Absorption of drug substances across the intestinal epithelium is a complex and dynamic process. Counter transport proteins are responsible for the efflux of specific drug molecules after they have been absorbed. One of the key counter transport efflux proteins, which is of importance in this study, is P–glycoprotein. The efflux pump P–glycoprotein plays a major role in altering the pharmacokinetics of a wide variety of drugs limiting their absorption and therefore also bioavailability. Many flavonoids have been shown to interact with P–glycoprotein mediated efflux in vitro studies. Numerous in vitro methods have been used to study drug absorption across the intestinal membranes, but it is often not possible to use only one in vitro model to accurately predict permeability characteristics. The purpose of this study was to determine the effect of four selected hydroxy– and methoxy– flavonoids on the in vitro transport of Rhodamine 123, a known P–gp substrate, across excised rat and pig intestinal tissue using the Sweetana–Grass diffusion apparatus. The results were further used to determine if the two different animal tissue models corresponded with regard to the flavonoids' effects on P–glycoprotein related efflux. Two control groups were included in the experimental design. In the negative control group, the transport of Rhodamine 123 was tested alone and no modulator was added. In the positive control group, the transport of Rhodamine 123 was determined in the presence of Verapamil, which is a known P–glycoprotein inhibitor. The experiments with the flavonoids Morin, Galangin, 6–Methoxyflavone and 7–Methoxyflavone were done in triplicate to determine repeatability of the results. The transport of Rhodamine 123 was evaluated in both the apical to basolateral (absorptive) and basolateral to apical (secretory) directions. The relative transport of Rhodamine 123, the apparent permeability coefficient (P app) values and flux (J) values in both directions as well as the efflux ratio (ER) and net flux (J net) were calculated. The concentration Rhodamine 123 present in the acceptor chamber was determined by means of a validated HPLC method. Statistical analysis was used to compare the results of the test groups with the control groups in order to indicate significant differences. It has been found that Morin, Galangin and 6–Methoxyflavone have a significant inhibitory effect on the Rhodamine 123 efflux (probably P–glycoprotein related) in both the rat and pig intestinal tissue models with p–values smaller than 0.05. On the other hand, 7–Methoxyflavone showed a significant effect on the efflux of Rhodamine 123 in the pig intestinal tissue model (p < 0.05) but not in the rat intestinal tissue model (p > 0.05). These flavonoids may increase the bioavailability of drugs that are substrates for P–glycoprotein and thereby cause clinically significant pharmacokinetic interactions, however, this should be confirmed with in vivo studies. On the other hand, these flavonoids may be used for drug absorption enhancement when applied under controlled circumstances. With regard to the different animal tissue models used it can be concluded that data obtained from the rat intestinal tissue model cannot be compared and extrapolated to data obtained from the pig intestinal tissue model. It is recommended that the in vitro results be correlated to in vivo findings to identify the most suitable model. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Absorption of drug substances across the intestinal epithelium is a complex and dynamic process. Counter transport proteins are responsible for the efflux of specific drug molecules after they have been absorbed. One of the key counter transport efflux proteins, which is of importance in this study, is P–glycoprotein. The efflux pump P–glycoprotein plays a major role in altering the pharmacokinetics of a wide variety of drugs limiting their absorption and therefore also bioavailability. Many flavonoids have been shown to interact with P–glycoprotein mediated efflux in vitro studies. Numerous in vitro methods have been used to study drug absorption across the intestinal membranes, but it is often not possible to use only one in vitro model to accurately predict permeability characteristics. The purpose of this study was to determine the effect of four selected hydroxy– and methoxy– flavonoids on the in vitro transport of Rhodamine 123, a known P–gp substrate, across excised rat and pig intestinal tissue using the Sweetana–Grass diffusion apparatus. The results were further used to determine if the two different animal tissue models corresponded with regard to the flavonoids' effects on P–glycoprotein related efflux. Two control groups were included in the experimental design. In the negative control group, the transport of Rhodamine 123 was tested alone and no modulator was added. In the positive control group, the transport of Rhodamine 123 was determined in the presence of Verapamil, which is a known P–glycoprotein inhibitor. The experiments with the flavonoids Morin, Galangin, 6–Methoxyflavone and 7–Methoxyflavone were done in triplicate to determine repeatability of the results. The transport of Rhodamine 123 was evaluated in both the apical to basolateral (absorptive) and basolateral to apical (secretory) directions. The relative transport of Rhodamine 123, the apparent permeability coefficient (P app) values and flux (J) values in both directions as well as the efflux