Abstract:
The present invention is directed toward a method for inhibiting COX-2 in an organism. In particular, the method is preferably directed toward selectively inhibiting COX-2 in an organism. The method comprises administering to the organism an organic extract isolated from a plant wherein such extract inhibits COX-2. A method to purify a composition that exhibits COX-2 inhibition and COX-2 selective inhibition from the organic extract is also provided. In addition, a method for treating and/or preventing COX-2 mediated inflammation or inflammation-associated disorders in an organism is provided.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application is a continuation of and claims priority to U.S. application Ser. No. 10/022,862, filed Dec. 13, 2001, which claims priority to U.S. Provisional Application Serial No. 60/304,207, filed Dec. 15, 2000, both of which are hereby incorporated herein by reference in their entirety. 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    The current invention is generally directed toward nutraceuticals that are nonsteroidal anti-inflammatory agents capable of inhibiting cyclooxygenase-2 (COX-2). The present invention relates to a method for inhibition of COX-2, or selective inhibition of COX-2 in an organism by administering to the organism organic extracts isolated from plants wherein such extracts inhibit COX-2 activity. The present invention also relates to purified compositions of the plant organic extracts. In addition, the current invention is directed toward a method for treating and/or preventing COX-2 mediated inflammation or inflammation-associated disorders in an organism.  
         BACKGROUND OF THE INVENTION  
         [0003]    The prostaglandins are a potent class of biologically active lipid derivatives that play a crucial role in the inflammatory response. The inflammatory response is a localized tissue response to injury or other trauma characterized by pain, heat, redness and swelling. Prostaglandins mediate this response by inhibiting platelet aggregation, increasing vascular permeability, increasing vascular dilation, inducing smooth-muscle contraction and causing the induction of neutrophil chemotaxis. Because of their central role in mediating the inflammatory response, significant efforts have been directed toward elucidating compositions that are capable of inhibiting the biosynthesis of prostaglandins.  
           [0004]    Toward that end, prostaglandin biosynthesis has been extensively characterized. Prostaglandins are a group of oxygenated fatty acids that are generally derived from arachidonic acid. The biosynthesis of prostaglandins from arachidonic acid occurs in a three step process that includes 1) hydrolysis of arachidonic acid from phospholipid precursors catalyzed by a phospholipase A 2 ; 2) cyclooxygenase (“COX”) catalyzed oxygenation of arachidonic acid to prostaglandin G2 (“PGG2”). This COX catalyzed reaction is the first committed and rate limiting step in prostaglandin synthesis; and 3) conversion of prostaglandin G2 to the biologically active end product, prostaglandin, catalyzed by a series of synthases and reductases. Upon their synthesis, prostaglandins exit the cell and act in a hormone-like manner by effecting the target cell via G protein linked membrane receptors.  
           [0005]    Inactivation of the COX enzyme is a natural target as a means to inhibit prostaglandin production due to this enzyme&#39;s pivotal role in the prostaglandin biosynthetic pathway. It is now known that two gene products possessing COX enzyme activity are expressed, termed COX-1 and COX-2. COX-1 was the first discovered isoform and is constitutively expressed in most tissue types. Because it is constitutively expressed, COX-1 is available to participate in activities requiring a rapid physiological response and causes the production of prostaglandins involved in “house-keeping” functions. For example, COX-1 is responsible for acute production of prostaglandins that regulate vascular homeostasis, maintain gastrointestinal integrity, and maintain kidney function. Thus, COX-1 activity is responsible for the synthesis of prostaglandins required for the maintenance of several cell types.  
           [0006]    COX-2, on the other hand, is a recently discovered isoform that is inducibly expressed in response to numerous stimuli such as bacterial lipopolysaccharides, growth factors, cytokines, and phorbol esters. In addition, COX-2 is only expressed in a limited number of cell types including monocytes, macrophages, neutrophils, fibroblasts and endothelial cells. COX-2 expression, but not COX-1 expression, has been shown to increase in rheumatoid synovial tissue. Contrastingly, COX-2 expression is inhibited in response to glucocorticoids and by anti-inflammatory cytokines. Thus, based upon these observations, COX-2 has been shown to be the isoform responsible for mediating the production of prostaglandins that participate in the inflammatory response and inflammatory related disorders. In addition, COX-2 has also been shown to participate in certain cancers, Alzheimer&#39;s disease, atherosclerosis, and central nervous system damage resulting from stroke, ischemia and trauma.  
           [0007]    Corticosteroids provide one means to reduce effects associated with the inflammatory response. These potent anti-inflammatory agents exert their effect by causing a reduction in the number and activity of immune system cells via various mechanisms. However, prolonged administration of corticosteroids results in drastic side effects that limit the therapeutic value of this class of anti-inflammatory agent.  
           [0008]    Nonsteroidal anti-inflammatory drugs (NSAIDs) are also utilized as a means to reduce effects associated with the inflammatory response. The principal pharmaceutical effects of NSAIDs are due to their ability to prevent COX activity resulting in the inhibition of prostaglandin synthesis. Inhibition of prostaglandin synthesis by NSAIDs is anti-pyretic, analgesic, anti-inflammatory, and anti-thrombogenic. However, administration of NSAIDs may also result in severe side effects such as gastrointestinal bleeding, ulcers and incidence of renal problems. NSAIDs also inhibit both COX isoforms to varying degrees. For example, the most common NSAID, aspirin (acetylated derivative of salicylic acid), inhibits prostaglandin biosynthesis by irreversibly inactivating both COX-1 and COX-2 via acetylation of a serine residue located in the arachidonic binding domain. While aspirin inactivates both isoforms, it is 10 to 100 times more effective inactivating COX-1 as opposed to COX-2.  
           [0009]    The selective inhibition of COX-2 has been shown to be anti-inflammatory and analgesic without the associated gastric and kidney related toxicity problems. This phenomenon is due to the discovery of NSAIDs that are capable of inhibiting COX-2, which is responsible for the production of prostaglandins that mediate the inflammatory response, without causing the inhibition of COX-1, which is responsible for the production of prostaglandins that maintain both gastrointestinal integrity, and kidney function. Thus, the beneficial effects of NSAIDs are separable from their drastic side effects by the development of COX-2 selective inhibitors.  
           [0010]    Toward that end, several drugs that are COX-2 selective inhibitors of prostaglandin synthesis have been developed. The most extensively characterized class of COX-2 selective inhibitor is diarylheterocycles, which include the recently approved drugs celecoxib and rofecoxib. However, other classes include, but are not limited to, acidic sulfonamides, indomethacin analogs, zomepirac analogs, chromene analogs and di-t-butylphenols. For example, U.S. Pat. No. 5,380,738 describes oxazoles which selectively inhibit COX-2, U.S. Pat. No. 5,344,991 describes cyclopentenes which selectively inhibit COX-2, U.S. Pat. No. 5,393,790 describes spiro compounds which selectively inhibit COX-2, WO94/15932 describes thiophene and furan derivatives which selectively inhibit COX-2, and WO95/15316 describes pyrazolyl sulfonamide derivatives which selectively inhibit COX-2.  
           [0011]    In order to afford an alternative to drug-based selective COX-2 therapy, it would be highly beneficial to provide nutraceuticals that inhibit COX-2, or even more preferably that selectively inhibit COX-2. A nutraceutical, in this context, is a composition that is a naturally occurring product that can safely be consumed and that exhibits COX-2 inhibitory activity. In particular, it would be highly beneficial to obtain the nutraceutical composition or extract from a plant source due to the ability to derive a large quantity of the nutraceutical from a plant at a relatively affordable cost. These nutraceutical compositions could be utilized in the diet in a preventative manner to maintain a “healthy” physiological state. The nutraceutical compositions could also be used as a means to treat, cure or mitigate an existing inflammatory-related ailment either alone or in combination with another compound as a part of combination therapy.  
         SUMMARY OF THE INVENTION  
         [0012]    Among the several aspects of the invention therefore, is provided a method for inhibiting the activity of COX-2 in an organism, the method comprising the step of administering to the organism a therapeutically or prophylatically effective amount of an organic extract of a plant, wherein the plant is selected from the order consisting of Agavales, Apocynales, Arales, Asterales, Basidiomycetae, Brassicales, Caryophyllales, Cycadales, Ebenales, Euphorbiales, Fagales, Hydrocharitales, Lamiales, Liliales, Loasales, Malvales, Myrtales, Palmales, Pandanales, Papaverales, Piperales, Polemoniales, Polygalales, Primulales, Ranales, Rhamnales, Rosales, Rubiales, Rutales, Santalales, Sapindales, Scrophulariales, Umbellales, Urticales, and Violales.  
