Medicine use in swallowing-impaired patients: Pharmacists’ knowledge, practice and information needs
- Authors: Masilamoney, Mehrusha
- Date: 2018
- Subjects: Deglutition disorders , Drugs -- Administration , Oral medication -- Administration , Pharmacists -- Practice , South African Pharmacy Council
- Language: English
- Type: text , Thesis , Masters , MPharm
- Identifier: http://hdl.handle.net/10962/61940 , vital:28086
- Description: Dysphagia, or swallowing impairment, is a growing problem that affects 13.5% of the general population. The ability to swallow is essential for patients taking oral medicines, so this presents a challenge for swallowing-impaired (SI) patients as tablets and capsules will usually require modification prior to ingestion. Pharmacists should play a central role in advising SI patients about their medicine use, as well as problems that may impact on safety, adherence and therapeutic outcome. However, little is known about pharmacists’ level of knowledge, their practice and their information needs when dealing with SI patients and their use of medicines. The aim of this study was to investigate pharmacist knowledge, practice and information needs relating to the support of SI patients and their medicine-related needs. The study design included both quantitative and qualitative methods. A quantitative questionnaire was developed to collect data on the knowledge, practice and information needs of pharmacists and was piloted in 10 pharmacists, which resulted in minor modifications. The questionnaire was converted to a web-based survey and emailed to all pharmacists registered with the South African Pharmacy Council. Two knowledge scores were generated by summating correct responses: knowledge of dysphagia (KOD) and knowledge of medicine use (KOMU) in SI patients. Correlation analysis was used to investigate the strength of the relationship between specific variables with KOD and KOMU using the Pearson correlation coefficient. Qualitative semi-structured interviews were conducted with pharmacists from community, hospital and primary healthcare clinics in both a small town and a major metropole. The aim was to gain deeper understanding of issues arising from the survey, and to explore preferences for topic-specific information materials. All interviews were audio-recorded and transcribed verbatim. Thematic analysis was used to analyse the data. A total of 439 pharmacists responded to the survey, with 67% being females.The mean KOD score out of a maximum score of 10 was 6.1 ± 1.8. KOD was inadequate (<5) in just over one-third (37.8%) of pharmacists. The mean KOMU score achieved (maximum score 17) was 9.4 ± 2.0, with inadequate knowledge (<10) being established in just over two-thirds of pharmacists (70.8%). Age, length of registration as a pharmacist, and years of practice in a setting with direct patient interaction were significantly but weakly correlated with KOMU, whereas KOD showed no significant association with these variables. Qualification significantly influenced both KOD and KOMU; the highest group with adequate knowledge had either a Masters or a PharmD degree. Fewer than half the pharmacists (44%) never ask patients about their swallowing ability, and most (86%) reported no knowledge of locally available viscosity enhancers. Almost all pharmacists were interested in receiving information materials on assisting SI patients with their medicine use. Three major themes emerged from the semi-structured interviews. Pharmacists recognised their knowledge deficit and felt that lack of both undergraduate training and formal training during practice, as well as limited exposure to SI patients, were contributing factors. Barriers to their practice with SI patients included lack of time, lack of institutional support and lack of easily accessible references on the pharmacists’ role in supporting medicine use in SI patients. Lastly, most pharmacists were not prepared to take ownership of medicine-related problems in SI patients and had conflicting opinions of the pharmacists’ role, usually shifting the responsibility of medicine use in SI patients to nurses. This is the first study to investigate pharmacist knowledge of medicine use in SI patients. The findings indicate that pharmacists do not have the requisite knowledge when dealing with SI patients and their medicine-taking issues despite being the most highly trained healthcare professionals in this field. Lack of undergraduate training, in-house training and limited exposure to SI patients were reported to contribute to poor knowledge. Current practice revealed that there appears to be poor communication among different healthcare professionals, pharmacists were reluctant to work with and/or train nurses on appropriate medicine use in SI patients, and there appeared to be ambiguity surrounding the role of a pharmacist. This research identified that pharmacists regard this topic to be highly relevant to their everyday practice and are keen to receive more information and training relating to this area of study. Information materials were designed and will be made accessible to all pharmacists registered in South Africa.
- Full Text:
- Date Issued: 2018
An investigation of the neuroprotective effects of estrogen in a model of quinolinic acid-induced neurodegeneration
- Authors: Heron, Paula Michelle
- Date: 2002
- Subjects: Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3759 , http://hdl.handle.net/10962/d1003237 , Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Description: The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
- Full Text:
- Date Issued: 2002
The natural product chemistry of South African Plocamium species
- Authors: Knott, Michael George
- Date: 2003
- Subjects: Marine algae -- South Africa Red algae -- South Africa Green algae -- South Africa Halimeda -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3820 , http://hdl.handle.net/10962/d1004920
- Description: The brine shrimp lethality assay was used as a preliminary tool to screen eighteen seaweeds collected from the South African coast. Of the seaweeds tested, the red algae Plocamium corallorhiza and Hypnea rosea, and the green alga Halimeda sp., showed the most potent activity. The chemical investigation of P. corallorhiza resulted in the isolation and structural elucidation of five previously undescribed secondary metabolites, along with three known compounds and four possible artifacts of the extraction process. Standard spectroscopic methods and comparison with known compounds were used to determine the structures of the new metabolites. The new compounds included the linear halogenated monoterpenes 4,8-dibromo-1, 1-dichloro-3,7-dimethyl-2,6-octadiene (99), 4,6-dibromo-l, 1-dichloro-3,7-dimethyl-2,7-octadiene (100), 4,8-dibromo-l, 1,7-trichloro-3,7-dimethyl-2,5-octadiene (101) and 3,4,6,7-tetrachloro-3,7-dimethyl-l-octene (102) and the cyclic monoterpene 5-bromo-5-bromomethyl-I-chlorovinyl-2,4-dichloro-methylcyclohexane (103) while the known compounds were identified as 4-bromo-5-bromomethyl-1chlorovinyl-2,5-dichloro-methylcyclohexane (35), 1,4,8-tribromo-3, 7 -dichloro-3,7-dimethyl-1,5-octadiene (94) and 8-bromo-1,3,4,7-tetrachloro-3,7-dimethyl-1,5-octadiene (96). The four methoxylated compounds (104-107) were presumably formed via a standard substitution reaction between the halogenated monoterpenes 96 and 101 and MeOH, which was used as a component in the extraction solvent. With over 100 000 natural products having been reported, it has become necessary to employ an efficient dereplication strategy to quickly identify known compounds. A simple Gas Chromatography-Mass Spectrometry (GC-MS) method for the efficient physicochemical screening, identification and dereplication of Plocamium metabolites was developed. In this study the crude extracts of P. corallorhiza, P. cornutum and P. maxillosum were screened by GC-MS and the retention times and mass spectral fragmentation patterns of compounds 94, 96, 99 - 107 were used to quickly identify known and new compounds in the crude extracts of P. cornutum and P. maxillosum. This data indicated that compounds 99, 100, 103 were present in both P. corallorhiza and P.cornutum, while compound 102 was found to be present in P. corallorhiza, P. cornutum and P. maxillosum. These studies also indicated that ecotypes and chemotypes are not a significant feature of P. corallorhiza and P. cornutum. Different species of Plocamium (namely: P. corallorhiza, P. cornutum, and P. maxillosum) have very different chemical profiles, and GC may therefore have appreciable taxonomic application in the identification of the different Plocamium spp. which are endemic to South Africa.
