MXPA99001956A - Treatment of spasticity, convulsions by isovaleric acid derivatives cns depressants - Google Patents

Abstract

Preparations and extracts of valerian, as well as isovaleramide, isovaleric acid, and its pharmaceutically acceptable salts, esters, and substituted amides, exhibit clinically significant pharmacological properties which implicate a treatment for a variety of pathological conditions, including spasticity and convulsions, which are ameliorated by effecting a mild depression of CNS activity. The compositions in question generally are non-cytotoxic and do not elicit weakness or sedative activity at doses that are effective for the symptomatic treatment of such pathological conditions.

Description

TREATMENT OF SPASTICID DAD, CONVU LSION IS PO R OF CNS PRESSORS DERIVED FROM THE ISOVALERIC ACI BACKGROUND OF THE INVENTION The present invention relates to treating pathological conditions, such as spasticity and convulsions, the symptoms of which are alleviated by a mild depression of activity in the central nervous system (CNS), without producing undesirable excessive sedation. or muscle weakness in animal subjects, including humans. More particularly, the invention relates to the therapeutic use of isovaleramide, isovaleric acid, and related compounds in patients suffering from pathologies of this nature. Many agents currently employed in the treatment of pathologies such as spasticity and convulsions, show problematic lateral effect profiles, which limit their long-term clinical usefulness. For example, among these agents are benzodiazepines, which can cause cognitive numbness. Two other agents are valproate, which exhibits hepatotoxicity, and baclofen, which can produce excessive muscular weakness and sedation, limiting the therapeutic potential for both medications.

BRIEF DESCRIPTION OF THE INVENTION According to this, an objective of the present invention is to provide a therapeutic approach for the treatment of various pathologies by effecting a mild depression in CNS activity without producing excessive sedation, muscle weakness, fatigue or hepatotoxicity It is also an object of the present invention to provide a method for alleviating one or more symptoms associated with a condition, such as spasticity, which is improved by means of a centrally mediated decrease in muscle tone. Another objective of the present invention is to provide a novel anticonvulsant therapy. To achieve these and other objects, the use of a compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, has been provided according to one aspect of the present invention. , and a pharmaceutically acceptable amide of isovaleric acid in the preparation of a pharmaceutical formulation for use in a method for treating a pathology that is ameliorated by a mild depression of CNS activity, whereby at least one symptom of said disease is alleviated. pathology Thus, the present invention also contemplates a method of treatment comprising the step of administering, to a patient suffering from a pathology that is ameliorated by a mild depression of CNS activity, a therapeutically effective amount of a pharmaceutical formulation, It comprises a pharmaceutically acceptable carrier and a composition selected from the aforementioned group of agents. In accordance with one modality of the invention, the pathology treated is a disorder of affective mood, seizures, a central neuropathic pain syndrome, a headache, or a restlessness syndrome. For another modality, the pathology in question is improved by a centrally mediated decrease in muscle tone, and is illustrated by spasticity. According to another aspect of the present invention, there is provided the use of an extract of Valerianaceae, knotty bark, black viburnum, or hops in the preparation of a pharmaceutical formulation for use in a method for treating a spasticity symptom, wherein the extract it comprises at least one compound that is hydrolyzed in vivo to produce isovalent acid or isovaleramide. By the same sign, the present invention provides a method for alleviating a symptom of spasticity in a subject in need of such treatment, comprising the step of administering a therapeutically effective amount of an extract as described above. Other objectives, characteristics and advantages of the present will become evident from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating the preferred embodiments of the present invention, are given only by way of illustration, since various changes and modifications within the spirit and scope will become evident. of the invention for those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DIAMETERS Figure 1 shows the structures of several compounds, including isovaleramide. Figure 2 depicts the effect of isovaleramide (at 300 mg / kg, i.p.) on general observation spasticity records produced by a metal probe applied to the abdomen in the chronic spinalized rat. Each rat served as its own control; There were three rats per group. The bar at time zero represents the pre-treatment control values. Figure 3 illustrates a dose- and time-dependent reduction of the flexor muscle reflex, an electrophysiological measure of spasticity, in the chronic spinalized rat. The effects of isovaleramide (300, 600, and 1 200 mg / kg po), baclofen (10 mg / kg sc), and vehicle (water, 1.2 ml / kg po) are shown in pretreatment (time zero ) and 30, 60, 90 and 1 20 minutes of post-administration. At all doses, isovaleramide caused a significant decrease in the flexor muscle reflex magnitude, comparable to that observed with baciofen. Statistical significance was assessed by a one-way analysis of variance (ANOVA) and post-hoc Dunnett's t test: p < 0.05 (*); p < 0.01 (**); NS = not significant. Figure 4 shows that isovaleramide and baclofen, a known anti-spasticity agent, produced a similar reduction of the flexor muscle reflex in the chronic spinalized rat. The responses in Figure 3 were converted to a total area under the curve for the two-hour measurement. All groups related to the drug were significantly different from the vehicle (p <0.05, ANOVA).