           [0013]    Another aspect of the invention is a method for inhibiting the activity of COX-2 in an organism, the method comprising the step of administering to the organism a therapeutically or prophylactically effective amount of an organic extract of a plant, wherein the plant is selected from the order consisting of Agavales, Apocynales, Arales, Asterales, Basidiomycetae, Brassicales, Caryophyllales, Cycadales, Ebenales, Euphorbiales, Fagales, Hydrocharitales, Lamiales, Liliales, Loasales, Malvales, Myrtales, Palmales, Pandanales, Papaverales, Piperales, Polemoniales, Polygalales, Primulales, Ranales, Rhamnales, Rosales, Rubiales, Rutales, Santalales, Sapindales, Scrophulariales, Umbellales, Urticales, and Violales, wherein the organic extract is a purified composition obtained by a method comprising contacting the plant with an organic solvent to remove an extract from the plant wherein the extract inhibits COX-2 activity and then isolating the extract with COX-2 inhibitory activity.  
           [0014]    Still another aspect provides a method of treating or preventing COX-2 mediated inflammation or an inflammation-associated disorder in an organism, the method comprising administering to the organism a therapeutically or prophylactically effective amount of the purified composition of an organic plant extract wherein the purified composition is obtained by a method comprising contacting the plant with an organic solvent to remove an extract from the plant wherein the extract inhibits COX-2 activity and then isolating the extract with COX-2 inhibitory activity.  
           [0015]    Other features of the present invention will be in part apparent to those skilled in the art and in part pointed out in the detailed description provided below. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]    [0016]FIG. 1 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Trichilia hirta.    
         [0017]    [0017]FIG. 2 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Capsicum frutescens.    
         [0018]    [0018]FIG. 3 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Tradescantia virginiana.    
         [0019]    [0019]FIG. 4 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Tephrosia purpurea.    
         [0020]    [0020]FIG. 5 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Dracontomelon mangiferum.    
         [0021]    [0021]FIG. 6 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Erythrina rubrinervia.    
         [0022]    [0022]FIG. 7 depicts COX-2&gt;COX-1 inhibition by a plant extract isolated from  Pisonia aculeata.   
     
    
     ABBREVIATIONS AND DEFINITIONS  
       [0023]    To facilitate understanding of the invention, a number of terms and abbreviations as used herein are defined below:  
         [0024]    “Purified” means partially purified and/or completely purified. Thus, a “purified composition” may be either partially purified or completely purified.  
         [0025]    “Extract” means crude extract, purified extract, and purified composition obtained by purification of the extract.  
         [0026]    “COX activity” means the ability of either COX isoform, COX-1 or COX-2, to catalyze the oxygenation reaction of arachidonic acid to PGG2.  
         [0027]    “COX inhibitor or COX inhibition” means a composition, agent or extract, purified or otherwise, that prevents either COX isoform, COX-1 or COX-2, from catalyzing the oxygenation reaction of arachidonic acid to PGG2 either in whole or in part.  
         [0028]    “Selective inhibition of COX-2” means a composition, agent, or extract, purified or otherwise, which selectively inhibits COX-2 activity over COX-1 activity as determined by the ratio of the percentage of COX-2 inhibition divided by the percentage of COX-1 inhibition, unless otherwise indicated herein.  
         [0029]    “IC 50 ” means the concentration (in mol L −1 ) that reduces a specified response to 50% of its former value. As used herein this value measures the amount of composition, agent or extract (ug extract/ml solvent) causing 50% inhibition of PGE2 production. The IC 50  value may be used to determine COX-2 selectivity as specifically set-forth herein.  
         [0030]    “Plant or parts thereof” means either the whole plant, or any part of the plant such as an aerial part, fruit, leaf, stem, or root and any combination thereof.  
         [0031]    “Order”, as utilized herein, is a taxonomic category of related organisms with a category consisting of a number of similar families.  
         [0032]    “Family”, as utilized herein, is a taxonomic category of related organisms ranking below the order and above the genus.  
         [0033]    “Species”, as utilized herein, is a fundamental taxonomic category ranking below a genus and consisting of a group of closely related individuals.  
         [0034]    COX=the enzyme cyclooxygenase  
         [0035]    COX-1=the isoform cyclooxygenase-1  
         [0036]    COX-2=the isoform cyclooxygenase-2  
         [0037]    NSAIDs=nonsteroidal anti-inflammatory drugs  
         [0038]    PGE2=prostaglandin E2  
       DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0039]    Applicants have discovered that organic extracts of certain plants or parts therefrom inhibit COX-2 activity. Applicants have also discovered that organic extracts of certain plants or parts therefrom selectively inhibit COX-2 activity. The inhibitory effect is selective because inhibition of COX-2 is greater than inhibition of COX-1. Consequently, organic extracts of such plants or parts therefrom may be used to selectively inhibit the activity of COX-2 in an organism without causing an equivalent inhibition of COX-1 activity. Advantageously, these organic extracts are nutraceuticals that may be safely consumed and provide an alternative to traditional drug-based therapy for COX-2 inhibition.  
         [0040]    Accordingly, the extracts of the present invention preferably inhibit COX-2 activity more than COX-1 activity. Preferably, the inhibitory effect of the plant extract on COX-2 is at least about two times greater than its inhibitory effect on COX-1. More preferably, the inhibitory effect on COX-2 is at least about 10 times greater than the inhibitory effect on COX-1. COX enzyme inhibition and selectivity may be determined in accordance with any method generally known to those of ordinary skill in the field, as set forth in more detail below.  
         [0041]    In addition to inhibiting COX-2, the organic extracts of the present invention may be isolated from an edible or non-edible plant. In general, plants are classified as non-edible if they are utilized for a purpose other than nourishment and categorized as edible if they are consumed for the purpose of nourishment. For example, medicinal plants are considered non-edible because they are consumed for the purpose of correcting symptoms of illness and are considered too potent to be consumed on a daily basis. Classification of plants as edible versus non-edible, therefore, may be accomplished utilizing references commonly known to those skilled in the art for example, such references include, NAPRALERT; Tyozaburo Tanaka, (Edited by Sasuke Nakoa) Tanaka&#39;s Cyclopedia of Edible Plants of the World, Keigaku Publishing Co., Tokyo, Japan, 1976; Stephen Facciola, Cornucopia II: A Source Book of Edible Plants, Kampong Publications, Vista, Calif., 1998; James A. Duke, Database of Phytochemical constituents of GRAS Herbs and Other Economic Plants, CRC Press, Boca Raton, Fla., 1992; and George Macdonald Hocking, Dictionary of Natural Products, Plexus Publishing, Inc., Medford, N.J., 1997. The contents of these references are hereby incorporated in their entirety.  
         [0042]    In a particularly preferred embodiment, organic extracts are isolated from plants of the following plant orders: Agavales, Apocynales, Arales, Asterales, Basidiomycetae, Brassicales, Caryophyllales, Cycadales, Ebenales, Euphorbiales, Fagales, Hydrocharitales, Lamiales, Liliales, Loasales, Malvales, Myrtales, Palmales, Pandanales, Papaverales, Piperales, Polemoniales, Polygalales, Primulales, Ranales, Rhamnales, Rosales, Rubiales, Rutales, Santalales, Sapindales, Scrophulariales, Umbellales, Urticales, and Violales. The ability of extracts isolated from plants of these particular orders to inhibit COX-2, selectively inhibit COX-2 and their use is set-forth below in Tables 1-2.  
         [0043]    In order to prepare the extracts of the invention, a plant or parts thereof are ground into a fine powder, the resultant powder is extracted with a solvent, and the extraction solvent is removed from the extract. The whole plant may be used or parts of the plant including an aerial part, fruit, leaf, stem, or root and any combination thereof may be used. If desired, the resultant extract may be further purified to yield a purified extract or one or more purified compositions. The grinding step may be accomplished by any commonly known method for grinding a plant substance. For example, the plant or parts thereof may be passed through a grinder to obtain a fine powder.  
         [0044]    After the plant or parts thereof have been ground into a fine powder, they are combined with an extraction solvent. The solution is then stirred at a temperature, and for a period of time, that is effective to obtain an extract with the desired inhibitory effects on the activity of COX-2. The solution is preferably not overheated, as this may result in degradation and/or denaturation of proteins in the extract. The solution may be stirred at a temperature between about room temperature (25□ C.) and the boiling point of the extraction solvent. Preferably, the solution is stirred at about room temperature.  