- Full Text:
- Date Issued: 2003
Design, development and evaluation of encapsulated oral controlled release theophylline mini-tablets
- Authors: Munday, Dale Leslie
- Date: 1991
- Subjects: Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3777 , http://hdl.handle.net/10962/d1003255 , Drugs -- Administration , Drugs -- Bioavailability , Drugs -- Controlled release , Drugs -- Dosage forms , Tablets (Medicine) , Biopharmaceutics , Drugs -- Testing
- Description: Conventional solid dosage forms often lead to fluctuations which exceed the maximum safe therapeutic level and/or decline below the minimum effective level. It is recognised that many drugs for chronic administration should be administered on a schedule that maintains plasma drug concentration within the therapeutic window. Research in controlled release dosage forms aims at designing a system with a zero-order input (eg, ideally to deliver 8.33% of the dose per hour over a 12 hour duration), producing steady state plasma drug levels. Oral dministration of drugs prepared as a controlled release formulation is extremely popular, and has attracted the attention of pharmaceutical scientists during the last decade. This has been due to the simultaneous convergence of various factors (eg, discovery of novel polymers and devices, better understanding of formulation and physiological constraints, expiration of existing patents, prohibitive cost of developing new drug entities), involved in the development of these delivery systems. Controlled release oral products can be formulated as single or multiple unit dosage forms and the relative merits of multiple unit forms with their own rate controlling systems are well established. This work describes the development of a relatively inexpensive multiple-unit capsule dosage form of theophylline containing coated mini-tablets for drug delivery throughout the gastrointestinal tract. Preformulation studies on theophylline anhydrous included solubility and dissolution rate determinations. Techniques including X-ray powder diffraction, differential scanning colorimetry and infrared spectroscopy provided no evidence of true polymorphism after recrystallisation from various solvents. However, scanning electron micrographs showed the effects of solvent polarity and cooling rate on the size and shape of recrystallised particles. Theophylline granules were manufactured by using various binders and were film coated by fluidised bed technology with various proportions of ethylcellulose, containing varying amounts of PEG 1540. In vitro release rates were dependent upon coating thickness and the proportion of PEG, which, being water soluble, created pores in the coating during dissolution studies as observed by a scanning electron microscope. However, substantial proportions of the drug remained unreleased from the granules. In order to overcome the problems of drug retention, plain granules were used and theophylline mini-tablets (3 mm diameter, weighing 15 - 20 mg) were manufactured and film coated with various Eudragits ® and other polymeric mixtures (soluble and insoluble). In vitro dissolution profiles from samples enclosed in hard gelatin capsules were determined using the USPXXI paddle apparatus in test media at pH 1.2 (HCI), pH 5.4 and 7.4 (phosphate buffers) at 37'C. Monitoring of in vitro theophylline release over 12 h, under identical hydrodynamic conditions, showed that the dissolution rate at pH 1.2 is substantially greater (95% of total drug content released in < 10 h) than that in phosphate buffers. The maximum release after 12 h was approximately 20 and 30% of total drug content of the tablet at pH 5.4 and 7.4, respectively. However, in vivo bioavailability after oral administration of tablets to rabbits corresponded to over 95% of total drug, compared with the same dose administered intravenously. The retarded drug release during in vitro dissolution in phosphate buffer was attributed to a possible interaction of phosphate ions with theophylline molecules at the tablet core-coat interface. These findings indicate that both rate and extent of theophylline release from the slow release coated mini-tablets are highly sensitive to phosphate buffers. The data also emphasise the usefulness of an animal model for assessment of in vivo drug release and subsequent absorption during the development of modified release dosage forms. Mini-tablets were subjected to isothermal and cyclic stresses to reach conditions for up to 6 months at different temperatures and relative humidity. The film integrity was maintained but ageing of the coating occurred which impeded dissolution. Reduced drug release was temperature related while the effect of relative humidi% was insignific~t. Encapsulated mini-tablets (uncoated and coated with Eudragit RL and RS 2% w/w) equivalent to a 300 mg dose, were evaluated both in vitro and in vivo using beagle dogs. The pharmacokinetic parameters from single and multiple dose studies showed several advantages over Theo-Dur® 300 mg tablets. Precise dosage titration is possible by careful adjustment of the number of encapsulated mini-tablets. This multiple unit mini-tablet delivery system will allow for greater flexibility in dosage adjustment compared to the currently available preparations, allowing individualised fine dose titration in those patients requiring therapeutic drug monitoring. The developmentof the multiple unit mini-tablet formulation appears to provide an optimal dosage form with maximum flexibility in respect of dose, duration range and ease of production.
- Full Text:
- Date Issued: 1991
Aspects of the bioavailability of topical corticosteroid formulations
- Authors: Magnus, Ashley Denis
- Date: 1979
- Subjects: Adrenocortical hormones , Dermatopharmacology , Dermatologic agents , Transdermal medication
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3724 , http://hdl.handle.net/10962/d1001458
- Description: Two possible variables of the McKenzie/Stoughton blanching assay, namely amount applied to the test site and occlusion time have been investigated. Subsequently, two topical steroid preparations, Synalar cream (0,025% fluocinolone acetonide) and Betnovate cream (0,1% betamethasone 17- valerate) were extemporaneously diluted with five and six placebo bases respectively. Taking cognizance of the two possible variables, these diluted preparations were assessed in vivo using a modified version of the McKenzie/Stoughton blanching assay for blanching activity over a 14 month period. It was found that the base E45, which is slightly alkali, had the greatest effect on both preparations. In the case of betamethasone 17-valerate this base caused the conversion to the less active isomer, betamethasone 21-valerate whereas at the end of the 14 month test period it was found that the Synalar/E45 dilution contained no fluocinolone acetonide. Quantitative analysis of all the diluted preparations by high performance liquid chromatography using a reverse-phase system was performed. The data obtained from the systematic studies of the effects of varying concentrations and occlusion times were presented at the Eleventh National Congress of the South African Pharmacological Society
- Full Text:
- Date Issued: 1979
An illustrated information leaflet for low-literate HIV/AIDS patients on antiretroviral therapy : design, development and evaluation
