ABSTRACT
A recent discussion meeting convened by the Medicines for Malaria Venture examined how best to manage the discovery and preclinical pipeline to achieve novel combination therapies which would address the key clinical needs in malaria. It became clear that dose optimisation of components within combination therapy was a key issue in achieving antimalarial efficacy and for preserving that efficacy against parasite resistance emergence. This paper outlines some of the specific issues in malaria that cause dose-ranging and dose-optimisation studies to be particularly challenging and discusses the potential of factorial study design to address such challenges.
Subject(s)
Antimalarials/administration & dosage , Artemisinins/administration & dosage , Clinical Trials as Topic , Drug Resistance , Malaria/drug therapy , Models, Statistical , Biomedical Research/statistics & numerical data , Dose-Response Relationship, Drug , Drug Design , Drug Dosage Calculations , Drug Therapy, Combination , Humans , Malaria/prevention & control , Plasmodium/drug effects , Quinine/therapeutic useABSTRACT
Evidence has accumulated over the past ten years to implicate elevated plasma fibrinogen levels in cardiovascular disorders such as ischaemic heart disease, stroke and peripheral vascular disease. At a cellular level, insight has been gained into the molecular regulation of fibrinogen biosynthesis and the mechanisms through which fibrinogen may be involved in these disease processes. Here, Nigel Cook and David Ubben summarize this evidence and consider the possibilities for novel therapies targeted at fibrinogen. A variety of structurally diverse pharmacological agents, many of which were developed for their effects on plasma lipids, have serendipitously been found to lower plasma fibrinogen levels.
Subject(s)
Cardiovascular Diseases/etiology , Fibrinogen/physiology , Animals , Fibrinogen/analysis , Humans , Platelet Membrane Glycoproteins/analysis , Platelet Membrane Glycoproteins/physiology , Risk FactorsABSTRACT
We describe two types of new Tn1721-derivatives capable of random insertion and of generating transcriptional fusions at the site of insertion: transposable promoters (Tn1735) carrying a strong, inducible ptac promoter that turns on adjacent (cryptic) genes; and transposable promoter probes (Tn1736, Tn1737) carrying promoterless genes coding for chloramphenicol acetyl transferase or beta-galactosidase, and used to accurately determine the expression of external promoters. These elements are available with four different selectable resistance markers and on conjugative, temperature-sensitive and multicopy plasmid vehicles. Experiments are described that demonstrate the advantage of random insertions for expressing various genes and for studying gene regulation.
Subject(s)
DNA Transposable Elements , Promoter Regions, Genetic , Acetyltransferases/genetics , Chloramphenicol O-Acetyltransferase , Genetic Engineering/methods , Mutation , Plasmids , beta-Galactosidase/geneticsABSTRACT
New derivatives of the tetracycline-resistance transposon Tn1721 that carry resistances to chloramphenicol, tetracycline, kanamycin and streptomycin are described. These elements are provided on various plasmid vehicles and as chromosomal insertions to extend the range of targets for Tn mutagenesis. Single EcoRI sites at the ends of these transposons proved most useful for physical mapping, for the generation of new EcoRI sites in cloning experiments, for end-labelling and for sequencing of DNA adjacent to an insertion.