         [0045]    The length of time during which the plant powder is exposed to the extraction solvent is not critical. Up to a point, the longer the plant powder is exposed to the extraction solvent, the greater is the amount of extract that may be recovered. Preferably, the solution is stirred for at least 1 minute, more preferably for at least 15 minutes, and most preferably for at least 60 minutes.  
         [0046]    The extraction process of the present invention is desirably carried out using an organic solvent or a mixture of organic solvents. organic solvents which may be used in the extraction process of the present invention, include but are not limited to hydrocarbon solvents, ether solvents, chlorinated solvents, acetone, ethyl acetate, butanol, ethanol, methanol, isopropyl alcohol and mixtures thereof. Hydrocarbon solvents which may be used in the present invention include heptane, hexane and pentane. Ether solvents which may be used in the present invention include diethyl ether. Chlorinated solvents which may be used in the present invention include dichloromethane and chloroform. Preferably, the solvent utilized for such extraction is a nonpolar organic solvent, such as dichloromethane or hexane.  
         [0047]    The relative amount of solvent used in the extraction process may vary considerably, depending upon the particular solvent employed. Typically, for each 100 grams of plant powder to be extracted, about 500 ml of extraction solvent would be used. The organic solvent may be removed from the extract by any method known in the field of chemistry for removing organic solvents from a desired product, including, for example, rotary evaporation.  
         [0048]    It is believed that the inhibitory effect of the plant extract of this invention on the activity of COX-2 is due to the presence of one or more compounds in the extract. Compounds present in the extract which inhibit the activity of COX-2 may be isolated and purified by those of ordinary skill in the art employing methods known in the art. For example, column chromatography and fractional distillation may be used to obtain pure compounds from the plant extract of this invention.  
         [0049]    The isolation and purification of particular compounds from the organic plant extracts of this invention may be performed as described in Resch, et al., J. Nat. Prod., 61, 347-350 (1998), the entire contents of which are incorporated by reference herein. The methods disclosed therein may be used to isolate and purify compositions which inhibit COX-2.  
         [0050]    The ability of a particular organic extract to inhibit COX-1 or COX-2 is preferably determined by performing COX activity assays utilizing recombinant COX-1 and COX-2. The COX-1 and COX-2 genes may be subcloned from a variety of organisms, however in a preferred embodiment such genes are isolated from human or murine sources, using a variety of procedures known to those skilled in the art and detailed in, for example, Sambrook et al., Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, (1989) and Ausabel et al., Short Protocols in Molecular Biology, 3rd. ed., John Wiley &amp; Sons (1995). Additionally, the subcloned portion of the particular COX gene may be inserted into a vector by a variety of methods. In a preferred method, the sequence is inserted into an appropriate restriction endonuclease site(s) in a baculovirus transfer vector pVL1393 utilizing procedures known to those skilled in the art and detailed in, for example, Sambrook et al.,  Molecular Cloning, A Laboratory Manual,  2nd ed., Cold Spring Harbor Laboratory Press, (1989) and Ausubel et al.,  Short Protocols in Molecular Biology,  3rd ed., John Wiley &amp; Sons (1995).  
         [0051]    The recombinant baculoviruses may be isolated by transfecting an appropriate amount of baculovirus transfer vector DNA into a sufficient quantity of SF9 insect cells along with linearized baculovirus plasmid DNA by the calcium phosphate method or any other method generally know to those skilled in the art. (See M. D. Summers and G. E. Smith,  A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures , Texas Agric. Exp. Station Bull. 1555 (1987)). Recombinant viruses may be purified by three rounds of plaque purification and high titer (10 7 -10 8  pfu/ml) stocks of virus may be prepared.  
         [0052]    Preferably, for large scale production, cells may be infected in approximately 10 liter fermentors (0.5×10 6 /ml) with the recombinant virus stock such that the multiplicity of infection is greater than about 0.1. After several hours the cells are centrifuged and the cell pellet is homogenized in an appropriate buffer such as Tris/sucrose (50 mM/25%, pH 8.0). The homogenate may then be centrifuged at an appropriate speed and for an appropriate time (such as 10,000×G for 30 minutes) so as to cause the homogenate to separate into a pellet and supernatant fraction. The resultant supernatant fraction will contain the desired product and may be stored at −80° C. until use.  
         [0053]    In order to test organic extracts for COX-2 inhibition and selectivity, standard COX-1 and COX-2 assays may be performed by employing ELISA procedures generally known to those skilled in the art. In such procedures, COX-1 and COX-2 activities are assayed as PGE 2  formed/ug protein/time using ELISA to detect the amount of PGE 2  synthesized from arachindonic acid. PGE 2  formation may be measured using PGE 2  specific antibody. Indomethacin, a non-selective COX-2/COX-1 inhibitor, may be employed as a positive control. The relative ability of various organic extracts to inhibit COX-1 or COX-2 at a particular concentration may be determined by comparing the IC 50  value expressed as ug extract/ml solvent resulting in a 50% inhibition of PGE2 production. Selective inhibition of COX-2 may then be determined by the IC 50  ratio of COX-1/COX-2. Additionally, any other means to determine COX inhibition known to those generally skilled in the art may be employed.  
         [0054]    The extracts of this invention may be used to manage, prevent and/or treat an organism having, or at risk for developing, a condition which is mediated in whole or in part by COX-2. Accordingly, conditions which may be benefitted by inhibition of COX-2 or selective inhibition of COX-2 include, but are not limited to, the treatment of inflammation in an organism, and for treatment of other inflammation-associated disorders, such as, an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, extracts of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such extracts of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis, and from post-operative inflammation including ophthalmic surgery such as cataract surgery and refractive surgery. Extracts of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn&#39;s disease, gastritis, irritable bowel syndrome and ulcerative colitis, and treatment of cancer, including but not limited to the following types of cancer: colon, breast, prostate, bladder, or lung. In yet another preferred use, the extracts of the present invention may also be utilized as chemopreventive agents. Extracts of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin&#39;s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet&#39;s syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling occurring after injury, myocardial ischemia, and the like. The extracts would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. The extracts would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. Additionally, the extracts would be beneficial for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimer&#39;s disease. The extracts of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These extracts would also be beneficial in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma. Additionally, the extracts would be useful in the treatment of pain, including but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer.  
         [0055]    The present extracts may also be employed either alone or in combination with other compounds as a part of combination therapy, partially or completely, in place of other conventional anti-inflammatories. For example, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, leukotriene receptor antagonists, LTA4 hydrolase inhibitors, and LTC4 synthase inhibitors. Preferably, with combination therapy one will typically combine a drug or drugs and a nutraceutical, such as a plant extract of the current invention, in a manner such that the drug and the nutraceutical have different mechanisms of action, but yet target the same disease. For example, in a typical selection of agents for use in combination therapy to treat arthritis, one could utilize a plant extract of the present invention, which exhibits selective COX-2 inhibition with another agent known to attenuate inflammation associated with arthritis via an independent mechanism.  
         [0056]    Those of ordinary skill in the art of preparing pharmaceutical formulations can readily formulate pharmaceutical compositions having plant extracts using known excipients (e.g., saline, glucose, starch, etc.). Similarly, those of ordinary skill in the art of preparing nutritional formulations can readily formulate nutritional compositions having plant extracts. And those of ordinary skill in the art of preparing food or food ingredient formulations can readily formulate food compositions or food ingredient compositions having plant extracts.  
         [0057]    In addition, those of ordinary skill in the art can readily determine appropriate dosages that are necessary to achieve the desired therapeutic or prophylactic effect upon oral, parenteral, rectal and other administration forms. Typically, in vivo models (i.e., laboratory mammals) are used to determine the appropriate plasma concentrations necessary to achieve a desired mitigation of inflammation related conditions.  
         [0058]    The extracts of the present invention may be employed for the treatment and/or prevention of inflammation-related disorders, as identified above, in a number of organisms. Besides being useful for human treatment, these extracts are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, avians, and the like. More preferred animals include horses, dogs, cats, sheep, and pigs.  
         [0059]    The detailed description set-forth above is provided to aid those skilled in the art in practicing the present invention. Even so, this detailed description should not be construed to unduly limit the present invention as modifications and variation in the embodiments discussed herein can be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery.  
         [0060]    All publications, patents, patent applications and other references cited in this application are herein incorporated by reference in their entirety as if each individual publication, patent, patent application or other reference were specifically and individually indicated to be incorporated by reference.  
         [0061]    Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.  
