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You searched for subject:( halofantrine). Showing records 1 – 2 of 2 total matches.

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University of Alberta

1. Patel, Jigar. The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine.

Degree: PhD, Faculty of Pharmacy and Pharmaceutical Sciences, 2010, University of Alberta

In the past, hyperlipidemia (HL) has been shown to affect the pharmacokinetic and pharmacodynamic properties of lipophilic drugs extensively bound to lipoproteins, including halofantrine (HF). The present thesis examined the effect of HL on the biodistribution, metabolism and electrocardiographic (ECG) effects of HF in the poloxamer 407 rat model of HL. The HL state caused unexpected changes in the distribution of HF enantiomers. In contrast to plasma, concentrations of desbutyl-HF (DHF) were much higher in highly perfused tissues. Following in vitro incubation of racemic HF and DHF, HF and DHF enantiomers shifted from the lipoprotein deficient fraction to triglyceride-rich fractions in HL plasma. No significant differences were noted in HF metabolism between NL and HL liver microsomes. It appears that both reduced plasma unbound fraction and lipoprotein associated directed uptake of lipoprotein-bound drug by tissues play roles in enantiomer biodistribution. In everted gut metabolism, formation of DHF enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in DHF:HF ratio of (-)-enantiomers. Pre-treatment of rats with peanut oil had no significant effect on DHF formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal CYP450. The above results were consistent with previous in vivo evaluations showing that the DHF to HF ratio was decreased by the ingestion of a high fat meal. In the ECG study, HL by itself had no effect on the ECG. In HL rats, plasma but not heart concentrations of the HF enantiomers were significantly higher compared to NL rats. DHF did not impart significant ECG prolonging effects after HF administration. The unbound fraction of HF was the controlling factor for drug uptake by the heart. Despite the lack of difference in HF heart concentrations, the QT and QTc intervals were significantly higher in HL compared to NL rats, suggesting a greater vulnerability towards HF induced QT interval prolongation in the HL state. The HL serum resulted in decreased metabolism of HF enantiomers in the isolated primary rat hepatocytes. Studies with LLC PK1 and NRK 52E cells showed that HF is not a substrate of P-glycoprotein transporters.

Subjects/Keywords: Metabolism; Electrocardiography; Hepatocyte; Biodistribution; LLC-PK1 and NRK 52E; Halofantrine; Microsomes; Hyperlipidemia; Pharmacokinetics; Everted small intestine; Pharmacodynamics

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

APA (6th Edition):

Patel, J. (2010). The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine. (Doctoral Dissertation). University of Alberta. Retrieved from https://era.library.ualberta.ca/files/bn999768g

Chicago Manual of Style (16th Edition):

Patel, Jigar. “The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine.” 2010. Doctoral Dissertation, University of Alberta. Accessed August 11, 2020. https://era.library.ualberta.ca/files/bn999768g.

MLA Handbook (7th Edition):

Patel, Jigar. “The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine.” 2010. Web. 11 Aug 2020.

Vancouver:

Patel J. The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine. [Internet] [Doctoral dissertation]. University of Alberta; 2010. [cited 2020 Aug 11]. Available from: https://era.library.ualberta.ca/files/bn999768g.

Council of Science Editors:

Patel J. The effect of oral lipids and lipoproteins on the biodistribution, metabolism and electrocardiographic side-effects of halofantrine. [Doctoral Dissertation]. University of Alberta; 2010. Available from: https://era.library.ualberta.ca/files/bn999768g


University of Otago

2. Thomas, Nicky Dieter. Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) .

Degree: 2012, University of Otago

Purpose: The broader application of self-nanoemulsifying drug delivery systems (SNEDDS) has been hampered by the limited solubility of lipophilic, hydrophobic drugs, often requiring the inconvenient dosing of multiple units. In addition, the drug’s solubility in SNEDDS has not been fully utilised due to the current paradigm that crystalline drug precipitation during the digestion of the delivery system should be avoided. However, recently it has been reported that drugs might precipitate in an amorphous form during in vitro digestion. The purpose of this thesis was to investigate the feasibility of SNEDDS containing drug above the saturation solubility (super-SNEDDS) as a means to increase the drug load in SNEDDS. Methods: Using a partial phase diagram approach, mixtures of lipids, surfactant, and cosolvent were screened for their ability to generate fine dispersions in aqueous medium while keeping the lipid/surfactant/cosolvent ratio constant. Pre-concentrates were loaded with increasing amounts of the poorly water-soluble drug simvastatin (SIM) and were evaluated by dynamic light scattering with regard to their dispersion characteristics in water and simulated gastric fluid. The effect of increasing drug loads on the ability to keep SIM in solution was determined using the dynamic in vitro lipolysis. Following ultracentrifugation, the aqueous phase and the pellet were quantified for SIM by HPLC. Super-SNEDDS containing SIM up to 200% of the drug’s equilibrium solubility (Seq) were produced by subjecting the pre-concentrates to a heating and cooling cycle, while the drug load of halofantrine (HAL) super-SNEDDS was 150%. All super-SNEDDS were regularly investigated by polarising light microscopy to determine the physical stability during storage at room temperature. The super-SNEDDS were characterised during in vitro lipolysis and compared with single units or multiple units of conventional SNEDDS (75% drug load). The solid state properties of precipitates obtained after in vitro lipolysis were characterised by XRPD and dissolution studies of the precipitates were carried out in lipolysis medium. The in vivo performance after oral administration of super-SNEDDS (one capsule 150% drug load) was compared with one capsule SNEDDS (75% drug load) and two capsules SNEDDS (75% drug load), containing the same dose as super-SNEDDS. Results: Increasing the drug loads from 25% to 100% Seq affected the dispersion characteristics of SNEDDS depending on the type of lipid and surfactant used. During in vitro lipolysis of SIM (super-) SNEDDS the concentration of SIM in the aqueous phase increased proportionally to the drug loads and amount of SNEDDS employed, generating an initial supersaturation of the lipolysis medium followed by rapid precipi-tation of SIM. In contrast, rapid precipitation was observed for HAL super-SNEDDS from the beginning of in vitro lipolysis and the concentration of HAL in the aqueous phase could only be increased when multiple units of super-SNEDDS were subjected to in vitro lipolysis. Both HAL and… Advisors/Committee Members: Rades, Thomas (advisor).

Subjects/Keywords: supersaturation; super-SNEDDS; lipid-based formulations; in vitro lipolysis; amorphous precipitate; in vivo; dogs; simvastatin; halofantrine

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

APA (6th Edition):

Thomas, N. D. (2012). Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) . (Doctoral Dissertation). University of Otago. Retrieved from http://hdl.handle.net/10523/2518

Chicago Manual of Style (16th Edition):

Thomas, Nicky Dieter. “Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) .” 2012. Doctoral Dissertation, University of Otago. Accessed August 11, 2020. http://hdl.handle.net/10523/2518.

MLA Handbook (7th Edition):

Thomas, Nicky Dieter. “Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) .” 2012. Web. 11 Aug 2020.

Vancouver:

Thomas ND. Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) . [Internet] [Doctoral dissertation]. University of Otago; 2012. [cited 2020 Aug 11]. Available from: http://hdl.handle.net/10523/2518.

Council of Science Editors:

Thomas ND. Supersaturated Self-Nanoemulsifying Drug Delivery Systems (super-SNEDDS) . [Doctoral Dissertation]. University of Otago; 2012. Available from: http://hdl.handle.net/10523/2518

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