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Antiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model

Overview of attention for article published in Malaria Journal, December 2015
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2 tweeters

Citations

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8 Dimensions

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38 Mendeley
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Title
Antiplasmodial activity, in vivo pharmacokinetics and anti-malarial efficacy evaluation of hydroxypyridinone hybrids in a mouse model
Published in
Malaria Journal, December 2015
DOI 10.1186/s12936-015-1032-5
Pubmed ID
Authors

Ntokozo S. Dambuza, Peter Smith, Alicia Evans, Jennifer Norman, Dale Taylor, Andrew Andayi, Timothy Egan, Kelly Chibale, Lubbe Wiesner

Abstract

During the erythrocytic stage in humans, malaria parasites digest haemoglobin of the host cell, and the toxic haem moiety crystallizes into haemozoin. Chloroquine acts by forming toxic complexes with haem molecules and interfering with their crystallization. In chloroquine-resistant strains, the drug is excluded from the site of action, which causes the parasites to accumulate less chloroquine in their acid food vacuoles than chloroquine-sensitive parasites. 3-Hydroxylpyridin-4-ones are known to chelate iron; hydroxypyridone-chloroquine (HPO-CQ) hybrids were synthesized in order to determine whether they can inhibit parasites proliferation in the parasitic digestive vacuole by withholding iron from plasmodial parasite metabolic pathway. Two HPO-CQ hybrids were tested against Plasmodium falciparum chloroquine-sensitive (D10 and 3D7) and -resistant strains (Dd2 and K1). The pharmacokinetic properties of active compounds were determined using a mouse model and blood samples were collected at different time intervals and analysed using LC-MS/MS. For in vivo efficacy the mice were infected with Plasmodium berghei in a 4-day Peters' test. The parasitaemia was determined from day 3 and the course of the infection was followed by microscopic examination of stained blood films every 2-3 days until a rise in parasitaemia was observed in all test subjects. IC50 values of the two compounds for sensitive and resistant strains were 0.064 and 0.047 µM (compound 1), 0.041 and 0.122 µM (compound 2) and 0.505 and 0.463 µM (compound 1), 0.089 and 0.076 µM (compound 2), respectively. Pharmacokinetic evaluation of these compounds showed low oral bioavailability and this affected in vivo efficacy when compounds were dosed orally. However, when dosed intravenously compound 1 showed a clearance rate of 28 ml/min/kg, an apparent volume of distribution of 20 l/kg and a half-life of 4.3 h. A reduction in parasitaemia was observed when compound 1 was dosed intravenously for four consecutive days in P. berghei-infected mice. However, a rise in parasitaemia levels was observed on day 6 and on day 9 for chloroquine-treated mice. The hybrid compounds that were tested were able to reduce parasitaemia levels in P. berghei-infected mice when dosed intravenously, but parasites recrudesced 24 h after the administration of the least dose. Despite low oral bioavailability, the IV data obtained suggests that further structural modifications may lead to the identification of more HPO-CQ hybrids with improved pharmacokinetic properties and in vivo efficacy.

Twitter Demographics

The data shown below were collected from the profiles of 2 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 38 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 38 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 8 21%
Researcher 8 21%
Student > Bachelor 7 18%
Student > Master 5 13%
Lecturer 3 8%
Other 2 5%
Unknown 5 13%
Readers by discipline Count As %
Medicine and Dentistry 7 18%
Chemistry 6 16%
Biochemistry, Genetics and Molecular Biology 5 13%
Pharmacology, Toxicology and Pharmaceutical Science 4 11%
Agricultural and Biological Sciences 3 8%
Other 6 16%
Unknown 7 18%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 17 December 2015.
All research outputs
#4,796,831
of 6,787,729 outputs
Outputs from Malaria Journal
#1,759
of 2,326 outputs
Outputs of similar age
#177,412
of 287,950 outputs
Outputs of similar age from Malaria Journal
#101
of 166 outputs
Altmetric has tracked 6,787,729 research outputs across all sources so far. This one is in the 25th percentile – i.e., 25% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,326 research outputs from this source. They receive a mean Attention Score of 4.7. This one is in the 19th percentile – i.e., 19% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 287,950 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 32nd percentile – i.e., 32% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 166 others from the same source and published within six weeks on either side of this one. This one is in the 31st percentile – i.e., 31% of its contemporaries scored the same or lower than it.