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES 1 . REVIEW The inventors have discovered that isovaleric acid and its pharmaceutically acceptable salts, amides, such as isovaleramide, and alcohol esters, such as ethyl isovalerate and β-sitosterium isovalerate, can be administered in vivo to effect a mild depression of the activity of the CNS. That is, these agents depress CNS activity by centrally enhancing inhibitory neurotransmission (or decreasing the excitatory) without the complete suppression of all activity. According to the present invention, therefore, a subject receiving such an agent is not openly sedated, anesthetized or paralyzed in the context, for example, of decreasing attacks (not anesthesia), decreasing muscle tone (not paralysis), producing a calming effect (not sedation), or improving an outpatient syndrome such as spasticity (no weakness or flaccidity). A number of pathologies, exemplified by disorders of affective mood, headaches (chronic, concentrated, migraine), syndromes of neuropathic pain restlessness, movement disorders, spasticity and seizures, have at least one symptom that is alleviated by a depression soft of the CNS. Accordingly, an individual suffering from such pathology is a candidate for therapy which, in accordance with the present invention, causes the individual to receive a pharmaceutical formulation of isovaleramide, isovaleric acid or a related compound. It is believed that the compounds of the present invention act via a GABAergic mechanism and, hence, support a pharmacological similarity with known medicaments, which are considered to enhance central GABAergic neurotransmission. Like many of the existing drugs, such as barbiturates, benzodiazepines, gabapentin, valproate, vigabatrin, and progabide, the compounds of the present invention are effective in treating pathological conditions, illustrated by those mentioned above, which are believed to arise from a defect in the regulation of inhibitory neurotransmission (GABA- and / or glycine-related). This regulation can occur through a direct or modulating effect on the CNS receptors or through an impact on the metabolic pathway, which raises the levels of GABA or glycine and / or reduces the levels of an excitatory neurotransmitter such as glutamate. See Ruggero eí al. , in ANTI EPI LEPTIC DRUGS (4th ed.), pages 581 -88 (Raven Press 1 995); Nog Rady, MEDICI NAL CH EM ISTRY: A BIOCH EM I CAL APPROACH (2nd ed.), Pages 225-39 (Oxford University Press 1988); Fonnum and Morselli, respectively, in PSYCHOPHARMACOLOGY: THE THIRD GEN ERATI ON OF PROG RESS, pages 173-82 and 1 83-95 (Raven Press 1 987). However, despite a pharmacological analogy with the above-mentioned known medicaments, surprisingly, the present invention does not engender the disadvantageous side effects associated with conventional drug therapies in this area, such as, the hepatotoxicity that arises with the Valproate administration. 2. EXPLANATORY PATHOLOGIES M EXORPLED BY A SOFT DEPRESSION OF THE CNS ACTIVITY SPASTICITY: "Frequently spasticity is defined as a disorder of higher motor neurons [ie CNS] characterized by a speed-dependent increase in stretch reflexes. tonic (muscle tone) with exaggerated pulls of tendons that result from the hyperexcitability of the stretch reflex. " Lance, synopsis of symposiums at SPASTICITY - DISORDERED MOTOR CONTROL, Feldman et al. (eds.) (1 980). However, an increase in tonic stretch reflexes is only one of the many symptoms present in a disordered motor function caused by a lesion of superior neurons in a variety of neurological disorders; in this way, a disordered motor function is variable in its etiology and presentation. Conditions and conditions of major diseases associated with spasticity include multiple sclerosis, cerebral palsy, stroke, trauma or injury to the spinal cord, and closed head trauma. There are "positive symptoms" that can occur with spasticity, such as Babinski's response, painful flexor or extensor muscle spasms, exaggerated or increased deep tendon reflexes, and clonus. Other symptoms, referred to as "negative symptoms," include weakness, fatigue, lack of agility, and paralysis. The combination of these positive and negative signs and symptoms is clinically denoted as "spastic paresis" (spastic paralysis). Pain, deterioration of sleep, and various degrees of loss of general motor function are also associated with spasticity. The pathological states observed in spasticity are fundamentally different at the physiological level of commonly experienced acute muscle strains, relaxation and pain, which occur from an external attack localized to a particular muscle, that is, outside or peripheral to the CNS. These pathological states are also different from the relatively common involuntary spasms of smooth muscle, such as vascular spasms, bladder spasms, and bronchial spasms. Such non-spastic (not CNS), peripheral or localized symptoms are commonly treated with so-called "antispasmodic" or "spasmolytic" agents, but are generally not useful for treating spasticity. Cedarbaum & Schleifer, "Drugs for Parkinson's Disease, Spasticity and Acute Muscle Spasms," in GOODMAN AN D G I LMAN 'S TH E P HARMACOLOGICAL BAS I S OF THERAPEUTI CS, 8th ed. [hereinafter GOODMAN AND GI LMAN'S], pages 463-484 (Pergamon Press 1 990). The pharmaceutical formulations employed in accordance with the present invention can effect a centrally mediated decrease in muscle tone and, hence, are useful for the acute or chronic relief of one or more symptoms of spasticity. In this context, "spasticity" refers to an elevated tone of skeletal muscle which is manifested by symptoms, such as, (but not limited to) painful flexor muscle spasms or extenders, hyper-reflexes, loss of agility, muscle weakness, exaggerated tendon jerks, and clonus. The phrase "antispassticity agent" refers herein to a composition that is useful for the symptomatic treatment of spasticity, as demonstrated by the relief of at least one of the following manifestations of spasticity: painful spasms of the flexor or extensor muscle, reflexes of deep tendons exaggerated or increased, hyper-reflexia, loss of agility, muscle weakness, exaggerated tendon jerks, and clonus. Accordingly, the "relief" of spasticity refers here to the decrease of one or more symptoms of spasticity, including but not limited to painful flexor or extensor muscle spasms, exaggerated or increased deep tendon reflexes, hyper-reflexia , loss of agility, muscle weakness, exaggerated tendon pulls, and clonus. Spasticity is associated with multiple sclerosis, stroke, head trauma, spinal cord injuries, cerebral palsy, and other diseases, disorders, and neurodegenerative conditions. Spasticity is distinct from agonist muscle spasms, which may be associated with a variety of conditions different from those that lead to spasticity. These conditions that cause muscle spasm include trauma, inflammation, anxiety and / or pain. The difference between spasticity and acute muscle spasms is illustrated by the fact that agents useful for the treatment of muscle spasms are not useful for treating spasticity associated with chronic neurological diseases. Cedarbaum &; Schleifer (1990), supra. Likewise, the agents used hereinafter for treating spasticity associated with chronic neurological disorders have not been employed to treat acute muscle spasms, except for benzodiazepines, such as diazepam (Valium®), which are also recognized for having muscle-relaxing activity, as well as anxiolytic and analgesic properties. In contrast, the present invention achieves a centrally mediated decrease in muscle tone which, in turn, targets the particular symptoms of spasticity. CONVULSIVE DISORDERS: Due to the widespread availability of experimentally accessible and reasonably predictable animal models of convulsive states, a number of clinically useful anticonvulsants have been prepared and developed. For example, see Cereghino eí al. , "i ntroduction," in ANTI EPI LEPTI C DRUGS, 4th ed. , pages 1 -1 1 (Raven Press 1 995). "In many patients attacks with currently available antiepileptic drugs can be controlled, but 25 to 30 percent of patients continue to have attacks despite optimal therapy, while many others experience unacceptable side effects." Dichter went to. , Drug Therapy 334: 1 583 (1996). Thus, many anticonvulsants in clinical use are plagued by the occurrence of significant side effects, including annoying sedation during the day, muscle weakness, tolerance, gingival hyperplasia, blood dyscrasias, and potentially fatal hepatotoxicity. Many of these side effects are especially of concern in the clinical management (treatment) of epilepsy in children. The present invention can be used to treat seizure disorders, such as epilepsy. That is, the pharmaceutical compositions of the invention exhibit "anticonvulsant activity", which is evidenced by a reduction in the severity, number or duration of seizures in animal models of epilepsy. Accordingly, the inventive pharmaceutical compositions should be useful for treating conditions such as, but not limited to, simple partial seizures, complex partial seizures, epilepticus status, and trauma-induced seizures, as occur following surgery or injury of the patient. head. Epilepsy is a common disorder that has many causes, can be very difficult to control, often requires treatment for many years to keep the attacks under control. "At this time, there is no satisfactory treatment for epilepsy in a substantial proportion of patients Clinical trials have shown that certain patients have a better response to one drug than to another, even when patients have similar types of attacks and Medications have similar mechanisms of action.The frequency and severity of side effects also varies substantially.Thus, multiple medications with different mechanisms of action and concomitant side effects will be necessary for the treatment of epilepsy until, whether epilepsy can be cured or that a powerful new drug is discovered and developed, followed by extensive activity. " Dichter went to. (1996), supra. DISORDERS OF AFFECTIVE HUMOR: Under this heading are the conditions that vary from depression to dysphoric mania, that is, manía, schizoaffective disorder, aggression induced by traumatic brain injury, post-traumatic stress disorder, panic states, and syndromes. of behavior uncontrol. Affective mood disorders have been treated mainly prophylactically with lithium salts since the 1950s in Europe and since the 1970s in the United States. Emrich et al., J. Affective Disorders (: 243-50 (1985).) In recent years, alternatives for the treatment of lithium have been developed, given several problems with lithium therapy., newer, to the therapy of lithium for disorders of affective humor are therapies with anticonvulsants, such as, carbamazepina, benzod iazepinas, valpromida and valproato. Bernasconi eí al. , in ANTICONVU LSANTS I N AFFECTIVE DISORDERS, PAGES 14-32 (Excerpta Medica 1 984). Valproate has a lower propensity toward mental activity and the emergence of suppressed arousal, memory impairment, and cognitive numbness than what is seen with benzodiazepines. Despite the demonstrated efficacy of valproate in a multitude of affective disorders, the hepatoxicity, mutagenicity, and gastric disturbance observed with its administration draw the need for new therapeutic agents and treatments with profiles of improved side effects. A pharmaceutical formulation according to the present invention is effective for this purpose, especially with respect to the improved side effects. Notwithstanding any structural similarity perceived between, for example, valpromide and isovaleram ida (see Figure 1), a lack of side effects related to val proato is expected. which could otherwise decrease the effectiveness of the present invention to treat the range of affective mood disorders.

