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Topical immunotherapy for Pseudomonas keratitis : use of antilipopolyssacharide plasma

  • Authors: Rauch, Andrew Johan
  • Date: 1984 , 2013-03-13
  • Subjects: Pseudomonas infections , Immunotherapy
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3817 , http://hdl.handle.net/10962/d1004910 , Pseudomonas infections , Immunotherapy
  • Description: Pseudomonas aeruginosa is an opportunistic pathogen capable of infecting the human cornea. Such infections are difficult to treat, and are often fulminative, in that the infected eye is lost, or severely scarred. The use of alternative therapeutic agents has been necessitated by the frequent failure of conventional antibiotic therapy. Equine hyperimmune antilipopolysaccharide plasma (Anti-LPS) was obtained by the plasmapheresis of suitably immunized horses. The plasma contained 1,O- 1 ,5g/ml of LPS-precipitible IgG antibodies. Topical administration of Anti-LPS as a lavage was shown to be effective against Pseudomonas keratitis in rabbits and guinea pigs. Subsequent use of topical corticosteroids was found to further reduce corneal pathology. The improvement noted in these experimental infections involved all three parameters measured, area of keratitis, depth of lesion, and degree of vascularization. In vitro , Anti-LPS was shown to be rapidly bactericidal for Gram negative bacteria. The plasma can therefore be said to have a dual mechanism of action: antitoxic, and antibacterial. Ocular administration of Anti-LPS, by both the topical and subconjunctival routes, was well tolerated by both rabbits and baboons. In conclusion, Anti-LPS is a potentially useful immunotherapeutic agent with many applications in both veteriary and human medicine, particularly in the treatment of surface infections involving antibiotic-resistant Gram negative bacteria , KMBT_363 , Adobe Acrobat 9.53 Paper Capture Plug-in
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An investigation into the possible neuroprotective role of melatonin in copper-loading

  • Authors: Parmar, Paresh H
  • Date: 2001
  • Subjects: Melatonin , Copper , Nervous system -- Degeneration -- Treatment
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3783 , http://hdl.handle.net/10962/d1003261
  • Description: Copper is an extremely toxic metal in biological systems and thus, its availability to the system, must be effectively and efficiently controlled. Copper is vital for life, as it is essential for critical enzymes in biological systems. It is free copper in the biological systems that is toxic, as free copper induces free radical generation, which disrupts lipid membranes, interacts with DNA causing mutations, and eventually leads to cell death. Wilson’s disease is a inherited copper disease, which results in hepatolenticular disease. Copper is unable to be excreted, and thus accumulates, eventually spilling over into the bloodstream from the liver, and “poisons” the patient. The Wilson’s disease patient leads a short life, due to neurological and hepatological problems. There is no cure for Wilson’s disease, only chelation therapy using potent chelators such as penicillamine and EDTA. Zinc, in high doses, can be used to compete with copper absorption. This has proved to be the only successful therapy at present. This study investigates the possible use of melatonin as a copper binder/chelator. Melatonin has been shown to interact with copper in vitro. By binding/chelating to copper, melatonin may inhibit copper-induced free radical generation, and thus prevent copper from interacting with DNA to cause mutations and act as a cytotoxin. In vivo studies on copper (2mg/kg) administered for 2-weeks and 6-weeks were carried out on Wistar rats. The potential of melatonin (12mg/kg) to prevent copper-induced cellular damage was investigated. The results indicate that melatonin does not protect the lipid membranes from copper-induced lipid peroxidation. In vitro investigations using 1mM, 5mM and 10mM copper and 5mM melatonin, show that melatonin prevents copper-induced lipid peroxidation at a copper concentration of 1mM (p<0.001). The 5mM and 10mM copper induces less lipid peroxidation, compared to the 1mM copper. It has been reported that metal ions, antioxidants and chelating agents can influence peroxide decomposition during the assay. Melatonin (5mM) administration does not significantly prevent copper-induced lipid peroxidation at 5mM and 10mM copper. It is possible that due to melatonin’s relatively low concentration, it is unable to inhibit lipid peroxidation induced by the copper. The chemical nature of the interaction between melatonin and copper was also investigated, using NMR, IR and electrochemistry techniques. The NMR and IR techniques show that melatonin coordinates with Cu²⁺ and not Cu¹⁺, at the carbonyl group of melatonin. The electrochemistry experiments using cyclic voltammetry and adsorptive stripping voltammetry, show that melatonin forms a strong bond with Cu¹⁺. Cu²⁺ prefers binding to oxygen, and that is clearly seen in the NMR and IR. Cu¹⁺ prefers binding to nitrogen and then oxygen, and this is seen in the electrochemistry, as Cu¹⁺ is forced to bind through one of the nitrogens on the melatonin. Previously, it has been shown that melatonin binds/chelates with Cu²⁺. Histochemical investigations show that copper administration for 2-weeks and 6-weeks, causes extensive mitochondrial damage in liver and kidney’s proximal convoluted tubule epithelium cells. Melatonin (12mg/kg) co-administration with copper for 2-weeks and 6-weeks did not significantly protect the mitochondria from copper-induced damage. Copper-specific stains (rhodanine, silver sulphide and rubeanic acid) were used to stain liver, brain and kidney tissue samples. Rhodanine and silver sulphide were equally sensitive in staining copper in the 2-week samples, but not at all in the 6-week samples. This could not be explained. Rubeanic acid was ineffective in all samples tested. Thus, it appears that specific copper stains cannot be used in making a definitive diagnosis in cases of copper overload, and that specific copper stains do not always correlate with a high concentration of copper present in tissues. Pineal organ culture was used to determine the effect of copper administration on pineal indole synthesis. Exogenous (³H) tryptophan was administered to the pineal organ cultures, and the level of (³H) pineal indoles synthesised, were measured. Pineals from 2-week and 6-week copper/melatonin treated animals exhibited paradoxical 5- methoxytryptophol (ML) levels, as compared to the 2-week and 6-week copper treated animals. The 2-week copper/melatonin administered animals, showed a decrease in the ML level (p<0.01), and the copper/melatonin administered for 6-weeks, showed an increase in the ML levels (p<0.01). This indicates that melatonin interacts with the HIOMT enzyme. Pineals from 6-week copper/melatonin treated animals, as compared to the 6-week copper treated animals, showed an increase in N-acetylserotonin levels. This indicates that melatonin prevents the inhibition of the NAT enzyme. The final experiment was to determine in vitro, the effect of Cu²⁺ and Cu¹⁺ administration, on mitochondrial electron transport chain. Rat liver homogenate was incubated with and solutions of Cu²⁺ (10mM) and Cu¹⁺ (10mM) and melatonin (10mM). Cu²⁺ administration caused an inhibition of the electron transport at t=0 and t=60, whereas Cu¹⁺ administration at t=0 caused an inhibition of electron transport, but at t=60, Cu¹⁺ administration stimulated electron transport. Melatonin administered with Cu²⁺, resulted in an inhibition of the electron transport chain at t=0 and t=60. The findings of this study indicate that melatonin might have a potentially beneficial effect in copper overloading, by binding/chelating copper.
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Investigating the influence of ring substitution on indole hydrogen bonding, with amino acids