- Authors: Ramela, Thato
- Date: 2009
- Subjects: Antiretroviral agents -- South Africa HIV-positive persons -- Care -- South Africa AIDS (Disease) -- Study and teaching -- South Africa HIV infections -- Treatment -- South Africa AIDS (Disease) -- Treatment -- South Africa AIDS (Disease) -- Africa, Sub-Saharan -- Statistics Communication in medicine -- South Africa Communication in public health -- South Africa
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3834 , http://hdl.handle.net/10962/d1007563
- Description: South Africa's HIV prevalence rate is estimated to be 5.7 million and at the end of2007 a total of 45845 HIV/AIDS adult patients were taking antiretroviral therapy (ART). The global incidence of HIV/AIDS has been slowly decreasing over the years but is still widespread. This disease is still more prevalent in sub-Saharan Africa than in other parts of the world, with more than 60% people living with HIV/AIDS. Highly active antiretroviral therapy (HAART), the treatment of choice, slows the progression of the human immunovirus but demands a high adherence rate in excess of 95%. Patients who are poorly informed about antiretrovirals (ARVs) and misunderstand medicine-taking instructions or experience unexpected side effects may interrupt therapy, predisposing them to the development of resistance. Such patients need information but, given the poor literacy skills prevalent in South Africa, written information is often not fully comprehended and is often written at too high a reading level. The objectives of this research project were to design, modify and evaluate HIV / AIDS patient education materials for low-literate isiXhosa speaking adults residing in Grahamstown and to examine their impact on the understanding of various aspects of the disease and its treatment. Pictograms illustrating common side effects of ARVs (e.g. stavudine, efavirenz, lamivudine), as well as various sources 'for purchasing nonprescription medicines, storage and medicine-taking instructions were designed and evaluated both qualitatively, using group discussions, and quantitatively through individual interviews where interpretation of the pictograms was assessed. These pictograms were incorporated in a patient information leaflet (PIL) which had been specifically designed for people with limited reading skills and was a simple document containing the minimum of essential text. A previously developed PIL was modified in collaboration with the target population and two versions were produced, one incorporating pictograms illustrating side effects, the other with none. Pictograms were used in both to illustrate other medicine-taking instructions. The PILs were tested objectively to assess the readability, format, content, and general design. They were translated into isiXhosa prior to being qualitatively and quantitatively evaluated in a low-literate isiXhosa speaking population. Understanding of the PILs was assessed by asking a series of questions about the PIL content. Participant opinion of the readability and appearance of the PIL was recorded. The relationship between PIL understanding and selected demographic variables was investigated. Findings from this study illustrated that well designed pictograms assist in the location of information in written leaflets and they may enhance understanding of the information. It was further demonstrated that education influences total understanding of PIL content thus emphasizing the need for tailor-written information in accordance with the education level of the target population. A desire to receive PILs incorporating pictograms was expressed by the majority of participants. Collaboration with the intended target population is essential to design culturally acceptable, easily interpreted pictograms and to produce user-friendly, easy-to-read, comprehensible patient education materials. The rigorous, iterative design, modification and testing process described in this study is one that should be adopted in producing all health-related education materials.
- Full Text:
- Date Issued: 2009
The phytochemistry of several South African aloe species
- Authors: McCarthy, Terence John
- Date: 1967
- Subjects: Botanical chemistry Aloe -- Research -- South Africa Aloe -- Analysis Medicinal plants -- Research -- South Africa Drugs -- Research Chromatographic analysis
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3836 , http://hdl.handle.net/10962/d1007621
- Description: Introduction: Despite the tremendous advances made with regard to synthetic organic medicinals within the last two decades, heavy reliance is still placed on plant products. This is especially true of the anthracene derivatives used medicinally as purgatives, and which are derived principally from senna, cascara, rhubarb, frangula and aloes. While particular attention has been paid to the chemistry of the former group in recent years, aloes has been largely neglected, possibly due to the fact that the Aloe species are confined largely to areas where extensive research facilities are lacking, such as Africa , India and the West Indies. Thus research in Europe has been confined largely to the lump aloes of commerce, derived from relatively few species. In 1953 a comprehensive report by Hodge (103) appeared on "The Drug Aloes of Commerce, with Special Reference to the Cape Species". Hodge observed that South Africa abounds in species just as abundant as A.ferox, (which is the prime source of Cape aloes), and advised that a systematic chemical survey might show certain of these to be not only higher yielders of bitter aloetic juice but also sources of a superior drug product. Consequently an investigation along these lines is presented here, and it is observed that several species apart from A.ferox not only contain aloin, but also yield a large volume of aloetic juice. Only pharmacologic studies can reveal if the juice of these species is as safe as that of A.ferox, but without doubt they could be used for the extraction of crystalline aloin. Concurrently, the distribution of the Aloe resins, said by some to be purgative themselves, has been studied. The investigation has revealed that the structurally similar compound homonataloin enjoys an equally wide distribution as aloin. However, almost invariably it is confined to small species yielding little aloetic juice, apart from which nothing is known regarding its pharmacologic properties. It is interesting to note that the resin distribution in the homonataloin-containing species is very similar to that of the aloin-containing species, but differs widely from. that of the species containing neither of these principles. Apart from aloin and homonataloin, aloinoside and chrysophanol also occur in Aloe species, and together with the resins, these indicate that when all the South African Aloe species have been investigated, they may well be of chemotaxonomic value. Within the comparatively short space of the last decade some work has been performed on aspects of the metabolism of such anthracene-containing species as Rheum, Rhamnus and Rumex. These investigations have shown that the anthracene derivatives are not merely waste products, but perform definite metabolic functions. The latter portion of this work has been devoted to this relatively neglected aspect of the Aloe species.