SYNDROMES OF CENTRAL NEUROPATHIC DOLOR SYNDROMES: The conditions in this category, involving "neuropathic pain", affect a significant number of patients suffering from disorders of the brain or spinal cord, such as stroke, trauma, multiple sclerosis, and diabetes. Casey, in PAI N AND CENTRAL N ERVOUS SYSTEM DISEASE (Raven 1 991). Many GABAergic compounds are effective in several relevant analgesia models to identify therapeutic candidates to treat a neuropathic pain. See Lloyd & Morselli, in PSYCHOPHARMACOLOGY: TH E TH I RD GENERATION OF PROGRESS (Raven Press 1 987). In a related vein, the use of anticonvulsants such as valproate to treat various pain states has been extensively documented. Swendlow, J. Clin. Neuropharmacol. 7: 51 -82 (1988). In this way, a pharmaceutical formulation of the present invention can be applied in a similar manner to improve neuropathic pain. HEADACHES: Migraine-type headaches (Hering &Kuritzky, Cephalalgia 1 2: 81-84 (1992)), the concentrated type (Hering &Kuritzky, loc. Cit., 9: 195-98 (1 989)) and the chronic type (Mathew &Sabiha, Headache 31: 71-74 (1 991)) have been treated by administering valproate. It is thought that the interactions with the GABAergic system play a greater role in the etiology of these headaches and in the associated valproate therapy. For this reason, the present invention can alleviate symptoms associated with each of the three types of headaches, without the adverse side effects of the proato therapy.

CONCERNED SYNDROME: The phrase "restlessness syndrome" denotes a somatic (non-mental) restlessness characterized by involuntary limb movement, as well as a sense of physical (rather than mental) agitation, which is independent of mood and , from there, it is distinguished from restlessness per se. See Sachdev eí al., Austral. New Zealand J. Psychiatry 30: 38-53 (1996). The kind of syndromes of concern, including numerous indications, can be observed in association with many psychiatric organic and non-organic diseases. For example, medication-induced restlessness (late, chronic, and withdrawal "akathiasis"), such as drug-induced extrapyramidal symptoms, is one of the most common side effects of neuroleptic drug therapy. Also within the title of the restlessness syndrome are the so-called "restless leg syndrome" and "periodic leg movements in relation to sleep", pathologies that can be associated with trauma of the head and / or spinal cord and with injuries of spinal cord. The idiopathic syndrome of the restless leg follows an autosomal dominant inheritance, with a variable clinical expression of symptoms. Decreased GABAergic neurotransmission is implicated in the neurochemical basis of restlessness syndromes. Consistent with this notion, for example, is the efficacy of benzodiazepines, baclofen, valproate and g abapentin in the treatment of restless leg syndrome, an important indication. See O'Keefe, Arch. Intern. Med. 1 56: 243-48 (1 996); Danek ef al. , in N EU ROLOG ICAL DI SORDERS: COU RSE AND TREATM E NT. pages 81 9-23 (Academic Press 1 996); Mellick & Mellick, Neurology 45 (suppl): 285-86 (1995). More generally, the present invention provides an effective therapy for distress syndromes with minimal side effects. MOVEMENT DISORDERS: Several GABAergic agents are known to decrease the dyskinetic movement that characterizes movement disorders, such as Parkinson's disease, Hungtington dance, tardive dyskinesia, and stiff man syndrome. This fact has highlighted a role for the central GABAergic function in the control and modulation of the movement and excitability of the CNS. Lloyd & Morselli (1987), supra. By the same sign, a therapy within the present invention can effect a reduced level of CNS activity, presumably via a GABAergic mechanism, to alleviate one or more symptoms of a movement disorder. 3. METHODS FOR PREPARING PHARMACEUTICAL FORMULATIONS The rhizomes and roots of Valeriana spp. (Common name: valeriana, family Valerianaceae) have been used for medicinal purposes since ancient times. The most commonly used valerian preparations include aqueous and hydroalcoholic extracts, such as medicinal solutions, intended for oral administration. In addition, medicinal solutions of valerian ammonia were used medicinally in the English-speaking world since at least the beginning of the 17th century. Hobbs, HerbalGram No. 21: 19-34 (1989). In the last three decades. the sedative and antispasmodic properties of valerian preparations have been attributed mainly to the presence of chemically labile monoterpenoid iridoid triester compounds called valepotriates [valerian-epoxy-triesters (-ates)] (valerian epoxies or its salts)]. The most common and abundant of the valepotriatos, valtrato and didrovaltrato, each contain two isovalerate portions esterified to a "central" iridoid nucleus. Lin ei al., Pharm. Res. 8: 1094-02 (1 991). However, these substances labile to acid and heat do not survive intact in the stomach following oral administration, easily releasing two moles of isovaleric acid for each mole of valepotriate. Additionally, aqueous extracts of rhizomes and valerian roots retain their biological properties, even when valepotriate triesters are insoluble in water. Bos eí al. , Phytochem. Anal. 1: .143-51 (1 996). The active principle, soluble in water, principal of commonly used valerian extracts and other preparations, such as extracts or aqueous or hydroalcoholic medicinal solutions, isovaleric acid. Isovaleramid a and ammonium isovalerate are produced in ammoniated medicinal solutions. Balandrin ef al., J. Toxicol.-Toxin Rev. 14: 165 (1995). The structures of isovaleramide and related compounds are shown in Figure 1 In this form, the chemically labile valepotriates and other valerian-derived monoterpenoid isovalerate esters, such as borrelil, lavandulyl and ethyl sovalerates, act as "prodrugs" and chemical precursors for isovaleric acid, its salts and isovaleram ida.

