Thesis (M. Phil.)--University of Queensland, 2002. / Submitted for Master of Philosophy, University of Queensland June 2002 (rewrite). Includes bibliographical references.

Mefloquine hydrochloride is an antimalarial agent that has been used for the past 40 years. Numerous reports of neurological side effects have recently led the FDA to issue a strong warning regarding long-term neurological effects. This warning lead to the U.S. Army’s Special Forces and other components to discontinue its use in July of 2013. Despite reported adverse side effects, mefloquine remains in circulation and is recommended to travelers going to specific Asian countries. Mefloquine has been used as a treatment for those already infected with the malaria parasite (blood concentrations ranging from 2.1 to 23 µM), and as prophylaxis (blood concentrations averaging 3.8 µM) (Dow 2003). The purpose of this study was to quantify Mefloquine’s toxicity using spontaneously active nerve cell networks growing on microelectrode arrays in vitro and to identify compounds that alleviate or reduce toxic effects. The current literature on mefloquine toxicity is lacking electrophysiological data. These data will contribute to research on the mechanism of adverse side effects associated with mefloquine use. Sequential titration experiments were performed by adding increasing concentrations of mefloquine solution to cultured neurons. Network responses were quantified and reversibility was examined. In each network, activity decreases were normalized as a percent of reference activity yielding a mean IC50 value of 5.97 ± 0.44 (SD) µM (n=6). After total activity loss, no activity was recovered with two successive medium changes. To test for network response desensitization resulting from sequential applications over 5-6 hr periods, one-point titrations at varying concentrations were conducted with fresh networks. These experiments yielded a single concentration response curve with an IC50 value of 2.97 µM. This represents a statistically significant shift (p < 0.0001) to lower concentrations of mefloquine, demonstrating that sequential applications result in network desensitization. After mefloquine exposures, cells were evaluated for irreversible cytotoxic damage. Over a 12-hour period under 6 µM mefloquine, process beading and granulation of somal cytoplasm were observed. At 8 µM mefloquine cell stress was apparent after only 10 minutes with major glial damage and process beading at 120 minutes. In this study, quinolinic acid served as a neuroprotectant at 20 µM. There have been multiple studies on the endogenous concentrations of quinolinic acid and current literature is quite variable. Immunocompromised individuals have some of the highest blood levels of quinolinic acid (up to 20 µM). With 30 min pre-applications of quinolinic acid, the mefloquine IC50 value shifted from 5.97 ± 0.44 µM (n=6), to 9.28 ± 0.55 µM (n=3). This represents a statistically significant change to higher mefloquine concentrations and demonstrates neuroprotection.

No description available.

Malaria is currently one of the most imperative parasitic diseases of the developing world. Current effective treatment options are limited because of increasing drug resistance, treatment cost effectiveness and treatment availability. Novel drug delivery systems are a new approach for increased efficacy in the treatment of the disease. Pheroid™ technology, a proven drug delivery system, in combination with anti-malarial drugs was evaluated in this study. The aim of this study was to evaluate the possible enhancement of the efficacy of the existing anti-malarial drugs in combination with Pheroid™ technology. The efficacy of existing anti-malarial drugs in combination with Pheroids was investigated in vitro with a chloroquine RB-1-resistant strain of P. falciparum. Two different Pheroid formulations, vesicles and microsponges, were used and the control medium consisted of sterile water for injection. Parasitaemia levels were determined microscopically and expressed as a percentage. An in vivo pilot study was also conducted using the P. berghei mouse model. The mice were grouped into seven batches of three mice each. The control group was treated with a Pheroid vesicle formulation only. Three of the groups were treated with three different concentrations of chloroquine dissolved in water namely 2 mg/kg; 5 mg/kg and 10 mg/kg bodyweight (bw) respectively, while the other three groups received the same three concentrations of chloroquine entrapped in Pheroid vesicle formulations. The measure of parasite growth inhibition (percentage parasitaemia), the survival rates and the percentage chemosuppresion was determined. In the in vivo study, all concentrations of chloroquine entrapped in Pheroid vesicles showed suppressed parasitaemia levels up to 11 days post infection. From day 11, the parasitaemia increases rapidly and becomes higher than that in groups treated with chloroquine in water. Chloroquine entrapped in Pheroid vesicles showed improved activity against a chloroquine resistant strain (RB-1) in vitro. The efficacy was enhanced by 1544.62%. The efficacy of mefloquine, artemether and artesunate in Pheroid microsponges were enhanced by 314.32%, 254.86% and 238.78% respectively. It can be concluded that Pheroid™ technology has potential to enhance the efficacy of anti-malaria drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

<p>The direct addition of enolizable aldehydes and sulfonyl imines to &alpha;-halo thioesters to produce &beta;-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high <italic>syn</italic>-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic &alpha;-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic &alpha;-hydroxy aldehyde derivative is used. Using MgI₂ and Ph₃P, this method gives a wide range of aldol and Mannich products in good yields with high <italic>syn</italic>-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and &beta;-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.</p><p><p>Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral &alpha;-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.</p> / Dissertation

