Characterisation of synthetic beta-haematin and effects of the antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine on its formation.
Infrared spectroscopy, elemental analysis and X-ray powder diffraction show that the product of 30 min of reaction of haematin in 4.5 M acetate, pH 4.5 at 60 degrees C is identical to beta-haematin prepared in 4.5 M acetic acid at 70 degrees C overnight (pH 2.6). There is no evidence for formation of haem-acetate complex, which could not be isolated, even from 11.4 M acetate solution. The antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine were found to inhibit formation of beta-haematin, while 5-, 6- and 8-aminoquinoline and quinoline were found to have no effect. Quinidine was shown to form a complex with ferriprotoporphyrin IX in 40% DMSO with log K = 5.02 +/- 0.03. Log K values for halofantrine and desbutylhalofantrine are 5.29 +/- 0.02 and 5.15 +/- 0.02 respectively (solutions containing 30% acetonitrile in addition to DMSO to solubilise these drugs), which are both stronger than chloroquine under the same conditions (log K = 4.56 +/- 0.02).
The chemical mechanism of beta-haematin formation studied by Mössbauer spectroscopy.
Spontaneous formation of beta-haematin (malaria pigment) from haematin in acetate solution follows pseudo-zero-order and not autocatalytic kinetics. Acetate appears to facilitate the reaction by solubilizing the haematin and acting as a phase-transfer catalyst, a role which, in vivo, could be fulfilled by carboxylic acids or amino acids.
Complex Systems Architecture Framework: Extension to Multi-objective Optimization
This paper shows the utility to follow an architecture framework in order to design complex systems with a holistic approach. Multi-objective Optimization techniques extend and complete the architecture framework to support trade-off analysis and decision making in the Systems Engineering design process. The merging and combination of these two approaches, decision making and systems engineering, contribute to the efficient design of systems by helping to meet needs and constraints stemming mainly from the system analysis.