Isovaleramide has been isolated from valerian plants, most likely as an isolation device that follows treatment with ammonia. Buckova ef al. , Cesk. Farm. 26: 308 (1977); Chem. Abstr. 88: 860632 (1 978); see also Bos ef al., and Fuzzari ef al., Phytochem. Anal. 7: 143, 76 (1996). More recently, isovaleramide was shown to exhibit low acute toxicity in vivo, no mutagenic potential, and clinically useful anxiolytic properties. U.S. Patent No. 5,506,268; PCT application WO 94/28888. The methods for preparing isovaleramide are well known. The medicinal plant extracts that are useful for treating the symptoms of spasticity and convulsions can be prepared by aqueous, hydroalcoholic or alcoholic extraction, or by extraction with other suitable solvents using methods well known to those skilled in the art. In the context of the present invention, the useful extracts contain at least one of the following: isovaleric acid, its salts or complexes, ethyl isovalerate, isovaleramide, N-ethyl isovaleramide, and its chemical precursors. Useful extracts also share the common property of releasing isovaleric acid and / or sodium valerate on hydrolysis in vivo. Standard methods for preparing such extracts can be found in pre-1950 editions of the U.S. PHARMACOPOEIA (U. S. P.) and the NATIONAL FORMU LARY (N. F.), as well as in well-known references, such as Gennaro (Ed.), REMBY NGTON'S PHARMAC EUTICAL SCI ENCES, 1 8th ed. (Mack Publishing Co. 1 990), Tyler et al. , PHARMACOGNOSY, 9th ed. (Read and Febiger 1988), and Haré ef al. , TH E NATI ONAL STAN DARD DI SPENSATORY (Lea Brothers 1905). Additional citations appear in US Patent No. 5, 506,268 and PCT application WO 94 / 28,888. The main historical sources of isovaleric acid that occur naturally have been valerian rhizomes and roots, as well as those of closely related plants in the Valerianaceae family. As discussed by Hobbs (1989), supra, these include the common Valerian plant, Valeriana officinalis L., as well as the valerian from Eastern India, V. Wallichii DC. and the biblical tuberose, Nardostachys jatamansi (Roxb.) DC. In addition to valerian rhizomes and roots, other plants that have traditionally been used as sedative or "antispasmodic" herbal medicines are known to contain, or produce, isovaleric acid. These include hops (Humulus lupulus L., family Moraceae, which is frequently used in herbal formulations in combination with valerian), "knotty bark" or "mundillo" (Vibrium opulus L., family Caprifoliaceae), and "black viburnum" ( V. prunifolium L., root bark). I will ef el., THE NATIONAL STANDARD DISPENSATORY, pages 93, 94, 159, 160, 169, 256, 642, 692-694, 766, 767, 932, 1031, 1383, 1384, 1426, 1479, 1480, 1571, 1572 , 1619, 1620, 1631-1633, 1661, and 1662 (Lea Brothers 1905); Heyl ef al., J. Am. Chem. Soc. 42: 1744 (1929); Grier, Pharm. J. Pharm. 68: 302, 411-415, 744-746, 781, 782, and 824-830 (Hafner 1959); Holbert, J. Am. Pharm. Assoc., Sci. Ed. 35: 315 (1946); Hoffman, THE HERBAL HANDBOOK: A USER'S GUIDE TO MEDICAL HERBALISM, pages 38, 39. 83 and 84 (Healing Arts Press 1989). As in the case of rhizomes and valerian roots, the hops generate isovaleric acid from more chemically complex precursors on oxidation or enzymatic breakdown. Milsspaugh, AMERICAN MEDICINAL PLANTS, AN ILLUSTRATED AND DESCRIPTIVE GUIDE TO THE AMERICAN PLANTS USED AS HOMEOPATHIC REMEDIES, pages 622-626 (Dover 1974); I will make al., THE NATIONAL STANDARD DISPENSATORY, pages 766-767 (Lea Brothers 1905); Grier, Chem. Drug. (London) 110: 420 (1929); Grieve, A MODERN HERBAL, pages 411-415 (Hafner 1959); Stevens, Cehm. Rev. 67: 19 (1967); Duke, CRC HANDBOOK OF MEDICINAL HERBS, page 557 (CRC Press 1985). The pharmaceutically acceptable salts of organic acids, such as isovaleric acid, which have been approved by the U.S. Food and Drug Administration for commercialization include sodium, potassium, lithium, zinc, aluminum, calcium or magnesium salts. REMINGTON'S PHARMACEUTICAL SCIENCES, 18th ed., Page 1445 (Mack Publishing Co. 1990). Isovaleric acid salts that are commercially available in the United States include ammonium, sodium, potassium and zinc sovalerates. The pharmaceutically acceptable alcohols can form esters with isovaleric acid via the corresponding isovameric acid chloride and / or anhydride by methods that are well known in the art. See, for example, March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, AND STRUCTURE, 4th ed. (John Wiley and Sons 1992). Such alcohols contain at least a portion of phenol or hydroxyl, and are well tolerated in vivo. Examples of suitable alcohols include ethanol, certain carbohydrates and related compounds, such as glucose, fructose, sucrose, xylose and lactose, sugar alcohols, such as dulcitol, mannitol and sorbitol, sugar acids, such as gluconic and glucuronic acids, glycerol, the polyol inositol, benzyl alcohol, certain phenols, such as phenol, salicylic acid, saligenin, salicylamide, vanillin, p-hydroxycinnamic acid (p-coumaric acid), caffeic acid, ferulic acid, lactic acid, ellagic acid, quercetin and eugeni. Other examples of suitable alcohols include biogenic alkaloids and amines, such as ephedrine, pseudoephedrine, phenylpropanolamine, tyramine and dopamine, vitamins, such as ascorbic acid (vitamin C), thiamine (vitamin B 1), riboflavin (vitamin B2), pyridoxine (vitam ina B6), cyanocobalamin (vitamin B 1 2), tocopherols (vitamin E), choline, folic acid and pantothenic acid, monoterpenoid alcohols, such as geranium l, nerol, and linalool, triterpenoid alcohols that occur naturally, such as a- and ß-amyrins, lupeol, and oleanoolic and ursolic acids, bile acids, such as cholic acid, deoxycholic acid and taurocholic acid, and sterols from common plants that occur naturally (phytosterols), such as β-sitosterol, stigmaterol , campesterol and brasicasterol. Tyler ef al. , PHARMACOGNOSY, 9th ed. (Lea and Gebiger 1988). Other well tolerated hydroxyl and phenol containing compounds can be easily identified by those skilled in the art upon consulting standard reference works, such as THE M ERCK I NDEX and REM I NGTON 'S PHARMACEUTICAL SCI ENCES, 1 8a ED. (Mack Publish i ng Co. 1 990). The isovaleric acid esters which are commercially available in the United States include the bornyl, ethyl, n-butyl, isoamyl, and geranyl isovalerates.

Isovaleric acid, ammonium isovalerate, and esters isovalerate of ethyl, isoamyl isovalerate, 2-methylbutyl-2-valerate, cinnamyl isovalerate, methyl isovalerate, boron isovalerate, isobronyl isovalerate and menthyl isovalerate, among other esters of isovalerate, are listed in the Code of Federal Regulations by the FDA as acceptable flavoring agents, which can be used in foods. 21 CFR § 1 72.51 5 (1991). The rhizomes and roots of valerian (Valeriana officinalis L.) and bark of black viburnum (Viburnum prunifolium L.) are listed as acceptable natural flavoring substances and natural auxiliaries in 21 CFR § 1 72.51 0 (1 991). Hops and "lupulin" are listed among the substances that are generally considered to be safe ("GRAS"). 21 CFR § 1 82.20 (1991). Generally, esters of isovaleric acid are expected to be hydrolyzed in vivo by ubiquitous esterase enzymes, thereby releasing isovaleric acid and the alcohol or phenol constituent. Particularly preferred isovaleryte esters are mono-, di- and especially glyceryl tri-isovalerate ("triisovalerine"), salicylic acid or isovaleryl salicylate (salicylic acid isovalerate), ethyl sovalerate and ß-sovalerate. -Sitosteril. See Figure 1. Hydrolysis of these isovalerate esters in vivo releases isovaleric acid and glycerol (g licerin), salicylic acid (an analgesic, anti-inflammatory, and febrifuge), ethanol (common ethyl alcohol or "alcohol", a CNS depressant), and β-sitosterol (an innocuous phytosterol), respectively. With the exception of ethyl isovalerate, these esters are non-volatile or only slightly volatile. minimizing with it any unpleasant odor.