- Full Text:
- Date Issued: 1967
Formulation and evaluation of captopril loaded polymethacrylate and hydroxypropyl methycellulose microcapsules
- Authors: Khamanga, Sandile Maswazi Malungelo
- Date: 2010
- Subjects: Hypertension -- Treatment , Hypertension -- Chemotherapy , Angiotensin converting enzyme -- Inhibitors , Hypotensive agents -- Development , Pharmacokinetics
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3860 , http://hdl.handle.net/10962/d1013443
- Description: Angiotensin-converting enzyme (ACE) inhibitors are some of the most commonly prescribed medications for hypertension. They are cited in many papers as the treatment most often recommended by guidelines and favoured over other antihypertensive drugs as first-line agents especially when other high-risk conditions are present, such as diabetic nephropathy. The development of captopril (CPT) was amongst the earliest successes of the revolutionary concept of structure-based drug design. Due to its relatively poor pharmacokinetic profile or short half-life of about 1 hour, the formulation of sustained-release microcapsule dosage form is useful to improve patient compliance and to achieve predictable and optimized therapeutic plasma concentrations. Currently, CPT is mainly administered in tablet form. One of the difficulties of CPT formulation has been reported to be its instability in aqueous solutions. CPT is characterized by a lack of a strong chromophore and, therefore, not able to absorb at the more useful UV–Vis region of the spectrum. For this reason, an accurate, simple, reproducible, and sensitive HPLC-ECD method was developed and validated for the determination of CPT in dosage forms. The method was successfully applied for the determination of CPT in commercial and developed formulations. Possible drug-excipient and excipient-excipient interactions were investigated prior to formulating CPT microcapsules because successful formulation of a stable and effective solid dosage form depends on careful selection of excipients. Nuclear magnetic resonance spectroscopy, Fourier transform infra-red spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used for the identification and purity testing of CPT and excipients. The studies revealed no thermal changes during stress testing of binary and whole mixtures which indicate absence of solid state interactions. There were no shifts, appearance and disappearance in the endothermic or exothermic peaks and on the change of other associated enthalpy values on thermal curves obtained with DSC method. Characteristic peaks for common functional groups in the FT-IR were present in all the mixtures indicating the absence of incompatibility. The techniques used in this study can be said to have been efficient in the characterization and evaluation of the drug and excipients. The technique of microencapsulation by oil-in-oil was used to prepare CPT microcapsules. The effects of polymer molecular weight, homogenizing speed on the particle size, flow properties, morphology, surface properties and release characteristics of the prepared CPT microcapsules were examined. In order to decrease the complexity of the analysis and reduce cost response surface methodology using best polynomial equations was successfully used to quantify the effect of the formulation variables and develop an optimized formulation thereby minimizing the number of experimental trials. There was a burst effect during the first stage of dissolution. Scanning electron microscopy (SEM) results indicated that the initial burst effect observed in drug release could be attributed to dissolution of CPT crystals present at the surface or embedded in the superficial layer of the matrix. During the preparation of microcapsules, the drug might have been trapped near the surface of the microcapsules and or might have diffused quickly through the porous surface. The release kinetics of CPT from most formulations followed Fickian diffusion mechanism. SEM photographs showed that diffusion took place through pores at the surface of the microcapsules. The Kopcha model diffusion and erosion terms showed predominance of diffusion relative to swelling or erosion throughout the entire test period. Drug release mechanism was also confirmed by Makoid-Banakar and Korsmeyer-Peppas models exponents which further support diffusion release mechanism in most formulations. The models postulate that the total of drug release is a summation of a couple of mechanisms; burst release, relaxation induced controlled-release and diffusional release. Inspection of the 2D contour and 3D response surfaces allowed the determination of the geometrical nature of the surfaces and further providing results about the interaction of the different variables used in central composite design (CCD). The wide variation indicated that the factor combinations resulted in different drug release rates. Lagrange, canonical and mathematical modelling were used to determine the nature of the stationery point of the models. This represented the optimal variables or stationery points where there is interaction in the experimental space. It is difficult to understand the shape of a fitted response by mere inspection of the algebraic polynomial when there are many independent variables in the model. Canonical and Lagrange analyses facilitated the interpretation of the surface plots after a mathematical transformation of the original variables into new variables. In conclusion, these results suggest the potential application of Eudragit® / Methocel® microcapsules as suitable sustained-release drug delivery system for CPT.
- Full Text:
- Date Issued: 2010
Structural studies on the capsular antigens of some Escherichia coli serotypes
- Authors: Leslie, Margaret Ruth
- Date: 1995
- Subjects: Escherichia Polysaccharides Antigens Enterobacteriaceae
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3767 , http://hdl.handle.net/10962/d1003245
- Description: The research presented in this thesis forms part of an on-going collaborative programme concerned with the determination of the chemical structures of the surface antigens of bacteria belonging to genera within the family Enterobacteriaceae. Bacteria of this family are opportunistic pathogens and are frequently responsible for serious infections in animals and man. Surface antigens produced by virulent strains are largely polysaccharides and occur as lipopolysaccharides (the O-antigens) and capsular polysaccharides (the K-antigens) respectively. The extracellular polysaccharide antigens expressed by strains of the species Escherichia coli are of considerable . interest due to their effect on immunological processes and the relationship which exists between their chemical structure and virulence. To date, some seventy-four K-antigens have been distinguished serologically within the species E. coli and structures have been determined for most of these. The K-antigens of E. coli are structurally diverse and exhibit serological cross-reactivity with other pathogenic bacteria. The structures of five previously unstudied E. coli K-antigens, viz. those produced by serotypes 020:K1 01 :H-, 08:K45:H9, 08:K50:H-, 0101 :K1 03:H-, and 08:K43:H11, are presented in this thesis. A variety of chemical techniques has been employed in the structural analysis, and these are discussed. Two-dimensional NMR spectroscopic techniques proved invaluable for the structural elucidation of these complex carbohydrates, and high-field NMR spectroscopy alone was used in the analysis of the K43 antigen. Structural analysis of the K1 03 antigen was facilitated by specific enzymatic degradation, using a bacteriophage-borne endoglycanase. The K45 antigen was found to contain the unusual sugar 3-acetamido-3,6-dideoxygalactopyranose, while the K50 and K103 antigens join a minority group of polysaccharides which contain pyruvate as their only acidic component.
- Full Text:
- Date Issued: 1995
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.
- Full Text:
- Date Issued: 2003
A study of the biopharmaceutics and pharmacokinetics of the macrolide antibiotic, erythromycin
- Authors: Terespolsky, Susan Ann
- Date: 1992
- Subjects: Erythromycin -- Bioavailability , Erythromycin -- Pharmacokinetics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3795 , http://hdl.handle.net/10962/d1003273 , Erythromycin -- Bioavailability , Erythromycin -- Pharmacokinetics
