TITLE OF THE INVENTION <BR> <BR> A CETAMINOPHENlNON-STEROIDAL ANTI-INFLAMA TORY<BR> DRUG-GL UCOSAMINE COMPOSITION CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation-In-Part of co-pending application US SN 09/489,779, filed January 24,2000, entitled Dietary Regimen Of Nutritional For Relief Of Symptoms Of Arthritis and Other Joint Discomfort. Co-pending application US SN 09/489,779 also claims the benefit of pending Provisional Application 60/151,083 filed August 27,1999, to the extent that it discloses subject matter in common. Co-pending application US SN 09/489,779, filed January 24,2000, entitled Dietary Regimen Of Nutritional For Relief Of Symptoms Of Arthritis and Other Joint Discomfort is a Continuation-In-Part of US SN 09/193,474, filed November 18,1998, entitled Dietary Regimen Of Nutritional For Relief Of Symptoms Of Arthritis, which in turn is a Continuation of US SN 952,272, filed January 6, 1998, entitled Dietary Regimen Of Nutritional For Relief Of Symptoms Of Arthritis, now US Patent 5, 840, 715 (issued November 24,1998), which is the US National Stage Entry under 35 USC §371 of international application PCT/US95/16722, filed December 11,1995.

BACKGROUND OF THE INVENTION 1. Field of the Invention-This invention is directed to a composition, a dietary regimen and a method. More specifically, this invention is directed to a dietary regimen and formulation having improved gastrointestinal absorption and systemic utilization of nutritional materials for abatement of the symptoms associated with arthritis. The dietary regimen of this invention is also effective in the reversal of the degeneration caused by arthritis by the repair and/or replacement of mammalian joint connective tissue that has deteriorated and/or been damaged incident to disease and/or injury.

2. Description of the Prior Art-The increase in life expectancy of Americans from 1930 to 1980 can, in part, be attributed to the improvement in nutrition in the United States during that period. However, the situation today remains far from ideal, since six out of ten of the leading causes of death in this county, (including heart attack, cancer, cirrhosis of the liver, and diabetes), are linked to dietary excesses or deficiencies. It is, thus, becoming increasingly obvious that many of these common diseases can be prevented with a well-balanced diet and efficient nutritional supplementation with certain vitamins, minerals and nutrients.

The problem is particularly acute in older Americans. Approximately 30 percent of older Americans are deficient in meeting their dietary requirements of all the essential nutrients. These nutritional deficiencies are complicated in older individuals by both the inherent limitations on their bodies to efficiently process the nutrients in food, and factors which interfere with such processes (e. g. medications, <BR> <BR> illness, acquired allergies to certain types of food, etc. ). More specifically, the hazards of food-drug interactions, as a potential cause of depletion of essential nutrients, are well recognized. It is unavoidable that old age calls for increased use of medications. For example, the use of certain antibiotics decreases absorption of calcium and iron, while EDTA chelation therapy decreases absorption of zinc, iron, copper, and magnesium.

Moreover, as an individual's cholesterol level and triglyceride level increases, many of the foods which increase the risk of cardiovascular disease also have to be eliminated from the diet. Such additional dietary constraints further depletes the available sources of essential nutrients which are found in these high risk foods. For example, excellent sources of vitamin B and vitamin D, such as red meat, liver, egg yolk, cheese and dairy products, have to be limited because of their high cholesterol content. Moreover, to the extent that dietary limitations require exclusion of foods rich in antioxidants and other functionally equivalent nutrients, and/or foods that that impact immune system vitality, the risk of cancer is also increased.

Limiting menu choices also causes a depletion of essential amino acids, such as tryptophan which is important precursor of neurotransmitters and that may play a role in the prevention of memory function deterioration with aging. The availability of essential nutrients is further compromised by poor gastrointestinal absorption. The

traditional way to offset insufficient nutrients in the diet, insufficient gastrointestinal absorption and/or insufficient metabolic utilization of essential nutrients, is to administer relatively large doses of vitamins, mineral and other dietary/nutritional supplements. Unfortunately, simply increasing the quantity of such essential nutrients, via ingestion of such supplements, does not necessarily increase their systemic availability, because of self-limiting factors associated with digestion and/or the body's internal mechanism regulating their availability. This is particularly apparent in the case of the treatment and/or abatement of the degenerative processes associated with arthritis.

The physiological and biochemical pathways which define the disease complex know as"arthritis"are both distinct and yet inter-related. Accordingly, in order to effectively treat and relieve the symptoms associated with this disease complex, it is necessary to provide an integrated approach for reversal of the disease, while at the same time providing immediate symptomatic relief.