       EXAMPLES  
     Sample Preparation  
       [0062]    Plants or parts thereof were dried and sliced (“sample”). Samples of organic extracts were prepared from the plants listed in Table 1. The plant order and families that the various samples were prepared from are set-forth in Table 1. In addition, details regarding the use of these some of these plants is set-forth in Table 2. The particular sample was then ground into a fine powder using a coffee grinder. Approximately 100 grams of the resulting powder were added to approximately 500 ml of dichloromethane and stirred at room temperature for about 1 hour. The solvent was then removed by rotary evaporation, leaving several grams of the particular extract.  
       Inhibitory Effect of Various Plant Organic Extracts on COX-1 and COX-2 Activity  
       [0063]    The particular extracts resulting from the sample preparation procedure detailed above were each evaluated for inhibition of COX-1 and COX-2. The COX-1 and COX-2 inhibition activities were determined in vitro according to the method of Gierse et al.,  J. Diochem.,  305, 479-484 (1995). This method is summarized below.  
         [0064]    Preparation of Recombinant COX Baculoviruses  
         [0065]    Recombinant COX-1 was prepared by cloning a 2.0 kb fragment containing the coding region of human or murine COX-1 into a BamH1 site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-1 according to the method of D. R. O&#39;Reilly et al.,  Baculovirus Expression Vectors: A Laboratory Manual  (1992).  
         [0066]    Recombinant baculoviruses were then isolated by transfecting 4 ug of baculovirus transfer vector DNA into (2×10 8 ) SF9 insect cells along with 200 ug of linearized baculovirus plasmid DNA by the calcium phosphate method. (See M. D. Summers and G. E. Smith,  A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures , Texas Agric. Exp. Station Bull. 1555 (1987)). Recombinant viruses were purified by three rounds of plaque purification and high titer (10 7 -10 8  pfu/ml) stocks of virus were prepared.  
         [0067]    For large-scale production, SF9 insect cells were infected in 10 liter fermentors (0.5×10 6 /ml) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet was homogenized in Tris/sucrose (50 mM/25%, pH 8.0) containing 1% of 3[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The homogenate was then centrifuged at 10,000×G for 30 minutes, and the resultant supernatant was stored at −80° C. until use.  
         [0068]    Recombinant COX-2 was prepared by cloning a 2.0 kb fragment containing the coding region of human or murine COX-2 in accordance with the same method described above for COX-1.  
         [0069]    Assay for COX-1 and COX-2 Activities  
         [0070]    COX-1 and COX-2 activities were assayed as prostaglandin E2 (PGE2) formed/ug protein/time using ELISA to detect PGE2 synthesized from arachindonic acid. CHAPS-solubilized insect cell membranes containing recombinant COX-1 or COX-2 enzyme were incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme. Compounds were pre-incubated with the appropriate enzyme for approximately 10-20 minutes. Arachidonic acid (10 uM) was then added to the mixture and the reaction was permitted to occur for ten minutes at room temperature (25° C.).  
         [0071]    Any reaction between the arachidonic acid and the enzyme was stopped after ten minutes by transferring 40 ul of reaction mixture into 160 ul ELISA buffer and 25 uM indomethacin. Indomethacin, a non-selective COX-2/COX-1 inhibitor, was utilized as a positive control. The PGE 2  formed was measured by standard ELISA technology utilizing a PGE2 specific antibody (Cayman Chemical).  
         [0072]    Approximately 200 mg of each extract obtained from the sample preparation procedure set-forth above were each individually dissolved in 2 ml of dimethyl sulfoxide (DMSO) for bioassay testing to determine the COX-1 and COX-2 inhibitory effects of each particular extract. Potency was determined by the IC 50  value expressed as ug extract/ml solvent resulting in a 50% inhibition of PGE2 production. Selective inhibition of COX-2 was determined by the IC 50  ratio of COX-l/COX-2. The results of these bioassays performed utilizing extract isolated from the plant family indicated are reported in Tables 1 and FIGS. 1-7 delineated below.  
         [0073]    Table 1 below sets forth results of screening extracts of plants isolated from the orders, families, genera, and species indicated. A primary screen (indicated as 1° assay in Table 1) was performed in order to determine particular extracts that inhibit COX-2 at a concentration of 10 ug/ml. The extracts were then subjected to a confirmation screen to determine the extent of COX-2 inhibition at three different concentrations (10 ug/ml, 3.3 ug/ml and 1.1 ug/ml). The extracts were then tested for their ability to inhibit COX-1 at a concentration of 10 ug/ml. The percentage of COX inhibition is indicated as a percentage in each column, with a higher percentage indicating a greater degree of COX inhibition. In addition, the IC 50  value for COX-1 and COX-2 was also determined for certain extracts as indicated in Table 1. The selectivity for these extracts was then determined by the IC 50  ratio of COX-1/COX-2, as set-forth above. The COX-2 selectivity of extracts whose IC 50  value was not determined may be calculated by dividing the percentage of COX-1 inhibition (at a concentration of 10 ug/ml) by the percentage of COX-2 inhibition (at a concentration of 10 ug/ml).  
                                                                                                                                                                 TABLE 1                           COX-2 Inhibitory Activity from Plant Extracts                1* assay   Confirmation assay   COX-1   IC50   IC50               COX-2 (% Inhib.)   COX-2 (% Inhib.)   (% Inhib.)   (ug/ml)   (ug/ml)   Selectivity            Order   Family   Genus   Species   Common name   Part   10 ug/ml   10 ug/ml   3.3 ug/ml   1.1 ug/ml   10 ug/ml   COX-2   COX-1   COX-2/COX-1                    Agavales   Agavaceae     Pleomele       augustifolia     native dracaena   LF   63%   73%   23%   22%   40%   ***   ***   ***       Apocynales   Apocynaceae     Bleekeria       vitiensis             **   58%   34%   −16%   ***   ***   ***   ***       Apocynales   Apocynaceae     Strophanthus       hispidus     zwezwe (Africa)   LP   69%   72%   22%   −1%    6%   ***   ***   ***       Apocynales   Asclepiadaceae     Asclepias       asperula     antelope horn   RT   68%   70%   50%   24%    1%   ***   ***   ***       Arales 9     Araceae     Amorphophallus       campanulatus     telinga potato   CO   70%   58%   27%   2%   −3%   ***   ***   ***       Arales 9     Araceae     Anthurium       crenatum         PX   65%   65%   3%   1%   23%   ***   ***   ***       Arales 9     Araceae     Pinellia       ternata     ban xia (China)       *   64%   18%   2%   ***   ***   ***   ***       Arales 9     Araceae     Pinellia       ternata     ban xia (China)       *   98%   72%   38%   28%   ***   ***   ***       Asterales   Asteraceae     Vernonia       sericea         PX   77%   77%   30%   19%   12%   ***   ***   ***       Asterales   Asteraceae     Wedelia       reticulata         PX   77%   63%   37%   1%   17%   ***   ***   ***       Asterales   Asteraceae     Xanthium       strumarium     arishta (Sanskrit)   FR   99%   75%   62%   39%   37%   ***   ***   ***       Basidiomycetae   Polyporaceae   Grifola     frondosa     maitake   FB   67%   68%   26%   −2%   17%   ***   ***   ***       Brassicales 1     Brassicaceae 2       Brassica       chinensis     Chinese cabbage       50%   68%   38%   −5%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Brassica       chinensis     Chinese cabbage       61%   22%   16%   −14%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Brassica       oleracea     common cabbage       *   41%   31%   15%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Brassica       oleracea     common cabbage       *   74%   38%   6%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Raphanus       sativus     daikon; semen raphani       76%   81%   56%   5%   25%   ***   ***   ***       Brassicales 1     Brassicaceae 2       Raphanus       sativus     