The present study investigated pharmacological properties of Capsicum frutescens-derived capsaicin, including its analgesic, anti-inflammatory and coagulatory properties. The effects of capsaicin on gastrointestinal and myocardial muscles, as well as on myocardial ischaemic-reperfusion, were also investigated. Capsaicin pre-treatment in neonatal rats has been found to abolish the development of thermal hyperalgesia produced in a model of neuropathic pain in rats (Toth-Kasa et al., 1986). In addition, capsaicin sensitivity has been found to be dependent on continued presence of nerve growth factor (NGF), whose concentration increases in inflamed tissues (Bevan and Winter, 1995). By stimulating the release of excitatory amino acids (EAA); such as glutamate and neuropeptides [(CGRP, neurokinin A (NKA) and Substance P (SP)] from both the peripheral and central terminals of sensory neurones by two mechanisms (Kroll et al., 1990; Del Bianco et al., 1991; Lou et al., 1992; 1994; Woolf et al., 1994); capsaicin has been shown to produce a longer-term inhibitory effect. This is one likely mechanism for capsaicin analgesic and anti-inflammatory actions (Bleakman et al., 1990). Within the gastro-intestinal tract, SP and NKA are involved in the physiological control of several digestive functions, such as motility, fluid and electrolyte secretion, blood flow, and tissue homeostasis (Otsuka, 1993; Holzer et al., 1997). Consistent with this finding, upsurge of SP in irritable bowel syndrome (IBD) was confirmed by Mantyh et al, (1988). Pre-treatment of rats with either capsaicin or NK-1R antagonists dramatically reduced fluid secretion, mucosal permeability, and intestinal inflammation in animal models of acute and chronic inflammation (McCafferty et al, 1994; Pothoulakis et al., 1994). Capsaicin can modulate endocrine and paracrine activities, immune responses, as well as gastro-intestinal and cardiovascular functions. Moreover, up-regulation of Substance P receptors was found to be associated with chronic inflammatory conditions (De et al., 1990). Stimulation of transient receptor potential vanilloid 1 also results in the activation of nociceptive and neurogenic inflammatory responses (Rigoni et al., 2003). vi The pharmacodynamic effects of capsaicin on the cardiovascular system remain elusive. Some actions of capsaicin on the heart were attributed to an interaction at K+ channels (Castle, 1992), or liberation of neuropeptides, most notably calcitonin-gene-related-peptide (CGRP) from the vanilloid-sensitive innervation of the heart (Franco-Cereceda et al., 1988; 1991). The possibility of a direct effect of capsaicin on the heart via a cardiac vanilloid receptor (VR), or through interaction of vanilloid receptors with purinergic receptors, and subsequent release of nitric oxide (NO), leading to vasodilatation were considered. Evidence abound in the literature that Ca2+ ions are released through 1, 4, 5 inositol phosphatase by the release of phospholipase C, or through interaction of the vanilloid receptors with cannabinoids. In an earlier study, Jaiarj et al. (1998) found that capsaicin acting on the heat-sensitive vanilloid receptors, had thrombolytic effects. Though weak evidence, Jaiarj et al. (1998) observed that individuals who consume large amounts of Capsicum have lower incidence of thromboembolism. Following ethical approval, the study reported in this thesis was conducted in phases. Identification of Capsicum frutescens (facilitated by a botanist in the Department of Botany, Westville campus of the University of KwaZulu Natal). Chromatographic extraction of capsaicin from Capsicum frutescens was followed by Nuclear Magnetic Resonance (NMR) analysis of the extract. Animal studies were conducted using capsaicin extract (CFE) and/or a reference capsaicin (CPF), using „hot plate. and „acetic acid. test methods to investigate the role of capsaicin on analgesia. Fresh egg albumin-induced inflammation was used to investigate the role of capsaicin in inflammation, following pre-treatment with CFE and CPF. Concentraton-response curves of increasing concentrations of capsaicin, acetylcholine and other agonist drugs with specific antagonists on strips of chick oesophagus, guinea-pig ileum, and rabbit duodenum were constructed following investigations on gastrointestinal (GIT) smooth muscles. The effect of capsaicin on coagulation was assessed by measuring international normalized ratio (INR) of animals that were exposed to different concentrations of capsaicin (CFE and CPF). Furthermore, parallel control studies were conducted in each of these investigations using distilled water or saline as placebo-control or specific-prototype agonists. negative-control. Cardiovascular investigations included studies on the effects of capsaicin on the heart rate, inotropy, vii coronary perfusion pressure, and ischaemic-reperfusion injury, using Langendorf.s rat heart models. Collated data were triangulated by manual hand-written and PowerLab data acquisition, or computerised capture. Statistical analysis were performed by either one or two of the following: Student.s t-test, ANOVA (repeated or single–use modes), facilitated and confirmed by Graph Pad Prism, Microsoft Excel or CPSS software(s). Reproducibility and relevance to the stated objectives of the various studies were confirmed by assessing which of the Null or Alternative hypothesis is validated by the results from the test. Treatment with CFE or CPF at all doses significantly (p<0.01) increased MRT. By comparison with control, writhing responses to acetic acid were significantly reduced following pre-treatment with various doses of CFE or CPF. The results in both parallel groups of CFE and CPF in the hot plate and acetic acid tests had Pearson correlation of one (1). Compared to the diclofenac (DIC) group, the degree of inhibition of paw oedema by CFE and CPF was statistically significant (P<0.05-0.001), best in the first 4 hours of treatment. The results of the in vitro laboratory animal study indicate that relatively low concentration of CPF (20 or 40 .g) produced significant (p.0.05), concentration-related inhibitions of acetylcholine (0.1-5 .g)-induced contractions of the chick isolated oesophagus, guinea-pig isolated ileum and rabbit isolated duodenum. Biphasic effects, which were noticed at low concentrations, consisted of initial brief contractions, followed by longer-lasting relaxations and reductions of the contractile amplitudes of the muscle preparations. Percentage inhibitions of the smooth muscle contractions by CFE or CPF were concentration-dependent, ranging from 20-70% (p<0.02). / Thesis (Ph.D.)-University of KwaZulu-Natal, Westville, 2012.

This study was prompted by the inconsistent reports and apparent controversies that exist in the biomedical literature on the responses of diabetic bladder strips to cholinergic nerve stimulation or exogenous administration of muscarinic agonists, especially acetylcholine (ACh), in vitro. In the present study, acetylcholine-induced contractions of urinary bladders isolated from normoglycaemic (normal) and streptozotocin-treated, diabetic Wistar rats were examined under physiological conditions. Mechanical contractile changes of the isolated urinary bladders of STZ-treated, diabetic rats in response to bath-applied acetylcholine were compared with those obtained from isolated urinary bladders of normal, age-matched, control rats. Results obtained show that urinary bladders from diabetic rats consistently weighed more, and were always more spontaneously active after mounting, than those of the age-matched normal, control rats. ft A Acetylcholine (ACh, 10" -10" M) provoked concentration-related, atropine-sensitive contractions of the isolated urinary bladders of both diabetic and age-matched normal, control rats. However, acetylcholine always induced more powerful and greater contractions of the diabetic bladders compared with bladders from the age-matched normal, control rats. The enhanced contractile responses of the diabetic bladder strips to bath-applied ACh were detected soon after induction of diabetes, and the magnitude and/or intensity of the enhanced contractile responses to ACh continued to increase as the diabetic state of the animals progressed. Although this preliminary study could not establish the mechanism of the increased contractile responsiveness of the diabetic bladders to the muscarinic agonist (ACh) used, the results tend to suggest that alterations in diabetic urinary bladder synaptosomal, vesicle-bound neurotransmitter (ACh) concentrations and the compensatory increase in the density of muscarinic M3-receptor population in diabetic bladders are two of the most attractive plausible mechanisms of the increased diabetic bladder responsiveness to bath-applied acetylcholine. / Thesis (M.Sc.Pharm.)-University of KwaZulu-Natal, Westville, 2006.