Additionally, in pure form these esters have the advantage of having pleasant odors, in contrast to the extremely unpleasant odors of isovaleric acid and its salts, such as the salts of isovalerate of ammonium, sodium, potassium and zinc. Moreover, while ethyl isvalerate is a liquid, it is expected that glyceryl mono-, di- and tri-isovalerates, isovaleryl salicylate and β-sitosteryl isovalerate will be solid at room temperature, thereby facilitating formulation in various liquid oral dosage forms and solid standards well known in the art, such as tablets (e.g., uncoated tablets, enteric-coated tablets, and film-coated tablets), capsules, gel capsules, powders, concentrates (drops), Ixires, medicinal solutions and syrups. In addition to isovaleramide, several substituted amides of the sovaleric acid can be prepared by methods well known in the art. See, for example, March, ADVANCED ORGANIC CHEM I STRY: REACTI ONS, MECHAN 1SMS, AND STRUCTU RE, 4th ed. (John Wiley and Sons 1 992). Preferred amides include? / - ethyl isovaleramide,? -methyl isovaleramide,? /,? / - dimethylvalerate,? / - methyl,? / - ethyl isovaleramide, N-isovaleryl GAB and? / - isovaleryl glycine. See, for example, Tanaka ef al., J. Biol. Chem. 242: 2966 (1967). It has recently been shown that N, N-diethyl isovaleram ida ("Valila"), although it supposes to possess CN S depressant activity (sedative), possesses CNS stimulating properties (convulsants); See U.S. Patent No. 5,506,268 and PCT application WO 94/28,888, supra. An isovaleric acid amide with p-aminophenol can also be prepared using standard methods to provide a compound, "isovaleraminophen", which is structurally related to the drug acetaminophen (Tylenol®, see Figure 1). In a manner analogous to that of the isovalerate esters, these substituted amides should be hydrolysed in vivo (in this case, via hepatic amide enzymes), releasing sodium valeramide or isovaleric acid. The compounds and preparations discussed above represent alternative ways to deliver sovaleric acid or isovaleramide in vivo. In certain cases, such as with isovaleryl salicylic acid and ethyl isovalerate, it could be expected that the pharmacologically active portion corresponding to the alcohol or phenol moiety exerts its own pharmacological effects. For example, compounds such as "isovaleraminophen" would be expected to exhibit a "Tylenol®-like" effect, as well as the expected effect of the isovaleric acid or isovaleramide portion. Such novel chemical combinations of a previously known primary or secondary pharmacologically active alcohol, phenol or amine with isovaleric acid fall within the scope of the present invention.

The pharmaceutical formulations of the present invention can be prepared according to known methods to prepare pharmaceutically useful compositions, whereby the active agents are combined in a mixture with a pharmaceutically acceptable carrier. For example, see REM I NGTON'S PHARMACEUTICAL SCI ENCES and GOODMAN AN D G I LMAN 'S, both cited above. A composition is said to be in a "pharmaceutically acceptable carrier" if its administration can be tolerated by a recipient patient. Sterile phosphate buffered saline is an example of a pharmaceutically acceptable carrier. Other suitable carriers (e.g., Ringer's and saline solutions) are well known to those skilled in the art. See, for example, REMI NGTON'S PHARMACEUTICAL SCI ENCES, supra. In general, the dosages of antispasmodic and anticonvulsant agents described herein will vary depending on factors such as age, weight, height, sex, general medical condition and prior medical history of the patient. For therapy purposes, a compound of the present invention and a pharmaceutically acceptable carrier are administered to a subject in need of such treatment in a therapeutically effective amount. It is said that the combination of active agent and carrier will be administered in a "therapeutically effective amount"., if the amount administered is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient. In the present context, for example, an antispasmodic agent is physiologically important, if the presence of the agent results in the improvement of spasticity, while the anticonvulsant agent is physiologically important, if the presence of the agent results in the reduction of severity, number or duration of seizures. Isovaleramide and related compounds can be administered orally using forms of solid oral dosages, such as enteric-coated tablets, caplets, gel capsules or capsules, or via oral dosage forms such as syrups or elixirs The indicated dose of isovaleramide and related compounds as antispasmodic agents is in the order of 1 00-1000 mg per day osis, and preferably, 300-600 mg per dose. The solid oral dosage forms per unit preferably contain about 200-350 mg per tablet or capsule, which would normally be taken 1 -2 at a time for a maximum of four times per day, at a dosage of 1-20. mg / kg of body weight. The liquid formulations can also be employed with active ingredient compositions, in order to provide 1-2 teaspoons per dose. Additionally, corresponding reduced dosage liquid and pediatric chewable oral dosage forms may also be administered. These compounds can also be added to foods and beverages in the form of drops (with a dropper of a "concentrated" preparation) for oral administration. In addition, compounds such as isovaleramide can be formulated in chewing gum to facilitate oral delivery and absorption. Alternatively, the isovaleramide and related compounds can be administered by injection or other systemic routes, such as transdermal or transmucosal administration, for example, nasally, buccally or rectally, via suppositories. However, oral administration is much more convenient, and therefore is preferred. For use in an oral anticonvulsant composition, the dosage level of active ingredient (s) is in the order of 1 000-1000 mg per dose, and preferably, 200-600 mg per dose or 1-20 mg / kg of body weight.

