WO1997015299A1

WO1997015299A1 - Relief and prevention of suffering conditions

Info

Publication number: WO1997015299A1
Application number: PCT/US1996/017663
Authority: WO
Inventors: Arthur Vanmoor
Original assignee: Arthur Vanmoor
Priority date: 1995-10-27
Filing date: 1996-10-28
Publication date: 1997-05-01
Also published as: AU7605996A; EP0866694A1; CA2235746A1

Abstract

A method of determining the effectiveness of an agent for the relief and prevention of a suffering condition comprises the steps of a) exposing a susceptible person to a quantity of a trigger substance reproducibly effective in producing within an appropriate period a suffering condition perceptible by the person and in the absence of treatment, lasting for at least six hours after being perceived, b) orally administering to said person being exposed to said quantity of trigger substance a quantity of the agent whose effectiveness in said quantity in relieving said suffering condition is to be determined, c) measuring the extent of said suffering condition of the person upon administering said agent, and d) comparing the extent of said suffering condition with and without the administration of said agent. Also disclosed are effective quantities of certain nutrient substances which can reproducibly relieve a suffering condition produced in a susceptible subject by the administration of a trigger substance.

Description

Relief and Prevention of Suffering Conditions

5 Technical Field:

This invention relates to the relief and prevention of certain ailments and afflictions, conveniently termed suffering conditions, such as pain, elevated blood pressure, acne, and the common cold, to novel remedies for these io suffering conditions, and to novel methods for discovering remedies effective for such relief and prevention.

Background Art:

According to one of its aspects, this invention relates to

15 the relief of pain. More particularly, this invention relates to the relief of pain generally deemed (by others than the sufferer) mild to moderate, such as headache, muscle ache, low back pain, arthralgia and the like for relief of which the so-called minor analgesics such as

20 aspirin, acetaminophen, and ibuprofen are conventionally recommended. These minor analgesics are believed to have helped many people and are consumed in large quantities worldwide. They are, however, not free of unpleasant and even dangerous side effects, and new and improved remedies

25 are constantly being sought.

According to a further aspect, this invention relates to the relief and prevention of pain in one or more of a person's joints. More particularly, this invention relates to the

30 relief and prevention of pain associated with those musculosketal disorders that primarily affect the joints. Joint disorders are further classified into the particular tissue disorders (e.g. tennis elbow) and the true articular or joint diseases (e.g. osteoarthritis) . The MERCK MANUAL,

35 16th edition, published 1992, at pages 1297 to 1300, which portion is here incorporated by reference, contains a table titled "Classification of the Rheumatic Diseases" that includes ten major categories of disease including among others Diffuse Connective Tissue Diseases embracing rheumatoid arthritis and 17 other diseases and conditions; Arthritis associated with Spondylitis embracing 5 diseases and conditions; two kinds of Osteoarthritis; and 13 kinds of Arthritis, Tenosynovitis, and Bursitis associated with infectious agents. Most of these diseases and conditions are accompanied by pain. As pointed out by this publication, we do not yet fully understand the causes of nor can we completely control joint pain."

Also according to this reference, a few types of arthritis are treatable with specific therapy; for example, gout can be completely controlled with drugs, or Lyme disease can be treated with antibiotics, but there are no "magic bullets" for most chronic rheumatic disorders. Optimal management for patients with severe musculosketeal disease requires many skills and resources and the collaboration of rheumatologists, orthopedic surgeons, paramedical specialists, and support services. Drug therapy is synergistic to other treatment in providing symptomatic control and suppression of disease and rarely should be relied alone. Disease suppression can be achieved with hypouricemic drugs for gout, corticosteroids and immunosuppressive agents for immunologic and inflammatory diseases, and a range of miscellaneous slow-acting drugs for rheumatoid arthritis and the arthropathies associated with spondylitis. Aspirin has been used for pain and inflammation since early in this century. More recent drug therapy for rheumatoid arthritis includes gold injections, penicillamine, hydroxychloroquine, and sulfasalazine. However, drug control of these conditions remains imperfect, O 97/15299 PC17US96/17663

-3- and better understanding and new approaches are urgently needed.

For rheumatoid arthritis in particular, the same reference notes that among non-steroidal anti-inflammatory drugs (NSAIDs), salicylates are relatively safe, inexpensive, analgesic, and anti-inflammatory, and are the traditional cornerstone of drug therapy in rheumatoid arthritis. Aspirin is begun with 600 to 1000 milligrams four times daily and adjusted upward until achieving a maximally effective or mildly toxic dose (e.g. tinnitus, diminished hearing) to a final dose from 3000 to 6500 milligrams per day. Other NSAIDs are available for patients who do not tolerate sufficient aspirin to obtain a good effect, as shown in the following table:

Agent Recommended dosage

Indomethacin 25 mg 3x or 4x daily Ibuprofen 400-800 mg 4x daily

Naproxen 250 mg 2x daily or up to 1250 mg/day

Fenoprofen 300-600 mg 4x daily, 3200 mg max.

Tolmetin 400 mg 3x daily, 2000 mg max.

Sulindac 150-200 mg 2x daily Meclofenamate 200-400 mg/day

Ketoprofen 150-300 mg/day

Proxicam 20 mg lx daily

Flurbiprofen 100 mg 2x or 3x daily

Diclofenac 75 mg 2x daily or 50 mg 4x daily

While less irritating to the gastro-intestinal tract than aspirin, these NSAIDs can also produce gastric symptoms and bleeding. -4-

Gold and the other slowly acting drugs are considered for use when aspirin or other NSAIDs are not sufficiently beneficial after 3 to 4 months of treatment. These drugs, too, are unfortunately subject to toxic side effects.

Corticosteroids are the most dramatically effective short- term Antiinflammatory drugs, but rheumatoid arthritis is usually active for years, and clinical benefit from corticosteroids often diminishes with time.

U.S. Patent No. 4,772,591 to Meisner discloses accelerating the healing of wounds by administration of a composition comprising a mild anti-inflammatory agent and substances which in combination have been found to accelerate fibrous tissue growth and scar tissue formation. Meisner's method comprises the administration of four substances: a source of biologically available calcium, ascorbic acid, a precursor or stimulant of epinephrine or nor-epinephrine production selected from among tyrosine and phenylalanine, and a mild anti-inflammatory substance selected from the anti¬ inflammatory members of the group consisting of simple sugars, amino sugars, amino acids, and derivatives thereof. The preferred member of this anti-inflammatory group is glucosamine; specifically listed anti-inflammatory amino acids are cysteine, creatine, creatinine, L-tryptophan, valine, alanine, glycine, glutamine, aspartic acid, and S- methylcysteine.

As pointed out by W. Michne (Encyclopedia of Chemical Technology, third edition, vol. 2, pages 574-586), the search for new, more effective analgesics and anti¬ inflammatory agents with fewer and/or less severe side effects is a continual endeavor, and promising agents are ultimately (emphasis added) studied in man. The laboratory and clinical evaluations of new drugs are complex O 97/15299 PC17US96/17663

-5- disciplines..." The writer implies that before a "promising agent" is studied in man, it must be established by testing with animals that administration to humans is safe, and that the agent offers at least some promise of mitigating human pain. While methods of evaluating safety are well known, study of analgesic effectiveness in experimental animals is not straightforward and remains a controversial subject, especially with respect to correlation of effects in animals and in humans.

J.K. Saelens and F.R. Granat ("New Drug Discovery and Development", pages 263-) have described a phenylquinone writhing test in mice" that is sensitive to all known analgesics and therefore deemed an excellent primary screening test for new candidates. Male mice receive intraperitoneally 0.1 ml/10 g body weight of an 0.25 mg/ml solution of phenyl-p-quinone in 5% aqueous ethanol. Five minutes later they are placed in observation cages and the number of animals which do not perform a characteristic writhe during the next 10 minutes are recorded. The authors found that phenylquinone induces one or more writhes in 95% of the injected mice. Test compounds are then administered and evaluated for their effectiveness in inhibiting the characteristic writhe response to phenylquinone.

While this is only one test method of many that have been proposed, it serves to illustrate the laboriousness and complexity of the effort required. Yet this effort is merely that of one stage in the process, i.e. that of the primary screening for activity.

Application of these and similar methods has led to a number of successful products in the field of major analgesics, i.e. substances that mimic the pain relieving effectiveness of morphine with reduced tendency to physical dependence. - 6-

However, there have been fewer successes in the field of the NSAIDs and other drugs effective against joint disease related pain.