<p>In the first part of this dissertation, the first asymmetric anti selective aldol addition of a ketone-derived donor that is independent of the structure of the ketone is described. This transformation is facilitated by the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Under certain conditions, this transformation not only exhibits near perfect anti selectivity and enantioselectivity but also does so via thermodynamic control. Simple manipulation of the reaction conditions allows for the <italic>O</italic>-benzylation of the prepared aldol products and the subsequent removal of the ACC auxiliary to give the &beta;-benzyloxy ketone. Both symmetric and asymmetric ketones can be utilized, and aldol products that would otherwise be difficult if not impossible to prepare via conventional methods are able to be prepared.</p><p>The second part of this dissertation describes the asymmetric total synthesis of (+)- and (-)-mefloquine hydrochloride, a potent antimalarial compound. The synthesis is based on an ACC-mediated asymmetric Darzens reaction between an &alpha;-chloro ketone and a quinoline-based aldehyde. This novel methodology gives a highly enantioenriched epoxide that can be further functionalized to prepare both enantiomers of the antimalarial drug.</p> / Dissertation

Malaria is currently one of the most imperative parasitic diseases of the developing world. Current effective treatment options are limited because of increasing drug resistance, treatment cost effectiveness and treatment availability. Novel drug delivery systems are a new approach for increased efficacy in the treatment of the disease. Pheroid™ technology, a proven drug delivery system, in combination with anti-malarial drugs was evaluated in this study. The aim of this study was to evaluate the possible enhancement of the efficacy of the existing anti-malarial drugs in combination with Pheroid™ technology. The efficacy of existing anti-malarial drugs in combination with Pheroids was investigated in vitro with a chloroquine RB-1-resistant strain of P. falciparum. Two different Pheroid formulations, vesicles and microsponges, were used and the control medium consisted of sterile water for injection. Parasitaemia levels were determined microscopically and expressed as a percentage. An in vivo pilot study was also conducted using the P. berghei mouse model. The mice were grouped into seven batches of three mice each. The control group was treated with a Pheroid vesicle formulation only. Three of the groups were treated with three different concentrations of chloroquine dissolved in water namely 2 mg/kg; 5 mg/kg and 10 mg/kg bodyweight (bw) respectively, while the other three groups received the same three concentrations of chloroquine entrapped in Pheroid vesicle formulations. The measure of parasite growth inhibition (percentage parasitaemia), the survival rates and the percentage chemosuppresion was determined. In the in vivo study, all concentrations of chloroquine entrapped in Pheroid vesicles showed suppressed parasitaemia levels up to 11 days post infection. From day 11, the parasitaemia increases rapidly and becomes higher than that in groups treated with chloroquine in water. Chloroquine entrapped in Pheroid vesicles showed improved activity against a chloroquine resistant strain (RB-1) in vitro. The efficacy was enhanced by 1544.62%. The efficacy of mefloquine, artemether and artesunate in Pheroid microsponges were enhanced by 314.32%, 254.86% and 238.78% respectively. It can be concluded that Pheroid™ technology has potential to enhance the efficacy of anti-malaria drugs. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2008.

Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2009.

The aqueous solubility of an active pharmaceutical ingredient (API) is an important property that requires evaluation during early development and prior to formulation of the final product. With general, experimental, solubility testing of different APIs, the question always arises as to whether particle size had been determined beforehand or not. All available literature suggests that particle size, for pharmaceutical powders, does not significantly affect equilibrium solubility. The dissolution rate will differ according to different particle sizes, but the overall results should be identical after equilibrium is established. This study was therefore planned to investigate as to whether different particle size fractions of the same API, dissolving at different rates, would all reach solubility equilibrium within 24 hours. Also, APIs from different solubility classes were investigated, because poorly soluble substances would most likely require a longer period of time to equilibrate. The time period of 24 hours was selected, because many published solubility studies report using that interval and is it the standard for our research group also. Available APIs were selected to determine the influence (if any) of particle size on their equilibrium solubilities and the time required for attaining that status. For the purpose of this investigation, five APIs were selected from compounds at our disposal in-house, ranging from freely soluble to poorly soluble in the order: chloroquine phosphate > pyrazinamide > mefloquine hydrochloride > closantel sodium > roxithromycin. Solubility studies were successfully completed on four of the five APIs selected. For closantel sodium, pyrazinamide and roxithromycin it was demonstrated that the 24 hour test period was sufficient for the attainment of equilibrium solubility, regardless of the particle size fractions tested. Surprisingly, the only API in this study for which 24 hours was an insufficient test period was mefloquine HCl, which was not the least soluble compound tested. Further testing would be required to clarify this anomaly. What was evident from the outcomes of this investigation was that although the ubiquitous 24 hour solubility test may work well in many cases, its suitability should be reviewed on a case-by-case basis and not just for the most poorly soluble compounds. Researchers testing solubility at temperatures lower than 37°C should be especially cautious of using a standardised test period, because equilibrium solubility would take longer to achieve with less energy available to the system. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013