  • Authors: Nel, Donovan
  • Date: 2018
  • Language: English
  • Type: text , Thesis , Masters , MSc
  • Identifier: http://hdl.handle.net/10962/63509 , vital:28426
  • Description: Expected release date-April 2019
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An investigation into the neuroprotective properties of the non-steroidal anti-inflammatory agents tolmetin, sulindac and turmeric

  • Authors: Dairam, Amichand
  • Date: 2006
  • Subjects: Nonsteroidal anti-inflammatory agents , Antioxidants , Tolmetin -- Therapeutic use , Sulindac -- Therapeutic use , Turmeric -- Therapeutic use , Nervous system -- Degeneration -- Prevention , Alzheimer's disease
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3752 , http://hdl.handle.net/10962/d1003230
  • Description: Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.
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The South African community pharmacist and Type 2 Diabetes Mellitus a pharmaceutical care intervention

  • Authors: Hill, Peter William
  • Date: 2009
  • Subjects: Pharmacist and patient -- South Africa , Pharmaceutical services -- Patients , Pharmaceutical services -- South Africa , Pharmacists -- South Africa , Diabetes -- Treatment -- South Africa , Community health services -- South Africa
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3760 , http://hdl.handle.net/10962/d1003238 , Pharmacist and patient -- South Africa , Pharmaceutical services -- Patients , Pharmaceutical services -- South Africa , Pharmacists -- South Africa , Diabetes -- Treatment -- South Africa , Community health services -- South Africa
  • Description: Type 2 diabetes mellitus is a chronic disease of pandemic magnitude, increasingly contributing to the disease burden of countries in the developing world, largely because of the effects of unhealthy lifestyles fuelled by unbridled urbanisation. In certain settings, patients with diabetes are more likely to have a healthcare encounter with a pharmacist than with any other healthcare provider. The overall aim of the study was to investigate the potential of South African community pharmacists to positively influence patient adherence and metabolic control in Type 2 diabetes. The designated primary endpoint was glycated haemoglobin, with the intermediate health outcomes of blood lipids, serum creatinine, blood pressure and body mass index serving as secondary endpoints. Community pharmacists and their associated Type 2 diabetes patients were recruited from areas throughout South Africa using the communication media of various nonstatutory pharmacy organisations. Although 156 pharmacists initially indicated interest in participating in the study, only 28 pharmacists and 153 patients were enrolled prior to baseline data collection. Of these, 16 pharmacists and 57 patients participated in the study for the full twelve months. Baseline clinical and psychosocial data were collected, after which pharmacists and their patients were randomised, nine pharmacists and 34 patients to the intervention group and 8 pharmacists and 27 patients to the control group. The sample size calculation revealed that each group required the participation of a minimum of 35 patients. Control pharmacists were requested to offer standard pharmaceutical care, while the intervention pharmacists were provided with a scope of practice diabetes care plan to guide the diabetes care they were to provide. Data were again collected 12-months postbaseline. At baseline, proportionally more intervention patients (82.4%) than control patients (59.3%) were using only oral anti-diabetes agents (i.e. not in combination with insulin), while insulin usage, either alone or in combination with oral agents was conversely greater in the control group (40.7%) than in the intervention group (17.6%) (Chi-squared test, p=0.013). Approximately half of the patients (53.8% control and 47.1% intervention) reported having their HbA1c levels measured in terms of accepted guidelines. There was no significant difference in HbA1c between the groups at the end of the study (Independent t-test, p=0.514). In the control group, the mean HbA1c increased from 7.3±1.2% to 7.6±1.5%, while for the intervention patients the variable remained almost constant (8.2±2.0% at baseline and 8.2±1.8% at post-baseline). Similarly, there were no significant differences between the groups with regard to any of the designated secondary clinical endpoints. Adherence to medication and self-management recommendations was similarly good for both groups. There were no significant differences between the two groups for any of the other psychosocial variables measured. In conclusion, intervention pharmacists were not able to significantly influence glycaemic control or therapeutic adherence compared to the control pharmacists.
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Isolation and characterization of antiplasmodial metabolites from South African marine alga