- Description: Erythromycin, a macrolide antibiotic isolated from Streptomyces erythreus, was first introduced into clinical medicine in 1952. It is active against most gram-positive bacteria, some gram-negative bacteria and is currently the agent of choice for Legionella pneumophila. Erythromycin is an acid-labile compound rapidly degrading in acidic solutions such as the acid environment of the stomach. As such, erythromycin absorption following oral administration of solid dosage forms is relatively poor. Accordingly there have been various approaches used to protect the drug against gastric inactivation. These precautions include enteric-coating of tablets, capsules or pellets of erythromycin base, the synthesis of acid stable 2' esters of erythromycin (ethylsuccinate and propionate) and salts of these esters (erythromycin estolate), and more recently, the synthesis of a range of new acid-stable, semi-synthetic macrolide antibiotics. The 2' esters are antimicrobially inactive or much less active than the parent compound and must be converted to the free erythromycin base in vivo in order to exhibit antibacterial activity. Intrinsic dissolution rates determined on raw material can provide extremely useful information relating to the gastrointestinal absorption of drugs from solid dosage forms. The large inter- and intrasubject variability associated with erythromycin base has, to date, mainly been attributed to gastric acid inactivation of the drug. However, changes in duodenal pH resulting in altered solubility and intrinsic dissolution rates may account for the observed variability. Thus, the intrinsic dissolution rates of erythromycin base at pH 6.0, 6.5, 7.0, 7.5 and 8.0 were compared in order to investigate the possible effects of pH changes which may occur in the duodenal contents, on the in vivo dissolution and subsequent absorption of this compound. The standard intrinsic dissolution rate test procedure employing a rotating disc of pure erythromycin base powder which only allows for dissolution from a constant surface area, was adapted and the drug quantitatively determined by reversed phase high performance liquid chromatography (HPLC) using ultraviolet detection. Results of intrinsic dissolution studies at both 22°C and 37°C indicate that the solubility, and therefore the rate of dissolution of erythromycin base is pH dependent, being more soluble at pH 6.0 than pH 8.0 (an approximate 800 times and 1000 times reduction in the amount dissolved after 30 minutes, at 22°C and 37°C respectively, when the pH of the medium was increased from 6 to 8). Although the stability of erythromycin and its ester derivatives in aqueous acidic solutions has been well documented, very little has been reported on the compound's stability in organic solvents. Methanol is recommended by official drug compendia (U.S.P. and B.P.) for use in erythromycin identification tests as well as in the sample preparation steps during assay procedures. Thus, the effect of methanol and acetonitrile, organic solvents of similar polarities and densities, on the stability of erythromycin base, erythromycin ethylsuccinate, propionyl erythromycin and erythromycin estolate at room temperature (22°C ± 0.5°C), using HPLC with electrochemical detection, was investigated. Erythromycin base is relatively stable in both methanol and acetonitrile, remaining intact for over 168 hours in acetonitrile and showing less than 5% degradation in methanol over the same period. Erythromycin ethylsuccinate in acetonitrile shows less than 5% degradation over 168 hours whereas in methanol, rapid hydrolysis occurs resulting in almost total conversion to base within 40 hours. Approximately 87% of erythromycin propionyl ester remained intact after 168 hours in acetonitrile whilst methanol caused rapid hydrolysis to erythromycin base (35% remaining after 28 hours). Erythromycin estolate appeared to be unstable in both acetonitrile and methanol. In acetonitrile, only 13% of the estolate remained intact after 168 hours, whereas in methanol, the reaction was much more rapid with 35% of the estolate remaining after 28 hours. The use of methanol as a solvent for erythromycin estolate reference standards is thus contraindicated. A number of conflicting reports on the half- life as well as the body compartment model that best describes erythromycin base serum concentration-time profiles (lBCM generally used to describe orally administered erythromycin, whilst a 2BCM has been used to describe erythromycin administered intravenously), appear in the literature. These differences may be largely attributed to the sampling period (between 6 and 12 hours) used in the repective studies. The objective of this study was to determine the body compartment model that best describes erythromycin base serum concentration-time curves by increasing the sampling time to 24 hours. In addition, the effect of chronic dosing of erythromycin on erythromycin pharmacokinetics, in the same group of subjects, was investigated. The single and multiple oral dose pharmacokinetics of erythromycin enteric coated base pellets within a gelatin capsule (250mg), were studied in 6 healthy, normal volunteers (19.5 ± 0.76 years, 71.5 ± 8.18 kg, 180.33 ± 5.99 cm). Furthermore, steady state concentrations were predicted using the pharmacokinetic parameters obtained from the single dose study, and compared with those obtained in the multiple dose study. Plasma concentrations were determined using a sensitive high-performance liquid chromatographic method with electrochemical detection. For the single dose study, after a tlag of 2.5 ± 0.71 hr, Cmax (1.12 ± 0.47 μ/ml) was reached at a tmax of 4.08 ± 0.93 hr post dose, with serum concentrations ranging from 0.31 - 1.62 μ/ml. The half-life was found to be 5.42 ± 1.31 hr. On multiple dosing (250mg six hourly), serum concentrations for the fifth, ninth and thirteenth dosing intervals ranged from 0.67 - 2.92 μ/ml, 1.69 - 3.65 μ/ml and 0.61 - 3.01 μ/ml, occurring at 3.75 ± 0.69 hr, 3.17 ± 1.03 hr and 3.17 ± 1.03 hr post dose with a Cmax of 1.89 ± 0.68 μ/ml, 2.35 ± 0.70 μ/ml and 1.94 ± 0.74 μ/ml, respectively. The area under the serum concentration- time curve for the single dose study (AUC₀₋∞) was 4.67 ± 0.88 hr.μ/ml, whilst the AUC₀₋τ. for the fifth, ninth and thirteenth dosing intervals of the multiple dose study were 5.77 ± 1.76 hr.μ/ml, 6.46 ± 1.33 hr.μ/ml and 5.97 ± 2.36 hr.μ/ml respectively, indicating an approximately 33% increase in AUC on chronic dosing of erythromycin. The observed increase in AUC may be a result of increased bioavailability or a decrease in clearance on chronic dosing.
- Full Text: false
- Date Issued: 1992
Comparison of the neuroprotective potential of theanine and minocycline
- Authors: Mpofu, Tariro Ann-Maureen
- Date: 2010 , 2010-09-20
- Subjects: Nervous system -- Degeneration -- Treatment , Tetracyclines , Antibiotics -- Side effects , Theanine -- Evaluation , Drugs -- Administration , Cerebrovascular disease -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3775 , http://hdl.handle.net/10962/d1003253 , Nervous system -- Degeneration -- Treatment , Tetracyclines , Antibiotics -- Side effects , Theanine -- Evaluation , Drugs -- Administration , Cerebrovascular disease -- Prevention
- Description: Stroke is one of the most common causes of disability and death worldwide. The most commonly experienced stroke in the clinical setting is focal ischaemia in which the middle cerebral artery (MCA) is occluded and leads to a complex series of various pathophysiological pathways that ultimately lead to neuronal cell death. Several studies have been conducted on various therapeutic agents in the search for a neuroprotective drug and various animal models have been used to carry out this research. While theanine, a component of green tea and minocycline, a tetracycline antibiotic, have been shown to possess some neuroprotective properties, the mechanisms by which these two agents carry out these effects still remains unclear. The objectives of this study were to investigate the mechanisms by which these drugs carry out these neuroprotective effects and their neuroprotective ability in a MCA occlusion model of focal ischaemia. Ischaemia leads to oxidative stress due to the imbalance of free radicals and the endogenous antioxidant defence system. An antioxidant assay using the stable 2, 2-diphenyl-1-picrylhydrazyl (DPPH●) radical was used to assess the antiradical properties of each drug. It was found that minocycline showed superior antioxidant activity in vitro when compared to theanine. Further studies on the drugs‟ ability to attenuate the Fenton reaction (in which iron catalyses the formation of reactive species) were elucidated using electrochemical analysis, UV/VIS studies, ferrozine and ferritin assays. It was found that minocycline, in contrast to theanine, was able to bind to iron ions and thus potentially prevent the participation of iron in metal catalysed radical reaction. The antioxidant activity of both drugs was further investigated by assessing their effect on cyanide-induced superoxide generation and quinolinic acid (QA)-induced lipid peroxidation (LP). Experimental evidence shows that both drugs had no significant effect on the generation of superoxide in vitro and that there was a significant decrease in LP for minocycline in vitro and theanine in vivo. The metal binding and antioxidant properties were postulated to be a possible mechanism through which these agents reduced lipid peroxidation. A study was conducted to determine the effects of the drugs on the biosynthesis of the neurotoxin, QA and it was found that minocycline increases the levels of holoenzyme activity of tryptophan-2, 3-dioxygenase (TDO) in vitro and that theanine reduces the levels of the same enzyme in vivo after treatment for 10 days. TDO is the enzyme that converts tryptophan to other products that enable enzymatic activity to change it to QA. Minocycline was thought to bring about this effect as it has been shown from preceding experimental studies that it is an effective reducing agent. Theanine on the other hand is hypothesised to bring about a reduction in holoenzyme activity by changing the binding of tryptophan to the enzyme or affecting the radicals that participate in the enzymatic degradation of tryptophan. A focal ischaemic model of stroke was induced by occluding the MCA. Histological examination of the hippocampus post -ischaemia shows a reduction in the size of the infarct after pre-treatment with minocycline only. A further study into the effects of the drugs on the generation of superoxide and on the levels of the endogenous glutathione after a stroke was carried out. Pre-treatment of the animals with either theanine or minocycline showed no significant effects on the generation of the radical species or of the endogenous antioxidant which ruled out these as a mechanism of neuroprotection of both drugs, post-ischaemia.The findings of this study provide novel information on the possible mechanisms by which both theanine and minocycline act to bring about neuroprotection. In particular in this study, pre-treatment with minocycline has shown promise in the focal ischaemic model of stroke.