Early efforts at combining traditional arthritis medications (NSAID) and so- called dietary supplements in the treatment of arthritis have been suggested as early as 1961. More specifically, the use of therapeutic amounts of a NSAID (aspirin), in combination with one or more natural constituents of joint tissue, has been described as a potential remedy to abate the symptoms associated with arthritis in both the patent and technical literature. For example, US 3,008, 874 (to Feeney, et al, issued November 14,1961) discloses the co-administration of aspirin (including aspirin-like compounds) and glucosamine. The observed effect of the administration of this composition is a demonstrative increase in the blood level of the aspirin.

Similarly, aspirin has been disclosed in combination with glycosaminoglycans (e. g. chondroitin sulfate) as a therapy to abate the symptoms associated with arthritis, <BR> <BR> Kerzberg, E. M. , et al, Combination of Glycosaminoglycans & Acetylsalicylic Acid In Knee Osteoarthritis, Scand. J. Rheumatorlogy, 16: 377-380, (1987). The Kerzberg article concludes that, based upon the then available knowledge as to the physiological effects of the individual components, the aspirin and the chondroitin were likely synergists. Moreover, Kerzberg concluded that the administration of the chondroitin in the diet likely inhibited the enzymatic degradation or the breakdown of the healthy joint cartilage.

More recently, the patent and technical literature have disclose the additional benefits from the co-administration of glucosamine and chondoitin, specifically, that such combination is likely to be synergistic and, thus, very effective in the treatment of the causes and/or symptoms associated with this disease. More specifically, each of US Patent 5,364, 845 (to Henderson, filed March 31,1992), and US Patent 5843,919 (to Burger, filed October 22,1997) are representative of this more recent prior art. Each of the Henderson'845 and Burger'919 patents are incorporated herein in their entirety.

The Henderson'845 patent describes and claims a dietary regimen and composition for the abatement of the symptoms of arthritis comprising glucosamine salts, chondroitin salts and manganese. The Burger'919 patent describes and claims a dietary regimen and composition for the abatement of the symptoms of arthritis comprising one or more glucosamine salts and one or more omega-3 fatty acids (EDA, DHA and their mixture). Each of the Henderson and Burger patents are exclusive of co-administration of their respective compositions and an NSAID; and, must rely upon one or more additional ingredients in their formulation for immediate abatement of the inflammation associated with arthritis. Neither Henderson nor Burger patents contemplate the addition of any agent to enhance absorption and/or to increase the systemic availability of the glucosamine ; and, it is assumed that the prescribed dosage levels attain adequate systemic levels of the essential ingredients to achieve the intended results.

In each of the Henderson and Burger patents, the administration of their patented compositions is based upon a daily regimen, and contemplates a daily dosage sufficient to reverse the degeneration of the effected connective tissue. In each instance, the effectiveness of the dietary regimen is based, in part, on the ability of such nutrients to alter the metabolic pathways associated with cartilage formation so as to increase the utilization of essential nutrients in the synthesis of healthy cartilage.

The amount of supplements required to achieve this desired result is generally directly related to the weight of the individual and indirectly related to the absorption and availability of the supplement in sufficient amounts to drive the reaction equilibrium in the desired direction to accomplish the desired result. More specifically, the biochemical pathway for the synthesis of collagen from simple sugars is reversible

unless reaction conditions, favoring its formation, drive the reaction equilibrium in the direction of such synthesis. Such reaction kinetics are based upon the relative amounts of glucosamine that is formed, and the further transformation thereof into proteoglycans (the precursor of cartilage). Unless the amount of glucosamine present in the blood is in sufficient excess, the transformation thereof into proteoglycans does not occur. Accordingly, in order for glucosamine containing dietary supplements to be effective, such supplements must contain relative large amounts of glucosamine and/or be taken in accordance with a dietary regimen that insures adequate amounts be ingested to provide the required systemic level to accomplish the desired cartilage synthesis. Because of the factors enumerated above (relative to inefficiencies in absorption and other competing/interfering processes relating to the body's ability to provide systemic amounts of the supplement at the targeted levels), the administration of a specified amount of glucosamine in a given dietary regimen cannot be guaranteed to provide the desired symptomatic relief, or relief within a reasonable period following adoption of the dietary regimen containing glucosamine. Thus, in a number of instances, an individual may not attain relief from his symptoms at the recommended dosage, or attain only marginal relief or attain relief only after an extended period of treatment. Thus, there is continuing need to improve both the efficiency in the absorption of essential nutrients in such arthritis formulations, while at the same time maintaining a relatively uniform standard or dosage form for individuals within a given weight and age range.