The aim of the present study was to formulate oral modified release matrices of diclofenac sodium, using the Eudragit® polymers. In addition to the formulation processes, numerous variables had to be investigated, which included dissolution variables, formulation variables, and processing variables. The application of the tabletting technique as well as the use of Eudragit® polymers to modify the release of diclofenac sodium is motivated at the outset. A comprehensive review of modified drug release, the use of the tabletting methodologies and the application of Eudragit® polymers are presented. In-process quality control tests as well as the mechanisms and interpretation of the dissolution process are outlined. Diclofenac sodium, a potent nonsteroidal anti-inflammatory drug, was used in the present study, hence a brief review of this drug is also presented. The direct compression as well as the wet granulation tabletting methods were investigated. The major limitation of the direct compression method was found to be the lack of suitable flow properties of the powder blend. The wet granulation technique however, was successfully employed to prepare various diclofenac sodium Eudragit® matrix tablets. All tablets were prepared to contain 100 mg diclofenac sodium. The optimisation process was shown to be an integral procedure in influencing the matrix characteristics. In addition, it was shown that drug release was significantly influenced by different types and concentrations of Eudragit® polymers. A specific formulation was selected to investigate the integrity of the matrices produced by the wet granulation technique. The drug release profile of a commercially available modified release preparation containing diclofenac sodium viz. Veltex® 100 CR (reference standard) was also obtained. A comparison of the drug release profiles of Veltex® 100 CR capsules and the selected formulation showed them to be markedly dissimilar. Hence, a strong motivation is provided for rationalising the selection of the particular formulation in the present study, that was shown to release diclofenac sodium optimally. The selected formulation was prepared using a combination of the Eudragit® RL and Eudragit® RS polymers. In vitro dissolution studies on the selected as well as various other formulations demonstrated the wet granulation method to be both predictable and reproducible. However, absolute drug release independency of dissolution methods, media and agitation rates was unattainable. Furthermore, drug release was shown to be pH dependent. The selected formula was subjected to certain formulation and processing variables. An increase in the concentrations of lactose and starch was shown to increase drug release. Different types of diluents were also shown to influence drug release from the tablets. The method of incorporation of the lubricant, magnesium stearate, was investigated. Compression studies demonstrated the susceptibility of the tablets to changes in drug release behaviour and morphological characteristics as the hardness was varied. X-ray diffraction studies demonstrated that the processes of granulation and compression did not promote any atomic rearrangement of the drug and Eudragit® polymers. Scanning electron microscopy was useful in investigating the integrity and surface morphology of newly formulated as well as stored samples, while energy dispersive x-ray microprobe analysis adequately revealed the elemental composition of the tablets. The selected formulation was shown to be stable at room temperature (21 ±1°C) and low temperature (5± 1°C), while storage at 37°C with 80% relative humidity and 40°C demonstrated significantly decreased drug release behaviour during short term (3 months) stability testing. Tablet hardness evaluated during the stability testing showed that there were virtually no differences in tablet hardness between the room temperature and low temperature samples, while tablets stored at 37°C with 80% relative humidity and 40°C hardened considerably. However, tablet potencies and the moisture content of the samples were not significantly influenced during the storage period. In addition to usual observations and mathematical manipulation, some of the data generated from this study were also evaluated statistically. / Thesis (M.Sc.)-University of Durban-Westville, 1998.

The motivation for the present study is systematically presented and the aims and objectives of the study are clearly defined. A comprehensive review on modified release drug delivery has been presented to provide the basis for the meltable aqueous dispersion technique as an approach to the formulation of a multiple-unit oral modified release drug delivery system. In addition, a brief discussion on the theory of dissolution testing and the mechanisms and interpretation of the dissolution process has been presented. Naproxen sodium, a potent non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic activity employed in the study, has been briefly discussed. In the present study, the coacervation phase separation technique utilizing ethylcellulose was initially investigated but proved unsuccessful in producing a formulation displaying suitable drug release characteristics. Subsequently, the meltable aqueous dispersion technique utilizing cetostearyl alcohol was successfully employed to formulate a multipleunit modified release naproxen sodium preparation containing 550 mg of naproxen sodium. The use of cetosteary!alcohol, as·a·retarding material, generated modified ·drug release characteristics as a function of its content. Magnesium stearate (anti-tackiness agent) and Span 20 and Tween 60· (surfactants) were incorporated in the formulation to optimize particle size and sphericity. The influence. of various formulation variables on drug release characteristics were investigated: An optimized formulation displaying a desirable modified release profile of naproxen sodium was achieved employing a 1:1 ratio of naproxen sodium:cetostearyl alcohol, 2% m/m .. .. magnesium stearate, and 1%m/m Span 20 dispersed in a liquid manufacturing vehicle of pH 0.6 containing 2% m/m Tween 60. In vitro dissolution studies on the selected formulation showed drug release to be predictable and reproducible, dependent on the dissolution method, agitation rate, and the pH of the dissolution media (i.e. pH-dependent drug release). The density of the microspheres was shown to decrease as the concentration of cetostearyl alcohol increased whilst the mean specific surface area increased with increasing concentrations of cetostearyl alcohol. Differential scanning calorimetric studies reveals a change in the thermograms which is suggestive of eutectic formation. Scanning electron microscopy proved useful in evaluating the integrity and surface morphology of the microspheres as well as in elucidating the drug release characteristics of the formulation. Energy dispersive x-ray microprobe analysis revealed the elemental composition of the microspheres to be a composite of the pure ingredients. X-ray mapping and the line scan depicted the homogenous distribution of drug within the microspheres and confirmed that the formulation is a matrix-type modified release I' preparation. Stability studies were performed on the selected formulation at room temperature (21 :t 1°C), 40°C, 37°C with 80% relative humidity, and at low temperature (5 :t 1°C). The shelf-life of the selected formulation was determined to be 1.29 years. Applying the data to five different kinetic models to investigate the drug release mechanisms showed that first order and cube-root release characteristics were exhibited by the microspheres. / Thesis (M.Sc.)--University of Durban-Westville, 1997.

