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      Chloroquine and hydroxychloroquine binding to melanin: Some possible consequences for pathologies

      Toxicology reports

      Elsevier BV

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          Neuropathology of Parkinson's disease.

           L Forno (1996)
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            Melanosome evolution indicates a key physiological shift within feathered dinosaurs.

            Inference of colour patterning in extinct dinosaurs has been based on the relationship between the morphology of melanin-containing organelles (melanosomes) and colour in extant bird feathers. When this relationship evolved relative to the origin of feathers and other novel integumentary structures, such as hair and filamentous body covering in extinct archosaurs, has not been evaluated. Here we sample melanosomes from the integument of 181 extant amniote taxa and 13 lizard, turtle, dinosaur and pterosaur fossils from the Upper-Jurassic and Lower-Cretaceous of China. We find that in the lineage leading to birds, the observed increase in the diversity of melanosome morphologies appears abruptly, near the origin of pinnate feathers in maniraptoran dinosaurs. Similarly, mammals show an increased diversity of melanosome form compared to all ectothermic amniotes. In these two clades, mammals and maniraptoran dinosaurs including birds, melanosome form and colour are linked and colour reconstruction may be possible. By contrast, melanosomes in lizard, turtle and crocodilian skin, as well as the archosaurian filamentous body coverings (dinosaur 'protofeathers' and pterosaur 'pycnofibres'), show a limited diversity of form that is uncorrelated with colour in extant taxa. These patterns may be explained by convergent changes in the key melanocortin system of mammals and birds, which is known to affect pleiotropically both melanin-based colouration and energetic processes such as metabolic rate in vertebrates, and may therefore support a significant physiological shift in maniraptoran dinosaurs.
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              Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties.

              The 4-aminoquinoline drug hydroxychloroquine (HCQ) is reported to be as active as chloroquine (CQ) against falciparum malaria, and less toxic. Existing prophylactic regimens for areas where there is CQ-resistant malaria recommend CQ with proguanil as an alternative where none of the three preferred regimens (atovaquone-proguanil, doxycycline or mefloquine) is thought suitable. In such cases, toxicity is likely when CQ-proguanil is administered to persons being treated for autoimmune disease with daily HCQ. The question therefore arises whether in such circumstances HCQ could effectively replace the CQ component of the prophylactic combination. We confirmed similar activity of CQ and HCQ against CQ-sensitive Plasmodium falciparum, but found that whereas HCQ in vitro was 1.6 times less active than CQ in a CQ-sensitive isolate, it was 8.8 times less active in a CQ-resistant isolate. The result can also be predicted from an analysis of the physicochemical properties of CQ and HCQ. To give limited protective effect similar to 300 mg CQ base weekly against CQ-resistant P. falciparum would demand daily doses of HCQ above the recommended safe level. These observations contraindicate the use of HCQ in prophylaxis or treatment of CQ-resistant falciparum malaria. Where CQ-proguanil prophylaxis is the only option available in a patient on high-dose HCQ treatment, visiting a CQ-resistant area, replacement of the anti-inflammatory regimen by a daily CQ course at a suitable dose should be considered.
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                Author and article information

                Journal
                10.1016/j.toxrep.2014.10.019

                http://creativecommons.org/licenses/by-nc-nd/3.0/

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