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Biomedical subjects

K A Gration

Publications and source records attributed to K A Gration.

At least 19 recordsLinked to original sources
PubMed2000

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.

Administration, Topical↗
PubMed2000

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. One treatment consisted of the inert formulation ingredients (vehicle) administered as a negative control, and the other three treatments consisted of a single topical dosage of 3, 6, or 9mgkg(-1) of selamectin. In each study, selamectin was administered as a topical dose applied to the skin in a single spot at the base of the neck in front of the scapulae. Dogs and cats were infested with 100 viable unfed C. felis (50 males and 50 females) on days 4, 11, 18, and 27. Seventy-two hours (+/-2h) after each infestation, on days 7, 14, 21, and 30, a comb count to determine the number of viable fleas present on each animal was performed. Efficacy of selamectin on day 30 was used to select an appropriate dose. For dogs and cats, percentage reductions in geometric mean flea comb counts for the three selamectin treatments ranged from 94. 6 to 100% on days 7, 14, and 21, compared with the negative-control treatment. On day 30, reductions in flea comb counts were 81.5, 94.7, and 90.8% for dogs, and 79.8, 98.0, and 96.2% for cats treated with selamectin at 3, 6, or 9mgkg(-1), respectively. For day 30 flea comb counts for dogs and cats, analysis of variance showed that the three selamectin treatments resulted in significantly (P< or =0.05) lower counts than did the negative-control treatment. For dogs and cats, geometric mean flea counts for selamectin administered at a dosage of 3mgkg(-1) were significantly (P< or =0.05) higher than those for the 6 and 9mgkg(-1) treatment dosages combined. There were no significant differences in flea counts between the 6 and 9mgkg(-1) treatments. This analysis was confirmed by linear-plateau modeling. Thus, the optimal dose of selamectin for efficacy against adult fleas for both dogs and cats, as estimated by the turning point (plateau) in the dose response curve, was 6mgkg(-1).

Administration, Topical↗
PubMed2000

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.

Animals↗
PubMed1993

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. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.

Administration, Oral↗
PubMed1992

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. The worm counts in immunosuppressed control animals averaged 775 worms per rat. A range of benzimidazoles, levamisole hydrochloride, morantel tartrate, 22,23-dihydroavermectin B1a and alpha-milbemycin have been evaluated in the assay. The ED95 values obtained indicate that rats infected with T. colubriformis provide a highly predictive model for assaying the activity of experimental drugs in vivo prior to studies in ruminants.

Animals↗
PubMed1992

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. 2. In cells bathed in artificial perienteric fluid, depolarizing steps from a holding potential of -35 mV elicited outward currents at a threshold of -15 mV. These currents had inwardly directed inflections on the rising phase, suggesting the presence of more than one current. Hyperpolarizing steps did not activate current. 3. Tetraethylammonium (TEA+, 69 mmol l-1) blocked the outward currents and allowed a voltage-dependent inactivating Ca2+ current to be observed. The peak current-voltage relationship was U-shaped with a threshold around -15 mV and peak at +5 mV. The reversal potential of the Ca2+ current was estimated by extrapolation to be +45 mV. 4. The permeability of the voltage-activated outward currents was studied by examining reversal potentials of tail currents. The reversal potentials were linearly dependent on the logarithm of the extracellular potassium concentration if extracellular [K+] was greater than 10 mmol l-1. The Na+/K+ permeability ratio of the currents was 0.04. 5. Inactivation, seen as a decline following the peak of the K+ current, was produced by maintained depolarization. The recovery from inactivation was complex and could be described by the sum of two exponentials with time constants of 0.67 s and 20.1 s. Steady-state inactivation of the K+ currents was observed at a range of holding potentials. Only a proportion (34%) of the total K+ current was inactivated by holding potentials more positive than -20 mV. 6. Extracellular application of 5 mmol l-1 4-aminopyridine (4-AP) selectively abolished an early fast component of the K+ current (the peak). The 4-AP-sensitive current decayed quickly with a time constant of around 10 ms; a Boltzmann fit to its activation curve had a half-maximal activation voltage of +14 mV and a 'slope' of 10.5 mV. The 4-AP-resistant current decayed with a time constant of around 1 s; a Boltzmann fit to its activation curve had a half-maximal activation voltage of +29 mV and a 'slope' of 12 mV. 7. Depolarization activates a Ca2+ current and two K+ currents: the K+ currents were separated into lower-threshold, fast-inactivating (Ia-like) and higher-threshold, slowly inactivating (Ik-like) currents.