OBJECTS OF THE INVENTION It is the object of this invention to remedy the above as well as related deficiencies in the prior art.

It is the principle object of this invention to provide a dietary regimen and formulation having improved gastrointestinal absorption and systemic utilization of nutritional materials, specifically, supplements that can provide symptomatic relief from both the pain and stiffness associated with arthritis.

It is another object of this invention to provide a dietary regimen and formulation that is formulated to provide for immediate symptomatic and long term relief from degenerative effects of arthritis,

It is yet another object of this invention to provide a dietary regimen and formulation that is formulated to enhance the absorption of the components thereof, while providing immediate relief from the pain and stiffness associated with arthritis.

It is still yet another object of this invention to provide a dietary regimen and formulation that is both palatable, effective and yet relatively easy to digest.

Additional objects of this invention include the formulation of the dietary supplement of this invention in a convenient dosage form.

SUMMARY OF THE INVENTION The above and related objects are achieved by administration of a daily regimen of supplements, including a formulation comprising (a) natural ingredients and derivatives of natural ingredients generally characterized as chondroprotective nutrients/supplements, (b) acetaminophen or a non-steroidal anti-inflammatory (NSAID) at a level sufficient to enhance the bioavailability of said chondroprotective nutrients/supplements, and, optionally, (c) an additional bioavailablity enhancer for the natural ingredients and derivatives of natural ingredients.

The unique formulation of this invention has improved gastrointestinal absorption and systemic utilization of nutritional materials for abatement of the symptoms associated with arthritis. Moreover, it is believed that each of the acetaminophen/NSAID enhances the systemic bioavailability of the chondroprotective agents, and, thus, their more effective individual roles and synergy relative to each other.

In brief, the preferred dietary regimen of this invention involves the administration, on a daily basis, of effective amounts, (consistent with the attainment of one or more of the above stated Objects of the Invention), of the following supplements (a) glucosamine, glucosamine salts (e. g. glucosamine sulfate, glucosamine hydrochloride, N-acetyl-glucosamine) and mixtures thereof, (b) chondroitin, chondroitin salts (e. g. chondroitin sulfate) and mixtures thereof, (c) acetaminophen or a non-steroidal anti-inflammatory (NSAID) selected from the group consisting of aspirin, naproxen, piroxicam, indomethacin, sulindac,

meclofenamate, difusinal, tolmetin, ibuprofen, fenoprofen, etodolac, ketorolac, dicofenac, ketoprofen, and nabumetone, their corresponding salts, their corresponding isomers and mixtures thereof, and, optionally, (d) an alkaloid piperine extract from the Piperaceae fruit family.

It is understood that that the amount of acetaminophen or NSAID compound (s) in this formulation or administered in the daily regimen, can range from about 25% to 35% below an amount traditional regarded as therapeutic up to an including the 100% to 150% of the amount traditionally regarded within the therapeutic range (e. g. 325 to 500 mgs aspirin per therapeutic dosage; 200 to 300 mgs <BR> <BR> of ibuprofen per therapeutic dosage, etc. ). Similarly, the chondroprotective agent in the formulation and daily regimen can also be administered in an amount below that which is required of more traditional preparations because of the enhancement in the systemic bioavailability of such nutrients as a result of their co-administration with the acetaminophen or NSAID. Thus, the body's demands for chondroprotective agents and acetaminophen or NSAID is more than adequately met to abate the symptoms of arthritis, notwithstanding that the amounts thereof which is administered has been reduced from that normally prescribed. More specifically, the beneficial effects of the formulation are less dosage dependent, in that the systemic level of the chondroprotective agents are enhanced as a result of the presence of each of the acetaminophen or NSAID; and, can be further enhanced, as desired, by the addition of an alkaloid piperine extract to the formulation. Thus, the body's needs are more readily and consistently satisfied so as to abate the symptoms of arthritis at these reduced levels, notwithstanding, the potential interference from prescription medication, reduction in absorption in the gastrointestinal tract and competing processes, commonplace in older individuals, all of which have historically rendered such treatment unpredictable and often ineffective.

