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Title:
TREATEMENT OF COLIC AND GUT SPASM IN HORSES AND OTHER VERTEBRATES
Document Type and Number:
WIPO Patent Application WO/2000/044240
Kind Code:
A1
Abstract:
The present invention presents pharmaceutical compositions and methods of use of those compositions to treat colic in horses and other vertebrates, including humans. In a preferred embodiment, a first composition, made with an anti-spasmodic (such as dicyclomine), an analgesic, an anti-inflammatory, and an anxiolytic (such as alprazolam), is administered via rectal suppository or other route. In addition, an intestinal smooth muscle relaxant, or a nitric oxide donor may be used in the composition. Alternatively, a second composition is made of an analgesic and an anxiolytic, and, optionally, one or more components selected from an anti-spasmodic, an anti-inflammatory, an intestinal smooth muscle relaxant, and a nitric oxide donor. In another preferred embodiment, administration of the first composition is followed by administration of a second composition that is a laxative. Typically, the laxative is administered from about 10 minutes to about 2 hours after administration of the first composition, and preferably is by oral administration. Alternate anti-spasmodics, analgesics, anti-inflammatories, and anxiolytics may be used beneficially as well. For non-spastic colics, the anti-spasmodic may be eliminated. The use of nitric oxide donors are particularly beneficial in necrotizing enterocolitis.

Inventors:
Russell, Meri Charmyne (217 SW 39th Street Des Moines, IA, 50312, US)
Application Number:
PCT/US2000/002010
Publication Date:
August 03, 2000
Filing Date:
January 28, 2000
Export Citation:
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Assignee:
Russell, Meri Charmyne (217 SW 39th Street Des Moines, IA, 50312, US)
International Classes:
A61K45/06; (IPC1-7): A23K1/18; A01N43/00
Attorney, Agent or Firm:
Villacorta, Gilberto M. (Pepper Hamilton LLP 600 Fourteenth Street, N.W. Washington, DC, 20005-2004, US)
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Claims:
Claims
1. A nontopical composition for the treatment of colic in vertebrates, comprising: an antispasmodic; an analgesic; an antiinflammatory; and an anxiolytic.
2. The composition for the treatment of colic of claim 1 further comprising an intestinal smooth muscle relaxant.
3. The composition for the treatment of colic of claim 1 further comprising a nitric oxide donor.
4. A nontopical composition for the treatment of colic in mammals, comprising: an anxiolytic; and an analgesic.
5. The composition for the treatment of colic according to claim 4 optionally further comprising at least one selected from the group comprising an antiinflammatory, an antispasmodic, an intestinal smooth muscle relaxant, and a nitric oxide donor.
6. A method for the treatment of colic in mammals, comprising: administration to a vertebrate suffering from colic a nontopical composition comprising: an antispasmodic; an analgesic; an antiinflammatory; and an anxiolytic; and administration of a laxative.
7. The method for the treatment of colic of claim 6 in which the laxative is a composition comprising: a salt composition; a bicarbonate; polyethylene glycol base B; and water.
8. The method for the treatment of colic of claim 7 in which the salt composition comprises: a sulfate; sodium chloride; and potassium chloride.
9. The method for the treatment of colic of claim 8 in which the sulfate is selected from the group consisting of disodium sulfate and dipotassium sulfate.
10. The method for the treatment of colic of claim 9 in which the sodium sulfate is anhydrous disodium sulfate.
11. The method for the treatment of colic of claim 7 in which the bicarbonate is selected from the group consisting of sodium bicarbonate and potassium bicarbonate.
12. The method for the treatment of colic of claim 6 in which the laxative is selected from the group consisting of castoroil, mineral oil, glycerine suppositories, bisacodyl, senna, phenolphthalein, saline laxatives, lactulose, magnesium sulfate, magnesium hydroxide, magnesium citrate, sodium phosphate, cascara, casantharanol, or docusate.
13. The method for the treatment of colic of claim 6 in which the laxative is administered subsequent to the administration of the colictreating composition.
14. The method for the treatment of colic of claim 13 in which the laxative is administered from about 10 minutes to about 2 hours subsequent to the administration of the colictreating composition.
Description:
TREATMENT OF COLIC AND GUT SPASM IN HORSES AND OTHER VERTEBRATES

1. Field of the Invention The present invention relates generally to methods to treat colic and gut spasms in vertebrates.