Introduction: Although drug-related problems (DRPs) are known to be prevalent in elderly patients, there are not many studies that have been performed in geriatric outpatients at public health facilities in South Africa. Thus, the prevalence of DRPs in elderly outpatients attending Addington Hospital was investigated and suitable preventive intervention strategies to overcome or minimise these DRPs were developed. Research Methodology: The study was conducted in two phases. Phase 1 was conducted in March and April 1998, during which 281 elderly patients on chronic medical treatment were chosen for the study by systematic random sampling, according to specific inclusion criteria. Data collection was via a retrospective review of the elderly patient's medical notes and by personally interviewing the patient. Two research instruments were used in this phase. The customised Patient Profile (PF) form helped to delineate DRPs in the elderly patients. A Prescription Intervention Form (PIF) was used to inform the prescriber of the DRP and to make recommendations to change the drug therapy in order to overcome the DRP. In phase 2 of the study, intervention strategies were devised to address some of the major DRPs identified in phase 1 of the study. A patient counselling leaflet, prescribing guidelines for geriatric patients and a protocol for counselling of in-patients were developed. In addition, two DRP reporting systems were developed for surveillance of adverse drug reactions and medication errors during dispensing. Results and Discussions: Most geriatric subjects suffered from multiple, chronic conditions, these being hypertension (64.8%) followed by ischaemic heart disease (43.8%), musculoskeletal disorders (arthritis or gout) (42.7%), diabetes (29.2%), chronic obstructive airways disease (13.2%), hypercholesteremia (11.7%) and arrythmias (atrial fibrillation) (11.0%). The 281 patients were taking 1730 prescribed drugs, with a mean of 6.2 (range 3 to 15) prescribed drugs per patient. An astounding 45.6% of the total geriatric patients were taking or using between 7 to 9 medicines and 10.3% were taking or using between 10 to 15 medicines. The antihypertensives (15.9%) were the most widely prescribed drugs followed by medicines acting on CNS (10.9%), coronary vasodilators (9.1%), diuretics (9.1%) and medicines acting on the musculoskeletal system (8.7%). A total of 856 actual DRPs experienced by 262 geriatric patients (93.2%) ranged from 1 to 11 DRPs. The greater the number of prescribed drugs the greater the actual DRPs experienced by geriatric patients (p = 0.000). The most common DRPs were those involved in drug safety (56.6%); effectiveness of the drug therapy (20.8%); compliance (7.8%) and indication of drug therapy (7.6%). 159 elderly patients (56.6%) experienced 223 adverse effects either with their current or past prescribed medicines. The most common ADRs were as follows: gastro-intestinal ulceration (11.0%), cough (9.3%), diuretic side effects (dehydration, fatigue, hypotension, etc) (7.1%), constipation (6.8%), equilibrium problems (6.4%) and headaches (6.4%). For those DRPs warranting interventions, the mean number of prescription interventions in the entire sample population of 281 elderly patients was 0.65 ± 1.16. 87 elderly patients (30.1 %) had from 1 to 4 interventions on their current prescription. The most common prescription interventions were on problems involving drug therapy monitoring (26.9%), safety of drug therapy (26.5%), indication of drug therapy (17.5%), prescribing errors (15.3%) and prescription information omission (11.1 %). The three intervention strategies and DRPs surveillance reporting systems were successfully devised and developed. Conclusions: A profile related to the elderly patient's medical history and pharmacotherapy was completed for each of the 281 patients. General trends of prescribing pattern prevalence of DRPs and the prescribed inappropriate medication was established. The interventions of problem prescriptions were based on a newly developed PIF. The development and implementation of suitable intervention strategies to minimise DRPs were as follows: a compliance information leaflet, prescribing guidelines and the protocol for counselling in-patients. A medication error form as well as an adverse drug reaction reporting forms was developed for surveillance of DRPs. The recommendations for clinical practice and directions for future research that are presented should help to make drug therapy in the elderly safer and more effective. / Thesis (M.Pharm.)-University of Durban-Westville, 2000.