  • Authors: Afolayan, Anthonia Folake
  • Date: 2008
  • Subjects: Malaria -- Africa , Antimalarials -- Therapeutic use , Malaria -- Prevention , Malaria -- Drug therapy , Marine algae -- Therapeutic use , Natural products -- Therapeutic use , Plasmodium
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3739 , http://hdl.handle.net/10962/d1003063
  • Description: Malaria is one of the three most deadly diseases in Africa. Although there are available treatments, their efficacy has been greatly reduced over the past two decades due to the development of resistance to currently available drugs. This has necessitated the search for new and effective antimalarial agents. This project approached the search for new antimalarial compounds in two ways: (i) by screening natural products isolated from marine algae against the Plasmodium parasite and (ii) by modification of selected isolated active compounds to target 1-deoxY-đ-xylulose 5-phosphate reductoisomerase (DXR), an enzyme found in the nonmevalonate isoprenoid biosynthetic pathway of Plasmodium Jalciparum. It was envisaged that such a compound would exhibit dual action on the Plasmodium parasite. Extracts obtained from 22 marine algae were prefractionated by solvent partitioning and were screened for anti plasmodial activity against the chloroquine sensitive (CQS) P. Jalciparum D 10 strain. Overall, 50% of the algae screened produced at least one crude fraction with activity against P. Jalciparum. Extracts of the algae Sargassum heterophyllum, Plocamium cornutum, Amphiroa ephedrea and Pterosiphonia cloiophylla gave the most promising results. Fractionation of S. heterophyllum afforded three tetraprenyltoluquinols (3.1, 3.2 and 3.5) and an all-trans-fucoxanthin (3.6). Three new compounds (4.5, 4.6 and 4.7) and two known halogenated monoterpenes (4.1 and 4.4) were isolated from P. cornutum. Each of the isolated compounds from both S. heterophyllum and P. cornutum showed antiplasmodial activity with IC₅₀ values ranging from 2.0 - 15.3 μM for S. heterophyllum and 13 - 230 μM for P. cornutum. Attempts to synthetically modify halogenated monoterpene 4.4 by dihydroxylation and phosphorylation in order to inhibit the DXR enzyme was unsuccessful. However, the hemiterpene analogue (5.42) of the halogenated monoterpenes was successfully phosphorylated and dihydroxylated to give compound 5.45 which showed promising activity against DXR. The result obtained indicated that the proposed phosphorylation and dihydroxylation of the halogenated monoterpene 4.4 would result in the synthesis of a potent DXR inhibitor and therefore a potential antimalarial agent with dual mode of action on the Plasmodium parasite.
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Design and evaluation of illustrated information leaflets as an educational tool for low-literate asthma patients