In particular, the present invention relates to pharmaceutical compositions and methods of use of those compositions to relieve both symptoms and deleterious effects of intestinal colic and/or gut spasms in horses and other vertebrates, including humans.

2. Background of the Invention Intestinal colic (often simply referred to as"colic") refers to spasm of the abdomen that results in pain, and is the number one killer of horses in the United States. Signs of intestinal colic in horses may include such actions as repeatedly lying down and getting up (or so attempting), rolling, lying on the back, and sitting in a dog-like position. Intestinal colic also is a frequent problem in human infants, and in infants and adults of other vertebrates.

At least four general categories of intestinal colic are recognized, based on symptoms and known or suspected etiology. 1.) In Intestinal Dysfunction colic (including"spasmodic"/"gas"/ "spastic"colic, and"non-spastic"or"impaction"colic), the most common category of colic, bowel function is not proper because of gas distention, spasms, paralysis, and/or impaction of fecal material.

2.) In Enteritis or Ulceration colic (including"nonstrangulating infarction,"also known as "thromboembolic"colic), symptoms result from inflammation, infection (bacterial or parasitic), and/or lesions. 3.) In Intestinal Accident colic, sections of intestine are trapped or pinched in body cavities or in tears in body cavity walls (hernias), and may also include displacements and torsions. Emergency surgery typically is required to treat Intestinal Accident colic. 4.) Necrotizing enterocolitis, which may be life threatening, is defined as idiopathic coagulation necrosis and inflammation of the intestines in a neonatal patient. It has a multifactorial etiology, which may involve any of the following factors: ischemia, reperfusion injury, bacterial translocation with release of toxins, and activation of inflammatory and immune responses. Also, the intestinal mucosal barrier may break down, thereby permitting translocation of bacteria into the abdomen to produce a highly dangerous condition.

Intestinal Dysfunction and Enteritis/Ulceration colics (which two forms often present overlapping symptoms) and necrotizing enterocolitis are the objects of treatment in the instant application.

One factor that contributes to the high mortality rate of horses with colic is difficulty in diagnosis due to its transient, ephemeral nature, whereby symptoms in a horse or other vertebrate often have greatly subsided or vanished entirely by the time the veterinarian arrives at the farm. In addition, the ephemeral nature of intestinal colic, combined with its unpredictable recurrence, not only has impeded research to determine the etiologies of each of the forms of intestinal colic in horses and other mammals, but also has impeded research to develop better treatment modalities therefor. Thus, when there is no clear etiology, guesswork often provides the basis for treatment, or nothing is done and symptoms often (but not always) subside with the passage of a little time. In instances with a known etiology, separate pharmaceuticals are used to treat each symptom/etiology, and such pharmaceutical protocols sometimes are combined with modification of diet, etc.

With infections, treatment thereof with the appropriate antibiotic (s) or antiparasitic (s) is indicated. As one example, the incidence of thromboembolic colic due to infection by the parasite Strongylus vulgaris has become relatively rare in horses due to the widespread use of ivermectin, a first-generation derivative of the avermectin family. This dewormer drug kills the migratory stage larvae of S. vulgaris, which is believed to be the cause of some forms of colic.

United States Patent No. 5,719,197, issued to Kanios, et al. on February 17,1998, teaches the use of multiple drugs in a topical bioadhesive formulation. The teachings of this patent include the use of antispasmodics, analgesics, anti-inflammatories, and sedatives in a single formulation; however, the use is restricted to their combination in a topical bioadhesive composition. There is no teaching for the combination of such drugs in a suppository or other formulation other than as a topical bioadhesive.

Furthermore, the disclosure of this invention is not directed to treatment of colic or gut spasms.

United States Patent No. 4,668,684, issued to Tibes. et al. on May 26,1987, discloses the use of flupirtin and butylscopolammonium salt to achieve an analgesic and spasmolytic synergistic effect in various laboratory animal models (guinea pig small intestine, mouse gall bladder, etc.). However, this combination of drugs has not been used to treat colic in vertebrates.

