As a part of a continuing search for bioactive compounds with the International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), twelve plant extracts were investigated for their antiproliferative activity against the A2780 cell line, three plant extracts were investigated for their antimalarial activity against Plasmodium falciparum, and three plant extracts were investigated for their anti-inflammatory activity (PPAR-y inhibition). Bioassay-guided fractionation of extracts led to the identification of four new antiproliferative compounds (2.1-2.3, 3.1), five new anti-inflammatory compounds (6.4a, 6.5a-b, 6.6a, 6.6c), and twenty-eight known compounds from eight of the extracts. In addition, mallotojaponin C, an antimalarial natural product, and derivatives were synthesized and investigated for their antimalarial activity. / Ph. D.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, anti-pyretic and anti-inflammatory properties in both human and veterinary patients. Topical ophthalmic NSAIDs are commonly employed in the management of intraocular inflammation (uveitis), corneoconjunctival inflammatory disease and pre-operatively to prevent intraoperative miosis during cataract surgery. Despite their routine application in these clinical scenarios, little is known regarding the corneal penetration and relative anti-inflammatory efficacy of the available topical ophthalmic NSAIDs in the dog. Decisions regarding which of these agents to employ are therefore based upon factors such as cost and ease of acquisition as opposed to established efficacy. Objectives: To investigate the relative intraocular penetration and anti-inflammatory efficacy of two commonly utilized topical ophthalmic NSAIDs in dogs, diclofenac 0.1% and ketorolac 0.5%. Animals: Twenty-two client owned dogs (22 operated eyes) presenting to the VTH ophthalmology service for routine cataract surgery for mature or hypermature cataract. Methods: Subjects were randomized to be treated with either topical ketorolac 0.5% or topical diclofenac 0.1% ophthalmic solutions at specified times in the 24-hour period pre-operatively. Aqueous humor samples were obtained intra-operatively and stored for subsequent evaluation of drug concentrations and prostaglandin E2 (PGE2) concentrations via ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) and enzyme-linked immunoassay (ELISA) analysis, respectively. Results: Median aqueous humor drug concentrations were significantly higher in dogs treated with ketorolac 0.5% (1311.6 ng/mL) compared to those treated with diclofenac 0.1% (284.9 ng/mL). There was no significant difference in aqueous humor PGE2 concentrations between the two treatment groups. No significant association was determined between aqueous humor drug concentration and PGE2 concentration. There was no significant association between diabetic status and aqueous humor drug concentration or PGE2 concentration in either group. Conclusions and clinical importance: This study suggests that topical ketorolac 0.5% and diclofenac 0.1% are efficacious in decreasing aqueous humor PGE2 concentrations and are equally suitable for use based on their comparable anti-inflammatory profiles. The results of these assays provide clinically relevant information regarding intraocular penetration and anti-inflammatory efficacy of these medications in dogs with cataract. / Master of Science / Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, anti-pyretic and anti-inflammatory properties in both human and veterinary patients. Topical ophthalmic NSAIDs are commonly employed in the management of intraocular inflammation (uveitis), corneoconjunctival inflammatory disease and pre-operatively to prevent intraoperative miosis during cataract surgery. Despite their routine application in these clinical scenarios, little is known regarding the intraocular penetration and relative anti-inflammatory efficacy of the available topical ophthalmic NSAIDs in the dog. Decisions regarding which of these agents to employ are therefore based upon factors such as cost and ease of acquisition as opposed to established efficacy. Efficacy of topical anti-inflammatory medications in controlling intraocular inflammation is primarily related to the ability of the medication to penetrate the cornea and its efficacy at suppressing inflammatory mediators. The purpose of this study, therefore, is to investigate the relative intraocular penetration and anti-inflammatory efficacy of two commonly utilized topical ophthalmic NSAIDs in dogs, diclofenac 0.1% and ketorolac 0.5%. Twenty-two dogs presenting to the VTH ophthalmology service for routine cataract surgery with the presence of a mature or hypermature cataract were enrolled in a prospective, randomized clinical trial. Subjects were treated with either topical ketorolac 0.5% or topical diclofenac 0.1% ophthalmic solutions at specified times in the 24-hour period pre-operatively. Aqueous humor samples were obtained intra-operatively and stored for subsequent evaluation of drug concentrations (n=22) and prostaglandin E2 (PGE2) concentrations (n=19) via ultra performance liquid chromatography (UPLC) and enzyme-linked immunoassay (ELISA) analysis, respectively. Treatment with topical ketorolac 0.5% resulted in higher median aqueous humor drug concentrations when compared to treatment with diclofenac 0.1% (1311.6 ng/mL vs. 284.9 ng/mL). However, there was no significant difference in anti-inflammatory efficacy when comparing PGE2 concentrations between the two groups. Furthermore, no significant association was determined when drug concentration was directly compared with PGE2 concentration. The results of these assays suggest that topical ketorolac 0.5% and diclofenac 0.1% are equally suitable for use based on their comparable anti-inflammatory profiles, and provides clinically relevant information regarding intraocular penetration and anti-inflammatory efficacy of these medications in dogs with cataract.