daikon; semen raphani       71%   29%   18%   −10%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Raphanus       sativus     daikon; semen raphani       *   42%   34%   6%   ***   ***   ***   ***       Brassicales 1     Brassicaceae 2       Raphanus       sativus     daikon; semen raphani       *   54%   19%   10%   ***   ***   ***   ***       Caryophyllales   Caryophyllaceae     Saponaria       officinalis     soapwort       *   30%   13%   6%   ***   ***   ***   ***       Caryophyllales   Caryophyllaceae     Saponaria       officinalis     soapwort       *   42%   −4%   −33%   ***   ***   ***   ***       Caryophyllales   Chenopodiaceae     Beta       vulgaris     beet; Swiss chard   RT   85%   75%   48%   35%   37%   ***   ***   ***       Caryophyllales   Nyctaginaceae     Pisonia       aculeata     cockspur; una de gato   LP   61%   97%   63%   47%    6%   4.5   45   10       Caryophyllales   Phytolaccaceae     Trichostigma       octandrum     hoop vine   PX   73%   82%   40%   33%   43%   ***   ***   ***       Caryophyllales   Polygonaceae     Chorizanthe       diffusa             62%   46%   31%   −14%   ***   ***   ***   ***       Caryophyllales   Polygonaceae     Rumex       hymenosepalus     Indian root; wild rhubarb       *   58%   12%   5%   ***   ***   ***   ***       Caryophyllales   Polygonaceae     Rumex       hymenosepalus     Indian root; wild rhubarb       *   83%   67%   34%   36%   ***   ***   ***       Cycadales   Cycadaceae     Zamia       debilis     wild sago       30%   66%   29%   −4%   ***   ***   ***   ***       Cycadales   Cycadaceae     Zamia       debilis     wild sago       66%   2%   −11%   −1%   ***   ***   ***   ***       Ebenales   Ebenaceae     Diospyros     unidentified   persimmon   LF   85%   75%   53%   31%   10%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Croton       rigidus         PX   69%   79%   61%   21%   47%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Gymnanthes       lucida         PX   63%   79%   61%   9%   53%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Macaranga       conifera         LF   66%   64%   25%   13%   36%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Macaranga       triloba     mahang serindit (Malaysia)   LF   62%   57%   32%   48%   29%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Manihot       esculenta     cassava   RB   71%   69%   40%   21%   25%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Ostodes       paniculata     bijopari       *   48%   11%   −1%   ***   ***   ***   ***       Euphorbiales   Euphorbiaceae     Ostodes       paniculata     bijopari       *   41%   15%   −18%   ***   ***   ***   ***       Euphorbiales   Euphorbiaceae     Phyllanthus       cuneifolius         PX   64%   62%   25%   1%   46%   ***   ***   ***       Euphorbiales   Euphorbiaceae     Ricinodendron       heudelottii         ST   73%   82%   65%   32%   55%   ***   ***   ***       Fagales   Fagaceae     Castanopsis     unidentified       LF   86%   64%   23%   −1%   41%   ***   ***   ***       Fagales   Fagaceae     Castanopsis     unidentified       LF   73%   56%   15%   15%   30%   ***   ***   ***       Fagales   Fagaceae     Castanopsis     unidentified       LF   66%   60%   36%   4%   21%   ***   ***   ***       Hydrocharilales   Hydrocharitaceae     Elodea       densa     water weed       100%    90%   78%   30%   ***   ***   ***   ***       Lamiales   Verbenaceae     Callacarpa       cana         SB   66%   71%   56%   11%   45%   ***   ***   ***       Lamiales   Verbenaceae     Clerodendron       lecomtei         LF   60%   80%   54%   31%   23%   ***   ***   ***       Liliales   Commelinaceae     Tradescantia       virginiana     spiderwort       **   96%   56%   25%   13%   2.5   75   30       Liliales   Commelinaceae     Tradescantia       virginiana     spiderwort       **   67%   48%   −3%   ***   ***   ***   ***       Liliates   Liliaceae     Lilium       auratum     goldband lilly   R4   73%   78%   47%   31%   34%   ***   ***   ***       Liliales   Liliaceae     Lilium       auratum     goldband lilly   BU   73%   70%   61%   25%   40%   ***   ***   ***       Liliales   Liliaceae     Lilium       auratum     goldband lilly       *   75%   49%   30%   16%   ***   ***   ***       Liliales   Liliaceae     Smilax       havanensis     Cuban sarsaparilla   PX   60%   80%   −4%   21%   15%   ***   ***   ***       Loasales   Loasaceae     Mentzelia       aspera     dal pega   PX   79%   77%   46%   17%   35%   ***   ***   ***       Malvales   Bombaceae 8       Quararibea       turbinata     swizzle stick tree   PX   60%   70%   47%   12%   19%   ***   ***   ***       Malvales   Elaeocarpaceae     Elaeocarpus       bifidus             62%   85%   62%   1%   12%   ***   ***   ***       Malvales   Elaeocarpaceae     Elaeocarpus       bifidus             52%   37%   54%   −13%   ***   ***   ***   ***       Malvales   Sterculiaceae     Guazuma       ulmifolia     bay cedar   PX   77%   71%   40%   −6%   17%   ***   ***   ***       Malvales   Sterculiaceae     Helicteres       jamaicensis     Jamaican screw tree   PX   63%   66%   32%   33%   23%   ***   ***   ***       Malvales   Sterculiaceae     Melochia       pyramidata     meloch   PX   66%   61%   14%   −9%   −44%    ***   ***   ***       Myrtales   Myrtaceae     Myrcia       splendens         PX   61%   72%   30%   23%    3%   ***   ***   ***       Myrtales   Myrtaceae     Syzygium       malaccense     Malay apple   PX   65%   62%   15%   14%   −7%   ***   ***   ***       No order   Cyatheaceae     Cyatheae     unidentified   fern   PE   73%   100%   22%   −13%   45%   ***   ***   ***       No order   Umbilicariaceae     Umbilicaria       proboscidea     umbilicaria lichen   PL   76%   81%   25%   −7%   61%   ***   ***   ***       No order   Boletaceae     Boletus       rubricitrinus             87%   70%   59%   35%   34%   ***   ***   ***       Palmales   Arecacene     Caryota       mitis     sago palm   BK   61%   92%   62%   40%   37%   ***   ***   ***       Palmales   Arecaceae     Coccothrinax       alta     chestnut; silver palm   PX   76%   73%   35%   2%    0%   ***   ***   ***       Palmales   Arecaceae     Scheelea       phalerata     scheela palm   LQ   67%   76%   22%   12%   42%   ***   ***   ***       Pandanales 9     Sparganiaceae     Sparganium       ramosum     bur-reed       *   58%   42%   25%   ***   ***   ***   ***       Papaverales   Papaveraceae     Bocconia       frutescens     tree celandine   PX   71%   78%   40%   39%   32%   ***   ***   ***       Piperales   Chloranthaceae     Hedyosmum       arborescens         PX   73%   54%   25%   4%    7%   ***   ***   ***       Piperales   Piperaceae     Peperomia     unidentified       PL   95%   93%   66%   28%   90%   ***   ***   ***       Piperales   Piperaceae     Piper       aduncum     pepper   PL   72%   83%   23%   24%   34%   ***   ***   ***       Polemoniales 7     Boraginaceae 6       Cordia       laevigata         PX   66%   74%   42%   19%   42%   ***   ***   ***       Polemoniales 7     Boraginaceae 6       Lithospermum       erythrorhizon     red root gromwell   RT   61%   70%   31%   18%   −21%    ***   ***   ***       Polemoniales 7     Solanaceae     Capsicum       frutescens     habanero pepper   FR   60%   81%   50%   12%    4%   2.5   &gt;100    &gt;40        Polemoniales 7     Solanaceae     Capsicum       frutescens     habanero pepper       *   59%   11%   4%   ***   ***   ***   ***       Polemoniales 7     Solanaceae     Capsicum       frutescens     habanero pepper       *   82%   64%   40%   30%   ***   ***   ***       Polemoniales 7     Solanaceae     Solanum       acuminatum         KS   76%   81%   39%   27%   48%   ***   ***   ***       Polygalales   Polygalaceae     Polygala       penaca         PX   71%   72%   28%   22%    8%   ***   ***   ***       Primulales   Myrsinaceae     Myrsine       coriaceae         PX   78%   83%   58%   18%   57%   ***   ***   ***       Primulales   Theophrastaceae     Jacquinia       umbellata         PX   79%   79%   37%   19%   30%   ***   ***   ***       Primulales   Theophrastaceae     Jacquinia       umbellata         PX   75%   78%   42%   −2%   51%   ***   ***   ***       Ranales   Lauraceae     Cinnamonum       obtusifolium     cinnamon   LF   65%   65%   −22%   −1%   16%   ***   ***   ***       Ranales   