In addition to use in humans, isovaleramide and related compounds can be used, for example, as antispasmodic agents or anticonvulsant agents, in animals such as cats, dogs, birds, horses, cattle, mink, poultry and fish. In such cases, the active compound can be administered by injection or other systemic routes, such as transdermal or transmucosal administration (eg, rectal administration via suppositories), or orally by addition to the food or beverage. As an antispasmodic agent, the indicated oral dosage of isovaleramide and / or related compounds per kilogram of body weight of such animals is about 1-1000 mg / kg, depending on the species of animal and the route of administration. A preferred range for oral dosing is approximately 200-600 mg / kg body weight. The indicated oral dosage of isovaleramide and / or related compounds per kilogram of body weight as anticonvulsant agents for animals is in the range of about 1-1000 mg / kg, depending on the species of animal and the route of administration. A preferred range for oral dosing is approximately 100-600 mg / kg body weight. The present invention contemplates, in this manner, a variety of pharmaceutical compositions containing isovaleramide, isovaleric acid and / or its pharmaceutically acceptable salts, substituted amides and alcohol esters as active ingredients that are suitable for oral, parenteral, transdermal, transmucosal, intranasal, buccal or rectal. Although such compounds may be present as incidental by-products in certain pharmaceutical formulations, which are outside the scope of the present invention, the common feature of the present formulations is that isovaleramide, isovaleric acid and / or their pharmaceutically acceptable salts, amides, are present. substitutes and esters of alcohol, in a standardized amount. That is, the pharmaceutical formulations contain a predetermined, chemically defined and quantifiable amount of at least one such compound to allow determination of the amount of a particular composition required to achieve the dosage levels described herein. It is further understood that isovaleramide and / or related compounds can be used in combination with other pharmaceutically active ingredients. 4. DEMONSTRATION OF ACTIVITY INVOLVING THERAPY The stability and effectiveness of a given pharmaceutical formulation for the relief of a pathology, as discussed above, can be demonstrated using animal models such as (but not limited to) those described below. (a) The mutant spastic mouse The spastic mutant mouse is a homologous mouse that carries an autosomal recessive trait of genetic spasticity. The mouse is normal at birth, and then the mouse develops a gross tremor, abnormal walking, skeletal muscle rigidity and abnormal straightening reflexes at two to three weeks of age. No structural abnormality was found. Instead, the mouse has a deficit of glycine receptors throughout the central nervous system. Medicines that enhance either the binding or synthesis of GABA, such as valproate and benzodiazepines, are effective compounds to improve some of the symptoms of spasticity in this model, as well as in humans. The spatial assessment in the mutant spastic mouse can be performed by electrophysiological assessment similar to the EMG records described below. One can also, on a cruder scale, measure straightening. These mice have an abnormal delayed straightening reflex when they are placed on their backs. Any straightening reflex over a second is considered abnormal. Most normal mice can not even be placed on their backs. Tremor can be assessed by holding the mice by their tails and estimating tremor subjectively by "absent", "light", "moderate" or "severe". Flexibility is valued by placing the mouse on a glass lens with smoothly rounded edges and slots. The glass lens is raised approximately 30.48 centimeters on the table and slowly tilts until it is almost vertical. Normal mice would scale the target for a minute or more before falling to their feet. Spastic mice usually remain rigid in one position and soon fall on their backs. Chai et al., Proc. Soc. Exptl. Biol. Med. 109: 491 (1962). (b) The rat with spinally acute / chronic vertical cut and the acute brainless rat There are several models of spasticity including the acute brainless rat, and the rat with spinal cord injury chronically. The acute models, although of proven value to elucidate the mechanisms involved in the development of spasticity, have suffered criticism due to the fact that they are acute. Animals usually die or have total recovery from spasticity. The spasticity develops immediately upon the intervention, unlike the spasticity that develops in the human condition of spasticity, which very often manifests itself initially as a flaccid paralysis. Only after weeks and months does spasticity develop in humans. Some of the other models with spinal cross section or chronic injuries of spasticity show flaccid paralysis post-operatively. At approximately four weeks post-injury / cross section, the flacidex changed to spasticity of varying severity. Although all these models have their own particular disadvantages and lack of true representation of the human spastic condition, they have provided much information on the nature of spasticity. These models have also provided methods to test various treatment paradigms that have led to similar treatments being tested in humans. Many of these models have also made use of different species, such as cats, dogs, and primates. Baclofen, diazepam and tizanidine are effective in different spasticity parameters (EMG, H reflex, H / M ratio, mono- and polysynaptic reflexes, clonus, hyper-reflexia) in these models. (c) I rwin Primary Observation Test in the Rat This method is based on that described by Irwin, Psychopharmacologia á? k 1 3: 222-57 (1 968). It is used to detect the physiological, behavioral, and toxic effects of a test substance, and indicates a range of dosages that can be used for later experiments. Normally, the rats (three per group) are administered with the test substance and then observed in comparison with a control group to which the vehicle was administered. Behavioral modifications, symptoms of neurotoxicity, pupil diameter, and ^ P 10 rectal temperature are recorded according to a standardized observation grid derived from that of I rwin. The label contains the following items: mortality, sedation, excitement, aggression, tail Straub, contortions, convulsions, tremor, exophthalmos, salivation, lacrimation, piloerection, defecation, fear, traction, reactivity to touch, loss of reflexes of straightening, sleep, motor incoordination, muscle tone, stereotypies, snaking head, catalepsy, seizure, ptosis, breathing, corneal reflex, analgesia, abnormal walking, troddening of front legs, loss of balance, head shaking , rectal temperature, and diameter of pupils. The observations are performed at 1 5, 30, 60, 1 20 and 1 80 minutes following the administration of the test substance, and also 24 hours later. The test substance is usually administered intraperitoneally (i.p.). (d) Rotary bar test in the rat and the mouse This is a neurological deficit test using the method described by Dunham 'et al. , J. Am. Pharm. Assoc. 46: 208-09 (1957). The rats or mice are placed on a rod that rotates at a rate of eight turns per minute. The number of animals that fall from the bar is counted before three minutes and the fall times are recorded (maximum: 1 80 s). Ten rats were studied per group and the test is carried out blindly. The test compound is administered i. p. 60 min before the test. Diazepam, a benzodiazepine at 8 mg / kg, i.p. , as the reference substance. A control group to which the vehicle was administered was also included in the study. (E) Anti-convulsive activity There are numerous in vivo models that involve different kinds of attacks and behavioral effects that are relevant to the clinically distinct forms of epilepsy. Therefore, it is prudent to test effects in several models, because it can be an oversimplification to assume that the same mechanism serves as a foundation for all forms of attack activity. A useful model is provided by the mouse susceptible to audiogenic attack by Frings, a model of reflex epilepsy. At the time of testing, the individual mice are placed in a round Plexiglas bed and exposed to a sound of 1 1 0 decibels, 1 1 kHz, for 20 seconds. Animals that did not show extensions of tonic hind limbs were considered protected. In addition, the attack log for each mouse can be recorded as: (1) running for less than 1 0 sec undos; (2) running for more than 10 seconds; (3) clonic activity of limbs and / or vibrissae; (4) extension of front limbs / flexion of hind limbs; and (5) extension of hind limbs. The average attack record can be calculated for each group of mice used in the dose-response study. At each dose, the mice were also evaluated on a rotating bar to test motor deterioration (toxicity). The test for motor deterioration in the rotating bar involves placing a mouse during a three-minute test period on a bar with a diameter of 2.54 centimeters that rotates at six revolutions per minute. If the mouse falls off the rotary bar three times within the three minute time period, it is considered a toxic response. (f) Anti-manic activity To assess the possible use of the compounds in the treatment of affective mood disorders, one can employ the model of hyperactivity induced by amphetamine in rats. In addition to being a test for classic and atypical antipsychotic activity, this procedure has also been proposed as a simple animal model of manic behavior. Costall ef al., Brain Res. 123: 89-111 (1977). (g) Neurogenic Inflammation of the Meninges Neurogenic inflammation within the meninges has been proposed as a case in the implicit pathology of migraine headaches. The compounds are tested for their ability to block the leakage of radiolabeled bovine serum albumin within the stimulation of the post trigeminal dura mater. (h) Analgesic properties There are many trials in whole animals to determine analgesic properties, such as contortion, hot plate, tail flutter, arthritic pain, claw pressure tests, and Bennett or Chung models of neuropathic pain. Albe-Fessard I went to. , in 13 ADVANCES I N PAI N RESEARCH AND THERAPY, pages 1 1 -27 (Raven Press 1 990). (i) Therapeutic benefit in relation to movement disorders and restlessness syndromes There are animal models for the study of disorders of movement and syndromes of concern, for example, drug-induced akathiasias, serotonin syndrome, rotation induced by unilateral nigral lesions. Lloyd & amp; Morselli (1987), supra. Additionally, reports of individual cases of anecdotal efficacy of compounds in humans have been a source of support for these indications. Mellick & Mellick (1995), supra; Olson ef al., Am. J. Med. 1 02: 60-66 (1 997). ** ************* ******************* The therapeutic effects of isovaleramide, isovaleric acid and related compounds in several of the assays described above, combined with a general lack of toxicity, make the compounds of the present invention ideal agents for the treatment of the pathologies described above, including spasticity and seizures / attacks. With this support, the present invention will be more readily understood by reference to the following examples, which are provided for purposes of illustration and are not intended to be limiting of the invention.

