in incidence and prevalence of neurodegenerative disorders. With the advances in technology and life expectancy, the rates of the common forms (Alzheimer’s disease and Parkinson’s disease), are expected to increase exponentially by 2050. Unfortunately, there is still no clinically approved treatment or therapy to slow down or halt the degenerative process as most registered drugs only offer symptomatic relief. Confounding this issue is the lack of definite mechanism of neurodegeneration, which is still poorly defined and not completely understood. Nonetheless, the pathology of most neurodegenerative disorders is believed to be a combination of interrelated processes that eventually leads to neuronal cell death. Among the postulated processes, the impact of excitotoxicity mediated by NMDA receptor over-activation is prominent and it is implicated in virtually all neurodegenerative disorders. With this basic insight, it is believed that molecules capable of inhibiting NMDA receptors and associated calcium channels, without affecting the normal physiological functions of the brain, could potentially serve as good neuroprotective drugs. Competitive and uncompetitive blockers (MK-801 and ketamine) have been explored, but none were clinically accepted due to undesirable side effects such as hallucinations, sedation and depression. However, NGP1-01, a polycyclic cage molecule, has been shown to be neuroprotective through modulation of NMDA receptors and voltage gated calcium channels and attenuation of MPP+ -induced toxicity. A similar approach could be useful in the design and development of new neuroprotective drugs. The aim of this study was to synthesise a series of open and rearranged cage-like molecules and explore their neuroprotective potential in neuroblastoma SH-SY5Y cells. The proposed structures, with norbornane scaffolds that contained different moieties, were designed to structurally resemble NGP1-01 and MK-801. Once synthesised, the compounds were purified and characterised, and were evaluated for their biological activities. Compounds were first screened for cytotoxicity at different concentrations. Thereafter, they were evaluated for neuroprotective effects against MPP+ -induced excitotoxicity and for calcium flux modulatory effects on NMDA receptor and voltage gated calcium channels. The norbornane derivatives were synthesised and characterised, and all final products were afforded in sufficient yields. All compounds with the exception of two compounds displayed good cytotoxic profiles towards the SH-SY5Y neuroblastoma cells at 10 µM, 50 µM and 100 µM concentrations as they demonstrated percentage cell viabilities close to 100% (control treated cells). Only two compounds showed percentage cell viability of 51% and 59% at 100 µM. Utilising the same cell line, all compounds, tested at 10 µM, attenuated MPP+ -induced toxicity after 24 hours of exposure to a neurotoxin. This was evident in the 23% to 53% enhancement (significant with p < 0.05) in cell viability when compared to the MPP+ only treated cells. In comparison to known NMDA receptor and/or voltage gated calcium channel blockers (MK-801, NGP1-01 or nimodipine), the synthesised compounds demonstrated mono or dual inhibition of calcium channels as they effectively attenuated calcium influx by blocking NMDA receptors and/or voltage gated calcium channels expressed in neuroblastoma SHSY5Y cells. This group of compounds were found to be more potent NMDA receptor inhibitors, probably due to similarities with MK-801 and memantine, than voltage gated calcium channel inhibitors. All compounds demonstrated moderate to good calcium inhibitory effects at NMDA receptors in the range of 23% to 70% while a selected few displayed very little or no activity at the voltage gated calcium channels. In conclusion, 27 compounds with norbornane scaffolds were successfully synthesised and evaluated for cytotoxicity and neuroprotection. The abilities of the synthesised compounds to protect neurons from the neurotoxin MPP+ and reduce calcium flux into neuronal cells were successfully demonstrated. These characteristics are essential in neuroprotection as they may prove significant in halting or slowing down the disease progression. The compounds showing a good cytotoxicity profile, neuroprotective effects and ability to reduce calcium overload, could potentially act as neuroprotective agents with good safety profiles or contribute as lead structures to the development and design of structurally related molecules that could clinically benefit people with neurodegenerative disorders.

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