  • Authors: Wrench, Wendy Merle
  • Date: 2012 , 2012-10-08
  • Subjects: Asthma -- South Africa -- Study and teaching , Asthmatics -- South Africa -- Education
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3867 , http://hdl.handle.net/10962/d1016236
  • Description: Asthma is a chronic non-communicable disease associated with an increase in morbidity, mortality and economic burden. Globally 300 million people have asthma and it is estimated that one in every 250 deaths worldwide are due to asthma. South Africa has the highest asthma prevalence (8.1%) in Africa and the disease is 18th in the top 20 causes of death. Inadequate home management, poor availability of health care, and poor transport and emergency services are recognised as important contributing factors. Patients with a low level of education and limited literacy skills may be unable to understand instructions on frequency and use of asthma medicines, which could result in unintentional non-adherence leading to serious complications and increased health care costs. The aim of this study was to investigate the impact of a tailored educational intervention on low-literate patients with asthma. Objectives to achieve this aim included designing patient information leaflets (PILs) containing information on asthma, management of asthma and asthma therapy, and using the PILs to educate low-literate asthma patients. A before-andafter intervention type design evaluated self-reported selected health-related quality of life measures, self-reported self-efficacy, knowledge of asthma and asthma management, knowledge of the use of metered dose inhalers (MDIs) and MDI technique. The acceptability and understanding of the tailored PILs was also investigated. Two simple, readable PILs containing pictograms were developed in English and then translated into isiXhosa, the home language of the majority of the target population. Various guidelines on the design of health-related information for people with low-literacy were consulted and input on the design was received from health care providers, patients and graphic artists. A pilot study was conducted at a local primary health care (PHC) clinic to evaluate the PILs and final modifications to the PILs were made based on feedback received. For the main study, patients were recruited from the KwaNonqubela PHC clinic in Alexandria in the Eastern Cape, South Africa. Patients were 18 years or older, dependent on public sector health care facilities, diagnosed with asthma, prescribed a MDI (beclomethasone and/or salbutamol) for at least one month and English or isiXhosa-speaking. The exclusion criterion for patients in this study was involvement in any other asthma educational intervention during the period of study. Interviewer-led structured questionnaires were administered to 55 patients at the baseline and follow-up. Data collected include demographics, brief medical history and current asthma medications. Self-efficacy and iii health-related quality of life were assessed. Knowledge of asthma and asthma management was evaluated, and the use of beclomethasone and/or salbutamol metered dose inhalers was assessed. The PIL ‘Understanding asthma and trigger factors of asthma’ formed part of the educational intervention to explain asthma and aspects related to its management. Inhaler technique was evaluated and corrected using the PIL ‘How to use your pump’ together with a demonstration of correct technique by the investigator. Follow-up interviews were conducted approximately four weeks after baseline. PIL acceptability, readability and understanding of each pictogram were investigated at follow-up only. The educational intervention resulted in a significant increase in mean knowledge of asthma from 52.7% at baseline to 75.5% at follow-up. Gender was not associated with knowledge, but there was a significant age effect at baseline only, with the younger patients achieving better knowledge results. In both phases, patients with higher education had improved scores. A significant increase (2.4% to 38.6%) in the number of patients taking the minimum recommended adult dose of beclomethasone was noted but it is a matter of concern that the majority of patients were taking less than this. Patient self-reports suggested a significant increase in adherence, with the number of patients taking beclomethasone daily increasing from 33.3% to 61.3%. Self-reported management and control of asthma improved and this was reflected by the enhanced HRQOL results. MDI technique also improved significantly with an increase in the mean number of correct steps from 4.6 ± 2.2 to 7.9 ± 2.7. Education had a significant effect on MDI technique with more errors associated with lower educational status. There were no significant age or gender effects on the total number of correct steps in either phase. The illustrated PILs were received favourably with the majority of literate patients reporting that they were easy to read. Patients commented positively on the inclusion of pictograms and stated that the pictograms had served as aids in the understanding of asthma, trigger factors of asthma and correct MDI technique. The results of this study show that specially designed illustrated PILs can be an effective tool in educating low-literate patients with asthma. , Adobe Acrobat Pro 11.0.0 Paper Capture Plug-in
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The design, synthesis and antiplasmodial activity of a series of halogenated fosmidomycin analogues and hybrid drugs

  • Authors: Afolayan, Anthonia Folake
  • Date: 2012
  • Subjects: Uncatalogued
  • Language: English
  • Type: text , Thesis , Doctoral , PhD
  • Identifier: http://hdl.handle.net/10962/64370 , vital:28538
  • Description: Malaria continues to be a devastating disease and a major cause of death in sub-Saharan Africa. With resistance against most of the available antimalarial drugs, there is a need for ongoing research and development of antimalarial agents. Fosmidomycin and its acetyl analogue FR900098 have been identified as potent inhibitors of Plasmodium falciparum, the causative agent of the most deadly form of malaria. Clinical trials of these agents have revealed poor absorption due to their high hydrophilicity. In the present studies the effect of halogenation of the acyl chain as well as the biological effect of extending the acyl sidechain was explored. This provided the basis on which fosmidomycin hybrids were designed to investigate the feasibility of hybrid extending into NADPH binding pocket. Synthesis of a series of halogenated FR900098 analogues was carried out in three stages. This included i) The introduction of the phosphonate group by reaction with 1,3dibromopropane in an Arbuzov reaction, ii) The introduction of a hydroxamate group by reaction of the propyl phosphonate by means of a nucleophilic substitution reaction with BocNHOBn and iii) The introduction of a halogenated acyl side chain on a protected fosmidomycin backbone. The synthesis of fosmidomycin-hybrids for which chloroquinefosmidomycin hybrids were used as the prototype, involved convergence of the two separately constructed moieties i.e. fosmidomycin and the quinoline moieties in a covalent linkage. The quinoline moiety was easily synthesized from the reaction of 4,7dichloroquinoline with 1,2-diamino ethane. The aminoquinoline so formed resulted in chloroquine-fosmidomycin hybrids 3.8 and 3.9 when reacted with halogenated FR900098 analogues. Antiplasmodial assays were conducted on the chloroquine-fosmidomycin hybrids and the halogenated fosmidomycin derivatives against the chloroquine resistant Gambian FCR-3 strain of P. falciparum. The most potent iodoacetyl fosmidomycin analogues 2.21 gave an IC50 value of 5.54 µM which is eight times more potent than the known antiplasmodial FR900098 which gave an IC50 value of 41.67 µM. All the halogenated FR900098 analogues showed better antiplasmodial activity than their non-halogenated derivatives. This indicated that the presence of halogens in the FR900098 analogues contributes to their biological Chapter 1 Literature review activity. The acetyl and propyl linked hybrids 3.8 and 3.9 showed potent antiplasmodial activity with IC50 values of 0.18 and 0.82 µM respectively. These were by far the most potent hybrids synthesized and provided leads for a new class of promising antimalarial agents. Preliminary E. coli DXR enzyme inhibition assays were carried out on the halogenated fosmidomycin analogues. The results showed good inhibition of the enzyme by the phosphonic acids of the chloroacetyl and chloropropyl analogues 2.1 and 2.2 respectively. Molecular modelling of the compounds on E. coli (PDB code: 2EGH) and P. falciparum (PDB code: 3AUA) DXR showed strong binding of the halogenated fosmidomycin analogues while the hybrids in the absence of docked NADPH showed minimum binding to the enzymes.
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Development and assessment of medicines information for antiretroviral therapy in Sub-Saharan Africa