- Full Text:
- Date Issued: 2010
Development, manufacture and assessment of Clobetasol 17-propionate cream formulations
- Authors: Fauzee, Ayeshah Fateemah Beebee
- Date: 2011
- Subjects: Adrenocortical hormones , Adrenocortical hormones -- Physiological effect , Adrenocortical hormones -- Testing , Drugs -- Testing , Drugs -- Development , Dermatopharmacology
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3856 , http://hdl.handle.net/10962/d1013324
- Description: Eczema or dermatitis is the most common dermatological condition accounting for one-third of all diagnoses in the total population surveyed in South Africa. The prevalence of seborrhoeic dermatitis, extreme photodermatitis and severe psoriasis has increased markedly over the last decade and this increase may be ascribed to the HIV epidemic, first diagnosed in South Africa in 1982. Potent innovator corticosteroids, such as clobetasol 17-propionate (CP) that are used to treat skin disorders, are expensive and there is therefore a need for the production of generic topical corticosteroid products. Formulation and manufacturing processes can be challenging aspects for formulation scientists to produce a robust product that will elicit an appropriate and desirable pharmacokinetic-pharmacodynamic profile. Laboratory scale CP creams were manufactured using different concentrations of Gelot® 64 and propylene glycol in order to establish a composition that would produce a formulation, with similar physical and chemical characteristics and in vitro release profile as an innovator product, Dermovate®. These formulations were assessed in terms of their viscosity, spreadability, pH, content uniformity and in vitro release characteristics using a Franz diffusion cell apparatus. A formulation containing 3% w/w Gelot® 64 and 46% v/v propylene glycol (CPLS-02) was found to exhibit similar viscosity and spreadability characteristics and released CP in a manner similar to Dermovate®. The mechanism of drug release was evaluated using mathematical models such as zero order, first order and Higuchi models. In addition, the in vitro release profiles were characterised by use of difference (f1) and similarity (f2 and Sd) factors. A scale-up formulation with the same % w/w composition as the laboratory scale was also investigated following manufacture using a Wintech® cream/ointment mixer. A Central Composite Design approach was used to investigate the effect of process variables on the performance of the scale-up cream formulations. The homogenisation speed, anchor speed, homogenisation time and cooling time were the process variables investigated. Thirty scale-up batches were manufactured and analysed in terms of their viscosity, spreadability, pH, % drug content and cumulative % drug released per unit area over 72 hours. Model fitting using Design-Expert® software was undertaken and revealed that a correlation between the process variables and the cream responses was most suitably described by quadratic polynomial relationships. The homogenisation speed had the most significant effect on the quality of the scale-up formulations, whereas the anchor speed had a secondary effect on the measured responses, for the formulations investigated. The qualitative interpretation and statistical analysis of the in vitro release data from the scale-up formulations using ANOVA and the f1, f2 and Sd factors revealed that one scale-up batch (CPSU-04), for which the process variables were a homogenisation speed of 1900 rpm, an anchor speed of 35 rpm, a homogenisation time of 100 minutes and a cooling time of 100 minutes, released CP at a similar rate and extent to Dermovate®. A diffusion-controlled mechanism appeared to be predominant in these formulations. A human skin blanching study, using both visual and chromameter assessments, was performed to establish whether batch CPSU-04 was bioequivalent to Dermovate®. The bioequivalence of the selected scale-up formulation to Dermovate® was confirmed, following the calculation of a 90% CI.
- Full Text:
- Date Issued: 2011
A self-emulsifying delivery system loaded with efavirenz: The case for flax-seed oil
- Authors: Mazonde, Priveledge
- Date: 2021-10-29
- Subjects: Drug delivery systems , Linseed oil , Antiretroviral agents , HIV (Viruses) , Drug carriers (Pharmacy) , Solubility , High performance liquid chromatography , Efavirenz
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/192944 , vital:45283
- Description: The feasibility of incorporating efavirenz (EFV), an antiretroviral agent against HIV into a lipid-based self-emulsifying drug delivery system (SEDDS) containing vegetable oils was investigated. EFV has poor aqueous solubility and is classified under the Biopharmaceutical Classification System (BCS) as a class II compound with highly permeability, its aqueous solubility is less than 10 mg/ml and is defined as a practically insoluble compound with a consequent poor bioavailability of approximately 40%, and erratic dissolution behaviour. SEDDS formulations have been shown to improve the aqueous solubility and consequently the bioavailability of BCS II compounds such as EFV. EFV is a first line antiviral agent used in combination with other agents in antiretroviral therapy (ART). Among the number of NNRTIs approved for use in HIV treatment, EFV is one of the most commonly prescribed drug. Statistical methods and Design of Experiments (DoE) using Response Surface Methodology (RSM), specifically a Central Composite Design (CCD), were used to facilitate the development of a reversed-phase high performance liquid chromatographic (HPLC) method for the quantitation of EFV during formulation product and process development studies. A rapid, accurate, precise and sensitive HPLC method with ultraviolet (UV) detection was developed, optimised and validated for the in-vitro analysis of EFV in a total run time under 10 minutes for the elution of both EFV and loratidine which was used as the internal standard (IS). The method was then successfully applied to the determination of EFV in commercially available tablets. Excipient screening was undertaken using solubility studies and revealed that EFV had highest solubility in flaxseed oil in comparison to soybean, macadamia, grapeseed, sunflower and olive oils. The non-ionic Tween® 80 and Span® 20 were selected as surfactant and co-surfactant, respectively with ethanol co-solvent as they exhibited improved miscibility with co-solvent. Pre-formulation studies were undertaken to investigate the compatibility of the API with excipients and to identify a nano-emulsion region and other emulsion types using pseudoternary phase diagrams. The phase behaviour of crude cold pressed flaxseed oil with the selected non-ionic surfactants revealed an area within pseudo-ternary phase diagrams for different surfactant-mixtures formed gels/semisolid structures which can be exploited for other drug delivery strategies that require such properties. Fourier transform infrared spectroscopy (FT-IR), powder x-ray diffraction (XRD) and Raman spectroscopy were used to identify and assess the compatibility of EFV with chosen excipients. 