As the treatment progresses, the glucosamine and chondroitin component (s) of the composition stimulate the biosynthesis of the glycosaminoglycans and the hyaluronic acid backbone needed for the formation of proteoglycans found in the structural matrix of the joints. The addition of the acetaminophen or NSAID compound, also participate in the process of symptomatic relief from the pain and

stiffness associated with arthritis, however, their role in this regard is perceived to be subordinate to the chondroprotective agents, and primarily in the enhancement of the absorption and systemic utilization of the chondroprotective agents. As the absorption of the chondroprotective agents is increased, the reaction kinetics which favor the synthesis and regeneration of joint cartilage, is biased in favor of cartilage synthesis/regeneration, thereby affording the individual afflicted with arthritis, long term relief. The addition of the alkaloid extract of piperine to the formulation is believed to enhance the systemic utilization of the acetaminophen or NSAID, even at what is generally regarded as sub-therapeutic levels, to further reduce inflammation of the effected joint, and thereby provide more immediate symptomatic relief from the pain and swelling of the arthritic joints.

In one of the preferred embodiments of the dietary regimen and composition of this invention the NSAID compound (also"cyclooxygenase inhibitor") is derived from a natural or synthetic form of a compound selected from the group consisting of methyl salicylic acid, salicylsalicylic acid, salicylic acid, trilisate, sadalcid, and salts thereof (hereinafter also collectively"aspirin"). The form of the aspirin and the amount thereof, is well tolerated at the contemplated daily dosage; and, its ingestion/digestion otherwise unremarkable at the contemplated daily dosage do to the form thereof, and/or the presence of additional ingredients (e. g. natural or synthetic buffers).

In one of the preferred dietary regimen of this invention, the recommended daily consumption of a combination of dietary supplements (based upon a body weight in the range of from about 50 to about 200 lbs.) is as follows: glucosamine, 50 to 2000 mg/day, 'chondroitin, 25 to 1500 mg/day, aspirin (Acetylsalicylic acid), 10 to 4000 mg/day, and . alkaloid piperine, 0.2 to 20 mg/day In functional terms, the glucosamine and chondroitin are present in a sufficient daily dosage to arrest the deterioration of the connective tissues in the joint and, over time, promote the regeneration of healthy tissue. In the near term, the other components of the composition (acetaminophen or NSAID) provide more immediate

symptomatic relief, a critical factor in maintaining the confidence of the patient to continue on the program.

The dosage form of the composition can include any conveniently dispensable <BR> <BR> preparation, (e. g. tablets, softgel capsules, liquid elixir, etc. ). In the preferred embodiments of this invention, the dosage form preferable contains all of the essential ingredients in a single, easily ingestible form, that can be taken at different times throughout the day (e. g. to correspond with meals). Once symptomatic relief has been attained, it is preferable that the daily dosage, be biased in favor or morning and mid-day administration of the composition, with little if any additional ingestion, taking place in the evening (to optimize digestion and uptake) Essentially continuous adherence to this regimen over a relatively brief period of time provides both effective symptomatic and essentially continuous relief from the debilitating effects of arthritis.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS This invention is hereinafter described, by way of reference, illustration and example, to the preferred class of NSAID, collectively referred to as"aspirin". It is understood that such reference, illustration and exemplification is intended for ease of understanding, and in no way is it to be construed, nor is it intended, to limit or otherwise restrict the scope of the protection to accorded to the invention, which is set forth in the Claims.

Novel Composition-It has been discovered that a combination therapy of glucosamine (and its corresponding salts), chondroitin (and its corresponding salts), and acetaminophen or NSAID provides effective symptomatic relief from the associated pain and discomfort associated with arthritis; and, can arrest, and in time reverse, the progression of the disease. The acetaminophen or NSAID functions in this formulation both to enhance absorption of the chondroprotective agents and as a source of immediate relief of the pain associated with arthritis. In one of the preferred embodiments of this invention, an alkaloid extract of piperine is also present to further enhance the absorption of all of the essential ingredient of the formulation, including specifically, the chondroprotective agents. To the extent not otherwise

present in the diet in adequate amounts, the formulation of this invention can also contain the mineral manganese, and preferably an organic salt of manganese, such as manganese ascorbate, to promote the conversion of nutrients to collagen.

In order to reduce potential discomfort and irritation associated with aspirin, the aspirin can be administered at 25 to 50% below an amount considered to be within the therapeutic range; or, alternatively, when administered at therapeutic levels (e. g. about 7.5 to 15 mgs/kg body weight) is enteric-coated or buffered. In addition, or as an alternative to enteric coating, the herb, Musa sapientum, (or the active ingredient thereof, flavonoid leucocyanidin), can also be included in such preferred composition to reduce the potential irritating side effects of aspirin and as protective agent for the GI tract and to inhibit aspirin-induced erosions of the stomach lining in sensitive individuals.