Twenty-four healthy, mixed breed dogs were divided into four groups. Group I received a placebo PO BID, group II received an average 16.5 (range, 15.1-17.8) mg/kg buffered aspirin PO BID, group III received an average 2.2 (range, 2.0-2.4) mg/kg carprofen PO BID, and group IV received an average 12.8 (range, 11.7-13.8) mg/kg etodolac PO QD (with a placebo in the P.M.). All treatments continued for 28 consecutive days. Gastroduodenal endoscopy was performed on days – 9, 0, 5, 14 and 28. Multiple gastric biopsies were obtained endoscopically on day – 9 to determine each dog's Helicobacter spp. status. Five areas, consisting of four regions in the stomach and one in the proximal duodenum, were evaluated endoscopically, and each was assigned a score from 1 to 11 based on qualitative assessment of submucosal hemorrhage, erosion, or ulceration. These scores for each region were then summed to give a total score for each endoscopic evaluation. Erosions and submucosal hemorrhages were seen in all dogs receiving aspirin. Only minor gastric lesions were observed in the carprofen, etodolac, and control groups. No adverse clinical signs were noted in any dog given any treatment during the course of the study. There was no predilection site for lesion development in any group. Median total score on days 0, 5, 14, and 28 were as follows: group I, 5.0, 5.0, 5.0, 5.0; group II, 5.0, 27.0, 26.0, 27.5; group III, 5.0, 5.0, 6.0, 5.0; group IV, 5.0, 7.0, 5.0, 5.0, respectively. There was no significant difference between dogs receiving carprofen, etodolac, or placebo. The administration of carprofen, etodolac, or placebo to healthy dogs resulted in significantly less gastroduodenal lesion development than in dogs receiving buffered aspirin. Thirty healthy, random source, dogs were evaluated to determine the prevalence of Helicobacter spp., and to compare the ‘Campylobacter-like organism’ test (CLOtest®) to histopathologic identification of Helicobacter spp. organisms. Gastric mucosal biopsies from each of four gastric regions (cardia, pyloric antrum, greater curvature, and angularis incisura) were obtained endoscopically for use in the CLOtest® and for histopathologic evaluation. Twenty-seven of 30 dogs (90%) were positive for spiral bacteria suspected to be Helicobacter spp. by histopathologic evaluation in at least one of the four gastric regions. Three dogs (10%) were negative for Helicobacter spp. in all gastric regions by histopathologic evaluation. The CLOtest® was found to have a sensitivity, specificity, and positive predictive value of 84%, 81%, and 92%, respectively, when compared to histopathologic evaluation. When only the angularis incisura was evaluated, the sensitivity, specificity, and positive predictive value increased to 92%, 94%, and 96%, respectively. The angularis incisura had the highest, whereas the pyloric antrum had the lowest, prevalence of positive test results when compared to dogs determined to be overall Helicobacter spp. positive (histopathologic positive in at least one gastric region). The results of this study suggest the prevalence of Helicobacter spp. in apparently healthy dogs is high. For accurate and economical detection of Helicobacter spp. in a dog undergoing upper gastrointestinal endoscopy, a tissue sample should be taken from the angularis incisura for CLOtest® sampling. / Master of Science