United States Patent No. 5,668,117, issued to Shapiro on September 16,1997, discloses the use of a carbonyl trapping agent in combination with any of various drugs to treat certain neurological diseases. Drugs that may be co-administered with a carbonyl trapping agent include anti-cholinergics, anti-depressants, tranquilizers, and non-steroidal inflammatories. Modes of administration disclosed include subcutaneous, intramuscular, oral, and intravenous. The disclosure of this invention is not directed to the treatment of colic or gut spasms, nor are analgesics per se used.

When colic is not clearly linked to an infectious agent (s), dietary factors may be controlled to decrease the incidence of colic. For example, in horses, the use of an abundance of good quality, long- stem hay that is free of heavy amounts of mold is known to reduce the incidence of colic. Similarly, avoidance of changes in diet (changes in the quantities and ratios of consumed hay, grain, etc.) and in feeding schedules and patterns has been correlated with a decreased incidence of colic. Providing a generous quantity of clean, fresh, cool water has also been recommended.

When a horse is in obvious pain, analgesic relief typically is provided, for example, by the use of xylazine and/or nonsteroidal anti-inflammatories (such as flunixin, meglumine, phenylbutazone, etc.). In addition, anti-spasmotic agents may be administered separately, such as dipyrone. With an infarct or infarct-like condition (e. g., thromboembolic colic), anticoagulant therapy may additionally be instituted, such as the use of heparin. In the case of impaction colic, mineral oil or surface active agents (such as docusate sodium) may be administered orally and separately.

Based on new knowledge regarding nitric oxide production and its role in maintaining"tonic vasodilation" (for example, see Elliott, Equine Vet. J. 28 (1): 1-2 (1996)), it further would be beneficial to provide a nitric oxide donor and/or stimulator (hereinafter"nitric oxide donor") as an additional aid to maintain blood perfusion and further promote relaxation of the intestines when colic presents.

As emphasized above, absent indications of etiology, guesswork often substitutes for definitive clinical data to direct or suggest a treatment modality. In addition, typically, multiple symptoms/conditions are evident in the horse or other vertebrate with colic, and each symptom or condition separately requires the administration of a pharmaceutical to treat that particular symptom or condition.

Therefore, it would be beneficial to provide a pharmaceutical treatment that, at a minimum, relieved a colic-afflicted horse or other vertebrate of pain and discomfort, and simultaneously provided relief from diarrhea and its deleterious effects of dehydration, acidosis, and even death. In addition, it would be beneficial to relieve colic-derived gastric spasms and pain regardless of the etiology. Even in cases in which the etiology were evident or otherwise discernible, it would be beneficial to provide a palliative that would"hold the animal over"until the benefits of the administered pharmaceutical or other"primary"treatment became effective. Furthermore, it would be beneficial to provide treatment for pain, spastic gut, and diarrhea in one simple, easily useable form. An additional, optional treatment agent that beneficially may be included in such formulations is compounds that promote relaxation of smooth muscles of the intestines. Finally, it would be beneficial to include a nitric oxide donor to produce vasodilation that promotes blood flow to further aid relaxation of the intestines and to counter necrosis that can result when intestines contract so strongly that blood flow is inhibited or even prevented all together in some areas.

3. Summary of the Invention Therefore, in view of the above referenced shortcomings in prior pharmaceutical formulations, it is an object of the present invention to provide an anti-colic pharmaceutical composition that is easy and simple to administer, preferably in one step.

It is another object of the present invention to provide an anti-colic pharmaceutical composition that simultaneously provides treatment for pain, spastic gut, diarrhea, inflammation of the gastrointestinal tract, and the anxiety that is provoked thereby.

It is yet another object of the present invention to provide a method of treating colic that utilizes a laxative subsequent to the administration of an anti-colic pharmaceutical composition, this method of used being especially beneficial in the treatment of impaction colics.

It is a further object of the present invention to provide a method of treating colic that optionally utilizes an intestinal smooth muscle relaxant to additionally relax the intestines.