Glucosamine Component-As above noted, glucosamine provides the primary substrate for both collagen and proteoglycan synthesis. Glucosamine is available from a number of natural sources and/or can be synthetically derived.

Glucosamine is the preferred substrate for proteoglycan synthesis, including chondroitin sulfates and hyaluronic acid. The glucosamine component of the novel combination is, preferably, in a salt form so as to facilitate its delivery and uptake by the digestive system. The preferred salts of glucosamine include N-acetyl- glucosamine, glucosamine hydrochloride and glucosamine sulfate and mixtures thereof. Once absorbed, glucosamine localizes to cartilage and joint tissues, where it remains for extended periods, until neeeded in the synthesis/regeneration of connective tissues. As recognized in the technical literature and indicated elsewhere herein, the retalive systemic level of glucosamine is critical to drive the reaction kinetics to collagen formation. Accordingly, it is preferable to provide sufficient glucosamine to increase the systemic level thereof to effectively drive the reaction equilibrium in the direction of collagen formation. Generally, because of enhancements in the absorption provided by the formulation of this invention, as little as 10 to 15 mgs/kg/body weight per day of glucosamine is effective to accomplish the purposes of this invention.

Chondroitin Component-Chondroitin is a polysulfonated glycosaminoglycan composed of repeating structural units of glucose which provides the framework or

template for the remodeling of connective tissue such as cartilage; and, further provides the cartilage with its flexibility, resiliency and resistance to compression (shock absorbing properties). More specifically, there are multiple synthetic pathways for the formatoin of cartilage (depending upon the substrate/starting materials); and, in each instance glucosamine is an intermediate in the formatoin of the desired product. The Henderson'845 patent (previously discusssed herein) is exemplary of this process. In brief, one pathway involves the conversion of simple sugars to a more complex sugar, mucopolysaccharides (e. g. glycosaminoglycans).

Alternatively, or concurrently, glucosamine (N-acetyly-glucosamine) is ingested pursuant to the dietary regimen of this invention; and, as the systemic level thereof increases (based upon the combination of the endogenous and exogenous contribution thereto), it matures to form collagen. This maturation step involves an accretive process wherein glycosaminoglycan simply increases in mass and thereby forms collagen. This maturation is facilitated by the chondroitin which provides a substrate for the synthesis of the proteoglycans, such glycosaminoglycans.

ACETAMINOPHEN or NSAID-The acetaminophen or non-steroidal anti- inflamatory drugs (NSAID) suitable for use in the formulation of this invention include many of the well-known over the counter and prescription products prescribed for relief of pain and discomfort associated with muscle and joint discomfort. The preferred acetaminophen suitable for use in this invention is a Tylenol-like preparation. The preferred NSAID suitable for use in this invention includes aspirin, naproxen, piroxicam, indomethacin, sulindac, meclofenamate, difusinal, tolmetin, ibuprofen, fenoprofen, etodolac, ketorolac, dicofenac, ketoprofen, nabumetone, and acetaminophen, their corresponding salts, their corresponding isomers and mixtures thereof. The accepted and prescibed unit dosage for the acetaminophen or NSAIDs contemplated for use in this invention can range from about 325 mgs for the lesser effective drugs (e. g. a single adult aspirin) to about 200 mgs for the more effective drugs (e. g. a single adult ibuprofen). Where a natural source of the NSAID is used (White Willow Bark, as source of salycic acid), the prescibed amount will vary proportionately because of the relatively low content of NSAID in such natural product.

Bioavailability Enhancer-In order to further enhance the systemic levels of nutrients within the context of this invention, the formulation of this invention optionally contains an additional nutrient, absortion enhancer effective amount of an alkaloid extract of piperine. This compound is available commercially from Sabinsa Corporation (Piscataway, NJ) under the brand name, Bioperines. This commercial product, which is an acceptable source of the piperine extract, is dereived from black pepper and reportedly contains at least 95% alkaloid piperine. This product is also reportedly described in US 5,536, 506, which is herein incorporated by reference in its entirety). This compound is effective to enhance the bioavailability of the active ingredients of the formulation when present at a concentration ranging from about 0.1 to about 1.0 weight percent.

