ABSTRACT
Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.
Subject(s)
Antimalarials/pharmacology , Benzimidazoles/therapeutic use , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Mice , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
AZD5847, a novel oxazolidinone with an MIC of 1 µg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration of AZD5847 to mice infected with M. tuberculosis H37Rv in a chronic-infection model resulted in a 1.0-log10 reduction in the lung CFU count after 4 weeks of treatment at a daily area under the concentration-time curve (AUC) of 105 to 158 µg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success in an acute-infection model was an AUC for the free, unbound fraction of the drug/MIC ratio of ≥ 20. The percentage of time above the MIC in all of the efficacious regimens was 25% or greater.
Subject(s)
Mycobacterium tuberculosis/drug effects , Oxazolidinones/pharmacokinetics , Oxazolidinones/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Animals , Area Under Curve , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Dosage Calculations , Drug Resistance, Multiple, Bacterial , Mice , Mice, Inbred BALB C , Microbial Sensitivity Tests , Tuberculosis, Pulmonary/microbiologyABSTRACT
Determination of obstructive site in obstructive sleep apnoea (OSA) is of paramount importance is planning the management. Cephalometric evaluation of lateral X-rays when combined with clinical assessment and fibreoptic examination of the airway helps in locating the site of obstruction. The usual technique of cephalometry has been modified so as to give a better delineation of the soft tissues. Holding a 2mm card board in the mouth and using barium paste helped in more accurate calculations. Using our technique, various parameters have been quantified and a number of controls were studied and normal range derived. Further improvement in cephalometry has been done by using C.T. cephlometry topogram technique. A topogram is a scan done on a running table top cranio-caudally. Using the topogram technique 38 OSA patients were evaluated for all the parameters. The technique, its advantages over traditional cephalometry and the values obtained in the study are discussed in this paper.