It is a yet further object of the present invention to provide a method of treating colic that optionally utilizes a nitric oxide donor to increase blood flow to further promote relaxation of the intestines, including such use in the treatment of necrotizing enterocolitis.

It is an even further object of the present invention to provide a pharmaceutical composition that provides relief from one or more of the symptoms/etiologies of colic in horses and other vertebrates, including in humans.

The present invention provides several non-limiting examples of anti-colic pharmaceutical compositions, and methods of their use, in which a composition is administered in one step to treat symptoms and conditions that often occur in colic, namely, anxiety, gastrointestinal inflammation, pain, and gastric spasm, as well as the attendant diarrhea that produces acidosis and dehydration. In addition, in an alternative embodiment, a laxative may be administered in a second step, as is particularly useful in impaction colics. In yet another embodiment, a nitric oxide donor is included in the composition. Finally, in still another embodiment, an intestinal smooth muscle relaxant is a component of the composition.

4. Description of the Preferred Embodiments The anti-colic compositions, and methods of use of those compositions, of the present invention are designed to treat up to a full spectrum of the various constellations of symptoms and/or etiologies that tend to occur in Intestinal Dysfunction colics and/or in Enteritis or Ulceration colics and/or in necrotizing enterocolitis. Although all of the common potential symptoms may not occur in a given clinical episode of colic in a vertebrate, nonetheless, the full constellations of symptoms are sufficiently frequent to justify the full approach (i. e., multiple medicaments in a single formulation) of the present invention, including their methods of use. Thus, one of the major benefits of the present invention is the savings of time to the veterinarian, physician, or other clinician treating the horse or other vertebrate, including humans, with symptoms of colic. Another major benefit is that several common symptoms are efficiently treated simultaneously, possibly including treatment of symptoms for which no outwardly apparent need exists, but for which an actual (but unappreciated) need does exist. For example, it may not be clear that a given horse or other vertebrate is anxious over its condition, but, in fact, is in need of treatment therefor. Similarly, it may not be readily apparent that gastrointestinal inflammation is present in a given animal, or that another condition/symptom treated by the compositions and methods of the present invention is present and in need of treatment.

In its broadest embodiment, the present invention contemplates treatment of colic with a pharmaceutical composition that features the combination of an anti-spasmodic (possibly including an anti-cholinergic), an anti-inflammatory, an analgesic, an anxiolytic, and, optionally, 1) a nitric oxide donor, 2) an intestinal smooth muscle relaxant, or 3) both. In addition, various excipients may be added optionally, such as solid or liquid carriers, filles, activity enhancers, adherents, preservatives, absorption enhancers, glidants, emulsifiers, diluents, buffers, salts, sweeteners, gels, thickeners, starches, stabilizers, sustained release agents, sustained release enhancers, and suspending agents, to produce the final composition.

In narrower embodiments, the present invention contemplates treatment of colic with a pharmaceutical composition having fewer components, such as the combination of an analgesic, an anti-inflammatory, and an anxiolytic. Such a composition is particularly useful in treating colics that are non-spastic or impaction types of colic.

In another embodiment, the present invention contemplates treatment of colic with a pharmaceutical composition with only an analgesic and an anxiolytic; however, other embodiments additional comprise one or more of the group consisting of an anti-spasmodic, an anti-inflammatory, an intestinal smooth muscle relaxant, and a nitric oxide donor. Furthermore, embodiments are possible in which more than one constituent in each class is utilized, i. e., more than one analgesic, more than one

anxiolytic, more than one anti-spasmodic, more than one anti-inflammatory, more than one smooth muscle relaxant, and/or more than one nitric oxide donor.

For necrotizing enterocolitis, the use of a nitic oxide donor in the formulation is beneficial, such as nitroglycerine (fast-acting), erythrityl tetranitrate (fast-acting), isosorbide dinitrate (fast-acting), amyl nitrate (fast acting), and L-arginine (slow-acting) or D-arginine (possibly even slower-acting; possibly beneficial in only some vertebrates).