Lauraceae     Cinnamonum       parthenoxylon     cinnamon   LF   79%   52%   6%   6%   −16%    ***   ***   ***       Ranales   Ranunculaceae     Paeonia       officinalis     common peony       45%   51%   15%   −17%   ***   ***   ***   ***       Rhamnales   Rhamnaceae     Ziziphus       jujuba     jujube; date tree   SD   76%   69%   61%   41%   38%   ***   ***   ***       Rhamnales   Rhamnaceae     Ziziphus       jujuba     jujube; date tree       *   86%   72%   53%   26%   ***   ***   ***       Rhamnales   Rhamnaceae     Ziziphus       jujuba     jujube; date tree       *   88%   74%   42%   31%   ***   ***   ***       Rosales   Fabaceae     Adenanthera       microsperma     bead tree   LF   67%   58%   29%   21%   41%   ***   ***   ***       Rosales   Fabaceae     Albizzia       lucida         LF   81%   62%   26%   29%   13%   ***   ***   ***       Rosales   Fabaceae     Albizzia       longepedata             68%   −3%   14%   −14%   ***   ***   ***   ***       Rosales   Fabaceae     Cassia       quinquangulata     wampi       28%   57%   34%   2%   ***   ***   ***   ***       Rosales   Fabaceae     Erythrina       rubrinervia     culantro; gallito       68%   71%   18%   −32%   ***   ***   ***   ***       Rosales   Fabaceae     Erythrina       rubrinervia     culantro; gallito       100%    75%   36%   −10%   18%   4     45   11       Rosales   Fabaceae     Erythrina       rubrinervia     culantro; gallito       50%   48%   13%   −43%   ***   ***   ***   ***       Rosales   Fabaceae     Erythrina       rubrinervia     culantro; gallito       75%   61%   42%   −20%   ***   ***   ***   ***       Rosales   Fabaceae     Inga       edulis     guavo; ice cream bean   AR   84%   82%   57%   31%   34%   ***   ***   ***       Rosales   Fabaceae     Milletia     unidentified       LF   61%   81%   42%   25%   46%   ***   ***   ***       Rosales   Fabaceae     Tephrosia       purpurea     purple tephrosia       60%   68%   32%   −9%   ***   ***   ***   ***       Rosales   Fabaceae     Tephrosia       purpurea     purple tephrosia       98%   71%   46%   8%    7%   4     &gt;100    &gt;25        Rosales   Rosaceae     Eriobotrya     unidentified       LF   80%   55%   15%   10%   34%   ***   ***   ***       Rosales   Saxifragaceae     Mitella       japonica     tyraumeruso       *   60%   28%   22%   ***   ***   ***   ***       Rubiales   Rubiaceae     Berreria       ocymoides         LF   79%   72%   36%   10%   39%   ***   ***   ***       Rubiales   Rubiaceae     Genipa       americana     genip   FR   73%   63%   31%   32%   28%   ***   ***   ***       Rubiales   Rubiaceae     Hamelia       axillaris     yutobanco (Peru)   PX   75%   68%   14%   2%   32%   ***   ***   ***       Rubiales   Rubiaceae     Hamelia       axillaris     yutobanco (Peru)   PX   61%   68%   38%   10%   −4%   ***   ***   ***       Rubiales   Rubiaceae     Nauclea       orientalis     mau (Burma)   FU   84%   57%   17%   −16%   44%   ***   ***   ***       Rubiales   Rubiaceae     Psychotria       microdon     tapa camino   PX   74%   83%   48%   11%   30%   ***   ***   ***       Rubiales   Rubiaceae     Psychotria       pubescens     chak k&#39; anan   PX   74%   68%   44%   31%   13%   ***   ***   ***       Rubiales   Rubiaceae     Psychotria       uliginosa     tres cabezas (Mexico)   PX   69%   88%   70%   46%   63%   ***   ***   ***       Rubiales   Rubiaceae     Psychotria     unidentified       BK   95%   81%   66%   51%   79%   ***   ***   ***       Rutales 1     Meliaceae     Dysoxylum       excelsum         LF   85%   76%   27%   0%   48%   ***   ***   ***       Rutales 1     Meliaceae     Scindapsus       pictus         PL   76%   70%   28%   5%   23%   ***   ***   ***       Rutales 1     Meliaceae     Trichilia       hirta     broom wood       80%   90%   61%   20%   38%   ***   ***   ***       Rutales 1     Meliaceae     Trichilia       hirta     broom wood       98%   78%   57%   3%   17%   1.5   75   50       Rutales 1     Rutaceae     Clausena       lansium     Chinese wampee   SB   96%   85%   68%   43%   44%   ***   ***   ***       Rutales 1     Rutaceae     Clausena       lansium     Chinese wampee   LF   72%   70%   47%   27%   40%   ***   ***   ***       Rutales 1     Rutaceae     Zanthoxylum       fagara     wild lime       *   40%   6%   2%   ***   ***   ***   ***       Rutales 1     Rutaceae     Zanthoxylum       fagara     wild lime       *   57%   24%   6%   ***   ***   ***   ***       Rutales 1     Rutaceae     Zanthoxylum       piperitum     Japanese pepper       **   64%   42%   −20%   ***   ***   ***   ***       Rutales 1     Simaroubaceae     Brucea       javanica     kosam seed; java brucea   SD   66%   51%   27%   16%   16%   ***   ***   ***       Rutales 1     Simaroubaceae     Picramnia       pentandra     bitter bush   PX   64%   55%   10%   −1%   14%   ***   ***   ***       Santalales   Loranthaceae     Phoradendron       piperoid     pajar (Peru)   PX   69%   75%   43%   18%    9%   ***   ***   ***       Sapindales 1     Anacardiaceae     Dracontomelon       dao     argus pheasant tree   FR   60%   74%   53%   13%    3%   ***   ***   ***       Sapindales 1     Anacardiaceae     Dracontomelon       mangiferum     sengkuang       56%   79%   47%   12%    3%   1.8   38   21       Sapindales 1     Anacardiaceae     Dracontomelon     unidentified           76%   86%   60%   32%    2%   3.5   80   23       Sapindales 1     Anacardiaceae     Dracontomelon     unidentified           59%   40%   −5%   −22%   ***   ***   ***   ***       Sapindales 1     Icacinaceae     Pyrenacantha       staudtii     abere (Nigeria)       **   73%   50%   11%   ***   ***   ***   ***       Scrophutariales   Bignoniaceae     Macfadyena       unguis-cati     cat&#39;s claw   PX   83%   69%   40%   17%   29%   ***   ***   ***       Scrophulariales   Gesneriaceae     Cyrtandra       grandis         PL   74%   54%   18%   10%   24%   ***   ***   ***       Umbellales   Apiaceae 5       Apium       graviolens     celery seed   SD   72%   68%   51%   25%   30%   ***   ***   ***       Umbellales   Araliaceae     Arthophyllum       diversifolium         LF   70%   74%   36%   −14%   30%   ***   ***   ***       Umbellales   Araliaceae     Arthophyllum       diversifolium         PE   69%   65%   32%   −15%   12%   ***   ***   ***       Umbellales   Araliaceae     Arthophyllum       diversifolium         SB   63%   49%   −3%   −19%    8%   ***   ***   ***       Umbellales   Araliaceae   VBrassaiopsis     glomerlata         LF   69%   66%   37%   −8%   52%   ***   ***   ***       Urticales   Moraceae     Dorstenia       contrajerva     contrayerba   PX   61%   69%   23%   15%    0%   ***   ***   ***       Urticales   Moraceae     Ficus       ribes     fig   LF   61%   61%   34%   20%   12%   ***   ***   ***       Urticales   Moraceae     Streblus     unidentified       LF   88%   61%   43%   27%   48%   ***   ***   ***       Urticales   Ulmaceae     Cellis     unidentified       LF   60%   62%   19%   16%   13%   ***   ***   ***       Violales   Flacourtiaceae     Pangium       edule     kluwak; pakem   LF   96%   92%   59%   45%   71%   ***   ***   ***       Violales   Flacourtiaceae     Pangium       edule     kluwak; pakem   FR   80%   75%   66%   55%   82%   ***   ***   ***       Violales   Flacourtiaceae     Pangium       edule     kluwak; pakem   BK   77%   72%   28%   31%   44%   ***   ***   ***       Violales   Flacourtiaceae     Ryparosa       caesia         TW   77%   69%   31%   −10%   23%   ***   ***   ***       Violales   Flacourtiaceae     Ryparosa       caesia         LF   67%   59%   20%   −6%   35%   ***   ***   ***                                                                                                  
 
         [0074]    The order, family, genus, and species of each plant extract are indicated.  
         [0075]    As illustrated by the data in Table 1, the organic extracts isolated from the indicated plant orders inhibit COX-2. In fact, several of the extracts selectively inhibit COX-2 over COX-1 by greater than 10 fold.  
         [0076]    Table 2 below provides a description detailing the particular use of some of the plant extracts tested for COX-2 inhibition as set-forth in Table 1. In addition, a comprehensive listing of references known to those generally skilled in the art is provided.  