According to another aspect, this invention relates to the relief of arterial hypertension defined as elevation of systolic and/or diastolic blood pressure, either primary (essential hypertension) or secondary (see MERCK MANUAL, 16th edition, 1992, pages 413-429) . As stated here, "primary or essential hypertension is of unknown etiology, and it seems improbable that a single cause will explain its diverse hemodynamic and pathophysiologic derangements. Heredity undoubtedly predisposes individuals to hypertension, but the exact mechanism is unclear." It has been estimated that there are more than 50 million hypertensives in the United States, that is persons with systolic blood pressure of 140 millimeters of mercury or more and/or diastolic blood pressure of 90 mm or more, or taking antihypertensive medication.

Primary hypertension is asymptomatic until complications develop. Symptoms and signs are non-specific and arise from complications in target organs. Complications include left ventricular failure; atherosclerotic heart disease; retinal hemorrhages, exudates, papilledema, and vascular accidents; cerebrovascular insufficiency with or without stroke, and renal failure.

As to treatment, the same reference states that "there is no cure for primary hypertension, but therapy can modify its course." In cases of mild hypertension, non-drug therapies such as weight reduction to ideal levels, modest dietary sodium restriction to less than 2000 milligrams per day, limitation of alcohol intake to less than one ounce of ethanol per day and prudent exercise can make drug therapy unnecessary. However, it is recommended that when complications are present or impending, or when the diastolic blood pressure is greater than 95 mm, drug therapy should not be deferred while awaiting the uncertain results of dietary therapy." The goal of drug therapy is stated to be reducing the blood pressure to normal, i.e. 140/90 or less.

Recommended antihypertensive drugs include four major classes of agents, identified as diuretics, beta-blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors. The reference lists 19 different diuretics grouped in three subclasses, 13 different beta-blockers, nine different calcium antagonists grouped in three subclasses, and five different antiotensin-converting enzyme inhibitors. The choice among these many agents is said to be based on the patient's age, race, and the presence or absence of particular complications and conditions associated with high blood pressure.

From the 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (Archives of Internal Medicine, 1988, vol. 148, pages 1023- 1038) the reference reproduces a "stepped care therapy" scheme for hypertension which suggests trying a non-drug approach first; then, as a second step, a drug from the above indicated classes; then as a third step increasing the dose of the first drug, substituting a drug of another class, or adding a second drug; as a fourth step, adding a third drug of a different class or making a substitution for the second drug, and, if necessary, adding a third or fourth drug; and ultimately "evaluate further and/or refer; consider step-down therapy and continue non-drug approaches." The large number of choices, and the far from categorical promise of success, coupled with the fact that the listed drugs are not free of unpleasant and even dangerous side effects, provides clear evidence that new and improved remedies for high blood pressure are still needed.

According to another aspect, this invention relates to the prevention of facial pimples, also known as acne. More particularly, this invention relates to the avoidance or at least mitigation of a tendency in some individuals to develop the symptoms of superficial acne, characterized by comedones, either open (blackheads) or closed (whiteheads) , inflamed papules, superficial cysts, and papules; as well as deep acne, deep inflamed nodules and pus-filled cysts, which often rupture and become abscesses (see MERCK MANUAL, 16th edition, 1992, pages 2430-2431 ) . As stated there.

Acne is often exacerbated in winter and improved in summer, probably because of the sun's beneficial effect. Diet has little effect, if any; however, if a food is suspected, it should be omitted for several weeks and then eaten in substantial quantities to see if eating it makes any difference. Most such trials prove that the acne is unrelated to food. Acne may cycle with the menses, and it may clear or become worse during pregnancy. In many women who first develop acne in their 20s and 30s certain cosmetics may act as aggravating agents.

Thus the sufferer is told that the problem may have any of a number of possible causes, and the probability of success in controlled experimentation attempting to correlate the problem with a particular food is small.

While the disease is stated to be almost universal and the prognosis for eventual healing without scars is considered good, disfiguring or even mild acne may embarrass young people and lead to psychological complications, so that supportive counseling for both patients and their parents is often recommended. Specific treatments for superficial acne include cautious mechanical removal of comedones, topical clinda ycin solution or other antibiotics, or 5-10% preparations of benzoyl peroxide, considered the best non- prescription topical drug (Merck Manual) .

For deep acne, topical treatment is stated in this reference to be unsatisfactory. Treatment of patients with a few deep lesions is usually a broad-spectrum oral antibiotic; the most effective antibiotic with the fewest side effects is said to be tetracycline in doses of 250 mg four times a day or 500 mg twice a day, except that for pregnant patients similar doses of erythromycin are said to be preferred. Treatment should be continued for four weeks and then decreased to the lowest amount that gives a good response. However, because relapse ordinarily follows short periods of treatment, therapy must be continued for months to years with as little as 250 or 500 mg per day of tetracycline often sufficient.

Oral isotretinoin is considered the best treatment for patients in whom treatment with antibiotics is unsuccessful or with very severe deep acne but is subject to severe side effects and cannot be given to pregnant women because it is teratogenic.

U.S. Patent No. 5,459,153 to L H Leung discloses a method for treatment of acne vulgaris which comprises systemic administration to a patient suffering from acne vulgaris divided doses about 1 to 5 times a day of a combination of pharmaceutical agents consisting essentially of approximately 2 to 10 grams pantothenic acid, approximately 0.3 to 3 grams nicotinic acid, and approximately 5 to 50 milligrams biotin.

According to a further aspect, this invention relates to the relief and prevention of the so-called common cold, also -10- known as upper respiratory infection and as acute coryza. More particularly, this invention relates to the avoidance or at least mitigation of a tendency in some individuals to develop the symptoms of nasal or throat discomfort, followed by sneezing, rhinorrhea (running nose), and malaise (see MERCK MANUAL, 16th edition, 1992, pages 190-192) . As stated there,

Many viruses cause the common cold, including those in thepicornavirus (rhinovirus, certain echoviruses, and, influenza, parainfluenza, respiratory syncytial, coronavirus, and adenovirus groups. Most colds (30-50%) are caused by one of the > 100 serotypes of the rhinovirus group. Pinpointing the specific cause of each illness by virus isolation or serologic tests is impractical....

Predisposing factors have not been clearly identified. Chilling the body surface does not by itself induce colds, and an individual's susceptibility is not affected by either health and nutritional status or upper respirator tract abnormalities (e.g. enlarged tonsils or adenoids) . Infection may be facilitated by excessive fatigue, emotional distress, or allergic nasopharyngeal disorders and during the midphase of the menstrual cycle. However, the most important determinant of infection is the presence of specific neutralizing antibody, which indicates previous exposure to a virus and offers relative protection.

Thus the sufferer is told that the condition may have any of a number of possible causes, and the clinical symptoms and signs are non-specific. The condition is stated to be widespread and, when no complications occur, symptoms normally resolve in 4 to 10 days. Also according to the MERCK MANUAL,

Many means of preventing acquisition and spread of common colds have been tried, including polyvalent bacterial vaccines, alkalis, citrus fruits, vitamins, ultraviolet lights, and glycol aerosols, but none has been effective. In controlled trials, large (as much as 2 grams per day) prophylactic oral doses of vitamin C have not altered the frequency of acquisition of rhinovirus common colds or the amount of virus shedding. However, some studies have shown a reduction in duration of disability among persons who took as much as 8 g/day on the first day of disease, although no reduction in virus shedding has been noted."

Remarkably, the only treatments recommended by this reference are a warm, comfortable environment and measures to prevent direct spread of infection for all patients, rest at home for those with fever or acute symptoms of infection, and steam inhalation to mobilize secretions and help relieve chest tightness. Many other treatments including antipyretics and analgesics such as aspirin, antihistamines, and antibiotics, are listed but also deprecated as being of little benefit and/or subject to various drawbacks.

U.S. Patent No. 4,265,888 to Kagitani et al. discloses a pharmaceutical composition comprising an injection powder preparation of an acetylsalicylate (aspirin salt) obtained by reacting acetylsalicylic acid and a basic amino acid and incorporated with 1% w/w or more of calcium chloride. The preferred basic amino acid is DL-lysine. In DL-lysine acetylsalicylate, both reactants are combined in a molar ratio of 1:1. In using the preparation, it is dissolved in distilled water for injection. The diseases for which the preparation is efficacious include post-operational pain and other pains for which oral administration of an analgesic is effective; rheumatoid diseases (especially efficacious for progressive rheumatoid), neuralgia and neuritis; and hypothermia (common cold, bronchitis, and other central fever) . In this disclosure, the active agent is clearly the acetylsalicylate and the basic amino acid and calcium chloride act to solubilize and stabilize the preparation for injection use.