For impaction colics, the use of laxatives, emulsifiers, and/or lubricants as at least part of an additional step is beneficial, such as use of mineral oil, docusate, castoroil, lactulose, glycerin, bisacodyl, senna, phenolphthalein, saline laxatives, magnesium (such as the sulfate, the hydroxide, the citrate, etc.), sodium phosphate, cascara (especially as the sagrada), and/or casanthranol (A or B).

In some pharmaceutical compositions according to the present invention, a single compound may fill more than one of the required functions. For example, the pharmaceutical ketoprofen is both an analgesic and an anti-inflammatory, and thus may be used in conjunction with an anti-spasmodic and an anxiolytic in the broadest embodiment. As another example of dual function pharmaceuticals, dipyrone is both an analgesic and an anti-spasmotic.

Vertebrates that will benefit from the various embodiments of the instant invention include primates, mammals, reptiles, amphibians, fish, and birds.

The following examples are exemplary and non-limiting pharmaceutical compositions that embody the principles of the present invention. In particular, each pharmaceutical composition comprises a plurality of compounds that separately treat one (or more) of the symptoms and/or etiologies of colic as is frequently observed in horses and other vertebrates, including humans. In addition, a laxative may be use in conjunction therewith, especially in cases of impaction colics. Also, a nitric oxide donor and/or stimulator may be added, for example, nitroglycerine when a fast-acting formulation is desired, and L-arginine when a more slowly-acting formulation is desired.

5. Examples 5.1 Suppositories for Non-spastic or Impaction Colic (a) Alprazolam about 5 mg Ketoprofen about 0.5 g to about 1 g Silica about 0.16 g MBK Base about 13.3 g

The above ingredients are mixed, in any order, to homogeneity at a temperature above the melting point of the MBK Base (about 35-37 °C), i. e., about 37 to about 40°C. The mixture is then allowed to cool toward room temperature within a suppository mold, or molded by hand to a tapered, rod-like shape or other shape generally that of a suppository, including rounded edges to minimize cutting and trauma upon insertion and/or use.

(b) Alprazolam about 2.5 mg Ketoprofen about 0.5 g to about 1.0 g Silica about 0.16 g MBK Base about 13.3 g The above ingredients are mixed, in any order, to homogeneity at a temperature above the melting point of the MBK Base (about 35-37 °C), i. e., about 37 to about 40°C. The mixture is then allowed to cool toward room temperature within a suppository mold, or molded by hand to a tapered, rod-like shape or other shape generally that of a suppository, including rounded. edges to minimize cutting and trauma upon insertion and/or use.

5.2 Suppositories for Spastic or Gas Colic (a) Alprazolam about 5 mg Ketoprofen about 0.5 g to about 1 g Dicyclomine about 50 mg to about 100 mg Silica about 0.16 g MBK Base about 13.3 g The above ingredients are mixed, in any order, to homogeneity at a temperature above the melting point of the MBK Base (about 35-37 °C), i. e., about 37 to about 40°C. The mixture is then allowed to cool toward room temperature within a suppository mold, or molded by hand to a tapered, rod-like shape or other shape generally that of a suppository, including rounded edges to minimize cutting and trauma upon insertion and/or use.

(b) Alprazolam about 2.5 mg Ketoprofen about 0.5 g to about 1 g Dicyclomine about 50 mg to about 100 mg Silica about 0.16 g MBK Base about 13.3 g

The above ingredients are mixed, in any order, to homogeneity at a temperature above the melting point of the MBK Base (about 35-37 °C), i. e., about 37 to about 40°C. The mixture is then allowed to cool toward room temperature within a suppository mold, or molded by hand to a tapered, rod-like shape or other shape generally that of a suppository, including rounded edges to minimize cutting and trauma upon insertion and/or use.

