MXPA00011647A - The treatment of renal colic with gaba analogs - Google Patents

Abstract

The instant invention is a method of using certain analogs of glutamic acid and gamma-aminobutyric acid to relieve the pain associated with renal colic.

Description

TREATMENT OF RENAL CHLORINE WITH GABA ANALOGS BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the use of glutamic acid analogues and gamma-aminobutyric acid (GABA) for the treatment of renal colic. 2. Prior art GABA analogs are known agents useful for anticonvulsant therapies for central nervous system disorders such as epilepsy, Huntington's chorea, cerebral ischemia, parkinson's disease, tardive dyskinesia and spasticity. It has also been suggested that the compounds can be used as antidepressants, angiolytics, and antipsychotics. See WO 92/09560 (U.S. Patent Serial Number 618,692 filed November 27, 1990) and WP 93/23383 (U.S. Patent Serial Number 886,080 filed May 20, 1992). WO 97/33858 teaches that compounds related to gabapentin are useful for treating epilepsy, fainting fits, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. WO 97/33858 does not specify what forms of pain it treats.

Additionally, the compounds of the invention are known for the treatment of neuropathic pain. For example, see Rosner H; Rubin L; Kestenbaum A., Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain, 1996 Mar, 12: 1, 56-8; Segal AZ; Rordorf G., Gabapentin as a novel treatment for postherpetic neuralgia. Neurology, 1996 Apr, 46: 4, 1175-6; Wetzel CH; Connelly JF., Use of gabapentin in pain management. Ann Pharmacother, 1997 Sep, 31: 9, 1082-3; Zapp JJ., Postpoliomyelitis pain treated with gabapentin [letter]. Am Fam Physician, 1996 Jun, 53: 8, 2442, 2445; Cheville A, et al., Neuropathic pain in radiation myelopathy case report. Program book, American Pain Society (14th Annual Scientific Meeting). Abstract # 95823, p.A-115; Sist T; Filadora V; Miner M; Lemma M., Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology, 1997 May, 48: 5, 1467; Waldman SD, Tutorial 28: Evaluation and Treatment of Trigeminal Neuralgia. Pain Digest (1997) 7: 21-24; Mellick LB; Mellick GA., Successful treatment of reflex sympathetic dystrophy with gabapentin [letter]. Am J Emerg Med, 1995 Jan, 13: 1, 96; Mellick GA; Seng Ml. The use of gabapentin in the treatment or reflex sympathetic distrophy and a phobic disorder. Am J Pain Manage 1995; 5: 7-9; Mellick GA; Mellicy LB, Mellick LB., Gabapentin in the management or reflex sympathetic dystrophy [letter]. J Pain Sympton Manage, 1995 May, 10: 4, 265-6; Mellick GA; Mellick LB., Reflex sympathetic dystrophy treated with gabapentin. Arch Phys Med Rehabil, 1997 Jan, 78: 1, 98: 105 and Mackin GA., Medical and pharmacologic management of upper limb neuropathic pain syndromes. J Hand Ther, 1997 Apr-Jun, 10: 2, 96-109. Renal colic is commonly known as kidney stones. The passage of these crystalline fragments is so painful that proverbially it is known as the equivalent in men of "labor". The patients are in such agony, that very often they are taken to the emergency rooms of the hospitals for their treatment. Although not a threat of death, the pain is so crippling that patients are often supplied with narcotic medications. The person suffering from typical renal colic makes an initial visit to the hospital and is medicated with morphine i. m. or its equivalent for 48 hours after diagnosis. Then, the patient returns home taking oral narcotic analgesics and lithotripsy (ESWL) is performed weekly. Typically all fragments pass at home at two weeks. The intensity of pain is universally above all pain scales. According to Urinary Calculi: ESWL, Endourology, and Medical Therapy, James E. Lingeman, et al., 1994: 51-71, the incidence of kidney stones is 335,000 patients / years (ie, those who are admitted to the emergency room due to renal colic). According to the Merck Manual, approximately 1 in every 1,000 adults is hospitalized annually in the United States due to urinary stones (which equals approximately 200,000 per year). Approximately 80% of urinary stones or gallstones are composed of Ca, mainly calcium oxalate; 5% are uric acid; 2% cystine; and the rest, magnesium ammonium phosphate. All these calculations have a crystal structure, very often with sharp edges that look like small pieces of broken glass. Whether the stones pass through the urethra intact and spontaneously or in fragments after extracorporeal shock wave lithotripsy, typically extreme pain accompanies the passage through the urethra. This pain is often only partially relieved, even with the use of narcotic analgesics such as morphine.

BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for treating renal colic which comprises administering to a subject suffering from such pain an effective amount of a GABA analogue. A preferred embodiment uses an amino acid cyclic compound of Formula I wherein Ri is hydrogen or a lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof. An especially preferred embodiment using a compound of Formula I wherein Ri is hydrogen and n is 4, which compound is 1- (aminomethyl) -cyclohexane acetic acid, known generically as gabapentin. In another embodiment, the invention includes treating the pain of renal colic with a compound of Formula II. Formula ll R * II wherein R2 is a linear or branched alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R3 is hydrogen or methyl; and R 4 is hydrogen, methyl, or carboxyl; or an individual enantiomeric isomer thereof: or a pharmaceutically acceptable salt thereof, in a dosage unit form to a mammal in need of such treatment. Preferred compounds of the invention are those wherein R4 and R3 are hydrogen, and R2 is - (CH2) or - C4H9 as an isomer (R), (S), or (R, S). The most preferred compounds of the Formula II of the invention are (S) -3- (aminomethyl) -5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid, now known generically as pregabalin.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The method of this invention utilizes any GABA analog. A GABA analog is any compound derived or based on gamma-aminobutyric acid. The compounds are readily available, either commercially, or by a synthetic methodology well known to those skilled in the art of organic chemistry. The preferred GABA analogs to be used in the method of this invention are cyclic amino acids of Formula I. These are described in US Pat. No. 4,024,175, which is incorporated herein by reference. Another preferred method uses the GABA analogs of Formula II, and these are described in US Patent 5,563,175 which is incorporated herein by reference. All that is required to practice the method of this invention is to administer a GABA analog in an amount that is effective to treat the pain associated with renal colic. Such an anti-pain amount is generally given from about 1 to about 300 mg per kg of body weight of the subject. Typical doses are given from about 10 to about 5000 mg per day for an adult subject of normal weight. It is expected that the common doses that can be administered for renal colic can be 100 mg three times a day up to 600 mg four times a day. Commercially available capsules of 100 mg, 300 mg and 400 mg of gabapentin can be administered. Alternative forms include liquids and film-coated tablets. If a compound of Formula II, such as pregabalin, is used, the dose level is one sixth of that of gabapentin. The dose range for pregabalin is from about 0.15 mg to about 50 mg per kg of body weight per day. Typical doses for pregabalin will be from about 1.6 mg to about 840 mg per day with individual doses ranging from about 0.15 to about 65 mg per dose. The compounds of the present invention can form pharmaceutically acceptable salts with both organic and inorganic acids and with bases. For example, the acid addition salts of the basic compounds are prepared either by dissolving the free base in a solution of aqueous alcohol or aqueous solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution. Examples of the pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydrosulfates, etc., as well as the sodium, potassium, and magnesium salts. The compounds of Formula II may contain one or more asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixture thereof. The individual diastereomers or enantiomers can be prepared or isolated by methods known in the art.

The pharmaceutical compositions of the compound of the present invention or its salts are produced by formulating the active compound in a dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers that contain either one or a greater number of dose units and are capable of be subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as carboxymethylcellulose, ethylcellulose, methylcellulose, and cellulose phthalate acetate; jelly; talcum powder; stearic acid; magnesium stearate, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; propylene glycol, glycerin; sorbitol; polyethylene glycol; Water; agar; alginic acid; saline solution and phosphate buffers; as well as other compatible substances normally used in pharmaceutical formulations. These compositions of the invention may also contain other components such as coloring agents, flavoring agents, and / or preservatives. These materials, if present, are used in relatively small quantities. The compositions may, if desired, also contain other therapeutic agents. The percentage of active ingredients in the above compositions may vary widely, but for practical purposes preferably they are present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present. The routes of administration of the compound to the subject or its salts are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg and a useful oral dose is between 20 and 800 mg. The dose is within the dosage range used in the treatment of pain or as it would be with the needs of the patient as described by the doctor. A unit dose form of the GABA analog that is to be used in this invention may also comprise other compounds useful in the treatment of pain. These may include urinary analgesic, phenazopyridine, as well as systemic analgesic. The advantages of using the compounds of Formula I and II, especially gabapentin and pregabalin, in the present invention include the relatively non-toxic nature of the compounds, ease of preparation, the fact that the compounds are well tolerated, and ease of IV administration of the drugs. Gabapentin has few interactions with large classes of drugs since it is not metabolized in the liver, but is excreted without change of the body. In addition, drugs are not metabolized in the body. The subjects treated with the method of the present invention are mammals, including humans. Although not wishing to be bound by any theory, the present invention appears to work because GABA analogs have been proposed to work both peripherally and centrally to relieve pain and interact with a specific receptor in calcium channels. This interaction in calcium channels is of particular interest when considering its potential role in renal colic, since calcium channel blockers such as nifedipine have also been shown to relieve pain and promote the passage of kidney stones to through a vasodilator effect in the smooth muscle of the urethra. This action of GABA analogues, specifically gabapentin, is confirmed, in part, by a low documented incidence of peripheral edema and vasodilation. Thus, gabapentin may have a dual mechanism in the relief of acute renal colic through its interference with central and peripheral pain trajectories in addition to its potential to provide smooth muscle relaxation of the urethra. Based on this double possible mechanism, gabapentin provides superior pain relief for renal colic compared to existing analgesics.

Claims (9)

1. CLAIMS 1. A method for treating a mammal suffering from renal colic characterized in that it comprises administering to the mammal a pharmaceutical composition comprising an effective amount of a GABA analogue.
2. 2. The method according to claim 1, characterized in that the GABA analogue is the compound according to Formula I: H2N CHo C s CH COORI () "(CH2) n wherein Ri is hydrogen or a lower alkyl and n is an integer from 4 to 6, and pharmaceutically acceptable salts thereof.
3. 3. The method according to claim 2, characterized in that the Formula I comprises gabapentin.
4. 4. The method according to claim 2, characterized in that it comprises from about 10 mg to about 400 mg of Formula I.
5. 5. The method according to claim 3, characterized in that it comprises from about 10 mg to about 400 mg of Gabapentin
6. 6. The method according to claim 1, characterized in that the GABA analog is a compound according to Formula II: . II wherein R2 is a linear or branched alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl having from 3 to 6 carbon atoms; R3 is a hydrogen or methyl; and R4 is hydrogen, methyl, or carboxyl.
7. 7. The method according to claim 11, characterized in that Formula II comprises pregabalin. The method according to claim 11, characterized in that it comprises from about .15 mg to about 65 mg of Formula II. The method according to claim 12, characterized in that it comprises from about .15 mg to about 65 mg of pregabalin. SUMMARY The present invention is a method of using certain analogues of glutamic acid and gamma-aminobutyric acid to alleviate the pain associated with renal colic.