An analysis of the binding characteristics of a panel of recently selected ICAM-1 binding Plasmodium falciparum patient isolates.

The basis of severe malaria pathogenesis in part includes sequestration of Plasmodium falciparum-infected erythrocytes (IE) from the peripheral circulation. This phenomenon is mediated by the interaction between several endothelial receptors and one of the main parasite-derived variant antigens (PfEMP1) expressed on the surface of the infected erythrocyte membrane. One of the commonly used host receptors is ICAM-1, and it has been suggested that ICAM-1 has a role in cerebral malaria pathology, although the evidence to support this is not conclusive. The current study examined the cytoadherence patterns of lab-adapted patient isolates after selecting on ICAM-1. We investigated the binding phenotypes using variant ICAM-1 proteins including ICAM-1Ref, ICAM-1Kilifi, ICAM-1S22/A, ICAM-1L42/A and ICAM-1L44/A using static assays. The study also examined ICAM-1 blocking by four anti-ICAM-1 monoclonal antibodies (mAb) under static conditions. We also characterised the binding phenotypes using Human Dermal Microvascular Endothelial Cells (HDMEC) under flow conditions. The results show that different isolates have variant-specific binding phenotypes under both static and flow conditions, extending our previous observations that this variation might be due to variable contact residues on ICAM-1 being used by different parasite PfEMP1 variants.

Cytoadherence and severe malaria.

Malaria is a disease that causes enormous human morbidity and mortality. One feature of mature Plasmodium falciparum-infected erythrocytes leading to the development of severe malaria is thought to be cytoadherence and blockage of the microvasculature. Therefore, an understanding of mechanisms that mediate parasite adhesion leading to malaria pathology is needed to yield new treatments for malaria. However, to date, cytoadherence-associated pathology is still under debate. Is cytoadherence needed to develop severe malaria? This review will discuss the available information on associations of cytoadherence with the development of severe malaria.

Broad inhibition of plasmodium falciparum cytoadherence by (+)-epigallocatechin gallate.

BACKGROUND: The surface antigen PfEMP-1 is a key virulence factor of the human malaria parasite implicated in the cytoadherence of Plasmodium falciparum infected erythrocytes to a range of receptors on host endothelium. Among these host receptors, binding to ICAM-1 is related to cerebral malaria. The majority of the mortality in children with cerebral malaria is seen within 24 h of hospital admission despite the use of effective anti-parasite drugs, therefore, the development of adjunctive therapies is urgently needed.The polyphenolic compound (+)-epigallocatechin gallate ((+)-EGCG) has been previously evaluated for anti-adhesive properties using a small number of laboratory parasite isolates. Here, this property is further explored using a new panel of ICAM-1-binding patient isolates of P. falciparum to ascertain if (+)-EGCG might be effective as a broad spectrum inhibitor of ICAM-1-based cytoadherence. METHODS: Plasmodium falciparum lines, including A4 and ItG as positive controls and nine new ICAM-1 binding patient isolates, were allowed to bind with ICAM-1-Fc protein under static assay conditions in the presence and absence of 50 µM (+)-EGCG. Adhesion levels of all the parasite strains were quantified by microscopy as the mean number of infected erythrocyte (IE) bound per mm(2) of surface area and statistical comparisons were made to demonstrate the effect of (+)-EGCG on the binding of various parasite variants to human ICAM-1. RESULTS: This study revealed that binding of patient isolates to ICAM-1 was reduced significantly with inhibition levels of 37% in patient isolate BC-12 up to a maximum of 80% in patient isolate 8146 at 50 µM (+)-EGCG. CONCLUSION: Evaluation of the anti-adhesive property of (+)-EGCG against a new panel of ICAM-1-binding patient isolates of P. falciparum showed that this inhibitor, identified as potential mimic of the L43 loop of human ICAM-1, was effective at blocking cytoadherence.

Extended release felodipine self-nanoemulsifying system.

The purpose of the present study was to formulate a self-nanoemulsifying system (SNES) containing model lipophilic drug, felodipine (FLD), to improve its solubility. The SNES was formulated using varying amounts of Miglyol 840 (as an oil), Cremophor EL (as a surfactant), and Capmul MCM (as a co-surfactant). The SNES were characterized for turbidity, droplet size and in vitro FLD release. The SNES containing oil, surfactant, and co-surfactant in the weight ratio of 3.5:1.0:1.0, respectively, showed good emulsification, median droplet size of 421 nm, and rapid FLD release (>90% release in 15 min). Gelling was induced in the SNES by addition of Aerosil 200 (A 200). Rheological studies clearly demonstrated the formation of gelled microstructure with enhanced elasticity for SNES with A 200. Since FLD warrants extended delivery for management of hypertension, the gelled SNES was further encased within the hydrophobic Gelucire 43/01 (GEL) coat to extend the release of FLD. Caprol PGE-860 (CAP) was added to this coat as a release enhancer. No interaction was seen between GEL and CAP in differential scanning calorimetry. The effect of two formulation variables in the encased SNES, viz., the gelling agent (A200) and the release enhancer (CAP), on the in vitro FLD release was evaluated using 3(2) factorial design experiments. CAP by virtue of channel formation in GEL coat favored the FLD release, while the A200 retarded the FLD release by inducing gelling. At later time points, an interaction between these two variables was found to govern extended release of FLD. The developed gelled SNES encased within the GEL coat can be used as an extended release composition for lipophilic drugs.