U.S. Patent No. 4,684,528 to Godfrey discloses that compositions containing a zinc compound such as zinc gluconate, a base material such as a candy or syrup and certain amino acids in which the molecular ratio of amino acid to zinc is in the range of two twenty are very pleasant to the taste and leave no undesirable aftertaste. The amino acids found useful for this purpose are glycine, L-alanine, D,L-alanine, L-2-aminobutyric acid, D,L-2- aminobutyric acid, L-valine, D,L-valine, L-isovaline, D,L-isovaline, L- leucine, D,L-leucine, D-isoleucine, D,L-isoleucine, L- lysine, and D,L-lysine. It is also disclosed that certain other amino acids such as aspartic and glutamic acids are not useful for this purpose. Therefore, it has been found that it is not possible to predict which zinc and amino acid combination will have an acceptable taste unless it is prepared and tested. Furthermore, the zinc supplement compositions which include the select amino acid possess in general very pleasant flavors. This permits the formulation of compositions which will release over an extended period of time substantial amounts of zinc ions locally in the mouth or in the mouth and throat as necessary for certain applications, including the control of the common cold.

U.S. Patent No. 5,250,569 discloses compositions for use in treatments to relieve upper respiratory discomfort containing an aluminum compound, a base material such as a candy or syrup and certain amino acids in which the molecular ratio of amino acid to aluminum is in the range of two twenty are very pleasant to the taste and leave no undesirable aftertaste. The amino acids found useful for this purpose are glycine, L-alanine, D,L-alanine, L-2- aminobutyric acid, D,L-2- aminobutyric acid, L-valine, D,L- valine, L-isovaline, D,L-isovaline, L-leucine, D,L-leucine, D-isoleucine, D,L-isoleucine, L-lysine, and D,L-lysine. It is also disclosed that certain other amino acids such as aspartic and glutamic acids are not useful for this purpose. Therefore, it has been found that it is not possible to predict which aluminum and amino acid combination will have an acceptable taste unless it is prepared and tested. The aluminum compounds which can be used in combination with the amino acids noted above can be any of the forms commonly used such as the sulfate, chloride hexahydrate, acetate, acetotartrate, ammonium sulfate, diacetate, hydroxychloride, magnesium silicate, potassium sulfate, sodium sulfate, acetate oxide, gluconate, glucuronate, and ascorbate, as well as complexes of trivalent aluminum with the amino acids.

U.S. Patent No. 5,422,097 to Gwaltney, Jr. discloses a method to treat the common cold which utilizes both antiviral and anti-inflammatory compounds and employs the simultaneous administration of intranasal and oral medicaments. Also disclosed are investigations in which human volunteers were subjected to a virus challenge with intranasally administered Hank's strain of rhinovirus. Antiviral agents disclosed include interferon a-2 and others itemized at column 9 line 61, to column 10, line 40. Antiinflammatory agents disclosed include iprotrophen, naproxen, phenylephrine, chlorpheniramine, and others itemized at column 10, lines 41-64.

However, there is as yet no evidence that any of the above proposed treatments have succeeded in reliably controlling the so-called common cold.

Against this background, there clearly exists a need for improved oral remedies and preventive methods for relieving and preventing the so-called common cold, as well as improved methods for discovering such improved remedies and preventive methods.

For all these suffering conditions, the available drugs have been discovered by the methods of classical pharmacology, which while sometimes highly successful are always complex, laborious, time-consuming and costly.

For an overview of the entire process from the proposal of an idea by a researcher to the initiation of clinical trials of a remedy, reference can be had to Natural History of a Typical Drug a chapter by Dr. E. L. Harris in "The Principles and Practice of Clinical Trials" (Harris and Fitzgerald, editors, E. & S. Livingstone, Edinburgh and London, 1970) . Harris writes

The first stage is that of the idea. Whatever the source of the idea, it is considered by a research panel consisting of medical, chemical, pharmacological, pharmaceutical and commercial interests. If the panel feel that the idea has merit, then the research chemist sets about synthesizing the compound or a number of related compounds. This can be a very long and arduous task; it has been estimated that synthesis and initial biological screening of a single compound can take up to 400 man hours to achieve....

When sufficient quantities have been made the pure drugs are handed over to the pharmacologist who carries out a program of empirical screening tests, designed to cover as wide a range of pharmacological actions as economically as possible so as to expose any effects which might be of therapeutic use. If an action is detected more detailed experiments to elucidate this are carried out.

Many compounds are rejected at this stage either because of lack of activity or gross toxicity. Those that do survive are again considered by the research panel who decide whether the agent has sufficient promise to go forward to assess its safety in animals.

There are three phases in toxicity testing. The first is the acute toxicity study which deals with the quantitative assessment of the short term effects of a drug. The response is noted after a single oral or parenteral dose, or several doses given within 24 hours. These tests are carried out in a variety of species.

The next is sub-acute toxicity, and in general covers repeated dosage in at least two species, such as mice and rats, for periods up to 90 days. An additional non- rodent species, e.g. dog, is often included.

Chronic studies are for the duration of life in the animal rats and mice are suitable. Occasionally long term studies are employed in other animals such as dogs and monkeys for periods up to two years....

When the exacting toxicological studies are completed and the research panel is satisfied with all the data that has been generated, the drug is administered to healthy volunteers...

DEFINITION OF TERMS IN THE DESCRIPTION AND IN THE CLAIMS: Exposing, exposure: causing a person to inhale or ingest a substance.

Suffering condition: any one or more of such rapid onset ailments and afflictions as headache, elevated blood pressure, acne pimples, and the common cold, as well as slow onset ailments and afflictions such as pain in a joint and all varieties of arthritis, rapid onset referring to six hours or less following exposure to a trigger substance and slow onset referring to more than six hours following exposure.

Relief and Prevention: An action that results in lessening the duration and/or intensity of a suffering condition.

Susceptible person: A person capable of reproducibly perceiving a suffering condition:

Trigger substance: A substance which upon exposure to a susceptible person in sufficient amount reproducibly results in perception of a suffering condition within the period appropriate for a rapid onset condition or a slow onset condition as the case may be.

Extent of a condition refers to the duration and/or intensity of such condition.

Disclosure of the Invention:

In accordance with this invention, I have found that I can reproducibly cause a susceptible person to experience a measurable and reproducible suffering condition within an appropriate period of time upon the exposure to a sufficient quantity of certain substances which I propose to call trigger substances, the choice of a particular trigger substance and the appropriate period being a function of the particular suffering condition. These trigger substances are products in widespread consumer use, frequently common foods or household materials, and are without effect on the great majority of the human population. In a susceptible person, however, the effect of a trigger substance is both reproducible and sufficiently long lasting to serve as research tool for the evaluation of agents effective in relieving or preventing a suffering condition. Accordingly the method of determining the effectiveness of an agent for, the relief and prevention of a suffering condition, comprises the steps of

a) exposing a susceptible person to a quantity of a trigger substance reproducibly effective in producing within an appropriate period a suffering condition perceptible by the person and in the absence of treatment, lasting for at least six hours after being perceived,

b) orally administering to said person being exposed to said quantity of trigger substance a quantity of the agent whose O 97/15299 PC17US96/17663

-17- effectiveness in said quantity in relieving said suffering condition is to be determined,

c) measuring the extent of said suffering condition of the person upon administering said agent, and

d) comparing the extent of said suffering condition with and without the administration of said agent.

As a function of the particular suffering condition, the appropriate period for rapid onset ailments and afflictions such as headache, elevated blood pressure, acne pimples, and the common cold is six hours or less following exposure to a trigger substance. For slow onset ailments and afflictions such pain in a joint, an appropriate period can be up to ten days following exposure to a trigger substance.

Also in accordance with this invention, I have found that effective quantities of certain nutrient substances can reproducibly prevent a suffering condition such as headache and certain other kinds of pain, pain in a joint, elevated blood pressure" a common cold, or appearance of pimples on the face of a susceptible person following the exposure to a trigger substance. Being nutrient substances that are ingested and metabolized by humans daily, such substances are inherently safe. Accordingly, the method of relieving or preventing a suffering condition in a person in need of such relief, comprises the administration to such person of a quantity of an agent determined to be effective in preventing the suffering condition in a susceptible person following exposure to a trigger substance for the suffering condition. Such administration of an agent can take place before exposure to a trigger substance, at the same time or shortly thereafter, or without exposure to a trigger substance at all, so that the perception of a suffering condition that would be produced without the agent is thereby prevented.

