Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2000-10-10
2004-06-01
Jones, Dwayne (Department: 1614)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C514S192000, C514S199000
Reexamination Certificate
active
06743440
ABSTRACT:
BACKGROUND OF THE INVENTION
Control of methane production by methanogenic bacteria in ruminant animals has important agronomic impact. Use of inhibitors to control the methane produced by ruminants has been recognized as a part of the mechanism for feed efficiency that results when mixed with cattle feed for both dairy and meat production. An effective additive to boost ruminant feed efficiency is a well-established part of the agronomic practice for commercial ruminant farming.
Methanogenic bacteria form methane by an anaerobic process. The group comprises the genera Methanococcus, Methanobacterium, Methanosarcina, Methanobrevibacter, Methanothermus, Methanothrix, Methanospirillum, Methanomicrobium, Methanococcoides, Methanogenium and Methanoplanus.
Inhibitors of methanogenesis in rumen perform two important functions. Cows and sheep lose 5-10% of their caloric intake to the formation of methane and the resulting loss of a carbon molecule that could have been incorporated in short chain fatty acid production. Inhibition of methane will, therefore, have a direct effect on the formation of short chain fatty acids in the rumen. Other investigators have reported the positive effect of inhibiting methane in rumen fermentation (C. J. Van Nevel, D. I. Demeyer, Manipulation of rumen fermentation, In: The Rumen Microbial Ecosystem, P. N. Hobson, and (Ed) Elsevier Publishing Co. (1988)).
Methane inhibitors have previously been developed for feedstock additives to increase feed efficiency. The inhibitors fall generally into two classes. The first class induces those that affect methane formation indirectly by interfering with the electron flow upstream of the methanogen in the microbial food chain. Examples of this group would be nitrates and nitrites. The second class includes those that affect methanogens directly. Examples of such compounds are ionophores, antibiotics, and polycyclic quinones. Ionophores include, for example, RUMENSIN® (monensin sodium), lasalocid A, salinomycin, avoparcin, aridcin, actaplanin, and penicillin. A more complete list is cited in: C. J. Van Nevel, D. I. Demeyer, Manipulation of rumen fermentation, In: The Rumen Microbial Ecosystem, P. N. Hobson, and (Ed) Elsevier Publishing Co. (1988). Polycyclic quione activity in this regard are referenced in U.S. Pat. No. 5,648,258 (Odom).
The inhibition of methane in rumen by polycyclic quinones (PCQ) operates by a different mechanism than ionophores. PCQ's are redox catalysts that block reduction of electron receptors at the cytochrome c-3 site in the cell wall of anaerobic bacteria, such as methanogens and sulfate reducers. Weimer reveals the action of 9,10-anthraquinone in U.S. Pat. No. 5,385,844 as it applies to reducing sulfate by sulfate reducing bacteria.
Ionophores act as antibiotics with the result that target bacteria concentrations in the rumen are reduced. Since 9,10-anthraquinone does not reduce target bacteria concentration in the rumen, the two mechanisms are clearly distinct.
Garcia-Lopez et al. has demonstrated the use of PCQ's and ionophores each separately can reduce biogenic methane. (P. M. Garcia-Lopez, L. Kung, Jr., J. M. Odom “In Vitro Inhibition of Microbial Methane Production by 9,10-anthraquinone”. Journal of Animal Science 1996, 74:2276-2284).
SUMMARY OF THE INVENTION
In its primary aspect, the invention is directed to a synergistic method for reducing methane formation in the rumen of ruminants comprising administering to the ruminant at least one ionophore compound, and at least one polycyclic quinone compound.
DEFINITIONS
As used herein, the term “rumen” refers to the gastrointestinal section found in ruminants (i.e. cattle, deer, moose, camels, sheep, goats, oxen, water buffalo, and musk oxen) where food is partially digested through bacterial fermentation.
