A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg for the degree of Master of Science / The antiinflammatory effects of lnterleukin-4 (IL-4) and the synthetic glucocorticoid dexamethasone were studied in adhered monocytes and the leukaemic cells HL-60 and THP-1, with respect to the expression of interleukin-l.B (IL-l.B), the (signalling) IL-l receptor type I (JL..IRtI), and the (inhibitory) JT_,.l receptor type n (IL-lRtII). (Abbreviation abstract) / AC 2018

Study Design: A single-blind, 2-factor (4 treatments by 8 time points) repeated-measures study design. Objective: To analytically determine dexamethasone and dexamethasone phosphate concentrations in plasma derived from proximal effluent venous blood, following cathodic iontophoresis. Methods and Measures: Six volunteers received the following dexamethasone phosphate (2.5 ml, 4 mg/ml) treatments to their wrists on separate occasions: cathodic iontophoresis (4 mA, 10 minutes or 4 mA, 20 minutes), passive application (10 or 20 minutes). Plasma samples from the ipsilateral antecubital vein were obtained 10 minutes prior to and half way through the treatment (5 or 10 minutes), at the end of the treatment (10 or 20 minutes), and posttreatment (15, 30, 60, 90, and 120 minutes). The present investigation examined: (1) the sensitivity and linearity of extraction and analysis of dexamethasone and dexamethasone phosphate; (2) the necessity for determining both; and (3) the plasma levels from proximal effluent venous blood following cathodic iontophoresis. Results: The aggregate (n= 18) of the 6-point standard curves were linear for dexamethasone (r > 0.974) and dexamethasone phosphate (r > 0.829). In vitro dephosphorylation of dexamethasone phosphate to dexamethasone occurred in plasma at 37°C and during freeze-thaw. Measurable dexamethasone or dexamethasone phosphate concentrations were absent at all time points and under all conditions in the human subjects. Conclusions. These results demonstrate the sensitivity of the current assay and the need for evaluating both forms of the drug, as in vitro dephosphorylation results in the presence of dexamethasone and dexamethasone phosphate in samples. Absence of measurable dexamethasone or dexamethasone phosphate in the proximal effluent venous blood may require re-evaluation of the extent of drug delivery during the clinical iontophoresis of dexamethasone phosphate.

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The role of inflammation poses a number of interesting facets. Frequently it appears as a mechanism of defense: at other times it appears to present itself as a pathologic situation of unknown etiology. In neither case have the underlying mechanisms been fully identified. A variety of tissues can be involved, but when occurring as a pathology entity, it is more frequently observed in the synovial tissues. As a general rule, inflammation used as a defense mechanism in benign and self- limiting. This is not the case whore it become matter of pathology. It is here where mankind has looked for effective weapons for relief.

研究目的：本論文之研究主要旨在採用兩種非甾體抗炎藥--布洛芬（IBP）及氟比洛芬（FBP）來考察一項新型的納米粒子製備技術--瞬時納米沉澱技術（FNP）。IBP和FBP具有不同理化性質，但其親油性屬大部分藥物所具的典型親油性 （log P = 2-5）。研究證實IBP和FBP有治療阿爾茨海默氏病的潛在藥效，但在血液中廣泛與血漿蛋白結合，導致其腦血管通透性很低。因此，本研究的另一目的為考察FNP製備的納米處方是否能改善此類藥物的大腦遞送。 / 方法：應用FNP，用多入口渦旋混合器（MIVM）將藥物載入聚乙二醇-聚乳酸（PEG-PLA）的納米粒中。通過改變關鍵工藝流程變量考察了變量對納米粒物理性質及穩定性的影響。使用動態光散射儀測定了納米粒粒徑和粒徑分佈，使用zeta 電位分析測定了粒子表面電荷，使用原子力顯微鏡（AFM）確定了納米粒形態，使用x射線光電子能譜（XPS）分析了粒子表面化學成分，使用高效液相色譜測定了的處方載藥量和包封率。使用MDCK和Caco-2細胞株評估了優化後納米處方的細胞通透性，使用健康小鼠進行了優化后纳米處方的体内腦攝取實驗。 / 結果：IBP和FBP納米粒的粒徑均在30-100 nm的範圍內，粒徑分佈均低於或接近0.2。AFM結果顯示，納米粒具有近球狀形態。由多次線性回歸分析各工藝流程變量對IBP納米粒粒徑的影響所得相對重要性的結果為：PLA對PEG之分子量比 > 過飽和比 > 藥物對聚合物比 > 雷諾數。用相同統計方法分析FBP樣品所得結果顯示，PLA對PEG之分子量比亦為影響粒子粒徑的最重要變量。最穩定的IBP納米處方可以在懸浮液狀態下穩定超過1個月，而FBP納米處方為2天。IBP和FBP納米粒的載藥量和包封率均分別超過25%和70%。XPS，AFM和zeta電位測定結果共同表明納米粒中的PEG均偏重位於粒子表面，而相比之下，IBP納米粒中的PEG較FBP納米粒更加偏向於分佈於粒子表面。優化後的IBP納米粒由聚山梨醇酯80包裹後，與IBP溶液相比，顯著增加了IBP的健康小鼠腦攝取量。 / 結論：應用FNP及MIVM製備的聚合物IBP和FNP納米粒，粒徑小，粒徑分佈窄，重現性高，且有較高的載藥量和包封率。納米粒的粒徑主要取決於所採用的共聚物。IBP 納米粒子明顯優越的物理穩定性可歸功於粒子表面較高的PEG濃度。用聚山梨醇酯80包裹納米粒子對於提高IBP的大腦遞送有決定性作用。 / Objectives: The present thesis work was primarily aimed at assessing a relatively novel nanoparticle (NP) production technology termed flash nanoprecipitation (FNP) using two non-steroidal anti-inflammatory drugs, ibuprofen (IBP) and flurbiprofen (FBP), with different physiochemical properties and lipophilicity typical of most drugs (log P = 2-5). Both model drugs were proven to be of potential benefits to the treatment of Alzheimer’s disease, but exhibited poor brain delivery in vivo which could be ascribed to their extensive binding with plasma proteins in the blood. Therefore another aim of the present thesis was to determine whether FNP-produced NP formulations could enhance the delivery of these drugs into the brain. / Methods: Drugs were loaded into NPs of polyethylene glycol (PEG)-polylactic acid (PLA) copolymers of different molecular weights (MWs) by FNP using a four-stream multi-inlet vortex mixer (MIVM). The influence of several key processing variables on the physical properties and stability of the NPs was investigated. The NP preparations were characterized for particle size and size distribution by dynamic light scattering (DLS) sizing analysis; surface charges by zeta potential measurement; particle morphology by atomic force microscopy (AFM); surface composition by x-ray photoelectron spectroscopy (XPS); and drug loading (DL) and encapsulation efficiency (EE) by high performance liquid chromatography. Optimal IBP NP samples were assessed in vitro for cellular permeability using Caco-2 and MDCK cell lines and in vitro for brain uptake in normal mice. / Results: Both IBP and FBP NPs exhibited mean particle size in the range of 30-100nm and polydispersity below or around 0.2. The particles were nearly spherical in shape, as examined by AFM. Multiple linear regression analysis revealed that the relative impact of the processing variables on the particle size of IBP NPs followed the order: PLA-to-PEG MW ratio > supersaturation ratio > drug-to-copolymer ratio > Reynolds number. Similar statistical analysis for FBP NPs also indicated PLA-to-PEG MW ratio being the most significant determinant of particle size. The most stable IBP and FBP NPs in suspension form could last for over 1 month and 2 days respectively. NPs with DLs > 25% and EEs > 70% could be obtained by FNP. XPS in conjunction with AFM and zeta potential analysis revealed that PEG was located more on the surfaces of both IBP and FBP NPs than in the core, but the surface PEG density was higher for the IBP NPs. Coating of optimal IBP NPs with polysorbate 80 significantly improved the brain uptake of IBP in normal mice, compared to IBP solution. / Conclusion: Polymer-stabilized IBP and FBP NPs with particle size below 100 nm and narrow size distribution can be consistently generated by FNP using the MIVM. The copolymer used is the most important determinant of particle size. The superior physical stability of the IBP NPs can be ascribed to their relatively high surface PEG density. High DLs and EEs are achievable with the FNP process. Nanoparticle coating with polysorbate 80 is critical to enhancing the delivery of IBP to the brain in normal mice. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Xinran. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 205-245). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese. / Table of Contents --- p.I / Acknowledgements --- p.VI / Abstract --- p.VIII / 摘要 --- p.X / List of Figures --- p.XII / List of Tables --- p.XVII / List of Abbreviations --- p.XIX / Chapter Chapter One --- Introduction / Chapter 1.1 --- Rationale of the study --- p.1 / Chapter 1.2 --- General review of nanoparticulate drug carrier systems --- p.4 / Chapter 1.2.1 --- Background of nanoscience --- p.4 / Chapter 1.2.2 --- Applications of nanoparticulate drug delivery systems --- p.4 / Chapter 1.2.2.1 --- Improved delivery of poorly water soluble drugs --- p.5 / Chapter 1.2.2.2 --- Targeted drug delivery --- p.6 / Chapter 1.2.2.3 --- Drug delivery across the blood brain barrier --- p.8 / Chapter 1.2.2.4 --- Other drug delivery applications --- p.10 / Chapter 1.2.3 --- Types of nanoparticulate drug delivery systems --- p.10 / Chapter 1.2.3.1 --- Nanocrystals --- p.10 / Chapter 1.2.3.2 --- Solid lipid nanoparticles --- p.11 / Chapter 1.2.3.2.1 --- Preparation methods --- p.12 / Chapter 1.2.3.2.2 --- Drug delivery --- p.12 / Chapter 1.2.3.3 --- Polymeric nanoparticles --- p.14 / Chapter 1.2.3.3.1 --- Preparation methods --- p.15 / Chapter 1.2.3.3.2 --- Drug delivery --- p.17 / Chapter 1.2.4 --- Characterization of nanoparticulate drug delivery systems --- p.20 / Chapter 1.2.4.1 --- Particle size and size distribution --- p.21 / Chapter 1.2.4.2 --- Morphology --- p.21 / Chapter 1.2.4.3 --- Zeta potential --- p.23 / Chapter 1.2.4.4 --- Surface chemical composition --- p.23 / Chapter 1.2.4.5 --- Crystallinity --- p.24 / Chapter 1.3 --- Flash Nanoprecipitation technique --- p.25 / Chapter 1.3.1 --- Mechanism and evolution --- p.25 / Chapter 1.3.2 --- Applications --- p.30 / Chapter 1.4 --- Ibuprofen and flurbiprofen --- p.32 / Chapter 1.4.1 --- General characteristics --- p.32 / Chapter 1.4.2 --- Physicochemical properties --- p.33 / Chapter 1.4.3 --- New therapeutic indications --- p.34 / Chapter 1.5 --- Scope of the thesis --- p.36 / Chapter Chapter Two --- Influence of Processing Variables on the Physical Properties and Stability of Ibuprofen and Flurbiprofen Nanosuspensions / Chapter 2.1 --- Introduction --- p.38 / Chapter 2.2 --- Materials and Methods --- p.39 / Chapter 2.2.1 --- Materials --- p.39 / Chapter 2.2.2 --- Solubility of ibuprofen and flurbiprofen in water and acetone mixtures --- p.39 / Chapter 2.2.3 --- Nanoparticle formulation preparation --- p.40 / Chapter 2.2.3.1 --- Determination of the minimum Reynolds number (Re) for homogenous mixing --- p.40 / Chapter 2.2.3.2 --- Effects of processing parameters on particle size and size distribution of ADCP-protected IBP and FBP nanoparticles. --- p.41 / Chapter 2.2.4 --- Particle size and size distribution measurement --- p.42 / Chapter 2.2.5 --- Statistics --- p.42 / Chapter 2.2.6 --- Assessment of nanosuspension stability --- p.42 / Chapter 2.3 --- Results and discussion --- p.43 / Chapter 2.3.1 --- Solubilities of ibuprofen and flurbiprofen in water and acetone mixtures --- p.43 / Chapter 2.3.2 --- Determination of the minimum Re for homogenous mixing --- p.44 / Chapter 2.3.3 --- Effects of processing parameters on particle size and size distribution of the ADCP-protected IBP and FBP nanoparticles. --- p.47 / Chapter 2.3.3.1 --- Effect of solvent type --- p.47 / Chapter 2.3.3.2 --- Effect of PLA-to-PEG MW ratio --- p.64 / Chapter 2.3.3.3 --- Effect of supersaturation --- p.64 / Chapter 2.3.3.4 --- Effect of Re --- p.70 / Chapter 2.3.3.5 --- Effect of drug-to-ADCP ratio --- p.71 / Chapter 2.3.4 --- Effects of processing parameters on the stability of ADCP-stabilized IBP and FBP nanoparticles --- p.72 / Chapter 2.3.4.1 --- Three-day stability --- p.72 / Chapter 2.3.4.2 --- Long-term stability --- p.83 / Chapter 2.4 --- Summary --- p.85 / Chapter Chapter Three --- Drying of Ibuprofen Nanoparticle Suspensions / Chapter 3.1 --- Introduction --- p.86 / Chapter 3.2 --- Materials and Methods --- p.88 / Chapter 3.2.1 --- Materials --- p.88 / Chapter 3.2.2 --- Preparation of IBP nanoparticle formulations with hydrophilic stabilizers or at refrigerated temperature --- p.89 / Chapter 3.2.3 --- Dialysis of nanoparticle formulations --- p.89 / Chapter 3.2.4 --- Freeze-thawing of selected nanoparticle preparations --- p.89 / Chapter 3.2.5 --- Freeze-drying of nanoparticle formulations --- p.90 / Chapter 3.2.6 --- Reconstitution --- p.90 / Chapter 3.2.7 --- Hydrogen bonding coacervate precipitation --- p.91 / Chapter 3.3 --- Results and discussion --- p.91 / Chapter 3.3.1 --- Preparation and dialysis of IBP nanoparticle formulations with hydrophilic stabilizers --- p.92 / Chapter 3.3.2 --- Freeze-drying using cryoprotectants and lyoprotectants --- p.94 / Chapter 3.3.3 --- Freeze-drying with different concentrations of glucose, sucrose and PVA --- p.101 / Chapter 3.3.4 --- Freeze-drying of nanoparticles prepared under other processing conditions --- p.105 / Chapter 3.3.5 --- Hydrogen bonding coacervate precipitation --- p.108 / Chapter 3.4 --- Summary --- p.110 / Chapter Chapter Four --- Physicochemical Characterization of Ibuprofen and Flurbiprofen Nanoparticles / Chapter 4.1 --- Introduction --- p.111 / Chapter 4.2 --- Materials and Methods --- p.112 / Chapter 4.2.1 --- Materials --- p.112 / Chapter 4.2.2 --- Encapsulation efficiency (EE) and drug loading (DL) of IBP nanoparticles --- p.112 / Chapter 4.2.3 --- HPLC analysis of IBP and FBP --- p.113 / Chapter 4.2.4 --- Nanoparticle morphology --- p.114 / Chapter 4.2.4.1 --- SEM --- p.114 / Chapter 4.2.4.2 --- AFM --- p.114 / Chapter 4.2.5 --- Zeta potential measurement --- p.115 / Chapter 4.2.6 --- Surface composition analysis --- p.115 / Chapter 4.3 --- Results and discussion --- p.116 / Chapter 4.3.1 --- Encapsulation efficiency (EE) and drug loading (DL) of IBP nanoparticles --- p.116 / Chapter 4.3.2 --- Nanoparticle morphology --- p.121 / Chapter 4.3.3 --- Surface charges of the nanoparticles --- p.126 / Chapter 4.3.4 --- Surface composition of nanoparticles --- p.128 / Chapter 4.4 --- Summary --- p.145 / Chapter Chapter Five --- Cellular Permeability and In Vivo Brain Uptake of Ibuprofen Nanoparticles / Chapter 5.1 --- Introduction --- p.146 / Chapter 5.2 --- Materials and methods --- p.148 / Chapter 5.2.1 --- Materials --- p.148 / Chapter 5.2.2 --- Methods --- p.148 / Chapter 5.2.2.1 --- Cellular permeability study --- p.148 / Chapter 5.2.2.1.1 --- Cell culture --- p.148 / Chapter 5.2.2.1.2 --- Cell viability study --- p.149 / Chapter 5.2.2.1.3 --- MDCK and Caco-2 cell monolayer permeability assay --- p.150 / Chapter 5.2.2.2 --- In vivo brain uptake study --- p.151 / Chapter 5.2.2.2.1 --- HPLC-UV analysis --- p.151 / Chapter 5.2.2.2.2 --- Preparation of calibration samples --- p.151 / Chapter 5.2.2.2.3 --- Sample preparation --- p.152 / Chapter 5.2.2.2.4 --- Validation of assay methods --- p.153 / Chapter 5.2.2.2.5 --- Animal experiments --- p.154 / Chapter 5.2.2.2.6 --- Data Analysis --- p.155 / Chapter 5.3 --- Results and discussion --- p.155 / Chapter 5.3.1 --- Cellular permeability study --- p.155 / Chapter 5.3.1.1 --- Cell viability study --- p.155 / Chapter 5.3.1.2 --- MDCK and Caco-2 cell monolayer permeability assay --- p.157 / Chapter 5.3.2 --- In vivo brain uptake study --- p.158 / Chapter 5.3.2.1 --- Method validation --- p.158 / Chapter 5.3.2.2 --- Brain uptake of IBP nanoparticles --- p.159 / Chapter 5.4 --- Summary --- p.166 / Chapter Chapter Six --- Conclusions and Future Studies / Chapter 6.1. --- Conclusions --- p.167 / Chapter 6.2. --- Future studies --- p.172 / Appendices --- p.174 / References --- p.205

Schistosome is the causative agent of schistosomiasis which is one of the world's most prevalent tropical diseases. In the skin of infected host, significant inflammatory response to the parasite is not observed. Previous studies from Schistosoma mansoni showed that this subdued inflammatory response was due to a 16-KDa protein, Sm16, which is present abundantly in the secretions of schistosomulae. Provided that Schistosoma japonicum shares the same infective pathway as S. mansoni by penetrating the skin, it seems logical that S. japonicum has a protein with a similar role to Sm16 to down-regulate host immune responses. According to the cDNA sequence of Sm16, a corresponding gene (designated Sj16) of Sm16 has previously been amplified and cloned from the cercarial cDNA of S. japonicum. Sequence analysis showed that Sj16 shares 99% identity with Sm16 in its nucleotide sequence, and 100% identity in its