Aminopyridines↗
PubMed1988

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. Evidence that these drugs were acting at the same site of action was obtained with the antagonist, mecamylamine, which abolished the responses to all these agents. It is concluded that the weak insecticidal action of these potent anthelmintics may result in part from their weak cholinergic agonist action on insect neurones, which contrasts with their potent agonist actions on acetylcholine receptors of helminth nerve and muscle tissues. The striking differences in potency on different invertebrate tissues appears to reflect differences in the properties of acetylcholine receptors between insects and nematodes. Further characterization of neurotransmitter receptors in invertebrates is needed in order to facilitate the rational design of broad-spectrum antiparasitic agents with low toxicity in mammals.

Animals↗
PubMed1982

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.c.) in a glutamate receptor activation-dependent manner. The rate of recovery from the effects of the toxin is reduced following either prolonged application of L-glutamate or repetitive iontophoretic application of this amino acid or high frequency neural stimulation of the muscle in the presence of delta-PTX. The decay phase of the e.j.c. is shortened by delta-PTX. The effects of delta-PTX on the e.j.c. are not voltage dependent. The open-close kinetics of glutamate channels in extrajunctional muscle membrane are modified by delta-PTX as shown by patch clamp analysis. The mean life time of the glutamate channel is reduced, whilst the mean interval between single opening events is increased with the events often occurring in bursts. These data are consistent with glutamate channel blocking by this toxin. It is proposed that the toxin blocks open channels gated by both junctional and extrajunctional glutamate receptors on locust muscle. It is further proposed that delta-PTX enters a compartment of the muscle through the glutamate open channels and that it can also block the open channels from this site.

Animals↗
PubMed1982

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. The kinetics of desensitization were measured ionophoretically. 3. Replacement of Na by equimolar concentrations of the permeant cations Li, NH4 and guanidine and the impermeant cation choline accelerated desensitization onset, increased the steady-state leve of desensitization and reduced the rate of recovery from desensitization. 4. Desensitization onset rates and steady-state levels of desensitization were not significantly altered either by changing the extracellular Ca concentration or by changing the membrane potential of voltage clamped muscle fibres.

Ammonia↗
PubMed1981

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.

Animals↗
PubMed1981

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. The kinetics of onset of and recovery from desensitization were determined ionophoretically either with trains of glutamate/agonist pulses of different frequencies ('conditioning trains') followed by a single 'test' pulse at different intervals after cessation of the conditioning train or with trains of constant frequency drug pulses superimposed upon steady 'conditioning' doses. Both methods gave quantitatively similar results. 3. For approximately equipotent doses, L-glutamate and agonists produced different rates of desensitization onset. Qualitatively similar results were obtained when changes in input conductance of single muscle fibres were measured during bath application of the amino acids. 4. The time courses of recovery from desensitization for receptor populations activated by glutamate and agonists could be described adequately by single exponentials and were independent of the concentration of amino acid except when desensitization exceeded ca. 90%. 5. The rate of recovery from desensitization was different for each agonist.

Animals↗
PubMed1980

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. These results do not exclude a role for an active uptake system in sequestering neurally released transmitter at locust neuromuscular junctions, but they suggest that it has a negligible influence on the time course of the synaptic currents.

Animals↗