DETAILED DESCRIPTION OF THE INVENTION
A. In General
It is recognized that the administration of an ionophore compound or the administration of a polycyclic quinine (PCQ) to a ruminant will reduce methane and boost feed efficiency in the ruminant. However, applicant has discovered that when the two classes of compounds (ionophores and PCQ's) are administered simultaneously to a ruminant, a synergistic reduction of methane occurs. The advantage of employing this technique is to provide additional feed efficiency for agronomic benefits in ruminant raising. In addition, the levels of antibiotics in feed can be reduced which helps lower the adaptive challenge by non-target bacteria in the rumen and, thereby, lessens the likelihood of adaptation and resistance by rumen bacteria to the antibiotic.
B. Polycyclic Quinones (PCQ's)
A wide variety of polycyclic quinones can be used in the invention. As used herein, the term “polycyclic quinone” or “PCQ” refers to bicyclic, tricyclic and tetracyclic condensed ring quinones and hydroquinones, as well as precursors thereof. On the whole, the non-ionic polycyclic quinones and polycyclic hydroquinones (herein referred to collectively as PCQ's) have very low solubility in water at ambient temperatures. For use in the invention, it is preferred that such PCQs have water solubility no higher than about 1000 ppm by weight.
In addition, as noted above, certain precursors of such PCQ's can also be used in the invention either combined with the relatively insoluble PCQ's or by themselves. Such precursors are anionic salts of PCQ's, which are water soluble under alkaline anaerobic conditions. However, these materials are not stable and are easily converted to the insoluble quinone form upon exposure to oxygen.
Among the water-insoluble PCQ's, which can be used in the invention, are anthraquinone compounds. As used herein, the term “anthraquinone” or “AQ” refers to 9,10-anthraquinone, naphthoquinone, anthrone (9,10-dihydro-9-oxo-anthracene), 10-methylene-anthrone, phenanthrenequinone and the alkyl, alkoxy and amino Derivatives of such quinones, 6,11-dioxo-1H-anthra[1,2-c]pyrazine, 1,2-benzanthraquinone, 2,7-dimethylanthraquinone, 2-methylanthraquinone, 3-methylanthraquinone, 2-aminoanthraquinone and 1-methoxyanthraquinone. Of the foregoing cyclic ketones, 9,10-anthraquinone and methylanthraquinone are preferred because they appear to be more effective. Naturally occurring anthraquinones can be used as well as synthetic anthraquinones.
“Anthraquinone” or “AQ” compounds can further include insoluble anthraquinone compounds, such as 1,8-dihydroxy-anthraquinone, 1-amino-anthraquinone, 1-chloro-anthraquinone, 2-chloro-3-carboxyl-anthraquinone, 1-hydroxy-anthraquinone and unsubstituted anthraquinone. Various ionic derivatives of these materials can be prepared by catalytic reduction in aqueous alkali.
In addition, a wide variety of anthrahydroquinone compounds can be used in the method of the invention. As used herein, the term “anthrahydroquinone compound” refers to compounds comprising the basic tricyclic structure, such as 9,10-dihydroanthrahydroquinone, 1,4-dihydroanthrahydroquinone, and 1,4,4a,9a-tetrahydroanthrahydroquinone. Anthrahydroquinone itself is 9,10-dihydroxyanthracene.
More particularly, both water-insoluble and water-soluble forms can be used. The non-ionic compounds are largely insoluble in aqueous systems, while ionic derivatives, such as di-alkali metal salts, are largely soluble in water. The water-soluble forms are stable only in high pH anaerobic fluids. Low pH fluids (pH less than about 9-10) will result in the formation of the insoluble molecular anthrahydroquinone. Aerobic solutions will incur oxidation of the anthrahydroquinones to anthraquinone. Thus, anthrahydroquinones will not exist for long periods of time in an aerated environment. For these reasons, anthrahydroquinone treatments are usually implemented with the soluble ionic form in a caustic solution. Sodium hydroxide solutions are preferred over the hydroxides of other alkali metals for economic reasons. Rumen physiology may limit the pH of such a preparation, but use of sodium hydroxide in ruminant feed is an established practice.
The extraordinary effectiveness of various
Arkion Life Sciences LLC
Delacroix-Muirheid C.
Jones Dwayne
Krikelis Basil S.
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