No / High personal UVR doses can be gained during leisure activities, causing intense self-resolving inflammation (sunburn) of unprotected skin. UVR activates release of membrane fatty acids and upregulates their metabolism by cyclooxygenases (COX) and lipoxygenases (LOX) to different eicosanoids. While COX-derived prostaglandin (PG)E2 is a potent mediator of sunburn vasodilatation, LOX-derived 15-hydroxyeicosatetraenoic acid (HETE) and its lipoxin metabolites may contribute to sunburn limitation. We explored the relationships between expression of these lipid mediators and the clinical and histological outcomes, comparing responses of individuals prone and more resistant to sunburn. An acute UVR exposure of 12 SED (standard erythema dose) was applied to buttock skin of 32 white Caucasians (n = 16 phototype I/II, n = 16 phototype III/IV), and over the subsequent 72 h assessments were made of skin erythema, immunohistochemical expression of leukocyte markers, COX-2, 12-LOX, 15-LOX and nitric oxide synthase (NOS), and eicosanoid levels by LC/ESI-MS/MS. Evidence of a significant inflammatory response was seen earlier in phototype I/II with regard to expression of erythema (4h, p < 0.001), neutrophil infiltration (24 h, p = 0.01), epidermal COX-2 (24 h, p < 0.05) and 12-LOX (24 h, p < 0.01), and dermal eNOS (24 h, p < 0.05) proteins, although CD3+ lymphocyte infiltration showed an earlier increase in phototype III/IV (24 h, p < 0.05). Although erythema was equivalent at 72 h in both groups, phototype I/II showed higher PGE2 accompanied by elevated 15-HETE, and a strong positive correlation was seen between these mediators (n = 18, r = 0.805, p = 0.0001). Hence anti-inflammatory eicosanoid 15-HETE may temper the pro-inflammatory milieu in sunburn, having greater influence in those prone to sunburn than those more resistant, given the same high UVR exposure conditions. / The Wellcome Trust

The anti-inflammatory properties of four medicinal plants were investigated. These plant extracts were subjected to screening for their possible effects as antioxidative, analgesic, and anti-inflammatory agents. In the antioxidant activity, the Plantago lancelota extracts resulted in an IC50 value of 0.4 mg/mL compared to the positive control quecertin with IC50 0.04 mg/mL Plantago lanceolata inhibited COX-2 activity with IC50 values of 0.41 mg/mL. However, the COX-1 inhibition indicated an IC50 of 68.99 mg/mL. The lipoxygenase assay indicated that Plantago lanceolata was the most active plant species with an IC50 value of 4.86 mg/mL compared to the positive control (quecertin) with an IC50<2mg/mL. The nitric oxide assay of the plant extracts indicates a dose-dependent activity of our plant extracts. Likewise the cell viability result indicated a good activity at dose 100 mg/mL. / Life and Consumer Sciences / M. Sc. (Life Sciences)

Ko, Wai Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 243-257). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.ix / Abbreviations --- p.x / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Prevalence of arthritis --- p.1 / Chapter 1.2 --- Pathogenesis of arthritis --- p.4 / Chapter 1.2.1 --- Histological changes --- p.6 / Chapter 1.2.1.1 --- Synovium changes --- p.6 / Chapter 1.2.1.2 --- Articular cartilage degradation --- p.8 / Chapter 1.2.1.3 --- Bone erosions --- p.10 / Chapter 1.3 --- Western medicines for arthritis --- p.14 / Chapter 1.3.1 --- Nonsteroidal anti-inflammatory drugs (NSAIDs) --- p.15 / Chapter 1.3.2 --- Glucocorticoids (GCs) --- p.18 / Chapter 1.3.3 --- Disease modifying antirheumatic drugs (DMARDs) --- p.20 / Chapter 1.3.4 --- Biological therapies --- p.22 / Chapter 1.4 --- Traditional Chinese medicines for arthritis --- p.24 / Chapter 1.4.1 --- Ganoderma lucidum (靈芝））) --- p.26 / Chapter 1.4.1.1 --- Major chemical constituents --- p.27 / Chapter 1.4.1.2 --- Functions --- p.27 / Chapter 1.4.2 --- Cortex Phellodendri (黃柏） --- p.28 / Chapter 1.4.2.1 --- Major chemical constituents --- p.29 / Chapter 1.4.2.2 --- Traditional description --- p.29 / Chapter 1.4.2.3 --- Functions --- p.30 / Chapter 1.4.3 --- Atractylodisa Rhizoma (蒼术) --- p.31 / Chapter 1.4.3.1 --- Major chemical constituents --- p.31 / Chapter 1.4.3.2 --- Traditional description --- p.32 / Chapter 1.4.3.3 --- Functions --- p.32 / Chapter 1.4.4 --- Radix Achyranthis Bidentatae (牛膝) --- p.33 / Chapter 1.4.4.1 --- Major chemical constituents --- p.34 / Chapter 1.4.4.2 --- Traditional description --- p.34 / Chapter 1.4.4.3 --- Functions --- p.34 / Chapter 1.5 --- Animal models of arthritis --- p.36 / Chapter 1.5.1 --- Adjuvant-induced arthritis --- p.37 / Chapter 1.6 --- Aims of study --- p.42 / Chapter Chapter 2 --- Materials and Drugs --- p.44 / Chapter Chapter 3 --- Methodology --- p.49 / Chapter 3.1 --- Induction of anaesthesia --- p.49 / Chapter 3.2 --- Induction of monoarthritis --- p.49 / Chapter 3.3 --- Measurements of knee extension angles --- p.50 / Chapter 3.4 --- Measurements of knee joint sizes --- p.51 / Chapter 3.5 --- Assessment of changes in articular blood flow --- p.52 / Chapter 3.6 --- Assessment of morphological changes --- p.53 / Chapter 3.6.1 --- Fixation --- p.53 / Chapter 3.6.2 --- Decalcification --- p.53 / Chapter 3.6.3 --- Processing --- p.54 / Chapter 3.6.4 --- Embedding --- p.54 / Chapter 3.6.5 --- Sectioning --- p.55 / Chapter 3.6.6 --- Staining --- p.55 / Chapter 3.6.7 --- Scoring --- p.56 / Chapter 3.7 --- Statistical analysis --- p.57 / Chapter Chapter 4 --- Adjuvant-induced Monoarthritic Rats / Chapter 4.1 --- Adjuvant-induced monoarthritic rats (1 week) --- p.58 / Chapter 4.1.1 --- Method --- p.58 / Chapter 4.1.2 --- Results --- p.59 / Chapter 4.1.2.1 --- Body weight --- p.59 / Chapter 4.1.2.2 --- Knee joint sizes --- p.59 / Chapter 4.1.2.3 --- Knee extension angles --- p.59 / Chapter 4.1.2.4 --- Knee joint blood flow --- p.60 / Chapter 4.1.2.5 --- Histological evaluation --- p.60 / Chapter 4.1.2.5.1 --- Cell infiltration --- p.60 / Chapter 4.1.2.5.2 --- Synovial tissue proliferation --- p.61 / Chapter 4.1.2.5.3 --- Cartilage degradation --- p.61 / Chapter 4.2 --- Adjuvant-induced monoarthritic rats (2 weeks) --- p.68 / Chapter 4.2.1 --- Method --- p.68 / Chapter 4.2.2 --- Results --- p.69 / Chapter 4.2.2.1 --- Body weight --- p.69 / Chapter 4.2.2.2 --- Knee joint sizes --- p.69 / Chapter 4.2.2.3 --- Knee extension angles --- p.69 / Chapter 4.2.2.4 --- Knee joint blood flow --- p.70 / Chapter 4.2.2.5 --- Histological evaluation --- p.70 / Chapter 4.2.2.5.1 --- Cell infiltration --- p.70 / Chapter 4.2.2.5.2 --- Synovial tissue proliferation --- p.71 / Chapter 4.2.2.5.3 --- Cartilage degradation --- p.71 / Chapter 4.3 --- Discussions --- p.78 / Chapter Chapter 5 --- Effects of intra-articular injection of LS in adjuvant-induced monoarthritic rats --- p.82 / Chapter 5.1 --- Method --- p.82 / Chapter 5.2 --- Results --- p.83 / Chapter 5.2.1 --- Body weight --- p.83 / Chapter 5.2.2 --- Knee joint sizes --- p.83 / Chapter 5.2.3 --- Knee extension angles --- p.85 / Chapter 5.2.4 --- Knee joint blood flow --- p.87 / Chapter 5.3 --- Discussions --- p.98 / Chapter Chapter 6 --- Effects of oral administration of LS in adjuvant-induced monoarthritic rats --- p.102 / Chapter 6.1 --- Oral administration of LS for 6 days after induction of arthritis --- p.102 / Chapter 6.1.1 --- Method --- p.102 / Chapter 6.1.2 --- Results --- p.103 / Chapter 6.1.2.1 --- Body weight --- p.103 / Chapter 6.1.2.2 --- Knee joint sizes --- p.103 / Chapter 6.1.2.3 --- Knee extension angles --- p.105 / Chapter 6.1.2.4 --- Knee joint blood flow --- p.106 / Chapter 6.1.2.5 --- Histological evaluation --- p.107 / Chapter 6.1.2.5.1 --- Cell infiltration --- p.107 / Chapter 6.1.2.5.2 --- Synovial tissue proliferation --- p.107 / Chapter 6.1.2.5.3 --- Cartilage degradation --- p.108 / Chapter 6.2 --- Oral administration of LS for 7 days before and 7 days after induction of arthritis --- p.131 / Chapter 6.2.1 --- Method --- p.131 / Chapter 6.2.2 --- Results --- p.132 / Chapter 6.2.2.1 --- Body weight --- p.132 / Chapter 6.2.2.2 --- Knee joint sizes --- p.132 / Chapter 6.2.2.3 --- Knee extension angles --- p.134 / Chapter 6.2.2.4 --- Knee joint blood flow --- p.137 / Chapter 6.2.2.5 --- Histological evaluation --- p.137 / Chapter 6.2.2.5.1 --- Cell infiltration --- p.137 / Chapter 6.2.2.5.2 --- Synovial tissue proliferation --- p.138 / Chapter 6.2.2.5.3 --- Cartilage degradation --- p.138 / Chapter 6.3 --- Oral administration of LS for 13 days after induction of arthritis --- p.165 / Chapter 6.3.1 --- Method --- p.165 / Chapter 6.3.2 --- Results --- p.166 / Chapter 6.3.2.1 --- Body weight --- p.166 / Chapter 6.3.2.2 --- Knee joint sizes --- p.166 / Chapter 6.3.2.3 --- Knee extension angles --- p.168 / Chapter 6.3.2.4 --- Knee joint blood flow --- p.169 / Chapter 6.3.2.5 --- Histological evaluation --- p.170 / Chapter 6.3.2.5.1 --- Cell infiltration --- p.170 / Chapter 6.3.2.5.2 --- Synovial tissue proliferation --- p.170 / Chapter 6.3.2.5.3 --- Cartilage degradation --- p.171 / Chapter 6.4 --- Discussions --- p.194 / Chapter Chapter 7 --- Effects of intra-peritoneal administration of LS in adjuvant-induced monoarthritic rats --- p.203 / Chapter 7.1 --- Method --- p.203 / Chapter 7.2 --- Results --- p.204 / Chapter 7.2.1 --- Body weight --- p.204 / Chapter 7.2.2 --- Knee joint sizes --- p.205 / Chapter 7.2.3 --- Knee extension angles --- p.207 / Chapter 7.2.4 --- Knee joint blood flow --- p.209 / Chapter 7.2.5 --- Histological evaulation --- p.209 / Chapter 7.2.5.1 --- Cell infiltration --- p.209 / Chapter 7.2.5.2 --- Synovial tissue proliferation --- p.210 / Chapter 7.2.5.3 --- Cartilage degradation --- p.210 / Chapter 7.3 --- Discussions --- p.237 / Chapter Chapter 8 --- Conclusions --- p.239 / References --- p.243

The anti-inflammatory properties of four medicinal plants were investigated. These plant extracts were subjected to screening for their possible effects as antioxidative, analgesic, and anti-inflammatory agents. In the antioxidant activity, the Plantago lancelota extracts resulted in an IC50 value of 0.4 mg/mL compared to the positive control quecertin with IC50 0.04 mg/mL Plantago lanceolata inhibited COX-2 activity with IC50 values of 0.41 mg/mL. However, the COX-1 inhibition indicated an IC50 of 68.99 mg/mL. The lipoxygenase assay indicated that Plantago lanceolata was the most active plant species with an IC50 value of 4.86 mg/mL compared to the positive control (quecertin) with an IC50<2mg/mL. The nitric oxide assay of the plant extracts indicates a dose-dependent activity of our plant extracts. Likewise the cell viability result indicated a good activity at dose 100 mg/mL. / Life and Consumer Sciences / M. Sc. (Life Sciences)

