ABSTRACT
Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.
Subject(s)
Aminoacetonitrile/analogs & derivatives , Aminoacetonitrile/pharmacology , Anthelmintics/classification , Anthelmintics/pharmacology , Drug Resistance , Nematoda/drug effects , Parasitic Diseases, Animal/parasitology , Aging , Amino Acid Sequence , Aminoacetonitrile/adverse effects , Aminoacetonitrile/pharmacokinetics , Animals , Anthelmintics/chemistry , Anthelmintics/pharmacokinetics , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/genetics , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/chemistry , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Cattle , Cattle Diseases/drug therapy , Cattle Diseases/parasitology , Drug Resistance/genetics , Larva/drug effects , Larva/genetics , Molecular Sequence Data , Nematoda/genetics , Nematoda/physiology , Parasitic Diseases, Animal/drug therapy , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/genetics , Receptors, Nicotinic/metabolism , Sheep/parasitology , Sheep Diseases/drug therapy , Sheep Diseases/parasitologyABSTRACT
In this investigation, the water-soluble drugs nitenpyram and clomipramine HCl were encapsulated using coacervation, solvent evaporation and film-coating. The effect of different process factors on the encapsulation efficiency and the release profile of the microparticles was evaluated. For coacervation it was shown that the core to wall ratio was the most important factor. For solvent evaporation using an w/o emulsion the type and concentration of the surfactant were the most important parameters for a successful encapsulation. Additionally the coated material was tested for its stability under different conditions as a powder or compressed into tablets. It could clearly be demonstrated that the coated drug substance exhibited a better stability then the uncoated material. The particles prepared by film-coating showed the best stability.