Also in accordance with this invention, I have found that an agent found effective in accordance with this invention in preventing a suffering condition can be combined with a pharmaceutically acceptable carrier to provide an effective palatable remedy composition for such condition. Moreover, I have found that a combination of two or more selected agents found effective in accordance with this invention in preventing the perception of a suffering condition can be combined with a pharmaceutically acceptable carrier to provide a pleasant tasting as well as effective and palatable remedy composition.

Best Mode of Carrying Out the Invention:

A trigger substance according to this invention is defined as a substance which upon exposure to a susceptible person in sufficient amount reproducibly results in perception of a suffering condition within the period appropriate for a rapid onset condition or a slow onset condition as the case may be. Preferred trigger substances are those known to be safe to administer to a human subject, particularly substances known to be in consumer use or authoritatively regulated for such use under observance of appropriate limitations

Accordingly, a trigger substance for pain such as headache is any substance that, when administered to a susceptible person, reproducibly gives rise to a sensation of pain in such person in a time period of thirty minutes to a few hours. Included among preferred trigger substances are substances commonly added to foods in order to modify their taste; this category of taste-modifiers embraces non- nutritive sweeteners including (but not limited to) saccharin, aspartame, and acesulfame-K as well as flavors and flavor enhancers including (but not limited to) acetoin, anethole, benzaldehyde, cinnamaldehyde, ethyl vanillin, methyl anthranilate, monosodium glutamate, and vanillin; additional categories of trigger substances are preservatives including (but not limited to) phenols such as butylated hydroxyanisole and butylated hydroxytoluene, benzoate compounds such as ammonium benzoate, potassium benzoate, sodium benzoate, and benzoic acid, sulfite compounds such as potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, sulfur dioxide, and sulfurous acid, and sorbate compounds such as potassium sorbate, sodium sorbate, and sorbic acid; and pesticides and pesticide residues permitted to be present in or on food including (but not limited to) products known under the names Captan, Chlorpyrifos, Diazinon, Diquat, Glyphosate, Malathion, Paraquat, pyrethrins, and Thiabendazole.

Trigger substances can also include whole products in which it may or may not be possible to identify a particular ingredient as responsible for the trigger effect. Such trigger substances for pain include diet carbonated beverages, identified by their effect differing from that of similar beverages formulated with nutritive sweetener; whether the trigger substance in such diet beverages be the non-nutritive sweetener contained therein, or the preservative contained therein, or a combination of both, or neither of these, is less important than that a reproducible trigger effect has been observed. Another such whole product is beer imported into the United States, of which brands imported from Europe, Japan, and Latin America have been observed to have a reproducible trigger effect while brands brewed in the United States have less effect. Reproducible pain sensations noted by a susceptible individual upon ingestion of a trigger substance include (but are not limited to) headache, stomach cramps, nausea, tearing eyes, and fits of coughing or sneezing.

The quantity of trigger substance to be administered for pain sensation to be reproducible is readily determined empirically. For example, a reproducible headache has been noted by a susceptible individual upon consumption of two twelve ounce cans of diet cola beverage, and upon consumption of one twelve ounce bottle of imported beer on an empty stomach.

For pain in a joint, a trigger substance is any substance that, when administered to a susceptible human subject, reproducibly gives rise to a sensation of pain in a joint of such subject in a time period of at most ten days and frequently four to six days. In the absence of treatment such pain continues after being first noted for a week or longer. Many trigger substances for pain already noted are also effective in triggering pain in a joint in the longer periods required.

Trigger substances for pain in a joint that include whole products such as commercially prepared foods in which it may or may not be possible to identify a particular ingredient as responsible for the trigger effect.

Among such products are many varieties of prepackaged frozen meals as sold in retail markets; whether the trigger substance in such meals be a non-nutritive sweetener contained therein, or a preservative contained therein, or a combination of both, or neither of these, is less important than that a reproducible trigger effect has been observed. Reproducible pain sensations in a joint noted by a susceptible individual upon ingestion of a trigger substance can occur, for example, in a shoulder, fingers, the lower back, a knee, or a toe.

The quantity of trigger substance to be administered for pain sensation in a joint to be reproducible is readily determined empirically. For example, a reproducible pain in a shoulder has been noted in a susceptible individual on consuming six prepackaged frozen chicken meals daily for one week on an empty stomach and in the absence of other solid foods.

A trigger substance for elevated blood pressure is any substance that, when administered to a susceptible human subject, reproducibly gives rise to an elevation of systolic and/or diastolic blood pressure in such subject in a time period of six hours or less. Included among preferred trigger substances are certain common foods and substances commonly added to foods as seasoning, such as table salt. Also included are substances known to lead to elevated blood levels of cholesterol. It is well known that elevated cholesterol levels can lead to narrowed arteries and elevated blood pressure, but such changes occur slowly over many years. An immediate effect of such cholesterol increasing agents on blood pressure within six hours has not previously been reported.

Trigger substances for elevated blood pressure can also include whole products in which it may or may not be possible to identify a particular ingredient as responsible for the trigger effect. Such products include chopped beef, many kinds of manufactured meat products such as sausages, and hamburger meat as served in many large fast food chain establishments. Whether the trigger substance in such meats and meat products be the meat itself or minor constituents possibly contained therein, or a combination of both, or neither of these, is less important than that a reproducible trigger effect has been observed.

The quantity of trigger substance to be administered for elevation of the blood pressure to be reproducible is readily determined empirically. For example, a reproducible increase in both systolic and diastolic blood pressure has been noted by a susceptible individual upon consumption of one hundred grams of bologna sausage.

A trigger substance for acne is any substance that, when administered to a susceptible human subject, reproducibly gives rise to the appearance of at least two pimples on the face of such person in a time period of four hours or less. Included among such trigger substances are certain common foods and substances commonly added to foods to improve their taste, texture, mouth feel and palatability in general such as fats and oils, especially polyunsaturated oils and oils and fats used in deep frying and other methods of processing food at elevated temperatures, such as 120°C and even higher. An immediate effect of such fats and oils in triggering the appearance of face pimples within eight hours or less has not previously been reported.

Trigger substances for acne can also include whole products in which it may or may not be possible to identify a particular ingredient as responsible for the trigger effect. Such products include French fries and other high fat forms of potatoes as served in many large fast food chain establishments or sold frozen for home use and certain meats and meat products, especially pork processed by such techniques as roasting, baking, frying, smoking, curing or sausage making. Whether the trigger substance in such fats and oils, potato preparations, or meats and meat products be the product itself or minor constituents possibly contained therein, or a combination of both, or neither of these, is less important than that a reproducible trigger effect has been observed.

The quantity of trigger substance to be administered for appearance of face pimples to be reproducible is readily determined empirically. For example, a reproducible appearance of two face pimples within eight hours or less has been noted by a susceptible individual upon consumption of two "large" portions of french-fried potatoes as served in a fast food establishment.

A trigger substance for the common cold is any substance that, when exposed in the form of a vapor to a susceptible human subject, reproducibly gives rise to a running nose condition in such subject in a time period of thirty minutes or less. Preferred trigger substances are those whose vapors are known to be safe to expose to a human subject in the amounts needed, particularly substances known to be present in products sold in retail establishments for household use or authoritatively regulated for such use under observance of appropriate limitations. Included among such trigger substances are basic nitrogen compounds such as alkanolamines and especially ammonia as found in aqueous ammonia solutions, formulated liquid household cleaning products, hair waving preparations, and the like. An immediate effect of such basic nitrogen compounds in triggering symptoms of the common cold such as running nose within thirty minutes or less has not previously been reported.

The quantity of trigger substance to be exposed to a susceptible person for appearance of cold symptoms to be reproducible is readily determined empirically. For example, a reproducible appearance of a running nose condition within thirty minutes or less has been noted by a susceptible individual upon exposure within 4 feet of a 40 milliliter 5 sample of household ammonia for less than five minutes.

Agents effective in relieving and preventing appearance of suffering condi tions.

io In accordance with this invention, any desired agent can be tested for its effectiveness in relieving or preventing the appearance of suffering conditions otherwise produced in a susceptible person by exposure to a trigger substance. The only limitation is the practical requirement of not doing

15 harm to such person. For that reason, I have sought effective agents principally among substances known to be safe to administer to a human subject, particularly substances known to be nutrients ingested and metabolized by human beings on a daily or at least frequent basis. I have

20 tested many nutrient substances and found effective among these a restricted group of water soluble aminocarboxylic acid compounds at dose levels in the range from 200 to 20000 milligrams. I use the term water soluble to refer to a solubility of at least three grams in 100 ml of water at

25 25°C.