Development and assessment of a smart thermosetting intranasal hydrogel for lamotrigine

  • Authors: Melamane, Siyabonga
  • Date: 2018
  • Language: English
  • Type: text , Thesis , Masters , MSc
  • Identifier: http://hdl.handle.net/10962/62975 , vital:28349
  • Description: Expected release date-April 2020
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A study of the rabbit eye test system to determine the activity of acidic non-steroidal anti-inflammatory agents

  • Authors: Wiseman, Ian Charles
  • Date: 1977
  • Subjects: Nonsteroidal anti-inflammatory agents , Anti-inflammatory agents
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3855 , http://hdl.handle.net/10962/d1013276
  • Description: From introduction : "Inflammation per se, has been defined sufficiently to permit a rational approach to the search for drugs that modify this process, but satisfactory animal models for most rheumatoid diseases are not available". (Swingle 1974) In the search for new meaningful procedures for the detection and evaluation of anti-inflammatory drugs, the rabbit eye as a test system was studied.
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Interactions between steroidal anti-inflammatory agents and collagen

  • Authors: Kanfer, Isadore
  • Date: 1975
  • Subjects: Anti-inflammatory agents , Collagen
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3849 , http://hdl.handle.net/10962/d1012620
  • Description: Much research has been done on the formation of fibrils from solutions of soluble collagen in vitro in order to gain some knowledge of the mechanisms which may occur in vivo. The in vitro formation of fibres from solutions of collagen has been shown to be extremely sensitive to the nature of the solution environment and the presence of added chemical compounds, and thus constitutes an interesting system for the study of collagen-small molecule inter actions. The present study is concerned with the effects of various corticosteroid drugs, used medicinally as anti-inflammatory agents, on collagen in solution. As these corticosteroids are administered to reduce inflammation in conditions such as rheumatoid arthritis and a host of other pathological conditions in which collagen is implicated, this work has been undertaken in order to establish and charac teri ze any binding mechanisms which may be involved. Furthermore, the corticosteroid drugs available commercially in pure form as the free base or as the water-soluble ester salts offer an interesting range of structural and stereochemical variants for the study of their reaction with a complex and biologically important protein molecule such as collagen. A great deal of research on drug- protein interactions (Goldstein, 1949; Meyer and Guttman, 1968a) and more specifically, steroid-protein interactions have been reported over the years (Daughaday, 1959; Sandberg et al., 1966; Villee and Engel, 1961; Westphal , 1971). Comprehensive reports, however, on steroid-collagen interactions in vitro are conspicuously absent from modern scientific literature although relatively superficial accounts have been published (Menczel and Maibach, 1972; Eik-Nes et al., 1954). Although work involving the above has appeared relating specifically to the effects of steroids on collagen biosynthesis both in vivo and in vitro there have been minimal accounts of steroid-collagen interactions tailored to characterize the binding at the molecular level. The effect of corticosteroids on the metabolism of connective tissue has also received special attention (Asboe-Hansen, 1959; Kivirikko, 1953; Nakagawa and Tsurufuji, 1972). Recently, Uitto et al. (1972) reported the effects of several anti-inflammatory corticosteroids on collagen biosynthesis in vitro, whilst Aalto and Kulonen (1972) reported the effects of several antirheumatic drugs on the synthesis of collagen and other proteins in vitro. The interactions between collagen and certain drugs has also been briefly reviewed (Chvapil, 1967). Much data also exists on the binding of a wide range of small molecules and ions with serum albumin (Steinhardt and Reynolds, 1969; Scatchard, 1949; Klotz, 1950). Serum albumin, being specialized for a very general transport function and apparently designed for the purpose of combining with a large range of small molecules, has a proportion of possible reactive sites 'buried' within the molecule itself because of its folded conformation. In addition, serum albumin shows a high degree of cooperative binding in contrast to collagen. The latter molecule, with its larger molecular size and weight is specialized for a biologically structural function and has a higher proportion of possible reactive sites which appear relatively more accessible to ligands. A study of the interactions between corticosteroids and collagen thus provides the opportunity to investigate a protein which is very different from the much studied serum albumin. Because of the limited information available regarding the interaction of steroid drugs and collagen at the molecular level, studies of this nature are relevant to the understanding of the mode of action of steroid compounds which are such an important group of therapeutic substances used in modern medicine.
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The applicability of anaerobically digested pasteurized pit latrine faecal sludge as a fertilizer to grow Radish and Garden cress

  • Authors: Madikizela, Phindile
  • Date: 2017
  • Language: English
  • Type: text , Thesis , Masters , MSc
  • Identifier: http://hdl.handle.net/10962/59235 , vital:27487
  • Description: Expected release date-April 2019
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A critical evaluation of the human skin blanching assay and comparative bioavailability studies on topical corticosteroid preparations

