Chen Xiao. / "April 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

Effects of gastrointestinal transit on plasma concentrations of drugs from enteric-coated pellet formulations were demonstrated using pharmacokinetic models describing plasma concentrations of drugs from various enteric-coated pellet formulations. Gastric emptying time, lag time of emptying, and drug release rate from pellets in the small intestine, along with other pharmacokinetic parameters of drugs, were used to construct pharmacokinetic models. The models were then evaluated by comparing simulated plasma concentrations of model drugs from Monte Carlo simulations to observed plasma concentrations of these drugs from the literature. Results showed that the models described plasma concentrations of drugs from enteric-coated pellet formulations very well. Pharmacokinetic models describing plasma concentrations of drug from mixed immediate-release and enteric-coated pellet formulations were also used in simulations of bioequivalence studies. Results from the research are very useful in designing generic products of mixed pellet formulation and in refining or selecting the final product for actual bioequivalence study. Development of crushable enteric-coated formulations was presented. Nonpareil sugar pellets were spray-loaded with mixed amphetamine salts. Drug-loaded pellets were subsequently spray-coated with enteric polymer, hydrophilic gel-forming polymer, enteric polymer and/or mixture of insoluble polymer and hydrophilic polymer. The resulting pellets were then spray-coated with disintegrant and compressed to form crushable tablets. Dissolution testing of both non-compacted crushable enteric-coated tablets and crushed tablets showed that the intact crushable tablet formulations and the crushed tablet formulations were able to prevent the majority of the drug from being released in a simulated gastric dissolution medium within first 2 hours. Concept and formulations of "leaky" enteric-coated pellets were presented. "Leaky enteric-coated pellets" formulation is defined as enteric-coated pellets that allow some of the drug to be released from the formulation in acidic dissolution medium. Different approaches of making leaky enteric-coated pellets using spray-coating techniques were presented. Plasma concentrations of drug from leaky enteric-coated pellet formulations were simulated using computer simulations. The present research was based on the hypothesis that leaky enteric-coated pellets formulations were able to provide sustained-release effect on plasma concentration profiles of drugs that have the absorption window without jeopardizing their bioavailability or with improved bioavailability. / Graduation date: 2005

Graduation date: 1998

Thesis (M. Sc.)(Chemistry)--University of Pretoria, 2005. / Includes summary. Includes bibliographical references. Available on the Internet via the World Wide Web.

No description available.

There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver’s metabolic capacity, may be associated with adverse effects. In this study, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1 mg or 5 mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation (p < 0.05), however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid.

There are increasing concerns that exposure to unmetabolized folic acid, which results from folic acid intakes that overwhelm the liver’s metabolic capacity, may be associated with adverse effects. In this study, we examined the folic acid status of women of reproductive age in relation to dietary intake and the effect of folic acid supplementation (1.1 mg or 5 mg). Plasma unmetabolized folic acid was not significantly correlated with folate intake estimated by food frequency questionnaire or biomarkers. The proportion of women with detectable levels of unmetabolized folic acid increased from 65% to 100% after twelve weeks of supplementation (p < 0.05), however, the increase in concentrations did not reach statistical significance and the effect was not sustained. Moreover, there were no significant differences between the two doses. This suggests that there are mechanisms by which the body adapts to high folic acid intakes to limit exposure to unmetabolized folic acid.

Sustained concentrations of active compound were maintained in vitro and in vivo for an oral and a parenteral dosage form respectively. The vehicle of a oral dosage form was modified and the molecular structure of a parenteral dosage form was modified. An oral dosage form was tested in vitro using dissolution apparatus. A parenteral dosage form was tested in vivo using rats. A new oral suspension dosage form for acetylsalicylic acid was compared to two controlled release forms and two immediate release dosage forms which are currently commercially available. A parenteral thrombomodulin analogue conjugated to polyethylene glycol was compared to the unconjugated thrombomodulin analogue. In each case the goal was to maintain sustained concentrations of active compound. / Graduation date: 1991

University of Macau / Institute of Chinese Medical Sciences

Natural Health Products (NHPs) are regulated and require safety and efficacy information for their approval into the Canadian market. Flaxseed lignans are NHPs with putative health benefits in a number of chronic diseases. In the flaxseed the principal lignan is secoisolariciresinol diglucoside (SDG). After oral consumption SDG is converted into its aglycone secoisolarisiresinol (SECO) and subsequently into mammalian lignans (enterodiol (ED) and enterolactone (EL)) in the presence of gastrointestinal microflora. In my Ph.D. research, I conducted a series of in vitro and in vivo PK studies to enable the design of prospective safety and efficacy studies of lignans. In vitro PK studies in the Caco-2 cell monolayer suggest that SDG has poor intestinal permeation and intestinal conjugation characteristics (glucuronidation and sulphation); however, SECO, ED and EL undergo passive permeation and extensive conjugation (SECO<ED<EL) by Caco-2 cells. Single oral and intravenous dose pharmacokinetics in male Wistar rats showed that these lignans exhibit high volumes of distribution, high systemic clearance values, and short half-lives. EL was fatal to the rats at the given intravenous and oral doses while SDG was not orally bioavailable and may not likely be the bioactive lignan form. I investigated the effect of acute SDG and chronic BeneFlax oral administration in blunting the postprandial hyperglycemia in healthy and streptozotocin induced male Wistar type II diabetic rats, respectively; however, my pilot study failed to show any change in postprandial blood glucose levels. Further, I conducted selective cytotoxicity evaluations in prostate and breast cancer cell lines. Only EL caused selective cytotoxicity of breast and prostate cancer cells with IC50 values that may be physiologically achievable. To elucidate the mechanism of action, I tested concentration and time dependent effects of EL on various enzymes and transcription factors of fatty acid metabolism at mRNA and protein levels in cancer (PC-3) and normal (RWPE-1) prostate cell lines. mRNA and protein expression analysis showed a concentration and time dependent inhibition of fatty acid synthase (FAS) and suggested that EL may inhibit FAS to show anti-proliferative effect on prostate cancer. The pharmacokinetic characteristics and pharmacodynamics properties of flaxseed lignans warrant their further investigation.