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         TABLE 2                           USES OF PLANT EXTRACTS                    Isolate/                   Scientific Name   Common Name   Chemical ID   Sample ID   Extract #   Reference                      Adenanthera     bead tree           P-01683   5         microsperma              Medicinal              Albizza lucida     No common           P-01679               name avail.            Seeds are oily and edible.              Albizzia     Species   81259   935226                 longepedata     not found.            Other species edilble.              Amorphophallus     telinga           P-00723   3         campanulatus     potato            Leaves and tubers are eaten.              Apium graveolens     celery           P-01897   1, 2, 3, 4            Leaves and leafstalks are used in salad, for flavoring       soups, or as vegetable. The seed is the source of celery, containing       d-limonene, sefinene and sesquiterpene, used in culinary sauces       or for manufacturing celery salt.              Asclepias     Antelope           P-00264   5         asperula     horns            Medicinal              Beta vulgaris     beet or           P-01120   1, 2, 3, 4           Swiss           chard            Roots are consumed as vegetable when cooked, in salads.       Leaves are sometimes eaten as potherb.              Bleekeria     No common   81255   935185       5         vitiensis     name           available.            Medicinal              Bocconia     Ree           P-02163   6         frutescens     celandine            Medicinal              Boletus     Species           P-01876             rubricitrinus     not found.            Fruiting bodies of some species of this mushroom are edible.              Brassica     Chinese   81272   935202       1, 2, 3, 4         chinensis     cabbage            Eaten like lettuce.              Brassica oleracea     common   81437   936937       1, 2, 3           cabbage            Eaten raw or cooked.              Brucea javanica     kosam           P-00090   5           seed; Java           brucea            Medicinal              Callicarpa cana     No common           P-01942   5           name            Berries sometimes eaten.              Capsicum     habanero   81442   936997       1, 2, 3, 4         frutescens     pepper            Fruits are edible, eaten as vegetable or used as condiment.              Caryota mitis     sago palm           P-01601   2            Buds and seeds are edible.              Cassia     wampi   81274   935204       5         quinquangulata              Medicinal              Castanopsis                 P-01955           unidentified            Fruits of most species edible.              Celtis                 P-01958           unidentified            Species not found, but fruits of some species are edible.              Chorizanthe         81260   935227       5         diffusa              Ornamental; not edible              Cinnamonum             P-01961                 obtusifolium              Species not found. Genus of true cinnamons. Edible as condiment.              Cinnamonum             P-01964                 parthenoxylon              Species not found. Genus of true cinnamons. Edible as condiment.              Clausena lansium     Chinese           P-01967   1, 2, 3           wampee            The fruit is eaten fresh, preserved, made into jam, pies, or refreshing drinks.       Leaves are put into curries.              Clerodendron                 P-01969   5         lecomtei              Species not found, but others are medicinal.              Coccothrinax alta     silver           P-02204   5           palm            Buds and seeds are edible              Cordia laevigata     Species           P-02102               not           found.            The fruits of many species are edible.              Croton rigidus                 P-02092   5            Species not found but most other Crotons are poisonous or medicinal.              Cyatheae                 P-01256           unidentified            Other species of this fern used to make a starch.              Cyrtandra grandis                 P-01741                Species not found. Leaves of several other species used as       flavorings or chewed like betel.              Diospyros                 P-01606           unidentified            Genus of persimmons. Fruits of many species edible.              Dorstenia     contrayer           P-02213   6         contrajerva     ba            Medicinal              Dracontomelon dao     argus           P-02250   3           pheasant           tree            Fruits are edible, usually mixed with soy sauce in rice.              Dracontomelon     sengkuang   81282   935212       5         mangiferum              Fruits are edible, usually mixed with soy sauce in rice.              Dracontomelon         81283   935213               unidentified       ( Draconotomelum)              Fruits of most species edible.              Dysoxylum                 P-01743   5         excelsum              Species not found, but others are medicinal.              Elaeocarpus     No common   81268   935235       5         bifidus     name.            Fruits edible.              Elodea densa     water   81278   935245       5           weed           genus            Medicinal              Eriobotrya                 P-01670           unidentified            Species not found.  Eriobotrya japonica  fruit edible.              Erythrina     culantro   81252   935182       3         rubrinervia              Flowers and flower buds eaten cooked like string beans       in El Salvador and Guatemala. Leaves eaten in soups.              Ficus ribes     fig genus           P-01736   2            Medicinal              Genipa americana     genip           P-01810   3            Fruits are edible when soft and overripe.              Grifola frondosa     maitake           P-00001   1, 2, 3            Fruit bodies are edible.              Guazuma ulmifolia     bay cedar           P-02234   3            Green fruits are eaten raw, cooked, crushed in water to make a beverage, or       used to flavor other foods.              Gymnanthes lucida     No common           P-02183   5           name           available            Medicinal              Hamelia     yutobanco           P-02210   5         axillaries     (Peru)            Medicinal              Hedyosmum     sago           P-02238             arborescens     palm;           species           not found            At least on other species (mexicana) has edible fruits and leaves may be used as tea.              Helicteres     Jamaican           P-02142   5         jamaicensis     screw           tree            Medicinal              Inga edulis     guavo,           P-02780   1, 5           ice cream           bean            Pulp of the fruit is eaten.              Jacquinia     Species           P-02137   5         umbellata     not           found.            Other species are fish poisons or insecticides.              Lilium auratum     goldband   81431   936986       3           lily            Mucilaginous bulb is eaten boiled, sweetened, powdered and added to dumplings.              Lithospermum     red root           P-00002   5         erythrorhizon     gromwell            Medicinal              Macaranga     Species           P-01168   5         conifera     not           found.            Medicinal              Macaranga triloba     Mahang           P-01128   5           serndit           (Malaya)            Medicinal              Macfadyena     cat&#39;s           P-02215   5         unguis-cati     claw            Medicinal              Manihot esculenta     cassava           P-00204   1, 2, 3, 4            Young leaves and stems are eaten steamed. Tubers are eaten cooked or fried.       They are ground into flour.              Melochia     meloch           P-02127   5         pyramidata              Fruit fermented as a beverage.              Mentzelia aspera     dal pega           P-02126   5            Medicinal              Milletia                 P02035   5       unidentified            Most species used as insecticides, fish poisons and medicinals.              Mitella japonica     tyraumeruso   81439   936994       5            Medicinal              Myrcia splendens                 P-02236   5            Medicinal              Myrsine coriaceae                 P-02159                Species not found. Fruit of other species edible.              Nauclea     mau           P-01239   3         orientalis     (Burmese)            Young leaves and tender tips are steamed and eaten with rice.              Ostodes     bijopari   81445   936975       5         paniculata              Medicinal              Paeonia     common   81266   935196       3         officinalis     peony            Hot seeds were ground into a spice in Europe. Mongolians mad a tea from them.       Flowers are eaten as a vegetable or used to scent tea.              Pangium edule     pakem           P-02986   2            Seeds are edible.              Peperomia                 P-02465   5       unidentified            Most species are medicinal.              Phoradendron     pajar           P-02205   5         piperoid     (Peru)            Medicinal              Phyllanthus     Species           P-02144   5         cuneifolius     not           found.            Medicinal              Picramnia     bitter           P-02214   5         pentandra     bush            Medicinal              Pinellia ternata     ban xia   81434   936989       2           (Chinese)            Subterranean tubers are edible.              Piper aduncum     pepper           P-02466   3            Peppery fruits used to season foods. Very sweet when black and ripe.       Leaves eaten as potherb.              Pisonia aculeate     cockspur;           P-01806   5           una de           gato            Medicinal              Pleomele     native           P-02692   2         angustifolia     dracaena            Young leaves are eaten cooked. Sometimes used to add green color to foodstuff.              Psychotria     tapa           P-02099   5         microdon     camino            Medicinal              Psychotria     chak k&#39;           P-02212   5         pubescens     anan            Medicinal              Psychotria     tres           P-02077   5         uliginosa     cabezas           (Mexico)            Medicinal              Psychotria                 P-01592   5       unidentified            Most species are medicinal.              Pyrenacantha     abere   81271   935201       5         staudtii     (Nigeria)            Medicinal              Quararibea     swizzle           P-02190   2,         turbinata     stick               3, 5           tree            Twigs used in mixing beverages. Fruit may be edible.              