ratio (ER) and net flux (J net) were calculated. The concentration Rhodamine 123 present in the acceptor chamber was determined by means of a validated HPLC method. Statistical analysis was used to compare the results of the test groups with the control groups in order to indicate significant differences. It has been found that Morin, Galangin and 6–Methoxyflavone have a significant inhibitory effect on the Rhodamine 123 efflux (probably P–glycoprotein related) in both the rat and pig intestinal tissue models with p–values smaller than 0.05. On the other hand, 7–Methoxyflavone showed a significant effect on the efflux of Rhodamine 123 in the pig intestinal tissue model (p < 0.05) but not in the rat intestinal tissue model (p > 0.05). These flavonoids may increase the bioavailability of drugs that are substrates for P–glycoprotein and thereby cause clinically significant pharmacokinetic interactions, however, this should be confirmed with in vivo studies. On the other hand, these flavonoids may be used for drug absorption enhancement when applied under controlled circumstances. With regard to the different animal tissue models used it can be concluded that data obtained from the rat intestinal tissue model cannot be compared and extrapolated to data obtained from the pig intestinal tissue model. It is recommended that the in vitro results be correlated to in vivo findings to identify the most suitable model. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

The main goal of this study was to evaluate whether three dimensional musculoskeletal modelling (3D) is effective in assessing the safety and efficacy of resistance training equipment. The focus of the evaluation was on the biomechanical and anthropometric considerations of the end-user. 3D musculoskeletal modelling was used to evaluate four pieces of resistance training equipment, namely the seated biceps curl, abdominal crunch, seated row and chest press. Three anthropometric cases were created; these represented a traditional 5th percentile female as well as a 50th and 95th percentile male based on body mass index (BMI). Resistance on the training machines was set at fifty percent of the functional strength one repetition maximum (1RM), for each anthropometric case and piece of exercise equipment two repetitions were performed except for the abdominal crunch model during which four repetitions were simulated. Each piece of equipment presented unique challenges. In three of the four studies (seated biceps curl, seated row and chest press) the default model created by the modelling software was not adequate to solve the forward dynamics simulations and thus adjustments had to be made to the default model in order to complete the modelling process. 3D musculoskeletal modelling by means of LifeModelerTM software was able to identify some potential risk for musculoskeletal injury as well as highlight the discrepancies between the anthropometric cases, specifically the accommodation of the 5th percentile female and the machines’ engineered adjustability. 3D musculoskeletal modelling has the potential to indicate shortcomings in resistance training equipment design. Therefore it appears as if 3D musculoskeletal modelling can be used to evaluate resistance training equipment design however the limitations as indicated by this study must be taken into consideration especially when using default models.AFRIKAANS: Die doel van die studie was om die effektiwiteit van driedimensionele (3D) muskuloskeletale modellering te evalueer in terme van die tegniek se vermoë om die veiligheid en doeltreffendheid van weerstands oefenapparaat te evalueer. Die fokus van die evaluasie was op die biomeganiese en antropometriese oorwegings van die end-gebruiker. 3D muskuloskeletale modellering was gebruik in die evaluasie van vier weerstands oefenapparate genaamd die sittende biceps krul, abdominale krul, sittende roei en sittende borsstoot. Drie antropometriese gevalle is geskep, die het ‘n tradisionele 5e persentiel vrou, sowel as ‘n 50ste en 95ste persentiel man voorgestel en was gebasseer op liggaamsmassa indeks waardes. Die eksterne weerstand van die apparaat was bepaal teen vyftig persent van die funsionele krag een-repetisie- maksimum vir elk van die antropometriese gevalle en twee repetisies is uitgevoer behalwe vir die abdominale krul waartydens vier repetisies gesimuleer is. Elke apparaat het unieke uitdagings gestel. In drie van die vier studies (sittende biceps krul, sittende roei en sittende borsstoot) was die standaard model van die sagteware onvoldoende om die voorwaards dinamiese simulasie op te los en moes aanpassings aan die modelle gemaak word vir suksesvolle simulasies. Die modellerings proses met die Lifemodeler™ sagteware kon potensiële risiko vir muskuloskeletale besering sowel as verskille tussen die verskeie antropometriese gevalle uitwys. Dit was veral opvallend vir die akkomodasie van die 5e persentiel vrou asook betreffende die apparaat se vervaardigde verstelbaarheid. 3D muskuloskeletale modellering beskik oor die vermoë om voorstelle vir verbetering in die ontwerp van weerstands oefenapparaat uit te wys. Dit blyk dus dat 3D muskuloskeletale modellering beslis gebruik kan word vir die evaluasie van weerstands oefenapparaat ontwerp, die beperkings van die studie moet egter in gedagte gehou word, veral wanneer standaard modelle gebruik word. / Thesis (DPhil)--University of Pretoria, 2011. / Biokinetics, Sport and Leisure Sciences / unrestricted