5.3 Laxative PEG Base B about 1.18 kg Na Sulfate about 113.7 g Na Bicarbonate about 33.7 g NaCI about 29.3 g KC1 about 14.85 g The above dry ingredients are mixed to homogeneity. The resulting powder then is mixed with 1-3 gallons of water to form a laxative solution when administration is in order. Typically and preferably, the laxative solution is administered orally about 10 minutes to about 2 hours after administration of one of the above suppository compositions; however, rectal administration of such a laxative solution is also possible according to an alternative embodiment. In addition, the laxative may be administered orally after oral administration of an anti-colic pharmaceutical composition, provided that a proper intervening period is first allowed for absorption of the components of the anti-colic pharmaceutical composition. Typically, an intervening period from about half an hour to about 2 hours is sufficient. Potassium sulfate and potassium bicarbonate may optionally be employed, respectively, for the sodium sulfate and the sodium bicarbonate, optionally including adjustments in the quantities of NaCI and KCI to maintain comparable total values of sodium and potassium.

In addition to the above laxative solution, other formulations may be used, such as commercially available compositions made from or including castoroil, mineral oil, glycerine suppositories, bisacodyl, senna, phenolphthalein, saline laxatives, lactulose, magnesium (for example, the sulfate, the hydroxide, the citrate, etc.), sodium phosphate, cascara, casantharanol (A or B), or docusate (for example, sodium, potassium, or calcium forms).

5.4 Clinical Applications (a) Case #1 A 3 year old gelding presented classic symptoms of colic, including rolling, biting at the stomach, and few discernible intestinal sounds. He was in intense pain to the extent that the owner was considering euthanizing the animal. An intramuscular dose of banamine had no effect on the symptoms. A suppository made as described above in section 5.2 (a) was inserted into the rectum.

Within 20 minutes, the horse was calm. Then, a laxative solution according to section 5.3 was administered orally with a tube. Subsequently, a bowel movement released a blockage of fecal material. There were no recurrent symptoms over the next two weeks.

(b) Case #2 A 5 year old mare presented in a starved condition. The owner fed her regular hay, which produced symptoms of colic, including rolling and nosing at the belly. A suppository made as described above in section 5.2 (a), except with the deletion of dicyclomine, was inserted into the rectum. Within 20 minutes, the horse was calm and walking about normally with no symptoms.

Subsequent to feeding on a less rich hay, she had a normal bowel movement, and was symptom free thereafter.

5.5 Notes on Above Compositions The above suppository and laxative compositions represent formulations appropriate for horses and other large vertebrates. For adult horses and foals alike, the following approximate guidelines for administration should be followed. Alprazolam is used in treatment plans that deliver from about 3 to about 17 micrograms per kg of body weight, preferably from about 6 to about 11 micrograms per kg of body weight. Similar proportions apply to other large vertebrates. However, for smaller vertebrates, the above figures should be reduced by about 20 to about 60%.

Ketoprofen is used in treatment plans that deliver from about 0.4 to about 4 mg per kg of body weight of a horse or other large vertebrate, preferably from about 1 mg to about 2.2 mg per kg of body weight. With smaller vertebrates, these figures should be reduced by about 20 to about 60%.

Dicyclomine calculations are based on the use of the hydrochloride of dicyclomine.

Dicyclomine is used in treatment plans that deliver from about 0.02 mg to about 0.33 mg per kg of body weight of a horse or other large vertebrate, preferably from about 0.1 mg to about 0.22 mg per kg of body weight. With smaller vertebrates, these figures should be reduced by about 20 to about 60%.

MBK Base is a 10: 1 (w/v), homogeneous mixture of PEG 400 Distearate and Cottonseed Oil.

PEG 400 Distearate, also known as Poly (Ethylene Glycol-400) Distearate, is identified as CAS No.

9005-08-7. Cottonseed Oil is partially hydrogenated, has a maximum free fatty acid content of 0.05%, and has a maximum melting point of 73 °F.

PEG Base B is PEG 4600, also known as Carbowax 4600, and is identified as CAS No. 25322- 68-3.

Sodium Sulfate is the anhydrous salt, and also is known as Disodium Sulfate. It is identified as CAS No. 7757-82-6.