The deleterious effects of MPO make it a new target for medicinal research. The aim of our study is to find promising inhibitors of MPO for using them as starting point of new anti-inflammatory drugs. Depending on previous researches on MPO inhibitors, we selected 5-fluorotryptamine as starting compounds. Using docking experiments, we designed a series of compounds derived from 5-fluorotryptamine. Two modifications were proposed: <p>& / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Thesis (MScMedSc (Pathology. Medical Microbiology))--University of Stellenbosch, 2005. / The aim of this study was to investigate the anti-inflammatory and immunosuppressive effects of the synthetic progestins, MPA and NET-A on human cells in vitro. These injectable contraceptives are used extensively throughout the world, including Africa. The potential of these two synthetic hormones to have certain immunosuppressive and GC properties have previously been shown. Therefore, it was of concern to us to investigate whether these two hormones could possibly demonstrate any of these GC-like properties at contraceptive doses. This was achieved by determining the effects of these two synthetic hormones in vitro on certain immunologic parameters. Chapter 1 is a literature review on MPA, NET and GCs. This chapter starts with a short introduction that sets the scene. The mode of action, effectiveness, sideeffects as well as previously reported relevant data on both MPA and NET-A is portrayed in this review. Research on the known GC, Dex, is also included in the section dealing with GCs, because this synthetic hormone was used as a comparative GC in all our experiments. This chapter soon makes the reader realize how much evidence exists that indicate the possible immunosuppressive effects these two contraceptive hormones, in particular MPA, could have. The possible anti-inflammatory or pro-inflammatory effects of MPA and NET-A are investigated in Chapter 2. This was done in vitro by measuring the effects of these two synthetic hormones on the inflammatory markers, IL-6 and TNFα, by means of ELISA. In this chapter we demonstrate that MPA, even at contraceptive doses, exhibits significant anti-inflammatory properties on both cytokines tested, while NETA displayed considerably less anti-inflammatory tendencies. In its true antiinflammatory manner, we found that Dex significantly inhibited the release of both inflammatory markers from human monocytes. In Chapter 3, we investigated the effects of MPA and NET-A on the activation of human lymphocytes. This was achieved by flow cytometric measurement of the expression of the activation membrane marker CD69 by CD4 and CD8 T cells. Here we discovered that MPA had a very significant inhibitory effect on the activation of both CD4+ and CD8+ T cells, while NET-A only significantly inhibited the activation of CD8+ T cells. In addition, we found that the inhibition of CD4+ and CD8+ T cell activation by MPA was more or less the same as the known GC, Dex, and in some cases even more potent. Chapter 4 consists of an investigation of the effects of MPA and NET-A on the cytokines belonging to TH1 and TH2 subsets of CD4 T cells. This was achieved by determining whether MPA and/or NET-A targeted specific subsets of T helper cells by measuring the distinct regulatory cytokines, IFNγ and IL-4. The mechanism and role of the T helper subsets are discussed in the introduction of this chapter. Our results were portrayed as a ratio of TH2: TH1 on which the statistical analysis was done. In addition to the analysis done on the ratio, we analyzed the helper subsets separately in order to determine which subset(s) were influenced. The results of this chapter showed that neither MPA nor NET-A significantly affected either one of the helper subsets, while Dex significantly decreased this ratio. After our observed effects of MPA and NET-A on CD8 T cells, it became of interest in Chapter 5 to investigate the effects of these two synthetic hormones on the CD8 T cell-specific chemokine, RANTES. This