Raphanus sativus     daikon, se   81438   936993       1, 2, 3, 4           men           raphani            Fresh roots are eaten as salad or appetizer, occasionally cooked. Leaves are       eaten as greens. Inflorescences are similarly eaten.              Ricinodendron                 P-00183   2         heudelottii              Probably  Ricinodendron heudelotii  var.  africanum . Seeds are edible.              Rumex     Indian   81450   937005   937005   3         hymenosepalus     root,           wild           rhubarb            Leafstalks eaten like rhubarb. Leaves eaten after       wash to remove tannins. Seeds are edible.              Ryparosa caesia     No common           P-01756   2           name           available            Fruit is edible.              Saponaria     soapwort   81451   937006       3         officinalis              An extract of the roots used a an emulsifying agent in foods. The flowers       are occasionally added to salads.              Scheelea     scheela           P-02777             phalerata     palm            Oil used in cooking              Smilax havanensis     Cuban           P-02128   5           sarsaparilla            Medicinal              Solanum                 P-02461   5         acuminatum              Species not found. This is the genus of nightshades, so most are either       medicinal or poisonous.              Sparganium     bur-reed   81433   936988       2         ramosum              Young stems are peeled and boiled down for food.              Streblus                 P-01665           unidentified            Milk from stem of  Streblus asper  is used to curdle milk. Fruit is edible.              Strophanthus     zwezwe           P-00294   5         hispidus     (African)            Medicinal              Syzygium     Malay           P-02201   3         malaccense     apple            Used with seeds to make beverage.              Tephrosia     purple   81267   935234       1, 2, 3, 4         purpurea     tephrosia            Seeds used as a substitute for coffee. Roots are used as a flavoring for milk.              Tradescantia     spiderwort   81279   935246       3         virginiana              Very young shoots and leaves eaten in salads. Flowers are an edible garnish.              Trichilia hirta     broom   81264   935194       5           wood            Species not found, but others are medicinal.              Trichostigma     hoop vine           P-02162             octandrum              Medicinal              Umbilicaria     umbilicaria           P-02749   5         proboscidea     lichen            An edible lichen.              Veronina sericea     Species           P-02110   5           not           found.            Medicinal              Wedelia retculata     Species           P-02209   5           not           found.            Medicinal              Xanthium     arishta           P-01830   2         strumarium     (Sanskrit)            Young shoots are eaten cooked, as are young plants. Seeds are ground into       flour and made into noodle. Fruit is sun-dried, roasted and put into       dumplings or cooked with rice.              Zamia debilis     wild sago   81261   935228       5            Tubers are source for starch.              Zanthoxylum     wild lime   81429   936959       5         fagara              Medicinal              Zanthoxylum     Japanese   81247   935177       1, 2, 3         piperitum     pepper            Young leaves and fruit are used in dishes; the former being used in Japanese soups,       the latter is cooked into tsukudani. Bark is also employed for seasoning.              Ziziphus jujuba     jujube;   81435   936965   936965   3           date tree            Fruits are edible.                  
 
       References  
       [0077]    1. NAPRALERT (NATural Products ALERT), which currently contains the extracted information from over 116,000 scientific research articles and books from 1650 A.D. to the present. The NAPRALERT database is housed and maintained by the Program for Collaborative Research in the Pharmaceutical Sciences (PCRPS), within the Department of Medicinal Chemistry and Pharmacognosy, in the College of Pharmacy of the University of Illinois at Chicago, 833 South Wood Street (M/C 877), Chicago, Ill. 60612, U.S.A.  
         [0078]    2. Tyozaburo Tanaka, (Edited by Sasuke Nakao)  Tanaka&#39;s Cyclopedia of Edible Plants of the World , Keigaku Publishing Co., Tokyo, Japan, 1976.  
         [0079]    This is a compendium of about 11,000 species of plants, including the essential wild species of the world. This book is considered to be one of the principle references on the world&#39;s edible plants.  
         [0080]    3. Stephen Facciola,  Cornucopia II: A Source Book of Edible Plants , Kampong Publications, Vista, Calif., 1998.  
         [0081]    This book records the more than 3,000 species available in the U.S. and abroad.  
         [0082]    4. James A. Duke,  Database of Phytochemical Constituents of GRAS Herbs and Other Economic Plants , CRC Press, Boca Raton, Fla., 1992.  
         [0083]    A database of approximately 1000 plants and 3000 compounds.  
         [0084]    5. George Macdonald Hocking,  Dictionary of Natural Products , Plexus Publishing, Inc., Medford, N.J., 1997. “Terms in the field of Pharmacognosy relating to natural medicinal and pharmaceutical materials and the plants, animals and minerals from which they are derived.” The work contains over 18,000 entries.  
         [0085]    6. Enrique Sanchez-Monge,  Flora Agricola: Taxonomia de las Magnoliofitas (Angiospermas) de interes agricola, con excepcion de las de aprovechamiento exclusivamente ornamental o forestall , Ministerio de Agriculture, Pesca y Alimentacion, Madrid, Spain, (date unknown).  
         [0086]    An excellent reference work in Spanish with descriptions of plants, common names in many languages and commercial use of agricultural organisms of the world.  
         [0087]    7. Anthony R. Torkelson,  The Cross Name Index to Medicinal Plants , Volumes !-IV, CRC Press, Boca Raton, Fla., (1998-1999).  
         [0088]    8. Umberto Quattrocchi,  CRC World Dictionary of Plant Names: Common Names, Scientific Names, Eponyms, Synonyms, and Etymology  (Volumes 1-4), CRC Press, Boca Raton, Fla. (2000).  
         [0089]    9 . W   3   TROPICOS , a web site providing access to the Missouri Botanical Garden&#39;s VAST (VAScular Tropicos) nomenclatural database and associated authority files.  
         [0090]    10 . Webster&#39;s Ninth New Collegiate Dictionary , Merriam-Webster Inc., Springfield, Mass., (1983).  
         [0091]    Tables 3-9 further illustrate the ability of certain extracts isolated from the families identified in Table 1 to selectively inhibit COX-2. A total of six different concentrations of the various extracts were tested for their ability to inhibit both COX-1 and COX-2. The IC 50  value for COX-1 and COX-2 was also determined and a selectivity ratio was then calculated as set forth above. FIGS. 1-7 are graphs that depict the data shown in Tables 3-9 as indicated.  
                                                         TABLE 3                       Extract isolated from  Trichilia hirta                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    46%   Not determined       33.3    63%   11%       11.1    79%   16%       3.70   102%   30%       1.23   112%   53%       0.41   135%   81%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               75   1.5   50                  
 
         [0092]    [0092]                                                         TABLE 4                       Extract isolated from  Capsicum frutescens                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    53%   Not determined       33.3   116%   12%       11.1   152%   17%       3.70   140%   42%       1.23   132%   63%       0.41   182%   104%                     IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               &gt;100   2.5   &gt;40                    
         [0093]    [0093]                                                         TABLE 5                       Extract isolated from  Tradescantia virginiana                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    37%   Not determined       33.3    89%   Not determined       11.1   124%   16%       3.70   112%   44%       1.23   113%   61%       0.41   144%   83%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               75   2.5   30                    
         [0094]    [0094]                                                         TABLE 6                       Extract isolated from  Tephrosia purpurea                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    80%   Not determined       33.3    92%   Not determined       11.1    95%   18%       3.70   106%   52%       1.23   102%   67%       0.41   133%   92%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               &gt;100   4   &gt;25                    
         [0095]    [0095]                                                         TABLE 7                       Extract isolated from  Dracontomelon mangiferum                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    25%   Not determined       33.3    53%   Not determined       11.1    91%   16%       3.70   117%   39%       1.23   114%   55%       0.41   141%   81%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               38   1.8   21                    
         [0096]    [0096]                                                         TABLE 8                       Extract isolated from  Erythrina rubrinervia                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    31%   Not determined       33.3    57%   Not determined       11.1    76%   16%       3.70   106%   51%       1.23   109%   72%       0.41   139%   73%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               45   4   11                    
         [0097]    [0097]                                                         TABLE 9                       Extract isolated from  Pisonia aculeata                                  Amount of   COX-1 Activity           Extract   Relative to   COX-2 Activity       (ug/ml)   Control   Relative to Control                    100    26%   Not determined       33.3    60%   10%       11.1   119%   27%       3.70   140%   56%       1.23   122%   71%       0.41   160%   87%                    IC 50  (ug/ml)   IC 50  (ug/ml)   C0X-2       COX-1   COX-2   Selectivity Ratio               45   4.5   10                    
         [0098]    As illustrated by these data, the organic extracts isolated from the indicated plants inhibit COX-2. In fact, all of the extracts selectively inhibit COX-2 over COX-1 by greater than or equal to 10-fold. In view of the above, it will be seen that the several objectives of the invention are achieved and other advantageous results attained.