A preferred group of water soluble aminocarboxylic acid compounds effective according to this invention in relieving and preventing appearance of rapid onset suffering 30 conditions such as headache and certain other kinds of pain, elevated blood pressure, facial pimples and the common cold can be represented by formula (I) : O 97/15299 PC17US96/17663

-25- X- (CH₂) _n-CH ( 0) _qH-CH-COO- ( I )

(NH₂+ ) _PH

in which X is selected from the group consisting of -SH,

-CONH₂,-NH₂, -NH-C=NH, -NH-C=0

I I NH₂ NH₂

and -CO-NH-CH-CO-NHCH₂CO-OH

CH₂SH, n is zero, one, or two, p is one and q is zero or one

Table 1 which follows includes particularly preferred water soluble aminocarboxylic acid compounds represented by formula (I) which I have found effective in preventing appearance of suffering conditions such as pain, elevated blood pressure, acne and the common cold when administered before exposure to a trigger substance.

TABLE 1 # Name X n p q

1 2-amino-3-mercapto- propanoic acid SH 0 1 0

2 2-amino-4-carbamoyl- butanoic acid C0NH₂ 1 1 0

3 2,5-diaminopentanoic acid

NH₂ 2 1 0 4 2-amino-5-guanido- pentanoic acid -NH-C=NH

I

NH₂ 2 1 0

5 2- (4-amino-5-carboxypentano- amido ) -3-mercapto-N- 1 1 0 carboxymethylpropanoamide

-CO-NH-CH-CO-NHCH₂COOH I

I

CH₂SH

A preferred group of water soluble aminocarboxylic acid compounds effective according to this invention in relieving and preventing appearance of slow onset suffering conditions such as pain in a joint can be represented by formula (II) :

X-(CH₂)n-CH(0)_qH-CH-COO- (II)

(NH₂+)_pH

in which X is selected from the group consisting of

-NH₂, -NH-C=NH, -NH-C=0

NH₂ NH₂

and - C0-NH-CH-C0-NHCH₂C0-0H

CH₂SH, n is zero, one, or two, p is one and q is zero or one.

Table 2 which follows includes particularly preferred water soluble aminocarboxylic acid compounds represented by formula (II) which I have found effective in preventing O 97/1529

-27- appearance of slow onset suffering conditions such as pain in a joint when administered before exposure to a trigger substance.

TABLE 2

# Name X n p

1 2,5-diaminopentanoic acid

NH₂ 2 1

2-amino-5-guanido- pentanoic acid -NH-C=NH I

NH₂

2-{4-amino-5-carboxypentano- amido)-3-mercapto-N- carboxymethylpropanoamide

-CO-NH-CH-CO-NHCH₂C00H

I

CH₂SH

Formulas (I)and (II) and all the effective compounds listed in Tables 1 and 2 contain an asymmetric carbon atom and hence exist in non-superimposable optically active forms (so-called D and L forms) and in racemic mixtures or DL forms. Both D and L forms of the effective compounds and racemic mixtures thereof are contemplated in accordance with this invention. Pharmaceutically acceptable salts of these aminocarboxylic acids, including hydrochlorides, sulfates, citrates, tartrates, and phosphates can be used.

There is nothing about the structures of the effective compounds of this invention or their known nutrient properties that would have enabled one to predict their -28- effectiveness in preventing appearance of suffering conditions in accordance with this invention. This unpredictability is further underscored by the finding that a number of aminocarboxylic acid compounds structurally similar to those effective according to this invention but not structured according to formula (I) or (II) are ineffective. In Table 3 following, there are listed a number of aminocarboxylic acid compounds found ineffective in preventing appearance of pain, elevated blood pressure, facial pimples or cold symptoms when administered before exposure to a respective trigger substance for each of these suffering conditions. Some of these compounds can be represented by formula (III)

X- (CH2)_n-CH(0)_qH-CH-C00- (III)

(NH₂+) _PH •

in which the assignments of X and/or n differ from those in formulas (I) and (II)

TABLE 3

Name n p q

A 2-aminopropanoic acid hydrogen 0 1 0

B 2-amino-3-phenylpropanoic acid phenyl 0 1 0

C 2-amino-3-imidazolyl- propanoic acid imidazolyl 0 1 0

2-aminoacetic acid N/A N/A O 97/15299 PC17US96/17663

-29- E 2-aminopenanedioic acid COOH 2 1 0

While these substances are ineffective in preventing appearance of suffering conditions, they do not act as trigger substances and thus can be present in modest amounts as companion substances to effective agents according to this invention. In this way such substances can contribute to the useful properties of the effective agents by enhancing their speed of action, palatability and/or taste characteristics. Where present as companion substances to effective agents their concentration will typically range from 1 to 10 weight percent of the effective agent.

Palatable oral dosage forms Also in accordance with this invention, a pharmaceutically acceptable carrier can be combined with effective amounts of an effective agent according to this invention to provide a palatable oral dosage form for administering to a person in need of preventing appearance of suffering conditions. Accordingly, palatable oral dosage forms according to this invention comprise at least one pharmaceutically acceptable carrier and an effective amount of an effective agent according to this invention. Preferably the effective agent is an aminocarboxylic acid nutrient compound having formula (I) or (II) . Particularly preferred effective agents are those listed in Tables 1 and 2.

One preferred palatable oral dosage form according to this invention is a tablet. A particularly preferred tablet according to this invention comprises a high percentage of at least one aminocarboxylic acid nutrient compound having formula (I) or formula (II) and minor amounts of carrier material acting as binder for the tablet. Suitable binder materials include naturally occurring carbohydrates such as cellulose, starch, galactomannan, fructose, lactose, and -30- sucrose; finely divided ingestible mineral substances such as calcium and magnesium carbonates, calcium and magnesium silicates, calcium and magnesium phosphates, alumina hydrates and hydrotalcite; waxy materials such as beeswax, stearin, stearates of calcium, magnesium, and aluminum, microcrystalline wax and paraffin, and mixtures thereof.

Another preferred palatable oral dosage form according to this invention is a capsule. Capsules have the advantage of delivering the effective agent directly to the alimentary canal without being tasted in the mouth. Suitable capsules are commercially available and are typically made of gelatin, but any sufficiently pure water soluble polymer can be used. Preferably the capsule is filled with the pure aminocarboxylic acid nutrient compound having formula (I) or formula (II) ; alternatively, suspensions of aminocarboxylic acid nutrient compound having formula (I) or formula (II) in a liquid carbohydrate such as corn syrup or honey, or in a lipid such as lecithin or canola oil can be encapsulated.

A further palatable oral dosage form according to this invention comprises an effective amount of an effective agent according to this invention in a liquid carrier such as a fruit flavored drink or a soup, as well as dry concentrates for reconstitution of such drink or soup upon adding water. Preferably the effective agent is an aminocarboxylic acid Nutrient compound having formula (I) or formula (II) . Particularly preferred effective agents are those listed in Table 1.

Suitable fruit flavored drinks include natural fruit juices such as pineapple juice, apple juice, grape juice, orange juice, grapefruit juice, cranberry juice, and mixtures thereof; reconstituted juices prepared from water and fruit juice concentrates, and fruit juice drinks containing water and at least 10% of natural fruit juice.

In oral dosage forms according to this invention, the proportions of carrier to effective agent can vary over a broad range in accordance with the kind of carrier selected and the strength desired. Thus the proportion of carrier can be as little as 0.1% by weight, as in a tablet, and as high as 85% or even more, as in a fruit flavored drink.

Tablets in accordance with this invention can be prepared, for example, from 750 milligrams of each of compounds #1, 2, and 5 of Table 1 and 5 milligrams each of stearin, magnesium stearate, and magnesium silicate. Capsules in accordance with this invention can be prepared, for example, by filling elliptical capsules of 1.5 ml capacity with 500 milligrams of each of compounds # 1, 2, 3, 4, and 5 of Table 1.

Fruit flavored drinks in accordance with this invention can be prepared, for example, from 3750 milligrams of each of compounds #1, 2, 3, 4, and 5 of Table 1 and 75 milliliters of commercially available apple-cranberry drink.

Pleasant tasting oral dosage forms Also in accordance with this invention, a pharmaceutically acceptable carrier can be combined with effective amounts of an effective agent according to this invention and a flavorant to provide a pleasant tasting oral dosage form for administering to a person in need of suffering condition relief. Accordingly, pleasant tasting oral dosage forms according to this invention comprise at least one pharmaceutically acceptable carrier, an effective amount of an effective agent according to this invention, and a flavorant. Preferably the effective agent is an aminocarboxylic acid nutrient compound having formula (I) or formula (II) . Particularly preferred effective agents are those listed in Table 1.