Example 1 Use of a valerian preparation to relieve the symptoms of spasticity associated with multiple sclerosis A 42-year-old female human subject suffering from one or more symptoms of multiple sclerosis was experiencing a considerable amount of stress and was experiencing difficulty sleeping and delayed sleep attack at night. The dream that occurred was disturbed by stressful dreams and frequent awakenings. The subject also experienced frequent painful spasms of the extensor muscle during the night of the lower extremities that would frequently awaken the subject of his sleep. The next day, these painful spasms of the extensor muscle resulted in deep muscle pain (bruised sensation), with muscle / joint stiffness. The subject decided to consume a preparation of valerian that was noted for its auxiliary properties to sleep. The valerian product, "Baldriparan stark N", consists of tablets manufactured in Germany that contain extracts of valerian root, hops and lemon balm. Pressed coated tablets each contain 95 milligrams of a dry 70% (v / v) ethanol extract of valerian root, 1 5 milligrams of a dry 45% methanol extract (m / m) of hops, and 85 milligrams of a dry aqueous extract of lemon balm. Surprisingly, the preparation of valeri ana not only facilitated the sleep attack and improved the subject's quality of sleep, but it was also noted that painful spasms of the extensor muscle were relieved. The subject noticed that upon awakening during the night to use the bathroom, he did not experience the painful spasms of the extensor muscle when getting out of bed or the usual stiff leg sensation. The subject continues to consume the same valerian product for the relief of these symptoms on a basis as needed (prn or pro re nata) and continues to experience relief.

EXAMPLE 2 Use of a valerian preparation to relieve symptoms of spasticity associated with spinal cord injury A 38-year-old male human subject suffers from symptoms of spasticity (hyper-reflexia, tendon jerks and extensor muscle spasms) , which developed from a lesion anterior to the spinal cord. All these symptoms interrupt and diminish the quality of sleep experienced by this individual. By taking the same preparation of German valerian described in Example 1, the subject noticed a considerable improvement in the quality of sleep, as well as a significant reduction in spasms of the extensor muscle during the night. This subject continues to consume the preparation on a basis as needed (prn) for the relief of the symptoms described above.

Example 3 Isovaleramide antispassticity tests (1) Assessment of spasticity in rats with spinally chronic cross section In these studies, rats derived from Holtzman male albinas (Harían Sprague-Dawley Laboratories) weighing 270-530 g were used as rats. The animals were housed independently and had continuous access to food and water throughout the experiments. All procedures were reviewed and approved by the Institutional Animal Care and Use Committee. The animals were anesthetized using a mixture of isoflurane and oxygen at a flow rate of 4 liters / minute. The rats were then placed in a stereotaxic frame and anesthesia was maintained. An incision was made so that the paraspinal muscles could be retracted and a laminectomy was performed between T6-T9. A portion of one or two millimeters of the spinal cord was removed by evacuation and replaced with a Gel foam to reduce blood loss., after which the incision was closed in layers. Following the cross section, the rats were placed in a room in which the room temperature was raised to approximately 26.67 ° C with a space heater to maintain body temperature. The next morning after surgery, the hindquarters of spinalized rats were washed and their urine expressed manually by applying pressure to their vejigas. The experiments were conducted between 21 and 28 days after surgery. During the first two weeks, these rats were given 0.25 ml of the antibiotic Sulfatrim Pediatric Suspension orally to prevent bladder infection. A commercial antibiotic cream was applied to any part of the skin that showed signs of decubitus injury. Within about two weeks, all the animals regained control of the bladder and no further antibiotic treatment was given. Advokat, Brain Res. 684: 8 (1995). The spasticity assessment was done before and after the medication treatment, so that each animal served as its own control. The initial assessment of spasticity was performed by a subjective recording method of estimating the resulting spasticity response with a harmless stimulus, that is, a metal probe, which was pressed against the lower abdomen at four specific sites. The spastic reaction was evaluated for each of the four trials using a scale ranging from zero (no spastic response in the four trials) to four (a maximum of tonic-clonic reactions produced in the four trials). All records of spasticity, pre- and post-treatment, were transformed to indicate the percentage of spasticity, so that a register of 0/4 = 0%, 1/4 = 25%, etc. These raw or normalized records were analyzed with an ANOVA of one-way repetitive measurements. As shown in Figure 2, isovaleramide at a dose of 300 mg / kg, i. p, was effective at 1 5, 30, 60 and 120 minutes post-administration to reduce spasticity records (45-65% >;). By the next day, that is, at 1 440 minutes (24 hours), the spasticity records had essentially returned to the values of the baseline. No apparent motor deterioration or behavioral toxicity was observed at this dose. The rats were alert and able to grasp with their front claws not paralyzed as were the untreated, control rats. With reference to Figure 3, the polysynaptic flexor reflex responses, to test the stimuli which activate high threshold afferents, were recorded as EMG activity of the ipsilateral hamstring muscle. Supramaximal electric shocks were applied to the rear claw, and recording electrodes were placed on the semitendinous biceps femoris muscle. Five sets of stimuli were made at each time point. The reflex of the flexor muscle was recorded, both in the pre-medication and post-medication periods, every 30 minutes once a stable baseline response was achieved.

See Hao ef al., Eur. J. Pharmacol. 191: 407 (1990). In this way, the responses were determined in the spinalized rats by observing the reflex response of the flexor muscle (Figure 3) before the treatment and at each of 30, 60, 90 and 1 20 minutes following the administration of isovaleramide ( 300, 600 and 1200 mg / kg p.o.), baclofen (10 mg / kg sc) and vehicle (water, 12 ml / kg po), respectively. It was shown that isovaleramide at all doses reduces the magnitude of flexor muscle reflex responses, at all time points in a chronic spinalized rat, with spasticity. In this model, no change was observed in the H / M reflex either with baclofen or isovaleramide. In Figure 4, the responses in Figure 3 are converted to a total area format under the curve, covering the entire measurement period of two hours. All groups treated with medication differed significantly from the vehicle (p <0.05), based on a one-way analysis of variance. Among the groups treated with medication, no differences were found in the total reduction in reflux of the flexor muscle over the two-hour period (multiple comparison in pairs, Student-Newman-Keuls method). (2) Irwin's Primary Observation Test in Rat L isovaleramide, administered i .p. in the rat, no changes were induced in the controls injected in saline at doses up to 256 mg (kg A 51 2 mg / kg, slight sedation of 60 to 1 20 minutes was observed, loss of traction (observed only in one of three rats) at 1 20 minutes, and muscle tone decreased from 60 to 1 20 minutes, at 1024 mg / kg, marked sedation was observed up to 30 minutes, becoming moderate up to 1 20 minutes, then slight at 1 80 minutes. it was observed that the fear decreased at this dose up to 30 minutes and in one of three rats up to 120 minutes.The dose was also observed at that dose that touch reactivity decreased to 1 20 minutes, muscle tone decreased to 1 80 minutes, slight hypothermia up to 1 20 minutes and an abnormal walking (rolling) from 60 hours to 80 minutes.The loss of seizure and loss of righting reflex occurred, in one of three rats, at 1 5 minutes at this dose. (3) Rotation bar test in the rat and the Frings mouse Isovaleramide, administered at doses of 128, 256 and 512 mg / kg (ip) 60 minutes before a test in the rotation bar, did not significantly affect the performance in the rotation bar in the rat. See Table 1. In contrast, the performance in the rotation bar decreased in a dose-dependent manner of diazepam.

