Disposition of 3H-selamectin and 3H-ivermectin in the brain of the cat flea Ctenocephalides felis felis using micro-image analysis.

In addition to intrinsic potency and metabolic stability, the disposition of an antiparasitic drug within the target parasite plays a major role in determining drug activity. A novel technique that allows the disposition of radiolabelled drugs to be visualised within the body of the cat flea (Ctenocephalides felis felis) is described. The concentrations of two macrocyclic lactones, (3)H-selamectin and (3)H-ivermectin, within the supra- and sub-oesophageal ganglia of the flea brain following in vitro feeding of fleas on different doses of drug solubilised in calf blood have been measured.

Comparison of the activity of selamectin, fipronil, and imidacloprid against flea larvae (Ctenocephalides felis felis) in vitro.

The activity of selamectin, fipronil and imidacloprid against larval cat fleas (Ctenocephalides felis felis) was evaluated in an in vitro potency assay system. One hundred microliters of each compound at various concentrations in acetone were added to glass vials (1.5 by 3 cm) to which had been previously added 20 mg of sand and 10 mg of flea feces.

Avermectins and flea control: structure-activity relationships and the selection of selamectin for development as an endectocide for companion animals.

Evaluation of a wide range of avermectin derivatives for flea activity in an in vitro feeding screen using the cat flea, Ctenocephalides felis, revealed a narrow structure-activity relationship (SAR) with activity surprisingly associated with monosaccharides and especially their C-5-oximes. We discovered commercially exploitable flea activity in a single compound, selamectin 33, which also possessed the necessary antiparasitic spectrum and margin of safety for development as a broad-spectrum companion animal endectocide.

Dose selection of selamectin for efficacy against adult fleas (Ctenocephalides felis felis) on dogs and cats.

Selamectin, a novel avermectin, was evaluated in two controlled studies (one in Beagles, one in domestic shorthaired cats) to determine an appropriate topical dose for efficacy against adult Ctenocephalides felis felis (C. felis) fleas on dogs and cats for 1 month. For each study, animals were allocated randomly to four treatments.

Selamectin: a novel broad-spectrum endectocide for dogs and cats.

Selamectin, 25-cyclohexyl-25-de(1-methylpropyl)-5-deoxy-22, 23-dihydro-5-(hydroxyimino)-avermectin B1 monosaccharide, is a novel endectocide with a unique combination of efficacy and safety in dogs and cats following both oral and topical administration. The compound is active against fleas and ticks, intestinal hookworms and ascarids, and immature heartworms. Also it is well tolerated at higher dosages than 22,23-dihydroavermectin B1a (DHAVM) or milbemycin oxime in Collies, which is a breed known to exhibit idiosyncratic sensitivity to avermectins.

Doramectin--a potent novel endectocide.

Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin.

Voltage-activated currents in somatic muscle of the nematode parasite Ascaris suum.

1. Voltage-activated currents in cell bodies of the somatic muscle cells of Ascaris suum were studied using a two-microelectrode voltage-clamp technique. Cells recorded from had resting membrane potentials around -35 mV and had input conductances in the range 1-10 microS.

C-13 beta-acyloxymilbemycins, a new family of macrolides. Discovery, structural determination and biological properties.

A family of novel milbemycins possessing C-13 beta-acyloxy substitution was produced by Streptomyces hygroscopicus ATCC 53718. These compounds were detected by HPLC diode array analysis and possess anthelmintic and ectoparasiticidal activity. The origin of the oxygen atom at C-13 is discussed.

A new anthelmintic assay using rats infected with Trichostrongylus colubriformis.

A new anthelmintic assay is described which uses immunosuppressed (60 ppm hydrocortisone acetate in diet) rats infected with the nematode Trichostrongylus colubriformis. Immunosuppressed rats were infected with 1500 T. colubriformis larvae, treated either orally or subcutaneously on Day 14 post-infection and necropsied 4 days after treatment.

Actions of potent cholinergic anthelmintics (morantel, pyrantel and levamisole) on an identified insect neurone reveal pharmacological differences between nematode and insect acetylcholine receptors.

Intracellular recording and current-clamp techniques were used to investigate the cholinergic activity of the anthelmintics, morantel, pyrantel and levamisole, applied to the fast coxal depressor motorneurone (Df) of the cockroach Periplaneta americana. Application of these agents and acetylcholine to the bath resulted in dose-dependent changes in conductance and corresponding depolarization of the neuronal membrane. Relative potencies of the drugs were determined from dose-response relationships and the rank order of effectiveness was as follows: carbachol much greater than levamisole greater than pyrantel greater than morantel.

Block of locust muscle glutamate receptors by delta-philanthotoxin occurs after receptor activations.

One component (delta-philanthotoxin (delta-PTX) of the venom from the wasp Philanthus triangulum blocks transmission postsynaptically at excitatory synapses on locust muscle. delta-PTX depresses both the iontophoretic glutamate potential and the excitatory junctional current (e.j.

Influence of sodium and calcium ions and membrane potential on glutamate receptor desensitization.

1. The effects of Na, Ca and membrane potential on desensitization of postjunctional glutamate receptors on locust muscle were investigated. 2.

Agonist potency determination by patch clamp analysis of single glutamate receptors.

Agonists (L-quisqualate, L-glutamate and L-cysteine sulphinate) of the locust muscle glutamate receptor differ in potency. Patch clamp analysis of single glutamate receptors reveals that the relative potencies of agonists are determined both by the life-times of the channels that they gate and their probability of activating the glutamate receptor-ionophore complex. Furthermore, agonists which most readily activate the receptor channel complex gate channels with longer life-times than agonists which are less efficient in this respect.

Influence of agonists on desensitization of glutamate receptors on locust muscle.

1. The desensitization, by ionophoretically and bath-applied L-glutamate and agonists, of excitatory post-junctional receptor populations on locust extensor tibiae muscle was investigated. 2.

Influence of glutamate and aspartate on time course of decay of excitatory synaptic currents at locust neuromuscular junctions.

The influence of glutamate and aspartate on the time course of decay of excitatory currents at neuromuscular junctions of locust skeletal muscle was examined. Both aspartate (up to 10 mM) and glutamate (up to 0.3 mM) had little influence on the decay time of the synaptic currents, whether measured intracellularly by voltage-clamp or extracellularly with a focal electrode.

Responses to DL-ibotenic acid at locust glutamatergic neuromuscular junctions.

1 The responses of excitatory junctions on locust skeletal muscle fibres to iontophoretically applied L-glutamic acid and DL-ibotenic acid, a rigidly extended analogue of glutamate, were recorded by means of intracellular microelectrodes.2 Iontophoresis of L-glutamate to junctional sites produced transient depolarizations. Ibotenate applied iontophoretically to these sites usually evoked small hyperpolarizations which probably resulted from the activation of glutamate H-receptors on the extrajunctional membrane surrounding the junctions.

Desensitization of glutamate receptors on innervated and denervated locust muscle fibres.

Depolarizations to L-glutamate, applied locally by microinophoresis to the extrajunctional membrane of locust extensor tibiae muscle fibres and measured either in current clamp or voltage clamp, increased in amplitude for equivalent doses of glutamate following chronic denervation of the muscle. 2. A two-pulse method was used to examine recovery from desentization of junctional and extrajunctional receptors.