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Biomedical subjects

R K Haynes

Publications and source records attributed to R K Haynes.

7 recordsLinked to original sources
PubMed2005

Artemisinins.

Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced.

Antimalarials↗
PubMed2001

Possible modes of action of the artemisinin-type compounds.

Artemisinin-type compounds are used for the treatment of uncomplicated and severe forms of malaria. They reduce parasitaemia more rapidly than any other antimalarial compound known, and are effective against multidrug-resistant parasites. However, uncertainties remain as to how they act on the parasite and cause toxicity. In this review, we summarize current ideas.

Animals↗
PubMed2001

Artemisinin and derivatives: the future for malaria treatment?

The isolation in 1972 of artemisinin by Chinese scientists, and their development of all the derivatives now used in the treatment of malaria today, were of outstanding importance. The results which have accumulated both from the Chinese work and from that subsequently conducted on a worldwide basis provide for a relatively comprehensive understanding of the chemistry, pharmacological profiles, toxicology, metabolism, and effects on the malaria parasite. The optimal regimens for use in the field are also apparent, particularly in combinations with longer half-life quinoline antimalarials. Thus the future use of the artemisinin class of drug appears assured. However, the mechanism of action needs to be clarified. More importantly from a clinical viewpoint, problems inherent in the current derivatives must be addressed, particularly that of neurotoxicity, if new artemisinin derivatives are to be introduced in a normal drug regulatory environment. The application of established principles of modern drug design should indeed allow for the first truly rationally designed, in so far as the target is still unknown, derivatives to come to hand.

Antimalarials↗
PubMed2000

Establishment of an in vitro screening model for neurodegeneration induced by antimalarial drugs of the artemisinin-type..

The establishment of an in vitro screening model for neurodegeneration inducing antimalarial drugs was conducted in stepwise fashion. Firstly, the in vivo selective neurotoxic potency of artemisinin was tested in neuronal cells in vitro in relation to the cytotoxic potency in other organ cell cultures such as liver and kidney or versus glial cells. Secondly, a comparison between different parts of the brain (cortex vs. brain stem) was performed and in the last step, a fast and sensitive screening endpoint was identified. In summary, non-neuronal cell lines such as hepatocytes (HEP-G2), liver epithelial cells (IAR), proximal tubular cells (LLC-PK(1)) and glial cells from the rat (C6) and human (GO-G-IJKT) displayed only moderate sensitivity to artemisinin and its derivatives. The same was found in undifferentiated neuronal cell lines from the mouse (N-18) and from human (Kelly), whereas during differentiation, these cells became much more sensitive. Primary astrocytes from the rat also were not specifically involved. In the comparison of primary neuronal cell cultures from the cortex and brain stem of the rat, the brain stem was found to be more sensitive than the cortex. The neurotoxic potential was determined by cytoskeleton elements (neurofilaments), which were degradated in vitro by diverse neurodegenerative compounds. In comparison of dog and rat primary brain stem cultures, the dog cells were found to be more sensitive to artemisinin than the rat cells. In addition to the primary brain stem cell cultures it was shown that the sprouting assay, which determines persistent delayed neurotoxic effects, is also useful for screening antimalarial drugs. To other compounds, artemether and artesunate, showed that use of the sprouting assay followed by primary brain stem cultures of the rat will be a good strategy to select candidate compounds.

Journal Article↗
PubMed1999

Simultaneous determination of artemether and its major metabolite dihydroartemisinin in plasma by gas chromatography-mass spectrometry-selected ion monitoring.

A sensitive, selective, and reproducible GC-MS-SIM method was developed for determination of artemether (ARM) and dihydroartemisinin (DHA) in plasma using artemisinin (ART) as internal standard. Solid phase extraction was performed using C18 Bond Elut cartridges. The analysis was carried out using a HP-5MS 5% phenylmethylsiloxane capillary column. The recoveries of ARM, DHA and ART were 94.9 +/- 1.6%, 92.2 +/- 4.1% and 81.3 +/- 1.2%, respectively. The limit of quantification in plasma was 5 ng/ml (C.V. < or = 17.4% for ARM and 15.2% for DHA). Calibration curves were linear with R2 > or = 0.988. Within day coefficients of variation were 3-10.4% for ARM and 7.7-14.5% for DHA. Between day coefficients of variations were 6.5-15.4% and 7.6-14.1% for ARM and DHA. The method is currently being used for pharmacokinetic studies. Preliminary data on pharmacokinetics showed Cmax of 245.2 and 35.6 ng/ml reached at 2 and 3 h and AUC0-8 h of 2463.6 and 111.8 ngh/ml for ARM and DHA, respectively.

Adult↗
PubMed1994

Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues.

The preparation of artemether from artemisinin is reviewed. Firstly, the extraction of artemisinin from Artemisia annua is described and an estimation of the yield per hectare based on literature data is given. Artemisinin is reduced with sodium borohydride to produce dihydroartemisinin as a mixture of epimers. The mixture is treated with methanol and an acid catalyst to provide artemether. Increasing demand for use of artemether places pressure on the supply of artemisinin, and an alternative means of preparing the drug from artemisinic acid, an abundant constituent of A. annua, which could triple current yields, is described. In anticipation of problems of drug resistance emerging with the continued use of artemether and artesunate to treat malaria, development of new derivatives of artemisinin which have enhanced stability is required. Examples of such derivatives which have been prepared in our laboratories, or proposed, are described.

Antimalarials↗