Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

High-resolution carbon dioxide concentration record 650,000800,000 years before present

Changes in past atmospheric carbon dioxide concentrations can be determined by measuring the composition of air trapped in ice cores from Antarctica. So far, the Antarctic Vostok and EPICA Dome C ice cores have provided a composite record of atmospheric carbon dioxide levels over the past 650,000 years. Here we present results of the lowest 200 m of the Dome C ice core, extending the record of atmospheric carbon dioxide concentration by two complete glacial cycles to 800,000 yr before present. From previously published data and the present work, we find that atmospheric carbon dioxide is strongly correlated with Antarctic temperature throughout eight glacial cycles but with significantly lower concentrations between 650,000 and 750,000 yr before present. Carbon dioxide levels are below 180 parts per million by volume (p.p.m.v.) for a period of 3,000 yr during Marine Isotope Stage 16, possibly reflecting more pronounced oceanic carbon storage. We report the lowest carbon dioxide concentration measured in an ice core, which extends the pre-industrial range of carbon dioxide concentrations during the late Quaternary by about 10 p.p.m.v. to 172–300 p.p.m.v

Trapped xenon in meteorites

Xenon in meteorites can be resolved into a mixture of component X and trapped xenon with the following composition,124Xe:126Xe: 128 Xe: 130Xe: 131Xe: 132Xe: 134Xe: 136Xe = 0.0276: 0.0248: 0.501: 1.00: 5.04: 6.19: 2.31: 1.90. This trapped meteoritic xenon is distinct from xenon trapped in the average carbonaceous chondrite which is shown to represent the average composition of the total xenon in meteorites containing various mixtures of component X and trapped meteoritic xenon

Terrestrial-Type Xenon in Meteoritic Troilite

Recently it has been realized that the isotopic composition of Xe in different phases of chondrites is not uniform and that AVCC Xe is a mixture of the different nucleogenetic components trapped in these phases1-4. We show here a similar abundance pattern for the nonradiogenic xenon isotopes in air and in meteoritic troilite (FeS), which suggests that the isotopic composition of atmospheric Xe was not produced by unique events in the history of terrestrial material but represents a particular mix of the different nucleogenetic components of Xe that was dominant in a central Fe- and S-rich region of the protoplanetary nebula5

Xenon Record of the Early Solar System

We suggest that xenon isotopes in meteorites and in outer regions of the Sun contain debris from a supernova which exploded in the vicinity of the present Solar System, and we conclude that xenon in the outer planets is enriched in this supernova debris

Mantle plume noble gas component in glassy basalts from Reykjanes Ridge

Basalts from the Reykjanes Ridge contain noble gases delivered from the non-degassed lower mantle by the Iceland plume. These lower mantle gases are thought to be a mixture of planetary and solar components, as would be expected if the Earth accreted from fine silicate particles