Preferred flavorants that can be used in a pleasant tasting oral dosage form according to this invention include herbs such as basil, cilantro, dill, oregano, tarragon, and thyme; spices such as cinnamon, clove, ginger, mace, and nutmeg, and essential oils such as oil of lemon, oil of orange, oil of peppermint, and oil of sassafras.

In a particularly preferred pleasant tasting oral dosage form according to this invention, there are present in amounts selected to complement the taste characteristics of each at least one first nutrient compound having the formula

X- (CH₂)_n-CH(0)_qH-CH-C00-

(NH₂+)_PH

in which X is selected from the group consisting of -NH₂, and

-NH-C=NH

NH₂

n is two, p is one and q is zero,

and at least one second nutrient compound having the formula X- (CH₂)_n-CH(0)_qH-CH-C00

(NH₂+)_PH

in which X is selected from the group consisting of -SH, - C0NH₂, and - CO-NH-CH-CO-NHCH₂CO-OH

I

CH₂SH, n is zero or one, p is each zero or one, and q is zero or one.

In such compositions, the taste characteristics of the first nutrient compound and the second nutrient compound interact in such a way as to produce an overall pleasant tasting composition.

Pleasant tasting tablets in accordance with this invention can be prepared, for example, from 750 milligrams of each of compounds #1, 2, and 5 of Table 1, 5 milligrams each of stearin, magnesium stearate, and magnesium silicate, and 10 milligrams of finely powdered cinnamon.

A pleasant tasting fruit flavored drink in accordance with this invention can be prepared, for example, by blending 4500 milligrams of each of compounds #1, 2, and 5, of Table 1, 110 milliliters of commercially available chilled grapefruit juice, and 5 drops oil of orange.

Pleasant tasting tablets containing a first nutrient compound and a second nutrient compound in accordance with this invention can be prepared, for example, from 500 milligrams of each of compounds #1, 2, and 5 of Table 1, 250 milligrams of each of compounds #3 and 4 of Table 1, and 5 milligrams each of stearin, magnesium stearate, and magnesium silicate.

Taste modifying compositions

Also in accordance with this invention, a taste-modifying material that is a trigger substance in a susceptible individual can be combined with effective amounts of an effective agent according to this invention to provide a taste modifying composition with reduced tendency to produce a perceptible sensation of pain in a susceptible person. Accordingly, taste-modifying materials according to this invention comprise at least one taste-modifying substance able to provoke perceptible pain in a susceptible individual and an effective amount of an effective agent according to this invention. Preferably the effective agent is an aminocarboxylic acid nutrient compound having formula (I) . Particularly preferred effective agents are those listed in Table 1.

In the preferred taste-modifying compositions of this invention, any of the above recited taste modifying substances can be combined with any one or more of the effective aminocarboxylic acid nutrient compounds having formula (I) . Particularly preferred examples include Saccharin combined with each of compounds #1, 2, 3, 4, and 5 of Table 1. Aspartame combined with each of compounds #1, 2, 3, 4, and 5 of Table 1. Monosodium glutamate combined with each of compounds # 1, 2, 3, 4, and 5 of Table 1.

In the particularly preferred examples of taste-modifying compositions according to this invention, the relative proportions of taste modifying substance to effective aminocarboxylic acid nutrient compound can range from 9:1 to 1:9 by weight.

The following Examples are provided to illustrate the invention without intending to limit its scope, which is defined by the appended claims.

EXAMPLE 1:

Quantities of Mexican beer were administered on alternate days on an empty stomach to a female human subject known to be susceptible to headaches believed to be associated with O 97/15299 PC17US96/17663

-35- the consumption of imported beer. The following observations were recorded

Trial Quantity Time to onset of headache a Half bottle 2 hours b Full bottle 1 hour c 2 bottles 1/2 hour

The results show that the quantities of imported beer given in these trials are clearly sufficient to trigger a headache in this individual.

EXAMPLE 2:

Quantities of diet cola were administered on alternate days on an empty stomach to a male human subject known to be susceptible to headaches believed to be associated with the consumption of diet cola. The following observations were recorded.

Trial Quantity Time to onset of headache a half of 12 oz can noι headache observed b full can 2 hours c 2 cans 1 hour d 3 cans 45 minutes e 4 cans 30 minutes

The results show that the quantities of diet cola given in trials b through e are clearly sufficient to trigger a headache in this individual.

EXAMPLE 3:

Quantities of white wine (fractions of a 750 ml bottle) known to contain sulfites were administered on alternate days on an empty stomach to a male human subject and a female human subject both known to be susceptible to headaches believed to be associated with the consumption of sulfites. The following observations were recorded.

Trial quantity Time to onset a 1/8 bottle no headache observed b 1/4 bottle 2 hours c 1/2 bottle 1 hour d 1 bottle 1/2 hour

The results confirm that the sulfite-containing wine given in trials b, c, and d reproducibly trigger a headache in these individuals. No such effect was noted with wine not containing sulfites.

EXAMPLES 4-5 and COMPARISON TRIALS 1-4:

In each of the following trials, a half bottle of sulfite- containing wine was administered to the same subjects as in Example 3. After the onset of headache was noted, approximately one hour after giving the wine, there was administered a dose of a substance as noted below.

Example # Substance Dose Time from administration to disappearance of headache

Blend of substances 2000 mg one hour from Table 1 ditto 4000 mg half hour

Comparison 1 none no effect in ten hours

Comparison 2 blend of substances 4000 mg no effect in ten from Table 3 hours O 97/15299 PC17US96/17663

-37-

Comparison 3 aspirin (three tablets = 975 mg) 90 minutes

Comparison 4 acetaminophen (1000 mg) 80 minutes

Comparison 5 ibuprophen (500 mg) 100 minutes

The results show the blend of substances shown in Examples 4 and 5 was an effective agent according to this invention in relieving headache triggered by sulfite containing wine in accordance with a method of this invention, and acted more rapidly than conventional pain remedies at doses at or above their maximum recommended level. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

EXAMPLE 6:

Nine ounce single servings of chicken meals stated to afford 230 calories, 4 grams fat, and 40 milligrams cholesterol as sold frozen and prepackaged in supermarket chains were heated as directed and fed daily for one week on an empty stomach and in the absence of other solid foods to a male human subject known to be susceptible to arthritic pain in joints believed to be associated with the consumption of certain prepackaged frozen foods. The following observations were recorded

Trial Number of Extent of pain in the left servings per day shoulder after one week

a 3 just noticeable pain when moving b 6 dull pain when moving c 9 appreciable pain when moving

The results show that 3 servings per day for a week as given in these trials are clearly sufficient to trigger a marked incidence of pain localized in a joint of this individual, -38- and that the extent of such pain increased with the quantity consumed.

EXAMPLE 7: Nine ounce single servings of chicken meals stated to afford 210 calories, 3 grams fat, and 30 milligrams of cholesterol were cooked as directed and fed each day for a week on an empty stomach and in the absence of other solid foods to a female human subject known to be susceptible to arthritic pain in joints believed to be associated with the consumption of certain pre-packaged frozen foods. The following observations were recorded.

Trial Servings Extent of pain in the fingers per day after one week

a 2 no pain b 4 just noticeable pain c 8 little pain d 10 appreciable pain

The results show that the quantities of substances contained in the meals given in trials b, c, and d are clearly sufficient to trigger a marked incidence of arthritic pain in a joint of this person increasing with the quantity consumed.

EXAMPLES 8-9 and COMPARISON TRIALS 6 and 7:

In each of the following trials, a quantity of six servings of prepackaged and frozen chicken as in Example 6 was prepared and served on each day for one week on an empty stomach and in the absence of other solid foods to the same male human subject as in Example 6. At the same time, there was administered a dose of a substance as noted below. The following observations were recorded. Example no. Substance Dose Occurrence of shoulder pain after one week

Blend of substances 2000 mg slight pain from Table 2

9 ditto 4000 mg no pain

Comparison 6 none steady dull pain

Comparison 7 blend of substances from table 3 4000 mg steady dull pain

The results show the blend of substances shown in Examples 8 and 9 was an effective agent according to this invention in diminishing or preventing the incidence of pain in a joint triggered by consumption of the prepackaged frozen meal in accordance with a method of this invention. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

EXAMPLE 10: Quantities of hamburger meat as served in large fast food chains were fed on alternate days on an empty stomach and in the absence of other foods to a male human subject known to be susceptible to elevation in blood pressure believed to be associated with the consumption of meat products. The following observations were recorded:

Trial Quantity Blood pressure reading at time shown: before eating 1/2 h after 2 h after 4 h after a 75 g 140/90 155/92 160/95 160/95 b 150 g 140/90 160/95 170/100 170/100 c 225 g 140/90 170/90 190/105 190/105

The results show that the quantities of hamburger meat given in these trials are clearly sufficient to trigger a marked dose-related increase in blood pressure in this individual.

