Ferriprotoporphyrin catalysed decomposition of artemether: analytical and pharmacological implications

The ability of the products of erythrocytic haemolysis and ferriprotoporphyrin (FP-IX)-containing substances of facilitate the decomposition of the antimalarial drug artemether has been evaluated in vitro. The products of haemolysis accelerate the degradation of artemether to unidentified compounds which are undetectable by currently available HPLC methods. This decomposition is temperature dependent and occurs after relatively brief artemether (ARM)-catalyst contact. Using radiolabelled [16-14C]ARM, we have demonstrated that the extractability of total radioactivity into the organic phase diminishes with increasing FP-IX concentration with an appreciable reduction in the organic extractability as ARM in the presence of FP-IX and associated increase in water solubility of radioactivity when the concentration of FP-IX increases from 0 to 7.7 mM. This effect appears to be temperature dependent for incubations with haematin. Characterisation of the organically extractable radioactivity from incubations of [16-14C]ARM with FP-IX has shown a loss of ARM and the formation of two radioactive products which occurs in proportion to the concentration of FP-IX. We believe these findings are of particular relevance to the determination of plasma concentrations of ARM and dihydroartemisinin (DHA) in malaria patients where extensive haemolysis and the presence of breakdown products of haemoglobin may contribute to a reduction in the circulating concentration of these substances. In these circumstances, measurement of ARM and DHA by conventional methods may be meaningless.     

Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice.

The synaptic Ras/Rap-GTPase-activating protein (SynGAP) regulates specific intracellular events following N-methyl-d-aspartate receptor (NMDAR) activation. Here, the impact of SynGAP heterozygous knockout (SG+/?) on NMDAR-dependent functions was assessed using different positive reinforcement schedules in instrumental conditioning. The knockout did not affect the temporal control of operant responding under a fixed interval (FI) schedule, but led to a putative enhancement in response vigor and/or disinhibition. When examined on differential reinforcement of low rates of response (DRL) schedules, SG+/? mice showed increased responding under DRL-4s and DRL-8s, without impairing the response efficiency (total rewards/total lever presses) because both rewarded and nonrewarded presses were elevated. Motivation was unaffected as evaluated using a progressive ratio (PR) schedule. Yet, SG+/? mice persisted in responding during extinction at the end of PR training, although an equivalent phenotype was not evident in extinction learning following FI-20s training. This extinction phenotype is therefore schedule-specific and cannot be generalized to Pavlovian conditioning. In conclusion, constitutive SynGAP reduction increases vigor in the execution of learned operant behavior without compromising its temporal control, yielding effects readily distinguishable from NMDAR blockade. (PsycINFO Database Record (c) 2010 APA, all rights reserved)