2 A reduction in the peak intensity was observed for EFV when combined with each hydrophobic/lipid excipient evaluated revealing that there was a marked reduction in the crystallinity of the EFV. A decrease in crystallinity in comparison with the bulk API may indicate that EFV were amorphous or sequestered in a molecular dispersion and exhibited an increased solubility for the molecule. Flaxseed oil was used as the oil phase in studies for the optimization of surfactant mixtures undertaken using DoE, specifically a D-optimal mixtures design with the flaxseed oil content set at 10% m/m was performed. Solutions from the desired optimization function were produced based on desirability and five nanoemulsion formulations were produced and characterized in terms of in vitro release of efavirenz, drug loading capacity, Zeta Potential, droplet sizes and polydispersity index (PDI). Kinetically stable nanoemulsions containing 10% m/m flaxseed oil were successfully manufactured and assessed. Droplet sizes ranged between 156 and 225 nm, Zeta Potential between −24 and −41 mV and all formulations were found to be monodisperse with polydispersity indices ≤ 0.487. SEDDS formulations of EFV in nano-sized carriers were developed and optimised, in vitro drug release varied with varying amounts of ethanol in the formulation producing formulations that exhibited differently modulated drug in-vitro release profiles that may be further manipulated for better performance and therapeutic outcomes in terms of solubility and possibly bioavailability of EFV when delivered using SEDDS rather than using tablets which in turn may lead to better therapeutic outcomes for patients with HIV. , Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 2021
- Full Text:
- Date Issued: 2021-10-29
Investigations of the bioavailability/bioequivalence of topical corticosteroid formulations containing clobetasol propionate using the human skin blanching assay, tape stripping and microdialysis
- Authors: Au, Wai Ling
- Date: 2010
- Subjects: Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3743 , http://hdl.handle.net/10962/d1003221 , Adrenocortical hormones -- Bioavailability , Drugs -- Therapeutic equivalency , Adrenocortical hormones -- Effectiveness , Adrenocortical hormones -- Testing , Adrenocortical hormones -- Side effects , Transdermal medication
- Description: Currently, clinical trials in patients are required by most regulatory authorities for the assessment of bioequivalence of topical products where the drug is not intended for systemic absorption. Hence there is a dire need for suitable methods for the assessment of bioavailability and bioequivalence of such products since clinical safety and efficacy studies are expensive, time-consuming and require very large numbers of patients. Except for topical corticosteroid products where the human skin blanching assay/vasoconstrictor assay has been approved by the US FDA for bioequivalence assessment of those products, no other method has been “officially” approved for use in those investigations. However, a few alternative methods such as tape stripping and microdialysis have been pursued and considered to have the potential for use in ioequivalence/bioavailability studies. The human skin blanching assay was used to assess the bioequivalence of commercially available topical products containing 0.05% clobetasol propionate. Both visual and chromameter data were obtained and a commercially available topical corticosteroid product, Dermovate® cream was used as both the “Test” and the “Reference” product. The results indicated that both visual and chromametric assessments were comparable to each other and that either could be used for the assessment of the bioequivalence of topical products containing clobetasol propionate. The screening procedure was optimized to identify potential “detectors” for inclusion in the bioequivalence studies. This resulted in fewer subjects being required in a bioequivalence pivotal study, still having the necessary power to confirm bioequivalence using the human skin blanching assay. Another objective of this research was to re-visit tape stripping and other possible alternative methods such as dermal microdialysis and to optimize these procedures for bioequivalence assessment of topical formulations where the drug is not intended for systemic absorption. In the past few decades, tape stripping has been used to investigate bioavailability/bioequivalence of various topical formulations. This technique involves the removal of the stratum corneum to assess drug penetration through the skin. A draft FDA guidance for tape stripping was initially published but was subsequently withdrawn due to high variability and poor reproducibility. This research project used an optimized tape stripping procedure to determine bioavailability and establish bioequivalence between three commercially available formulations containing 0.05 % m/m clobetasol propionate. Furthermore, tape stripping was validated by undertaking a study to assess the bioequivalence of a 0.05% topical cream formulation (Dermovate® cream) using the same cream as both the “Test” and “Reference” product, in which bioequivalence was confirmed. The findings highlight the potential of tape stripping as an alternative method for the assessment of bioequivalence of clobetasol propionate formulations and may possibly be extended for use in other topical products. Microdialysis is another useful technique that can assess the penetration of topically applied substances which diffuses through the stratum corneum and into the dermis. Microdialysis has previously been successfully used for in vivo bioavailability and bioequivalence assessments of topical formulations. However, the drugs which were under investigation were all hydrophilic in nature. A major problem with the use of microdialysis for the assessment of lipophilic substances is the binding/adherence of the substance to the membrane and other components of the microdialysis system. As a result, this necessitates the development of a microdialysis system which can be used to assess lipophilic drugs. Intralipid® 20% was investigated and successfully utilized as a perfusate to recover a lipophilic topical corticosteroid, clobetasol propionate, in microdialysis studies. Hence, the bioavailability of clobetasol propionate from an extemporaneous preparation was determined in healthy human volunteers using microdialysis. These findings indicate that in vivo microdialysis can be used to assess lipophilic drug penetration through the skin. A novel approach to investigate drug release from topical formulations containing 0.05% clobetasol propionate using in vitro microdialysis was also undertaken. The in vitro findings were found to be in agreement with the results obtained using tape stripping to assess bioequivalence of the same commercially available products, namely Dermovate® cream, Dovate® Cream and Dermovate® ointment. These results indicate the potential to correlate in vitro with in vivo data for bioequivalence assessment of such topical dosage forms.
