Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-07-23
2003-09-30
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06627613
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a readily water-soluble ingestible form of Ivermectin which can be used as a palatable, stable, safe solution for mass medication of animals.
BACKGROUND OF THE INVENTION
In the mid-1970's, a survey of natural products revealed that a fermentation broth of the soil actinomycete
Streptomyces avermitilis
ameliorated infection with
Nematospiroides dubius
in mice. Isolation of the anthelmintic components from cultures of this organism led to discovery of the avermectins, a novel class of 16-membered lactones. Ivermectin (MECTIZAN; 22,23 dihydroavermectin Bla) is a semisynthetic analog of avermectin Bla (abamectin), an insecticide developed for crop management. More specifically, it is a mixture in the ratio of approximately 80:20 of 22,23-dihydro C-076 Bla and Blb. It is disclosed in U.S. Pat. No. 4,199,569, issued Apr. 22, 1980 to Chabala and Fisher.
Ivermectin has the following forumula:
Other anthelmintic agents include; avermectin 5-oxime, abamectin, emamectin, eprinamectin, doramectin, doramectin monosaccharide 5-oximes, fulladectin, milbemycin, milbamycin 5-oxime, moxidectin, Interceptor.TM., nemadectin, imidacloprid, fipronil, lufenuron, thiabendazole, cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate, tetramisole-levamisole, butamisole, pyrantel, pamoate, oxantel and morantel.
Ivermectin is now used extensively to control and treat a broad spectrum of infections caused by parasitic nematodes (roundworms) and arthropods (insects, ticks, and mites) that plague livestock and domestic animals. The effects of these types of parasites can be can be serious. For example, ticks are responsible for the transmission and propagation of many human and animal diseases throughout the world. Ticks of major economic importance include Boophilus, Rhipicephalus, Ixodes, Hyalomma, Amblyomma, and Dermacentor. They are vectors of bacterial, viral, rickettsial and protozoal diseases, and cause tick paralysis and tick toxicosis. Even a single tick can cause paralysis consequent to injecting its saliva into its host in the feeding process. Tick-borne diseases are usually transmitted by multiple-host ticks. Such diseases, including Babesiosis, Anaplasmosis, Theileriosis and Heart Water are responsible for the death and/or debilitation of vast numbers of pet and food animals throughout the world. In many temperate countries, Ixodid ticks transmit the agent of a chronic, debilitating disease, Lyme disease, from wildlife to man. In addition to disease transmission, ticks are responsible for great economic losses in livestock production. Losses are attributable not only to death, but also to damage of hides, loss of growth, reduction in milk production, and reduced grade of meat.
Also, infestation of dogs and cats with fleas has several undesirable effects for the animals and their owners. Such undesirable effects include local irritation and annoying itching, leading to scratching. A high proportion of pet animals, particularly dogs, become allergic to flea saliva, resulting in the chronic condition known as flea bite allergy (or flea allergy). This condition causes the animal to bite and scratch, leading to excoriation of the skin, secondary pyogenic infection, hair loss, and chronic severe inflammatory skin changes. Furthermore, most dogs and cats that are infested with fleas also become infected with
Dipylidium caninum,
the tapeworm transmitted by fleas.
In human beings, Ivermectin is the preferred drug for mass control and treatment of onchocerciasis, the filarial infection responsible for river blindness. This compound also is undergoing extensive clinical trials for use in lymphatic filariasis. Additionally, Ivermectin is effective against strongyloidiasis and several other human infections caused by intestinal nematodes.
The milbemycins are macrocyclic lactone analogues of the avermectins. Some of these compounds have antiparasitic activity similar to the avermectins and probably act by similar mechanisms.
Ivermectin is effective and highly potent against at least some developmental stages of many parasitic nematodes and insects that affect animals and human beings. The drug immobilizes affected organisms by inducing a tonic paralysis of the musculature. Early studies suggested that avermectins caused this effect primarily by modulating gamma-aminobutyric acid (GABA)-mediated neurotransmission. However, recent work indicates that paralysis of the free-living nematode
Caenorhabditis elegans
is probably mediated by potentiation, direct activation, or both, of avermectin-sensitive, glutamate-gated Cl
−
channels. Found only in invertebrates, these channels and two of their cloned subunits have been expressed and characterized in
Xenopus lavis
oocytes. There is close correlation among activation and potentiation by avermectins and milbemycin D of glutamate-sensitive Cl
−
current, nematicidal activity, and membrane binding affinity in this system. Glutamate-gated Cl
−
channels probably serve as one site of Ivermectin action in insects and crustaceans as well. Avermectins also bind with high affinity to GABA-gated and other ligand-gated Cl
−
channels in nematodes such as ascaris and in insects, but the physiological consequences are less well defined. Lack of high-affinity avermectin receptors in cestodes and trematodes may explain why these helminths are not sensitive to Ivermectin. Avermectins do interact with GABA receptors in vertebrate (mammalian) brain, but their affinity for invertebrate receptors is about 100-fold greater.
In human beings infected with
Onchocerca volvulus,
Ivermectin causes a rapid, marked decrease in microfilarial counts in the skin and ocular tissues that lasts for 6 to 12 months. The drug has little discernible effect on adult parasites, but affects developing larvae and blocks egress of microfilariae from the uterus of adult female worms. By reducing microfilariae in the skin, Ivermectin decreases transmission to the Simulium black fly vector. Human infections caused by gastrointestinal nematodes (e.g., strongyloidiasis, ascariasis, trichuriasis, and enterobiasis) respond well to Ivermectin; hookworms are affected to a lesser extent.
In human beings, peak levels of Ivermectin in plasma are achieved within 4 hours after oral administration. The long terminal half-life of about 27 hours in adults primarily reflects a low systemic clearance (about 1.2 liters/hour) and an apparent volume of distribution of about 47 liters. Ivermectin is about 93% bound to plasma proteins; virtually none appears in human urine in either unchanged or conjugated form. In animals, Ivermectin is recovered in feces, nearly all as unchanged drug, and the highest tissue concentrations occur in liver and fat. Extremely low levels are found in brain, even though Ivermectin would be expected to penetrate the blood-brain barrier on the basis of its lipid solubility. Recent studies in transgenic mice suggest, however, that a P-glycoprotein efflux pump in the blood-brain barrier prevents Ivermectin from entering the CNS. This and the limited affinity of Ivermectin for CNS receptors may explain the paucity of CNS side effects and the relative safety of this drug in human beings.
A single oral dose of Ivermectin (150 micro g/kg) given every 6 to 12 months is considered effective, safe, and practical for the control of onchocerciasis in adults and children 5 years or older. Most important, such therapy results in reversal of lymphadenopathy and acute inflammatory changes in ocular tissues and arrests the development of further ocular pathology due to microfilariae. Marked reduction of microfilariae in the skin and ocular tissues is noted within a few days and lasts for 6 to 12 months; the dose should then be repeated. Cure is not attained, because Ivermectin has little effect on adult
O. volvulus.
Continuing annual therapy with Ivermectin reduces transmission of
O. volvulus,
but it is not yet known how long su
Dechert LLP
Peselev Elli
Ryan John W.
LandOfFree
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