Table 1 Effects of isovaleramide and diazepam on the rat rod test in the rat Isovaleramide and diazepam were administered i.p. 60 minutes before the test of the rotary bar. b Ten rats per group. c Not significant according to the Student's t test. d p < 0.01 according to the Student's t test. e p < 0.05 according to Fisher's Exact Test. f p < 0.001 according to the Student's t test.

Isovaleramide, administered at doses up to 150 mg / kg (i.p.) 15 minutes before a test on the rotary bar in Frings' mouse, did not significantly affect performance. In contrast, doses of 300 mg / kg, 600 mg / kg, and 1000 mg / kg (ip) decreased the performance on the rotary bar by 1/8, 4/8, and 8/8 of the Frings mice tested, respectively.

Example 4 Anticonvulsant activity in the mouse model susceptible to Fringe audiogenic attack of epilepsy The results of Table 2 demonstrate the anticonvulsant activity of isovaleramide in this animal model of epilepsy. The isovaleram ida also showed a rapid attack and a relatively short duration of action. The anticonvulsant activity was noted as early as 5 minutes, but decreased substantially in two hours. Therefore, all quantitative studies were conducted at 15 minutes. At this point in time, the mean effective dose (ED50) for protection against tonic extension was 26 mg / kg, i. p. In addition, a dose-dependent network was observed in the attack log at this time point. At doses markedly greater than those that provide anticonvulsant activity (>300 mg / kg), the animals treated with isovaleramide showed behavioral toxicity that was characterized by their inability to maintain their balance in the rotary bar. No remarkable toxicity was observed at doses of less than 300 mg / kg. The mean toxic dose (TD50) for rotary bar deterioration was 531 mg / kg, i. p. In this way, the calculated protective index (TD5o / ED5o) was approximately 4.2. Consequently, despite the relatively low potency of isovaleramide in this model, it still showed a relatively good separation between activity and toxicity. Thus, isovaleramide had surprising and unexpected efficacy, based on the existing structure-activity relationships for amides and their corresponding acids, as an anticonvulsant in the mouse model susceptible to Fringe's aiogenic attack of reflex epilepsy. The activity profile of isovaleramide is similar to that of the broad spectrum anticonvulsant, sodium valproate. It has been shown in previous literature that similar compounds in structure valproate, as well as isovaleric acid, raise GABA levels throughout the CNS. This function is mainly attributed to the anticonvulsant activity of valproate, although other mechanisms have been suggested. On the other hand, it was found that isovaleric acid is inactive as an anticonvulsant, although it is reported that it produces a slight increase in GABA levels in the brains of mice. For example, see Lóscher ef al., Neuropharmacology 24-427 (1 985); Keane et al. , loe. cit. 22: 875 (1983); Keane et al. Pharmacol Res. Commun. 1 7: 547 (1 985).

Table 2 Effect of isovaleramide on the audiogenic attack susceptibility of Frings mice following intraperitoneal administration a Measured at 1 5 minutes. b 95% confidence interval.

In general, the historical literature on the structure-activity relationships of anticonvulsant activity on valproate-like compounds has been instructed away from simple, non-substituted compounds, such as sodiumvaleramide. In this way it is a surprising and unexpected observation that the sovaleramide has demonstrated an efficacy profile similar to that of valproate in the mouse model susceptible to Frings audiogenic attack and a similar separation of activity between efficacy and toxicity as measured by performance of rotary bar. These observations indicate that isovaleramide is an effective therapeutic agent as a broad spectrum anticonvulsant. Isovaleramide is known for its relative lack of toxicity in cytotoxicity and mutagenicity tests. See U.S. Patent No. 5,506,268 and PCT application WO 94/28, 888. On the other hand, valproate has long been noted for its profile that causes hepatotoxicity. For example, see Lóscher ef al., Neuropharmacology 24: 427 (1 985).

Although the above refers to particular preferred embodiments, it will be understood that the present invention is not limited in that way. It will occur to those of ordinary skill in the art that various modifications may be made to the described embodiments, and such modifications are intended to be within the scope of the present invention, which is defined by the claims below. All publications and patent applications mentioned in this specification are indicative of the level of skill of those in the art to which the invention pertains. All publications and patent applications are incorporated herein by reference to the same extent as if each individual patent application or publication were specifically and individually indicated to be incorporated by reference in its entire title.

Claims (9)

REVIVAL NAME IS

1 . The use of a compound selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of isovaleric acid, a pharmaceutically acceptable ester of isovaleric acid, and a pharmaceutically acceptable amide of isovaleric acid other than N, N-diethylisovaleramide, in the preparation of a pharmaceutical formulation for use in a method for treating a pathology selected from the group consisting of an affective mood disorder, seizures, a central neuropathic pain syndrome, a headache, a restlessness syndrome, and a pathology that it is improved by means of a centrally mediated decrease in muscle tone, by means of which at least one symptom of said pathology is alleviated.

2. A use according to claim 1, wherein said pathology is convulsions.

3. A use according to claim 1, wherein said pathology is a disorder of affective mood.

4. A use according to claim 1, wherein said pathology is a central neuropathic pain syndrome.

5. A use according to claim 1, wherein said pathology is a headache.

6. Use according to claim 1, wherein said pathology is a restlessness syndrome.

7. A use according to claim 1, wherein said pathology is improved by a centrally mediated decrease in muscle tone.

8. A use according to claim 7, wherein said pathology is spasticity.

9. A use according to any of claims 2-8, wherein said composition is isovaleramide. 1. A use according to any of claims 2-8, wherein said composition is a pharmaceutically acceptable ester of sodium sovaleric acid. eleven . The use of an extract of Valerianaceae, knotty bark, black viburnum or hops in the preparation of a pharmaceutical formulation for use in a method for treating a symptom of spasticity, wherein said extract comprises at least one compound that is hydrogenated in vivo to produce isovaleric acid. 2. A method of treatment comprising the step of administering to a patient suffering from a pathology selected from the group consisting of an affective mood disorder, convulsions, a central neuropathic pain syndrome, a headache, a restlessness syndrome, and a pathology that is improved by a centrally mediated decrease in muscle tone, a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a composition selected from the group consisting of isovaleric acid, a pharmaceutically acceptable salt of sovaleric acid i. a pharmaceutically acceptable ester of isovaleric acid, and a pharmaceutically acceptable amide of isovaleric acid other than? ,? / - diethylisovaleramide, by means of which at least one symptom of said pathology is improved. 3. A method for alleviating a symptom of spasticity in a subject in need of such treatment, comprising the step of administering a therapeutically effective amount of an extract of Valerianaceae, knotty bark, black viburnum or hops, wherein said extract comprises at least one compound that is hydrolyzed in vivo to produce isovaiomeric acid. 14. A use according to any of claims 2-8, wherein said composition is selected from the group consisting of N-ethyl-valerateramide, N-isovaleryl GABA, N-isovaleryl glycine and N- (4-hydroxyphenyl). isovaleramide. SUMMARY The valerian preparations and extracts, as well as isovaleramide, isovaleric acid and its pharmaceutically acceptable substituted salts, esters and amides, exhibit clinically significant pharmacological properties that involve treatment for a variety of pathological conditions, including spasticity and convulsions, which are lessened by effecting a Moderate depression of CNS activity. The compositions in question are generally non-cytotoxic and do not produce weakness or sedative activity in doses that are effective for the symptomatic treatment of said pathological conditions.