Receptor-specific ligands distinguish natriuretic peptide receptors-A and -C in primate tissues

Systemic clearance of atrial natriuretic peptide (ANP) is in part due to neutral endopeptidase (NEP) proteolysis and natriuretic peptide receptor-C (NPR-C) mediated endocytosis. Biological responses to ANP are primarily mediated by the membrane guanylyl cyclase-A/natriuretic peptide receptor-A (NPR-A). Analogs of ANP selective for NPR-A and/or resistant to NEP may have increased activity in those tissues where NPR-C and NEP are coexpressed with NPR-A. The analog of ANP termed vANP; [(R3D, G9T, R11S, M12L, G16R)ANP] is selective for human NPR-A with at least 10,000 fold reduction in affinity for human NPR-C. We report that rat NPR-A is insensitive to 10 nM vANP, demonstrating the limitations of this species in evaluating human therapeutic candidates. As an alternative approach we tested the binding and potency of receptor-selective and NEP-resistant ANP analogs in rhesus monkey tissues. Competition binding studies with a simplified version of vANP, sANP [(G9T, R11S, G16R)rANP], in rhesus monkey kidney and lung membrane preparations shows displacement of ¹²⁵I-ANP from only a fraction of the total ANP receptor population, 30 and 85%, respectively. The remaining ANP binding sites can be occupied with the NPR-C selective ligand cANP(4-23). These data strongly suggest that only two classes of ANP receptor are present in these membrane preparations, NPR-A and NPR-C. The NEP resistant sANP derivative called sANP(TAPR) was 8 fold more potent (ED₅₀ = 0.6 nM) than rANP (ED₅₀ = SnM) in stimulating cGMP production in the lung membrane preparation. Our results demonstrate that the rhesus monkey natriuretic peptide receptors reflect the pharmacology of the human receptors, and that this species may be suitable to determine the role of NPR-C and NEP in peptide clearance and attenuating functional responses.     

On a drug-resistant malaria model with susceptible individuals without access to basic amenities

In this paper, a deterministic malaria transmission model in the presence of a drug-resistant strain is investigated. The model is studied using stability theory of differential equations, optimal control, and computer simulation. The threshold condition for disease-free equilibrium is found to be locally asymptotically stable and can only be achieved in the absence of a drug-resistant strain in the population. The existence of multiple endemic equilibria is also established. Both the Sensitivity Index (SI) of the model parameters and the Incremental Cost-Effectiveness Ratio (ICER) for all possible combinations of the disease-control measures are determined. Our results revealed among others that the most cost-effective strategy for drug-resistant malaria control is the combination of the provision of basic amenities (such as access to clean water, electricity, good roads, health care, and education) and treatment of infective individuals. Therefore, more efforts from policy-makers on the provisions of basic amenities and treatment of infectives would go a long way to combat the malaria epidemic.