  • Authors: Meyer, Eric
  • Date: 1989
  • Subjects: Dermatopharmacology , Skin, Effect of drugs on , Adrenocortical hormones
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:3727 , http://hdl.handle.net/10962/d1001464
  • Description: Several aspects of the human skin blanching assay were evaluated in an attempt to suggest improvements in the methodology of this assay. Three trials were performed in the unoccluded application mode, using two proprietary creams containing 0,1% betamethasone (as the 17-valerate). Preliminary observations of the influence of ambient temperature and relative humidity on the blanching response did not allow definite conclusions to be drawn. Studies on the number of observers required for reliable results of comparative blanching indicated that at least two trained observers should be employed. Analyses of the results of individual volunteers demonstrated the expected biological variability, and suggest that subjects selected for trials should represent a range of blanching responses. No sex-related differences in blanching responses were found, and both arms exhibited similar sensitivity to corticosteroids. Retrospective analysis of 95 040 observations of blanching responses showed that in the unoccluded application mode blanching is lowest close to the wrist, and in the occluded mode blanching is lowest close to the elbow. Studies on the method of transportation of Betnovate preparations suggest that topical formulations should not be exposed to temperature extremes during transportation. It is proposed that patients should not transport topical formulations in the holds of ships or aircraft, and that exporters and manufacturers should make use of special transportation and storage conditions. In a study of ten topical formulations from three countries it was found that there was no trend of products from one country consistently exhibiting superior blanching to products from the other two countries, or products from one country consistently exhibiting the lowest degree of blanching, although considerable differences in blanching responses were found in some cases. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses, blanching profiles and AUC values when drawing conclusions regarding comparative bioavailability. A study of the blanching profiles of Betnovate cream included in all 16 trials performed during this work indicated that this preparation behaved in a similar fashion during all trials, thereby giving credence to the results of the trials
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The isolation, characterisation and chemotaxonomic significance of secondary metabolites from selected South African Laurencia spp. Rhodophyta

  • Authors: Fakee, Jameel
  • Date: 2015
  • Language: English
  • Type: text , Thesis , Doctoral , PhD
  • Identifier: http://hdl.handle.net/10962/64696 , vital:28593
  • Description: Bioprospection of marine organisms as a potential source for lead drugs is becoming increasingly popular. The secondary metabolome of these organisms consists of structurally diverse molecules possessing unprecedented carbon skeletons, the biosynthesis of which occurs via complex metabolomic pathways driven by specialist enzymes. This structural novelty is highly influential on the favourable bioactivity these compounds display. A prominent example of such a compound is trabectedin marketed as Yondelis®. Registered for the treatment of soft tissue sarcomas, this marine drug was developed from extracts of the tunicate Ecteinascidia turbinata. South Africa is renowned for possessing a highly diverse marine biota including several endemic species of marine red algae belonging to the Laurencia sensu stricto genus, which falls within the Laurencia complex. Despite having a good reputation for fascinating secondary metabolites, the taxonomy of Laurencia natural products is proving challenging for reasons including the presence of cryptic species, as well as individual species displaying morphological variability. The aim of this study was thus to isolate secondary metabolites from various South African Laurencia spp. and subsequently assess their chemotaxonomic significance by analysis of a parallel plastid rbcL phylogeny study of Laurencia spp. This study reports the first phycochemical investigation into Laurencia natalensis Kylin, Laurencia cf. corymbosa J.Agardh, Laurencia complanata (Suhr) Kützing, Laurencia sodwaniensis Francis, Bolton, Mattio and Anderson submitted, Laurencia multiclavata Francis, Bolton, Mattio and Anderson submitted, and a South African specimen of Laurenciella marilzae Gil-Rodríguez, Sentíes, Díaz-Larrea, Cassano and M.T. Fujii (basionym: Laurencia marilzae) originally described from Spain. Additionally, the chemical profiles of previously explored species Laurencia flexuosa Kützing and Laurencia glomerata Kützing were re-investigated. The organic extracts of the above species afforded 31 compounds belonging to a wide array of structural classes including halo-chamigranes, linear C15 acetogenins, indole alkaloids, cuparanes and cyclic bromo-ethers. A new tri-cyclic keto-cuparane (4.4) was isolated from L.cf. corymbosa alongside the new cuparanes 4.1 and 4.7. Algoane (5.9), a unique marker compound isolated from L. natalensis, was previously only reported from a sea-hare. Such marker compounds which are exclusive to an individual algal species increase the ease of their subsequent identification. The feasibility of chemotaxonomy as an additional tool to classify Laurencia spp. Was established as broad predictions of a specimen’s phylogeny, based on representatives of its secondary metabolome, proved viable. The study specimens were shown to possess similar chemical profiles to their sister species e.g. L. complanata, L. sodwaniensis and L. multiclavata produced similar metabolites to their sister species as inferred by an rbcL phylogeny tree. Finally, a 1H NMR profiling study on the crude organic extracts of various Laurencia spp. generated distinctive, reproducible spectra, exposing the value of NMR spectroscopy as a rudimentary species discernment tool.
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Development and assessment of gastroretentive sustained release captopril micro-balloons

  • Authors: Oridota, Omoyosola Omolola
  • Date: 2018
  • Language: English
  • Type: text , Thesis , Masters , MSc
  • Identifier: http://hdl.handle.net/10962/63491 , vital:28419
  • Description: Expected release date-April 2020
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An assessment of African traditional medicines in pregnancy and on birth outcomes: pharmacists' perceptions of complementary medicines in pregnancy

