dc.contributor.author |
Onyango, Christopher Odhiambo |
|
dc.date.accessioned |
2018-06-12T08:24:15Z |
|
dc.date.available |
2018-06-12T08:24:15Z |
|
dc.date.issued |
2018-06-12 |
|
dc.identifier.citation |
Onyango2018 |
en_US |
dc.identifier.uri |
http://hdl.handle.net/123456789/4609 |
|
dc.description |
Degree of Master of Science in Biochemistry |
en_US |
dc.description.abstract |
The emergence of multidrug-resistant strains of Plasmodium falciparum, stalled efforts in malaria control coupled with low success rates for new chemotherapies to proceed into clinical trials pose a great threat of increased fatalities in cases of cerebral/ severe malaria infections in which parenteral artesunate monotherapy is the current drug of choice. This calls for preservation of efficacy of available effective drugs and to protect them from development of parasite resistance. The study aimed to investigate efficacy, safety and pharmacokinetic profile of a novel trioxaquine in a mouse model of human cerebral malaria whether this compound chemically synthesized by covalent linking of a 4,7-dichloroquinoline pharmacophore to artesunate through drug development approach termed ‘covalent bitherapy’ could improve the curative outcomes in cerebral malaria infections. In vivo acute oral toxicity for the trioxaquine was done according to Organization for Economic Co-operation and Development (OECD) guidelines 423, where female Swiss albino mice were orally administered with either 300 or 2000 mg/kg of the trioxaquine and monitored for signs of severity, and or mortality for 14 days post-treatment. Human cerebral malaria rodent model, the C57BL/6 male mice were infected intraperitoneally (ip) with Plasmodium berghei ANKA and intravenously (iv) treated with the trioxaquine from day 8 post-infection (pi) at 12.5 and 25 mg/kg, respectively, twice a day for 3 days. Treatments with the trioxaquine precursors (artesunate and 4,7-dichloroquine), and quinine were also included as controls. 20mg/kg of the trioxaquine was administered iv and plasma samples obtained at various time intervals (0 -12hrs) for pharmacokinetic analysis. The trioxaquine showed a good safety profile with 67% animals survival at the highest dose administered and a potent antiplasmodial activity with 80% parasite clearance in the first 24 hrs for the two dosages used with no recrudescence observed even beyond 60 days post-treatment. An apparent half-life of 3.52hrs was also reported. The curative effect together with the good safety, and pharmacokinetic profiles observed with the trioxaquine clearly demonstrated its potential as a drug candidate for management of CM, especially in a time of shrinking antimalarial armamentarium for management of CM. |
en_US |
dc.description.sponsorship |
Prof. Francis Wamakima Muregi
Department of Biological Sciences
Mount Kenya University.
Prof. Gabriel Nyamwamu Magoma
Biochemistry Department
Jomo Kenyatta University of Agriculture and Technology.
Dr Peter Gakio Kirira
Department of Physical Sciences
Mount Kenya University |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
JKUAT |
en_US |
dc.subject |
Pharmacokinetic Profile |
en_US |
dc.subject |
Trioxaquine |
en_US |
dc.subject |
Management of Cerebral Malaria in Mice |
en_US |
dc.title |
Evaluation of Efficacy and Pharmacokinetic Profile of a Novel Trioxaquine in Management of Cerebral Malaria in Mice |
en_US |
dc.type |
Thesis |
en_US |