was achieved by measuring the effects MPA and NET-A had on RANTES production in vitro by means of ELISA. Surprisingly, we discovered in this chapter that MPA and NET-A enhanced RANTES production before and after activation of CD8 T cells. We also found that Dex had the same effect on RANTES production, but to a lesser degree. Finally, a general conclusion depicting the significance and implications of our results as well as possible future research that is required is presented in Chapter 6. It was of great importance to discuss and interpret the magnitude of data generated out of all our experiments to the utmost of our capabilities. We found that MPA, even at contraceptive doses, displayed significant immunosuppressive as well as anti-inflammatory properties. NET-A, on the other hand, demonstrated weaker immunosuppressive properties in our research and no significant anti-inflammatory properties. These findings could have clinical implications in females being treated with these synthetic contraceptives. We also demonstrated significant variation found amongst genders in response to MPA, NET-A and Dex.

Thesis (MScMed (Pharmacology))--University of Stellenbosch, 2005. / During the last two decades the effects of ultrasound on the transdermal diffusion of a wide variety of drugs have been extensively investigated. Because there is much uncertainty regarding the efficacy of and mechanisms involved in this mode of permeation enhancement, the objective of the study was to investigate the effect of ultrasound on the transdermal permeation of the nonsteroidal anti-inflammatory drug, diclofenac. For this purpose a dual-stage experimental design and a continuous flow-through diffusion system was used. Therapeutic levels of continuous ultrasound of 3 MHz at an intensity of 2 W/cm2 for 10 min, were used. It was clear from the present study that ultrasound enhanced the permeability of human skin to diclofenac released from a commercially available gel. These results were in contrast with those obtained for ibuprofen in an in vitro study across human skin, but in agreement with those obtained in two in vivo studies of the latter nonsteroidal anti-inflammatory drug. Steady state flux values of diclofenac remained approximately 1.26 times higher than those of controls during the 24 h of the experiment. These observations concurred with those made in two previous in vivo studies. Furthermore, the in vitro flow-through diffusion model was shown to have predictive value as an in vivo method for sonophoresis. Temperature-dependent flux rates for 3H2O across human skin were also studied. The mechanistic effects of ultrasound on the permeability characteristics of human skin have been reported on in a number of studies. Although various mechanisms have been proposed, there is no consensus regarding their relative importance. In addition the temperature-dependent flux changes of 3H2O across human skin were investigated using a continuous flow-through diffusion system. The same ultrasound parameters as in the permeability experiments were used. The results obtained showed that temperature increases of approximately 10 °C occurred following sonication. The flux changes of 3H2O across human skin between 37 °C and 42 °C were shown to be reversible. The results from the present study do not support the sonication-heating theory in which permeability changes in skin are primarily attributed to thermally-induced changes in stratum corneum lipids. It was therefore concluded that the enhancement of diclofenac permeation by sonication could not be adequately explained primarily on a thermal basis.