protein sequence. While previous studiers reported their failure in obtaining the soluble recombinant protein of Sm16, we expressed and purified the recombinant Sj16 (rSj16) from E. coli in the present study. Western blot and ELISA analysis showed that S. japonicum-infected rabbit sera could not recognize rSj16, indicating that native Sj16 might fail to induce circulating antibodies during S. japonicum infection. In the in vivo study, rSj16 dramatically suppressed not only the recruitment of leukocytes to the peritoneal cavity of BALB/c mice injected with thioglycollate, but also the maturation of thioglycollate-induced peritoneal macrophages. The suppression effect was accompanied by a marked up-regulation of IL-10 and IL-1RA transcripts, and down-regulation of IL-12p35, IL-1beta and MIP-2 transcripts in peritoneal cells. Further analysis revealed that rSj16 also inhibited both humoral and cellular immune responses to heterologous antigens. In addition, rSj16 was found to induce macrophage differentiation of the murine myeloid leukemia WEHI-3B (JCS) cells, and regulate the differentiation of mouse hematopoietic cells towards the macrophage lineage. Although previous studies indicated the involvement of endogenous IL-1alpha, IL-1beta and TNF-alpha in the macrophage differentiation of JCS cells, the results from this study suggested that rSj16-induced JCS cell differentiation do not rely on the endogenous production of these three cytokines. This is the first study to successfully express and purify sufficient soluble rSj16, and demonstrate the anti-inflammatory and immunomodulatory effects of the rSj16. / Hu, Shaomin. / Adviser: Ming Chiu Fung. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0210. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 139-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (M.S.)--University of Michigan, 1993.

Dissertation submitted in partial compliance with the requirements for a Masters Degree in Technology: Chiropractic, Durban University of Technology, 2009. / Headaches are one of the most common clinical conditions in medicine, and 80% of these are tension-type headaches (TTH). TTH has a greater socioeconomic impact than any other type of headache due to its prevalence. Within the TTH category, episodic TTH are more prevalent than chronic TTH. The mainstay in the treatment of TTH are simple analgesics and NSAIDs. Unless contraindicated, NSAIDs are often the most effective treatment for ETTH. However patients suffering with TTH tend to relate their headaches to increased muscle stiffness in the neck and shoulders and thus the non-pharmacological treatment of ETTH could be directed at the associated musculoskeletal components of ETTH. It is therefore proposed that the Kinesio Taping® Method may have an effect in the treatment of the muscular component of ETTH. Method: This study was a prospective randomised clinical trial with two intervention groups (n=16) aimed at determining the relative effectiveness of a NSAID and the Kinesio Taping® Method in the treatment of ETTHs. The patients were treated at 5 consultations over a 3 week period. Feedback was obtained using the: NRS – 101, the CMCC Neck Disability Index and a Headache Diary. Results: The Headache Diary showed a reduction in the presence and number, mean duration and pain intensity of ETTH in both groups. These treatment effects were sustained after the cessation of treatment with the exception of mean pain intensity in the Kinesio Taping® Method group. The mean NRS score decreased in both groups but at a slightly faster rate in the Kinesio Taping® Method group. The CMCC showed an improvement in the functional ability of the patients in both groups. Conclusion: There seems to be no significant difference in the relative effectiveness of the treatment modalities. We can thus state that the overall short-term reduction in symptomatology supports the use of NSAIDs or Kinesio Taping® Method in the treatment of ETTH.