  • Authors: Mupfumira, Rudo
  • Date: 2012
  • Subjects: Traditional medicine -- South Africa , Pharmacists -- Attitudes -- South Africa , Medical ethics -- South Africa , Medical anthropology -- South Africa , Alternative medicine -- South Africa , Prenatal care -- South Africa , Pregnancy -- South Africa , Abnormalities, Human -- South Africa
  • Language: English
  • Type: Thesis , Masters , MPharm
  • Identifier: vital:3778 , http://hdl.handle.net/10962/d1003256
  • Description: Increasing numbers of medicines are being used by pregnant South African women in the public sector during pregnancy, for the treatment of different biomedical and supernatural disease states and conditions. The motivation for the research is to support the development of more local pregnancy registries in order to strengthen evidence for the safety and efficacy of medicines used in pregnancy. A mixed methods approach was used. Women in their ninth month of pregnancy in a public sector setting, and four community pharmacists were identified. The women who met the inclusion criteria were recruited. One in-depth semi-structured interview was conducted with each woman before giving birth and data on their pregnancy outcomes were collected after labour. Coincidentally, the mother of one of the participants was found to be a traditional healer. She was also interviewed on the topic. A structured questionnaire was administered to the pharmacists. Ten pregnant women between the ages of 19 to 39 who had used or were using a traditional medicine during the pregnancy were recruited. All the participants had had at least one antenatal check up during their pregnancy with one having attended five times. No abnormal results were reported from any of the check ups or tests done during the visits. All of them had been to school and had at least Standard 8/Grade 10 education. Ten babies were seen between one and four days postpartum and no birth defects were obvious or were reported for any of them. The traditional healer did not provide additional information to what the women had said and confirmed that some of the practices the women reported were known to her as traditional medicine practices. All four pharmacists indicated that they considered complementary and alternative medicines (CAMs) to be “somewhat effective” and sold them at their pharmacies although none of them were aware of whether or not they were registered with the MCC. None of the pharmacists appeared to have an in-depth knowledge of traditional, complementary and alternative medicines (TCAMs). All four pharmacists said that it is important to have a basic understanding of TCAMs before using them, although they did not agree on the reasons for this. All of them felt that pharmacists have a professional responsibility to provide information on TCAMs (especially herbal preparations) and two felt that providing this information is part of a medical doctors’ responsibility. No harm from taking TCAMs could be shown. However herbal medicines have numerous ingredients some of which are unknown and taking these medicines is risky. The pharmacists in this sample were unsure whether they were accessing unreliable CAM information. Reliable sources of information and reference materials on CAMs to assist pharmacists and other healthcare professionals are needed. The apparent widespread use of TCAM in pregnancy indicates a need for documentation about its efficacy and safety. The establishing of TCAM pregnancy registries should seriously be considered. Due to the increase in CAM use, CAM education during pharmacists’ training as well as continuing professional development (CPD) in CAM for pharmacists in practice should be encouraged.
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Pharmaceutical analysis and aspects of the quality control of St. John's Wort products