When additional ingredients are to be added to any of the above suppository formulations, a dosage of a) about 0.4 to about 50 mg of nitroglycerine (for example, about 3 mg in said suppositories) as a nitric oxide donor is added per 1000 pounds of large vertebrate, such as a horse; b) about 30 mg of L-arginine as a nitric oxide donor per 1000 pounds of large vertebrate, such as a horse; c) about 3 mg of atropine sulfate as an intestinal smooth muscle relaxant is added per 1000 pounds of large vertebrate, such as a horse; d) about 1.5 mg of belladonna alkaloids is added per 1000 pounds of large vertebrate, such as a horse; e) about 1.25 mg of L-hyoscyamine as an anti-spasmodic is added per 1000 pounds of large vertebrate, such as a horse; f) about 3.5 mg of scopolamine as an anti-spasmodic is added per 1000 pounds of large vertebrate, such as a horse; and the above additions are decreased by about 20% to about 60% in smaller vertebrates. Furthermore, the instant invention contemplates the use of nitric oxide donors in sustained release (also known as "timed release") forms.

Examples of smooth muscle relaxants include aminoglycosides, benzodiazepines, beta blockers, carbamazepine, lincosamides, corticosteriods, inhalation anesthetics, hydantoins, ketamine, lithium, loop diuretics, magnesium sulfate, nitrates, piperacillin, polypeptide antibiotics, quinine derivatives, ranitidine, theophyllines, thiazide diuretics, thiopurines, trimethaphan, verapamil, succinylcholine, carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, tizanidine, orphenadrine, baclofen, dantrolene, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Anti-spasmodics may include anti-cholinergics, anesthetics, dopaminergics, and anti- convulsants, such as dicyclomine, atropine, scopolamine, L-hyoscyamine, L-alkaloids of belladonna, alkaloids of belladonna, methscopolamine bromide, anisotropine methylbromide, clidinium bromide, glycopyrrolate, hexocyclium, isopropamide, mepenzolate bromide, methantheline bromide, propantheline bromide, tridihexethyl chloride, oxyphencycli-mine hydrochloride, procyclidine, trihexyphenidyl, benztropine, biperiden, ethopropazine, diphenylhydramine, thiopental, methohexital, pentothal, ketamine, etomidate, midazolam, propofol, droperidol, fentanyl combined with droperidol, atropine combined with meperidine, atropine combined with morphine, nitrous oxide, cyclopropane,