EXAMPLE 11:

Quantities of bologna sausage were fed on alternate days on an empty stomach and in the absence of other foods to a female human subject whose normal blood pressure was 140/85. The following observations were recorded.

Trial Quantity Blood pres

a 50 grams 150/90 b 100 grams 160/95 c 200 grams 175/100 d 300 grams 185/105

The results show that the quantities of bologna sausage given in these trials are clearly sufficient to trigger a marked increase in blood pressure in this individual.

EXAMPLES 12-13 and COMPARISON TRIALS 8-9: In each of the following trials, a 150 gram quantity of hamburger meat as served in large fast food chains was fed on alternate days on an empty stomach and in the absence of other foods to the same male human subject as in Example 10. After the onset of increased blood pressure was noted, approximately two hours after eating, there was administered a dose of a substance as noted below.

Example no. Substance Dose Time from administration to return of blood pressure to normal

12 Blend of substances 2000 mg 3 hours from Table 1

13 ditto 2000 mg 3 hours

Comparison 8 none Comparison 9 blend of substances 4000 mg no effect in ten hours

The results show the blend of substances shown in Examples 12 and 13 was an effective agent according to this invention in relieving elevated blood pressure triggered by hamburger meat in accordance with a method of this invention. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

EXAMPLE 14:

So-called "large" portion quantities of fried potatoes (french-fries) as served in large fast food chains were fed on alternate days on an empty stomach and in the absence of other foods to a male human subject known to be susceptible to acne believed to be associated with the consumption of high fat content foods. The following observations were recorded Trial No. of Number of pimples on face at time shown: "large" before 2h after 4h after 8h after eating eating eating eating a 1 1 1 2 2 b 2 1 1 3 4 c 3 1 1 4 6

The results show that two or more "large" portion quantities of french-fried potatoes as given in these trials are clearly sufficient to trigger a marked dose-related increase in facial pimples in this individual.

EXAMPLE 15:

Quantities of pan fried pork sausage were fed on alternate days on an empty stomach and in the absence of other foods to a female human subject whose face was free of pimples at the start. The following observations were recorded.

Trial Quantity No. of pimples four hours after eating a 50 gram none b 100 gram 1 c 150 gram 2 d 200 gram 3

The results show that the quantities of pork sausage given in trials b, c, and d are clearly sufficient to trigger a marked incidence of pimples in this individual.

EXAMPLES 16-17 and COMPARISON TRIALS 10 and 11: In each of the following trials, a quantity of two "large" portions of french fried potatoes as served in large fast food chains was fed on alternate days on an empty stomach and in the absence of other foods to the same male human subject as in Example 14. At the same time, there was administered a dose of a substance as noted below. The subject's face was observed at two hour intervals.

Example no, Substance Dose No. pimples at time after administration, hours

2 4 6 8

16 Blend of substances from Table 1 2000 mg 1 1 2 2

17 ditto 4000 mg 1 1 1 1

Comparison 10 none 1 3 3 4

Comparison 11 blend of substances from table 3 4000 mg 1 3 3 4

The results show the blend of substances shown in Examples 16 and 17 was an effective agent according to this invention in preventing the incidence of pimples triggered by consumption of fatty food in accordance with a method of this invention. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

EXAMPLE 18:

Conditions required to reproducibly trigger a running nose in a susceptible person were determined as follows:

A male volunteer subject known to be susceptible to attacks of running nose upon exposure to vapors of ammonia was seated in an enclosed room at varying distances from a 5 112 inch diameter dish placed 3 feet above the floor and containing 40 milliliters of household ammonia (approximately 9% ammonia by weight in water) . Trials were carried out on alternate days only to allow full recovery between trials. The time was noted from the start of exposure to the occurrence of a pronounced running nose, defined as having to blow clear 3 or more times in a 10 minute period and continuing for at least a six hour period. For each exposure distance, three trials were carried out, arranged in a random order.

Trials Distance of subject from source Time to onset of running nose a-1, a-2, a-3 12 feet no reaction in one hour b-1, b-2, b-3 8 feet 15,16, and 19 minutes c-1, c-2, c-3 4 feet 4, 4, and 3 minutes d-l, d-2, d-3 2 feet 2, 2, and 3 minutes

The results show that exposure to ammonia vapors at a distance of 8 feet or less is clearly sufficient to reproducibly trigger a running nose in this individual.

EXAMPLES 19-20 and COMPARISON TRIALS 12-13: In each of the following trials, the same subject as in Example 18 was exposed to a dish of household ammonia at a distance of 4 feet. After the onset of running nose was noted, approximately eight minutes after exposure, there was administered a dose of a substance as noted below. Example . Substance Dose Time from administration no. to abatement of running nose

19 Blend of substances from Table 1 2000 mg 30 minutes

20 same 4000 mg 20 minutes Comparison 12 none no effect in six hours

Comparison 13 blend of substances from table 3 4000 mg no effect in six hours

The results show the blend of substances shown in Examples 19 and 20 was an effective agent according to this invention in relieving cold symptom such as running nose triggered by ammonia in accordance with a method of this invention. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

EXAMPLES 21-22 and COMPARISON TRIALS 14-15: In each of the following trials, there was administered a dose of a substance as noted below to the same subject as in Example 18 and after a waiting period of 30 minutes he was exposed to a dish of household ammonia at a distance of four feet. The following results were noted.

Example no. Substance Dose Results

21 Blend of substances 2000 mg no running nose from Table 1 within 6 hours

22 ditto 4000 mg no running nose within 6 hours -46-

Comparison 14 none running nose after 4 min

Comparison 15 blend of substances 4000 mg running nose from Table 3 after 4 min

The results show the blend of substances shown in Examples 21 and 22 was an effective agent according to this invention in preventing cold symptom such as running nose triggered by ammonia in accordance with a method of this invention. The results also show that compounds of Table 3 with structural similarity to those effective according to this invention but differing in the assignments of X and/or n in the formula were ineffective.

Claims

1. The method of determining the effectiveness of an agent for the relief and prevention of a suffering condition, comprising the steps of

a) exposing a susceptible person to a quantity of a trigger substance reproducibly effective in producing within an appropriate period a suffering condition perceptible by the person and lasting, in the absence of treatment, for at least six hours from the time perceived,

b) orally administering to said person being exposed to said quantity of trigger substance a quantity of the agent whose effectiveness in said quantity in relieving said suffering condition is to be determined,

2. The method of claim 1 in which a perceptible suffering condition is triggered in not more than six hours from exposure and lasts for at least ten hours from the time perceived in absence of treatment.

3. The method of claim 1 in which the suffering condition is perceptible sensation of pain.

4. The method of claim 1 in which the suffering condition is elevated blood pressure.

5. The method of claim 1 in which the suffering condition is the common cold.

6. The method of claim 1 in which the suffering condition is acne.

7. The method of claim 3 in which perceptible sensation of pain is triggered within a period of thirty minutes and lasts for at least ten hours in the absence of treatment.

10

8. The method of claim 3 in which perceptible sensation of pain in a joint is triggered within a period of not more than ten days and lasts for at least one week in the absence of treatment.

9. The method of claim 4 in which a perceptible increase in blood pressure is triggered within a period of six hours and lasts for at least twenty-four hours in the absence of treatment.

20

10. The method of claim 5 in which a running nose is triggered within a period of thirty minutes and lasts for at least 6 hours in the absence of treatment.

11. The method of claim 6 in which there is triggered within a period of four hours appearance of at least two pimples on the face of the person and such pimples last for at least eight hours in the absence of treatment.

30 12. The method of claim 1 in which exposure to the trigger substance is by oral administration.

13. The method of claim 5 in which exposure to the trigger substance is by inhalation. O 97/15299 P

-49-

14. The method of claim 12 in which the trigger substance is selected from the group consisting of beer, wine, and diet beverage.

15. The method of claim 12 in which the trigger substance is salt or a meat product or a product increasing body cholesterol levels.