  • Authors: Wild, Tracy Joy
  • Date: 2003
  • Subjects: Hypericum perforatum , Hypericum perforatum -- Analysis , Hypericum perforatum -- Therapeutic use , Hypericum perforatum -- Physiological effect , Flavonoids -- Analysis
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3804 , http://hdl.handle.net/10962/d1003282 , Hypericum perforatum , Hypericum perforatum -- Analysis , Hypericum perforatum -- Therapeutic use , Hypericum perforatum -- Physiological effect , Flavonoids -- Analysis
  • Description: Most complementary medicines contain a multitude of chemical components, some of which are claimed to contribute to the biological activity of such products. Use of complementary medicines for preventative and therapeutic purposes is increasing rapidly worldwide. Unfortunately, although control of these products is essential to ensure quality, safety, and efficacy, the quality control of most herbal preparations is currently poor to non-existent, with little or no safety and efficacy data required to support the marketing and use of these products. The objective of this study was therefore to develop suitable analytical methods to qualitatively and quantitatively analyse the relevant components (rutin, isoquercitrin, hyperoside, quercitrin, quercetin, kaempferol, hypericin, pseudohypericin and hyperforin) in St John's Wort dosage forms for quality control purposes. A gradient HPLC method using a Luna 5·mC₁₈(2) 150 x 2.00mm internal diameter (i.d.) column and UV detection, was developed for the separation of six of the relevant flavonoid compounds in St John's Wort, namely rutin, isoquercitrin, hyperoside, quercitrin, quercetin and kaempferol. The development process involved a systematic investigation of gradient conditions, flow rate, and temperature. This method was subsequently applied to assay selected commercially available St John's Wort products. This system provided the necessary accuracy, precision and reproducibility and was associated with several advantages when compared to using standard bore (4.60 mm i.d.) HPLC columns. The method developed is currently the only known method that separates all six relevant flavonoids in a reasonable run time (less than 20 minutes). It is also one of the few methods that has sufficient separation between rutin, isoquercitrin and hyperoside. A qualitative method for the fingerprinting of flavonoid components was also developed, using capillary electrophoresis (CE). CE is a rapidly growing powerful analytical technique for the separation of charged compounds. Micellar electrokinetic chromatography (MEKC) is a very powerful electrophoretic technique that is capable of selectively resolving both neutral and ionic solutes in a single run. A MEKC method suitable for the separation and determination of various flavonoid constituents used as marker compounds in Hypericum perforatum was developed. Investigations into the effect of pH, ionic strength, applied voltage and capillary dimensions on separation were performed. The optimised method was then applied to qualitatively analyse various St John's Wort products on the market. This method was found to be advantageous in that it was simple, cost-effective, required minimal sample preparation and utilised very small quantities of sample. Due to the vast differences in chemical properties between the various marker and active components in St John's Wort, it was necessary to develop separate analytical methods for the flavonoids and for the other three relevant compounds (hypericin, pseudohypericin and hyperforin). An isocratic HPLC method using a Luna 5·mC₁₈(2) 150 x 2.00mm (i.d.) column and UV detection was developed for the separation of hypericin, pseudohypericin and hyperforin. The development process involved a systematic investigation of buffer molarity, mobile phase composition, pH, flow rate, and temperature. This method was subsequently applied to assay selected commercially available St John's Wort products on the South African market. This system also provided the necessary accuracy, precision and reproducibility, as well as the advantages associated with the use of a narrow bore column as opposed to the use of the more commonly used wider bore columns. This method was validated and used to quantitate these three compounds in various commercial St John's Wort products. By applying this method to liquid chromatography – tandem mass spectrometry (LC-MS-MS), qualitative analyses of the same products was performed to obtain confirmation of the quantitative HPLC results. Mass spectrometry is a powerful detection tool that is more selective and specific than many detection systems used with HPLC. Natural medicines usually constitute a multitude of constituents with much potential interference. In this regard LC-MS-MS is a powerful tool, with its ability to unequivocally identify target analytes regardless of the presence of interferences or complex matrices. ESI-MS-MS was used for the qualitative analysis of the content of the naphthodianthrones and hyperforin in the respective tablet products assayed with HPLC. LC-MS-MS analyses were performed in order to identify the constituents and to verify the specificity of the HPLC method. High inter-product and inter-batch variability was observed for all nine compounds assayed. These quantitative results were confirmed with the respective qualitative analyses. This study confirms the need for strict quality control of herbal medicinal products commercially available to consumers.
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An investigation into the neuroprotective properties of acyclovir

  • Authors: Müller, Adrienne Carmel
  • Date: 2006
  • Subjects: Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3776 , http://hdl.handle.net/10962/d1003254 , Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
  • Description: Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
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A comparative photostability study of four propyl piperzine-substituted phenothiazines

  • Authors: Drummond, Patricia Mary
  • Date: 1997
  • Subjects: Phenothiazine
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:3756 , http://hdl.handle.net/10962/d1003234 , Phenothiazine
  • Description: Four structurally related phenothiazines available in South Africa in a variety of dosage forms and as fine chemicals were investigated to ascertain whether their structural differences in terms of the 2-chloro-/ trifluoromethyl-substituents on the phenothiazine nucleus and the methyl-/ ß-hydroxethyl groups on the piperazine ring accouning for the differences in pharmacological activity can be correlated with their photostability².The four propyl piperazine-substituted derivatives are ranked in the following decreasing order of neuroleptic activity: fluphenazine> trifluoperazine> perphenazine > rochlorperazine. In order to assess their photostability an HPLC method was developed and validated for linearity, accuracy and precision, selectivity, limit of detection and quantitation and ruggedness. Preliminary solution photostudies under controlled light conditions (UV, sunlight, fluorescent light) indicated that the rate of degradation followed first-order kinetics with perphenazine the most susceptible to.photodegradation under all light conditions studied. In vitro and in vivo metabolism yielding the 5-sulphoxide and its reported presence on decomposition of the phenothiazines25 led to the development of a synthetic procedure suitable for the sutphoxides of all four derivatives based on the method proposed by Owens et al. in order to provide standards for comparison in the photostudies⁷. Since ICH regulations require that impurities> 0.1 % are examined and identified⁷⁴ and semi-preparative isolation of photoproducts proved unsuccessful, LC-MS having been well documented for structural.elucidation⁷⁵ ⁷⁵ ⁷⁶ ⁷⁷ was used to characterize solution (UV, sunlight, fluorescent light) and preliminary solid (UV) photostudies. The chloroderivatives underwent dechlorination and sulphoxidation with subsequent photosubstitution in the case of prochlorperazine to yield the 2-hydroxy derivative and sulphoxidation of the dechloro-derivative of perphenazine. The sulphoxides of both trifluoperazine and fluphenazine were formed with further oxidation to the respective sulphones occurring. Preliminary solid state (UV) photostudies showed fluphenazine to be the least stable with 30.71 % degradation as opposed to 7.57% for prochlorperazine, 4.28% for perphenazine and 7.10% for trifluoperazine witn sulphoxidation observed to be. the major degradation pathway. Since in vitro metabolism of perazine derivatives is reported to occur via N-oxidation, N-demethylation, sulphoxidation and aromatic hydroxylation¹⁸ it does appear that there is some correlation between metabolic and photoproducts. However the fact that solution (UV) photostudies indicates trifluoperazine to be the most and perphenazine the least stable does not concur with the proposed order of pharmacological activity.
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