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North-West University

1. Grobler, Lizette. The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler .

Degree: 2014, North-West University

Malaria is one the world’s most devastating diseases. Several classes of drugs are used to treat malaria. Artemisinin combination therapy is the first line treatment of uncomplicated malaria. The artemisinin derivative, artemisone in conjunction with the Pheroid® drug delivery system, is the focus of this thesis. The impact of the Pheroid® on the bioavailability of artemisone was evaluated in vervet monkeys. The resulting artemisone plasma levels were much lower (Cmax of 47 and 114 ng/mL for reference and Pheroid® test formulations respectively) than expected for the dosages administered (60 mg/kg). The Pheroid® improved the pharmacokinetic profile of artemisone in a clinically significant manner. The metabolism of artemisone was assessed in vitro by using human and monkey liver and intestinal microsomes, and recombinant CYP3A4 enzymes. The Pheroid® inhibits the microsomal metabolism of artemisone. In addition, there is a species difference in artemisone metabolism between man and monkey since the in vitro intrinsic clearance of the reference formulation with monkey liver microsomes is ~8 fold higher in the monkey liver microsomes compared to the human liver microsomes and the estimated in vivo hepatic clearance for the monkey is almost twofold higher than in humans. Artemisone has potent antimalarial activity. Its in vitro efficacy was approximately twofold higher than that of either artesunate or dihydroartemisinin when evaluated against P. falciparum W2, D6, 7G8, TM90-C2B, TM91-C235 and TM93-C1088 parasite strains. The Pheroid® drug delivery system did not improve or inhibit the in vitro efficacy of artemisone or DHA. Artemisone (reference and Pheroid® test formulations) and metabolite M1 abruptly arrested the growth of P. falciparum W2 parasites and induced the formation of dormant ring stages in a manner similar to that of DHA. Interaction of artemisone with the p-glycoprotein (p-gp) efflux transporter was investigated. Artemisone stimulates ATPase activity in a concentration-dependent manner, whereas the Pheroid® inhibited this p-gp ATPase activity. P-gp ATPase activity stimulation was fourfold greater in human than cynomolgus monkey MDR1 expressed insect cell membranes. Artemisone alone and artemisone entrapped in Pheroid® vesicles showed moderate apical to basolateral and high basolateral to apical permeability (Papp) across Caco-2 cells. The Papp efflux ratio of artemisone and artemisone entrapped in Pheroid® vesicles were both >5, and decreased to ~1 when the p-gp inhibitor, verapamil, was added. Therefore, artemisone is a substrate for mammalian p-gp. The cytotoxic properties of Pheroid® on Caco-2 cells were assessed and the pro-Pheroid® seems to be non-toxic at concentrations of 1.25%. Vervet monkey plasma caused antibody-mediated growth inhibition of P. falciparum. Heat inactivated or protein A treatment proved useful in the elimination of the growth-inhibitory activity of the drug-free plasma. Plasma samples containing artemisone could not be analysed by the ex-vivo…

Subjects/Keywords: Artemisone; Bioavailability; Clearance; Drug delivery; Efficacy; Malaria; Metabolism; Monkey; Pheroid®; Aap; Artemisoon; Biobeskikbaarheid; Effektiwiteit geneesmiddel aflewering; Metabolisme; Opruiming

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Grobler, L. (2014). The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler . (Thesis). North-West University. Retrieved from http://hdl.handle.net/10394/12241

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Grobler, Lizette. “The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler .” 2014. Thesis, North-West University. Accessed October 30, 2020. http://hdl.handle.net/10394/12241.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Grobler, Lizette. “The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler .” 2014. Web. 30 Oct 2020.

Vancouver:

Grobler L. The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler . [Internet] [Thesis]. North-West University; 2014. [cited 2020 Oct 30]. Available from: http://hdl.handle.net/10394/12241.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Grobler L. The effect of Pheroid® technology on the bioavailability of artemisone in primates / Lizette Grobler . [Thesis]. North-West University; 2014. Available from: http://hdl.handle.net/10394/12241

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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