16. The method of claim 12 in which said trigger substance is a fatty food processed at a temperature at least 120°C.

17. The method of claim 12 in which said trigger substance comprises a prepackaged frozen meal.

18. The method of claim 13 in which said trigger substance comprises ammonia water.

19. The method of claim 1 in which the quantity of trigger substance is in the range from 50 grams to 500 grams.

20. The method of relieving a suffering condition in a person in need of such relief, comprising the administration to such person of a quantity of an agent determined to be effective by the method of claim 2.

21. The method of relieving a suffering condition of pain in a joint in a person in need of such relief, comprising the administration to such person of a quantity of an agent determined to be effective by the method of claim 8.

22. The method of claim 20 in which the agent is at least one nutrient compound having the formula X- (CH₂ ) _n-CH (0) _qH-CH-C00-

I

(NH₂+ ) _PH

in which X is selected from the group consisting of -SH, -

C0NH₂,

-NH₂, -NH-C=NH, -NH-C=0

NH₂ NH₂

and - C0-NH-CH-C0-NHCH₂C0-0H

CH₂SH, n is zero, one, or two, p is one and q is zero or one.

23. The method of claim 22 in which X is -SH and n is zero.

24. The method of claim 22 in which X is -CONH₂ and n is one.

25. The method of claim 22 in which X is -NH₂ and n is two.

26. The method of claim 22 in which X is -NH-C=NH

NH₂ and n is two.

27. The method of claim 22 in which X is - C0-NH-CH-C0-NHCH₂C0-0H

CH₂SH and n is one.

28. The method of claim 21 in which the agent is at least one nutrient compound having the formula X- (CH₂ ) _n-CH (0) _qH-CH-C00

(NH₂+) _PH

in which X is selected from the group consisting of -NH -NH-C=NH, -NH-C=0

NH₂ NH₂

and - C0-NH-CH-C0-NHCH₂C0-0H

CH₂SH, n is zero, one, or two, p is one and q is zero or one.

29. The method of claim 28 in which X is -NH2 and n is two.

30 The method of claim 28 in which X is -NH-C=NH

NH₂ and n is two.

31. The method of claim 28 in which X is - C0-NH-CH-C0-NHCH₂C0-0H

CH₂SH and n is one.

32. A palatable oral dosage form for relieving a suffering condition in a person in need of such relief comprising a carrier and a quantity of an agent determined to be effective by the method of claim 2.

33. A palatable oral dosage form according to claim 32 in which the agent is at least one nutrient compound having the formula X- ( CH₂ ) _n-CH ( O ) _L|H-CH-COO

(NH₂+ ) _PH

in which X is selected from the group consisting of -SH, -

CONH₂,

-NH₂, -NH-C=NH, -NH-C=0

NH₂ NH₂

and - CO-NH-CH-CO-NHCH2CO-OH

CH₂SH, n is zero, one, or two, p is one and q is zero or one.

34. A palatable oral dosage form according to claim 32 in which X is -SH and n is zero.

35. A palatable oral dosage form according to claim 32 in which X is C0NH and n is one.

36. A palatable oral dosage form according to claim 32 in which X is -NH₂ and n is two.

37. A palatable oral dosage form according to claim 32 in which X is

-NH-C=NH

NH₂ and n is two.

38. A palatable oral dosage form according to claim 32 in which X is

- CO-NH-CH-CO-NHCH₂CO-OH

CH_^SH and n is one.

39. A palatable oral dosage form for relieving a suffering condition in a person in need of such relief comprising a carrier and a quantity of an agent determined to be effective by the method of claim 8.

40. A palatable oral dosage form according to claim 39 in which the agent is at least one nutrient compound having the formula

X- (CH₂)_n-CH(0)_qH-CH-C00

(NH₂+)_PH

in which X is selected from the group consisting of -NH₂ -NH-C=NH, -NH-C=0

NH₂ NH₂

and - CO-NH-CH-CO-NHCH₂CO-OH

CH₂SH, n is zero, one, or two, p is one, and q is zero or one.

41. A palatable oral dosage form according to claim 40 in which the agent comprises a compound in which X is -NH₂ and n is two.

42. A palatable oral dosage form according to claim 40 in which the agent comprises a compound in which X is

-NH-C=NH

NH₂ and n is two,

43. A palatable oral dosage form according to claim 40 in which the agent comprises a compound in which X is

-CO-NH-CH-CO-NHCH₂CO-OH

I

CH₂SH and n is one.

44. A palatable oral dosage form according to claim 32 selected from the group consisting of a tablet, a gelatin

10 capsule, a soup, and a fruit flavored drink.

45. A palatable oral dosage form according to claim 32 in which the proportions of carrier to agent are in the range of 4:1 to 1:4.

46. A palatable oral dosage form according to claim 32, in which the carrier is at least one naturally occurring carbohydrate.

20 47. A palatable oral dosage form according to claim 46, in which the carrier comprises lactose, sucrose, fructose, starch, or cellulose.

48. A palatable oral dosage form according to claim 32, in which the carrier comprises at least one ingestible mineral substance.

49. A palatable oral dosage form according to claim 48, in which the carrier comprises an alkaline earth metal

30 carbonate or alkaline earth metal silicate.

50. A palatable oral dosage form according to claim 32, in which the carrier comprises at least one lipid.

51. A palatable oral dosage form according to claim 50, in which the carrier comprises lecithin or a fatty oil.

52. A palatable oral dosage form according to claim 32 in which the quantity of agent is in the range of 200 to 20000 milligrams.

53. A pleasant tasting oral dosage form according to claim 32, comprising an added flavorant.

54. A pleasant tasting oral dosage form according to claim 53, in which the flavorant is selected from the group consisting of herbs, spices, and essential oils.

55. A pleasant tasting oral dosage form according to claim 32 comprising at least one first nutrient compound having the formula

X- (CH₂)n-CH(0)_qH-CH-COO I

in which X is selected from the group consisting of -NH₂, and -NH-C=NH

NH₂

, n is two, p is one and q is zero,

and at least one second nutrient compound having the formula

X- (CH₂)n-CH(0)_qH-CH-C00

I

( H₂+)pH in which X is selected from the group consisting of -SH, - C0NH₂,

and - CO-NH-CH-CO-NHCH₂CO-OH

CH₂SH, n is zero or one, p is one and q is zero or one.

56. The composition of claim 55 in which the proportions of 10 first nutrient compound and second nutrient compound are in the range from 4:1 to 1:4.

57. A flavorant composition having a reduced tendency to produce a perceptible sensation of pain in a person susceptible to the pain-inducing tendency of monosodium glutamate, comprising monosodium glutamate and an agent determined to be effective in relieving pain by the method of claim 15.

20 58. A flavorant composition according to claim 57 in which the agent is at least one nutrient compound having the formula X- (CH₂)_n-CH(0)_qH-CH-COO-

in which X is selected from the group consisting of -SH, - CONH2,

-NH₂, -NH-C=NH, =NH-C=0 30 I I

NH₂ NH

and - C0-NH-CH-C0-NHCH₂C0-0H CH₂SH, n is zero, one, or two, p is one and q is zero or one.

59. The flavorant composition of claim 58 in which X is -SH and n is zero.

60. The flavorant composition of claim 58 in which X is - CONH₂ and n is one.

10 61. The flavorant composition of claim 58 in which X is -NH₂ and n is two.

62. The flavorant composition of claim 58 in which X is -NH-C=NH

NH₂ and n is two.

63. The flavorant composition of claim 58 in which X is -CO-NH-CH-CO-NHCH₂CO-OH 0 I

CH₂SH and n is one.

64. A sweetener composition having a reduced tendency to produce a perceptible sensation of headache in a person susceptible to the headache-inducing tendency of aspartame, comprising aspartame and an agent determined to be effective in relieving pain by the method of claim 1.

65. A sweetener composition according to claim 64 in which 0 the agent is at least one nutrient compound having the formula

X-(CH₂)n-CH(0)_qH-CH-C00-

(NH₂+)_PH -58- in which X is selected from the group consisting of -SH, -

C0NH₂,

-NH₂, -NH-C=NH, -NH-C=0

NH₂ NH₂

and - CO-NH-CH-CO-NHCH₂CO-OH

CH₂SH, n is zero, one, or two, p is one and q is zero or one.

66. The sweetener composition of claim 65 in which X is -SH and n is zero.

67. The sweetener composition of claim 65 in which X is - C0NH₂ and n is one.

68. The sweetener composition of claim 65 in which X is -NH₂ and n is two.

69. The sweetener composition of claim 65 in which X is -NH-C=NH

NH₂ and n is two.

70. The sweetener composition of claim 65 in which X is -CO-NH-CH-CO-NHCH2CO•OH

CH₂SH and n is one.