- Full Text:
- Date Issued: 2010
In vitro effects of three organic calcium channel blockers on the rat pineal gland
- Authors: Brown, Clint
- Date: 1992
- Subjects: Calcium -- Antagonists , Pineal gland -- Research
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3745 , http://hdl.handle.net/10962/d1003223 , Calcium -- Antagonists , Pineal gland -- Research
- Description: The calcium signal has emerged as an imponant component of intracellular regulation. Pineal function was thought to be slowed by the prominent calcification seen with increasing age, but recently it has been shown that calcium plays a crucial role in the adrenergic regulation of the gland. Beta-adrenoceptor stimulation increases melatonin (aMT) synthesis by increasing the activity of cyclic 3 '-5' adenosine mono phosphate (cAMP). Cyclic-AMP regulates the production of the pineal hormone, melatonin, from serotonin via the rate-limiting enzyme N-acetyltransferase (NAT). Increased intracellular cAMP is essential to the adrenergic induction of NAT. Noradrenaline(NA)also elevates pinealocyte cyclic guanosine monophosphate (cGMP). Adrenergic regulation of these cyclic nucleotides involves both α₁ - and β-adrenoceptors. Beta-adrenoceptor stimulation is an absolute requirement. Alphal-adrenoceptor activation, which is ineffective alone, serves to amplify the β-stimulated cAMP and cGMP responses via a positive effect on a Ca²⁺⁻/ phospholipiddependent protein kinase (Protein kinase-C) and a net influx of Ca²⁺ into the pinealocyte. Previous studies suggest the use of organic calcium channel blockers (CCBs) as probes of calcium-mediated processes. Applying this concept, the study set out to investigate the influence of a representative of each of the structurally diverse groups of calcium channel blockers viz. verapamil, diltiazem and nifedipine, and to examine their effect on β-adrenoceptor stimulation. It used the β-agonist isoprenaline (ISO) and the mixed [α₁/β]agonist noradrenaline (NA), for its combined [α₁/β]adrenoceptor stimulation, on agonist-induced increases in the production of radio-labelled aMT and N-acetylserotonin(aHT) -measured as the sum of N-acetylated product- from [¹⁴C] serotonin. This was done using organ cultures of rat pineal glands. It was speciously assumed that this drug paradigm would allow the determination of Ca²⁺ influx and/or the blocking thereof in the reported potentiation by using ISO as a non Ca²⁺ -entry stimulating agonist, compared with NA and its Ca²⁺ -entry stimulating properties. Surprisingly, all 3 CCB's potentiated the effect of NA. Only diltiazem was found not to potentiate the effect of ISO. In an attempt to uncover the reason for these results, the study moved toward a mechanistic approach,focusing in an antecedent manner on the various steps in the indole metabolic pathway to identify the point at which the change occurred, and hence possibly elucidate the mechanism responsible for the paradoxical increase. Experiments which assayed the levels of NAT, under the same drug conditions, showed the paradoxical increase to be already evident at this stage. Secondary experiments confirmed that NA stimulation of the pineal is dependent on Ca²⁺, both in organ culture and with NAT: the Ca²⁺ chelator EGTA abolished adrenergically-induced stimulation, while Ca²⁺ added after EGTA, restored the enzyme activity. The ionophore A23187 (which is able to transport Ca²⁺ directly into the pinealocyte via a mechanism which differs from the α₁ - mechanism) when used in conjunction with ISO or NA, was able to potentiate the responses of these two agonists relative to control values (agonist-alone), but by itself had no effect. With the enzyme NAT critically dependent upon cAMP for its induction, it was decided to determine the levels of cAMP and then those of its regulator, cAMP-phosphodiesterase (cAMP-PDE). This reasoning was prompted by reports of anti-calmodulin activity shown by the CCBs, in addition to their channel blocking effects. By binding to calmodulin (CaM), the CCBs are reportedly able to inhibit the CaM-dependent activation of cAMP-PDE. Following NA stimulation, verapamil caused a significant decrease in cAMP-PDE levels and an increase in cAMP. The other CCBs showed a similar trend. Glands stimulated with ISO in the presence of verapamil and nifedipine showed no significant differences in cAMP or cAMP-PDE levels. Diltiazem, however, was found to decrease the effect of ISO on cAMP while causing a concomitant increase in cAMP-PDE. This i) supported a possible hypothesis that the observed enhancement is a result of cAMP levels remaining elevated due to an inhibition of cAMP-PDE by the CCEs and ii) pointed to the possible presence of a CaM-sensitive PDE within the rat pineal gland. To test this hypothesis, two drugs which are more specific in their actions on CaM effects were chosen to see if the earlier results could be mimicked and thereby confirmed. Glands stimulated with NA in the presence of the specific CaM inhibitor R 24571 showed increased NAT activity and [¹⁴C]-aMT production. cAMP-PDE levels were clearly down, thus corroborating the possibility of cAMP-PDE inhibition. Glands incubated in the presence of M&B 22948, a CaM-sensitive PDE inhibitor, showed similar increases in NAT activity and [¹⁴C]-aMT. These findings therefore support the initial results and although indirect, confirm the hypothesis that the paradoxical increase following predominantly NA stimulation could be a result of cAMP levels remaining elevated, due to inhibition by the CCEs of the CaM-dependent activation of its regulator cAMP-PDE. In summary, data presented herein concur with proposals that: i) the CCEs are not specific enough to be used as tools to research Ca²⁺ -mediated events, as they appear to have sites of action other than the voltage operated channel (VOC); eg. binding to calmodulin, ii) there are functional differences between the CCEs as shown by diltiazem in this series of experiments, iii) there is a CaM-sensitive-PDE present in the pineal.
- Full Text:
- Date Issued: 1992
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.
- Full Text:
- Date Issued: 1975
Neuroprotective mechanisms of nevirapine and efavirenz in a model of neurodegeneration
- Authors: Zheve, Georgina Teurai
- Date: 2008
- Subjects: HIV infections -- Treatment AIDS (Disease) -- Treatment AIDS dementia complex -- Treatment Nervous system -- Degeneration -- Treatment Melatonin Neurotoxic agents Quinolinic acid
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3807 , http://hdl.handle.net/10962/d1003285
- Description: AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.
- Full Text:
- Date Issued: 2008
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.
- Full Text:
- Date Issued: 2008
The isolation and characterisation of secondary metabolites from selected South African marine red algae (Rhodophyta)
- Authors: Fakee, Jameel
- Date: 2013
- Subjects: Metabolites Marine algae -- South Africa Marine algae -- Therapeutic use Metabolites -- Therapeutic use Marine metabolites Plocamocera Red algae Laurencia Delisea flaccida
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3733 , http://hdl.handle.net/10962/d1001472
- Description: Secondary metabolites from natural sources are fast growing as popular drug leads. The structural novelty and favourable biological activity that these compounds display contribute to their popularity as drugs of the future. Examples of such compounds include the potent anticancer drug paclitaxel isolated from the bark of a yew tree as well as the more commonly known analgesic aspirin which stems from the bark of the willow tree. The biological activities exhibited by these secondary metabolites are vast and range from antimicrobial to anticancer activity to mention but a few. As a result, the isolation of novel compounds from natural sources is on the rise. The South African seaboard is home to a wealth of various marine algal species which produce fascinating secondary metabolites. For example, Portierria hornemanii was shown to produce halomon, a halogenated monoterpene which has displayed promising cytotoxic activity. This study thus focused primarily on pursuing novel compounds from three endemic South African marine algal species which have never been analysed previously from a chemical perspective. These are Plocamium rigidum (Bory de Saint-Vincent), Laurencia natalensis (Kylin) and Delisea flaccida (Suhr) Papenfuss. Four known compounds and one new halogenated monoterpene, (2E,5E,7Z)-8-chloro- 7-(dichloromethyl)-4-hydroxy-3-methylocta-2,5,7-trienal, were isolated from Plocamium rigidum. The breast cancer (MCF-7 cell line) inhibitory activity for these compounds was assessed and it was observed that an increase in the lipophilic nature of the compounds produced more favourable IC50 values. A pre-cursor to bromofucin type compounds, cis-laurencenyne, was isolated from Laurencia natalensis, as well as a new acetoxy chamigrane type compound, 4-bromo- 3,10-dichloro-7-hydroxy-3,7,11,11-tetramethylspiro [6.6] undec-1-yl acetate. Delisea flaccida was seen to contain two known bromofuranone type compounds isolated as an isomeric mixture, 1-[(5Z)-4-bromo-5-(bromomethylidene)-2-oxo-2,5- dihydrofuran-3-yl] butyl acetate and 1-[(5E)-4-bromo-5-(bromomethylidene)-2- oxo-2,5-dihydrofuran-3-yl]butyl acetate. These compounds are famous for their ability to inhibit bacterial biofilm production and they have been isolated before from an Australian Delisea spp , Adobe Acrobat 9.53 Paper Capture Plug-in
- Full Text:
- Date Issued: 2013