ethylene, halothane, methoxyflurane, enflurane, isoflurane, desflurane, sevoflurane, barbituates, hydantoins, succinimides, oxazolidinediones, benzodiazepines, lamotrigine, primidone, valproic acid, carbamazepine, phenacemide, felbamate, gabapentin, levodopa, carbidopa, amantadine, bromocriptine, pergolide, selegiline, dipyrone, oxyphencyclimine, dicyclomine, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Non-anticholinergic anti-spasmodics include dipyrone, oxyphencyclimine, dicyclomine, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Dopaminergics suitable as anti-spasmodics include levodopa, carbidopa, amantadine, bromocriptine, pergolide, selegiline, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anesthetics suitable for use as anti-spasmodics include thiopental, methohexital, pentothal, ketamine, etomidate, midazolam, propofol, droperidol, fentanyl combined with droperidol, atropine combined with meperidine, atropine combined with morphine, nitrous oxide, cyclopropane, ethylene, halothane, methoxyflurane, enflurane, isoflurane, desflurane, sevoflurane, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anti-convulsants suitable as anti-spasmodics include barbituates, hydantoins, succinimides, oxazolidinediones, benzodiazepines, lamotrigine, primidone, valproic acid, carbamazepine, phenacemide, felbamate, gabapentin, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of analgesics include steroids, barbituates, anesthetics, and nonsteroidal anti- inflammatories, such as xylazine, ketoprofen, acetylsalicylic acid, ibuprofen, acetaminophen, flunixin, meglumine, phenylbutazone, hydrocordone, diclofenac, anaprox, lodine, meclomin, nalfon, naprosin, ponstel, relafen, toradol, tolectin, phenobarbitol, mephobarbital, amobarbital, aprobarbital, butabarbital, secobarbital, pentobarbital, indocin, diclofenac, anaprox, lodine, meclomin, nalfon, naprosin, ponstel, relafen, toradol, tolectin, indocin, ibuprofen, hydrocortisone, cortisone, prednisone, prednisolone, triamcinolone, betamethasone, methylprednisolone, dexamethasone, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Barbituates suitable as analgesics include phenobarbitol, mephobarbital, amobarbital, aprobarbital, butabarbital, secobarbital, pentobarbital, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Steroids suitable as analgesics include hydrocortisone, cortisone, prednisone, prednisolone, triamcinolone, betamethasone, methylprednisolone, dexamethasone, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Anesthetics suitable as analgesics include thiopental, methohexital, pentothal, ketamine, etomidate, midazolam, propofol, droperidol, fentanyl combined with droperidol, atropine combined with meperidine, atropine combined with morphine, nitrous oxide, cyclopropane, ethylene, halothane, methoxyflurane, enflurane, isoflurane, desflurane, sevoflurane, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Nonsteroidal anti-inflammatories suitable as analgesics include diclofenac, anaprox, lodine, meclomin, nalfon, naprosin, ponstel, relafen, toradol, tolectin, indocin, ibuprofen, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anti-inflammatories include ketoprofen, steroids, and nonsteroidal anti- inflammatories, such as diclofenac, anaprox, Iodine, meclomin, nalfon, naprosin, ponstel, relafen, toradol, tolectin, indocin, ibuprofen, hydrocortisone, cortisone, prednisone, prednisolone, triamcinolone, betamethasone, methylprednisolone, dexamethasone, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of nonsteroidal anti-inflammatories suitable for use as anti-inflammatories include diclofenac, anaprox, lodine, meclomin, nalfon, naprosin, ponstel, relafen, toradol, tolectin, indocin, ibuprofen, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of steroids suitable for use as anti-inflammatories include hydrocortisone, cortisone, prednisone, prednisolone, triamcinolone, betamethasone, methylprednisolone, dexamethasone, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anxiolytics include sedatives, hypnotics, anti-depressants, benzodiazepines, barbituates, and anti-psychotics, such as alprazolam, benzodiazepines, acetylcarbromal, chloral hydrate, ethchlorvynol, glutethimide, methyprylon, paraldehyde, propiomazine, zolpidem, buspirone, meprobamate, hydroxyzine, doxepin, chlormezanone, tricyclicamines, maprotiline, trazodone, bupropion, venlafaxine, nefazodone, selective serotonin reuptake inhibitors, monoaminine oxidase inhibitors, alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, midazolam, estazolam, flurazepam, quazepam, temazepam, triazolam, phenothiazines, thioxanthenes, phenylbutylpiperadines, dihydroidolones, dibenzepines, dibenzoxazepines, benzisoxazoles, phenobarbital, mephobarbital, amobarbital, aprobarbital, butabarbital, secobarbital, pentobarbital,

phenothiazines, thioxanthenes, phenylbutylpiperadines, dihydroidolones, dibenzepines, dibenzoxazepines, benzisoxazoles, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anti-depressants suitable for use as anxiolytics include tricyclicamines, maprotiline, trazodone, bupropion, venlafaxine, nefazodone, selective serotonin reuptake inhibitors, monoaminine oxidase inhibitors, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Example of benzodiazepines suitable for use as anxiolytics include alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, midazolam, estazolam, flurazepam, quazepam, temazepam, triazolam, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of barbituates suitable for use as anxiolytics include phenobarbital, mephobarbital, amobarbital, aprobarbital, butabarbital, secobarbital, pentobarbital, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

Examples of anti-psychotics suitable for use as anxiolytics include phenothiazines, thioxanthenes, phenylbutylpiperadines, dihydroidolones, dibenzepines, dibenzoxazepines, benzisoxazoles, pharmaceutically effective salts thereof, and pharmaceutically effective derivatives thereof.

The examples provided above are intended to be non-limiting. Thus, as further non-limiting alternatives which do not depart from the spirit and scope of the present invention, the skilled practitioner can envisage pharmaceutical compositions that are tailored to a specific clinical case or a specific syndrome or other condition such that the analgesic, the anti-inflammatory, and the anxiolytic are included within a formulation, and the anti-spasmodic is omitted; alternatively, just the anti- inflammatory may be omitted. Similarly, the pharmaceutical compositions may be utilized with animals not specifically enumerated herein and yet remain within the scope of the present invention.