CLOSANTEL PLUS

DRUG DESCRIPTION:
For the treatment and control of mature and developing immature gastrointestinal roundworms, lungworms and fluke over 6 weeks in sheep and lambs.
It is ovicidal against nematode eggs and delays egg laying in trematodes (fluke).

INDICATIONS:
Closantel is effective against mature and immature fluke over 6 weeks (Fasciola hepatica), haematophagous nematodes (Haemonchus contortus including benzimidazole resistant strains, Chabertia ovina and Gaigeric pachyscelis) and larval stages of some arthropods including oestrus ovis (sheep nasal bot fly larvae). In known fluke areas, parasitic infestations will generally be mixed involving nematodes, trematodes and occasionally cestodes.

Abamectin is effective against Gastrointestinal and pulmonary roundworms, lice, mites, horn flies; myiasis by screwworm flies, bot flies, warble flies, etc.Treatment with the abamectin/closantel combination will be of particular benefit in reducing parasite burden in such areas.

PHARMACOLOGY:
Mechanism of action of Closantel Sodium:
The molecular mode of action of salicylanilides, including closantel, is not completely elucidated. They all are uncouplers of the oxidative phosphorylation in the cell mitochondria, which disturbs the production of ATP, the cellular “fuel”. This seems to occur through suppression of the activity of succinate dehydrogenase and fumarate reductase, two enzymes involved in this process. This impairs the parasites motility and probably other processes as well. It seems that closantel also disturbs the liquid and ion transport mechanisms in the parasites membranes.
Recently it has been discovered that closantel also inhibits chitinase in Onchocerca volvulus. Chitinase is an enzyme involved in larval molting. Its inhibition interrupts their development to adult worms.

Mechanism of action of Abamectin:
As all macrocyclic lactones, abamectin acts as agonist of the GABA (gamma-aminobutyric acid) neurotransmitter in nerve cells and also binds to glutamate-gated chloride channels in nerve and muscle cells of invertebrates. In both cases it blocks the transmission of neuronal signals of the parasites, which are paralyzed and expelled out of the body, or they starve. It also affects the reproduction of some parasites by diminishing oviposition or inducing an abnormal oogenesis.

In mammals the GABA receptors occur only in the central nervous system (CNS), i.e. in the brain and the spinal chord. But mammals have a so-called blood-brain barrier that prevents microscopic objects and large molecules to get into the brain. Consequently macrocyclic lactones are much less toxic to mammals than to parasites without such a barrier, which allows quite high safety margins for use on livestock and pets.

PHARMACOKINETICS:
Absorption:
After oral administration closantel is readily absorbed into the bloodstream. Four days after treatment up to 60% of the injected and 30% of the drenched closantel is absorbed to blood. In the blood, unchanged closantel binds strongly and almost completely (>99%) to plasma albumins.

After oral administration of Abamectin to sheep, peak plasma levels were observed 12 to 36 hours after treatment.

Distribution:
Peak plasma levels are reached 10 to 48 hours after administration, both after oral or intramuscular administration. Half-life in plasma is 3 to 4 weeks.

Due to the strong binding to plasma albumins, closantel residues in the tissues are rather low; the highest ones were found in the lungs and the kidneys.Half-life plasma elimination of Abamectin was 50 to 90 hours.

Biotransformation: 
Closantel is poorly metabolized. About 80% of the administered dose is excreted through the feces, >98% in the form of the parent molecule.

Elimination:
Excretion 48 hours after oral administration reached ~45% of the administered dose, but only ~10% after intramuscular injection. Excretion half-life in the organism is 2 to 3 weeks.
In dairy cows about 1% of the administered dose is excreted unchanged through the milk.
Excretion of Abamectin was almost completely through feces, <0.5% through urine.

CONTRAINDICATIONS:
Do not exceed the stated dose.
Do not use in animals with known hypersensitivity to the active ingredients or any of the excipients.