Optional Ingredients-Other natural ingredients contemplated within the scope of this invention and which are reported to contribute, in a supporting role, to abatement of the one or more of the components of the disease complex referred to herein as"arthritis"are as follows: shark cartilage; cayenne; turmeric (curcuma longa); boswellia serrata ; devil's claw; cat's claw; sea cucumber; yucca; alfalfa; chlorella; quercetin; calcium, magnesium; type II collagen; vitamin C; vitamin E; CoQ 10; bromelain; zinc; manganese; MSM (methyl-sulfonyl-methane) ; and CMO (cetylmyristoleate).

Dietary Regimen-The composition is administered for a time sufficient to reduce or control the symptoms of arthritis and other joint discomforts. One or two doses of the composition may be sufficient, or the composition may be administered on an ongoing basis for several days or weeks, even months in duration. Variables related to the amount of the composition to be administered include the severity of symptoms, the species of animals to be treated, and the body weight of the animal.

Typically, the composition is administered at a dosage of between 1.5 to about 275 mgs of the combined glucosamine, chondroitin, and aspirin, (other natural ingredients) per kilogram of the body weight per day irrespective of species. The amount of alkaloid extract of piperine per dose, when present, is preferably in the range of from about 0.004 to 0.08 mg/kg of body weight.

The formulation of this invention may be administered, if desired, in divided doses, such as BID, TID, or QID. The following recommended treatment is both safe and effective for relief from the symptomatic effects of arthritis. Dosage Components Time of Day 10 to 2500 mg Aspirin Morning SO to 1000 mg Glucosamine Morning 25 to 750 mg Chondroitin Morning 10 to 2500 mg Aspirin Mid-Day 50 to 1000 mg Glucosamine Mid-Day 25 to 750 mg Chondroitin Mid-Day 10 to 1500mg Aspirin PM 50 to 1000 mg Glucosamine PM 25 to 750 mg Chondroitin PM The body's demand for glucosamine and chondroitin requires that both of them be taken a minimum of twice; and, for better results, three times a day. When the above treatment is followed, the pain associated with arthritis will begin to subside immediately, and, thereafter such treatment provides essentially continuous relief so long as the regimen is followed. In most individuals such treatment will slow down or even reverses the progression of the disease. However, when the regimen is discontinued, the debilitating pain may return within a brief period (4-7 days). In some instances, the therapeutic effects of the formulation provides pain relief for an even longer period (up to 14 days) after treatment has been discontinued. In any event, upon resumption of the regimen, the pain once again is abated, and no side effects are experienced even after several months of continued use.

EXAMPLES The Examples that follow further define and illustrate a number of the preferred embodiments of this invention. Parts and percentages appearing in these Examples are by weight unless otherwise indicated. The apparatus used in the

formulation and evaluation of the compositions of this invention are standard unless indicated otherwise.

EXAMPLE 1 A formulation of this invention is prepared in tabletted form by mixing unit doses of the following components: 325 mg enteric coated or buffered aspirin, 500 mg glucosamine sulfate, and 400 mg chondroitin sulfate. This unit dosage is efficacious in a dietary regimen wherein the individual weighs from about 100 to about 125 lbs. and takes at least one dose of this formulation in the morning and a second dose in the evening. For individuals weighing 150 to 1751bs, the dietary regimen contemplates that, at a minimum, one additional dose be taken in the morning and in the evening. Where the individual is in excess of 200 lbs., but less than about 2501bs, the unit dosage specified in the regimen is 2x to 3x the minimum dosage.

EXAMPLE 2 The procedures of Example 1 are repeated, except for the substitution of a unit dose of 200 mgs of the NSAID, ibuprofen, for a unit dose of the aspirin component of the formulation.

EXAMPLE 3 The procedures of Example 1 are repeated, except for the substitution of the a unit dose of 220 mgs of the NSAID, naproxen sodium, for a unit dose of the aspirin component of the formulation.

EXAMPLE 4 The procedures of Example 1 are repeated, except for the reduction in the unit dose of the aspirin component of the formulation from 325 mgs to 243 mgs/unit dose.

EXAMPLE 5 The procedures of Example 1 are repeated, except for the substitution of a natural source of an NSAID, White Willow Bark (15% salicylic acid), for the aspirin component of the formulation. The unit dose of White Willow Bark is adjusted to deliver the therapeutic equivalent of aspirin.

EXAMPLE 6 The procedures of Example 1 are repeated, except for the substitution of acetaminophen for the aspirin component of the formulation. The unit dose of acetaminophen is adjusted to deliver the therapeutic equivalent of aspirin.

EXAMPLE 7 The procedures of Example 1-5 are repeated, wherein each of the formulations of Examples 1-6 are modified to include 150 mgs manganese ascorbate.