Dataset Information

Artemether Does Not Turn ? Cells into ? Cells.

ABSTRACT: Pancreatic ? cells retain considerable plasticity and can, under the right circumstances, transdifferentiate into functionally mature ? cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used anti-malaria drug artemether suppresses the ? cell transcription factor Arx to promote transdifferentiation into ? cells. However, key initial experiments in this paper were carried out in islet cell lines, and most subsequent validation experiments implied transdifferentiation without direct demonstration of ? to ? cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary ? cells into ? cells. Moreover, artemether reduces Ins2 expression in primary ? cells >100-fold, suppresses glucose uptake, and abrogates ? cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote ? to ? cell transdifferentiation in treating diabetes.

SUBMITTER: van der Meulen T

PROVIDER: S-EPMC5762275 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Artemether Does Not Turn α Cells into β Cells.

van der Meulen Talitha T Lee Sharon S Noordeloos Els E Donaldson Cynthia J CJ Adams Michael W MW Noguchi Glyn M GM Mawla Alex M AM Huising Mark O MO

Cell metabolism 20171102 1

Pancreatic α cells retain considerable plasticity and can, under the right circumstances, transdifferentiate into functionally mature β cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used anti-malaria drug artemether suppresses the α cell transcription factor Arx to promote transdifferentiation into β cells. However, key initial experiments in this paper were carried out in islet cell lines, and most subsequent validation experiments implied transdif ...[more]

PMID: 29103923

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Project description:BACKGROUND:Dissolution of artemether (ART) and lumefantrine (LUM) active pharmaceutical ingredients (APIs) in fixed dose combination (FDC) ART/LUM tablets is one of the critical quality attributes. Thus, the verification of the release profile of ART and LUM from FDC ART/LUM tablets using a robust and discriminatory dissolution method is crucial. Therefore, the aim of this study was to develop and validate an appropriate dissolution method for quality control of FDC ART/LUM tablets. METHODS:The dissolution medium was selected based on saturation solubility data and sink conditions. The effect of agitation speed, pH and surfactant concentration on the release of ART and LUM was evaluated by employing a two-level factorial experiment. The resulting final method was validated for linearity, precision, robustness and API stability. In addition, the discriminatory power of the method was evaluated using expired and unexpired FDC ART/LUM products. RESULTS:A suitable dissolution profile of FDC ART/LUM tablets was obtained in 900 ml HCl (0.025 N, pH 1.6) with 1%Myrj 52 using paddle method at 100 rpm and 37 °C. ART and LUM were analysed using a HPLC method with UV detection at wavelengths of 210 and 335 nm, respectively. The results from the stability study showed that ART and LUM were sufficiently stable in HCl (0.025 N, pH 1.6) with 1%Myrj 52 at 37 °C. The method was linear (r2?=?0.999) over the concentration range of 6.25-100 ?g/ml. The results for precision were within the acceptance limit (%RSD?<?2). The percent relative standard deviation (<?2%) and statistically non-significant (p?>?0.05) difference in release of ART and LUM observed between deliberately changed dissolution method settings (pH?=?1.6?±?0.2 or agitation speed?=?100?±?2) and optimized dissolution conditions revealed the robustness of the dissolution method. The method was capable to discriminate among different FDC ART/LUM products with different quality. CONCLUSIONS:The developed dissolution method is robust and discriminatory. It can be used in the quality evaluation of FDC ART/LUM tablets.

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Artemether Does Not Turn ? Cells into ? Cells.

Publications

Artemether Does Not Turn α Cells into β Cells.

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