HK1068269A - Treatment of spasticity, convulsions by isovaleric acid derivatives cns depressants - Google Patents

Description

Application of isovaleric acid derivative CNS inhibitor in preparation of medicine for treating headache

This application is a divisional application filed 1997 at 29/8, with application number 97199257.6 entitled application of isovaleric acid derivative CNS inhibitor for the treatment of spasticity and convulsions.

Background

The present invention is concerned with the treatment of disease states such as spasticity and convulsions, which are alleviated by mild inhibition of Central Nervous System (CNS) function and which do not result in excessive sedation or muscle relaxation in animal subjects, including humans. More particularly, the invention relates to the therapeutic use of isovaleramide, isovaleric acid, and related compounds in patients with these disease states.

Many of the drugs currently used to treat disease states such as ankylosis and convulsions exhibit annoying side effects. This limits their long-term clinical use. For example, benzodiazepine  is one of them, which can cause cognitive impairment. Of the other two, 2-propylvalerate has hepatotoxicity and baclofen can cause excessive muscle relaxation and sedation. This limits their use in therapy.

Summary of The Invention

It is therefore an object of the present invention to provide a therapeutic approach that can mildly inhibit CNS function to treat a variety of disease states without excessive sedation, muscle relaxation, burnout or hepatotoxicity.

It is another object of the present invention to provide a method for alleviating one or more symptoms associated with a disease state, such as stiffness. The improvement in symptoms is due to a centrally mediated decrease in muscle tone.

It is a third object of the present invention to provide a novel anticonvulsant therapy.

To achieve the above and other objects, according to one aspect of the present invention, there is provided the use of a compound for the preparation of a pharmaceutical formulation for use in a method of treatment of a disease in which mild depression of CNS function is ameliorated, whereby at least one symptom of the disease is alleviated. The compound is selected from isovaleric acid, pharmaceutically acceptable salts of isovaleric acid, pharmaceutically acceptable esters of isovaleric acid, and pharmaceutically acceptable amides of isovaleric acid. Accordingly, the present invention also includes a method of treatment comprising the step of administering to a patient exhibiting a condition in which a mild depression of CNS function is ameliorated a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a composition selected from the group consisting of the foregoing.

According to one embodiment of the invention, the condition being treated is: an affective psychosis, convulsion, a central neuropathic pain syndrome, a headache or a restless syndrome (restlessness syndrome). For another embodiment, the condition under investigation may be improved by a central regulation that reduces muscle tone, exemplified by rigidity.

According to another aspect of the present invention, there is provided a use of an extract of patrinia plant, viburnum bark, black hawthorn, or hops for preparing a pharmaceutical preparation for use in a method of treating a symptom of stiffness, wherein the extract comprises at least one compound that hydrolyzes in vivo to form isovaleric acid or isovaleramide. Also provided is a method of alleviating tonic symptoms in a subject in need of such treatment. Comprising administering a therapeutically effective amount of an extract as described above.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Brief Description of Drawings

FIG. 1 depicts the structure of various compounds including isovaleramide.

FIG. 2 depicts the effect of isovaleramide (300mg/kg, i.p.) on the total score of stiffness observed, and a metal probe was used to prick the abdomen of chronic spinal-myelenized rats to induce stiffness. Each rat served as its own control; three rats per group. Bar graph at 0 represents the value of the control before treatment.

Figure 3. electrophysiological measurements of the rigidity of chronic myelogenous rats indicate a dose and time dependent decrease in the flexor reflex. The figure shows isovalerylThe effects of amine (300, 600, 1200mg/kg oral), baclofen (10mg/kg subcutaneous injection) and vehicle (water, 12ml/kg oral) before treatment (0 hours) and at 30, 60, 90 and 120 minutes after administration. Isovaleramide resulted in a significant reduction in the measurement of the flexor reflex compared to baclofen. The statistical significance of the differences was analyzed by one-way anova and post-hoc Dunnett's T test: p < 0.05: (^*)；P＜0.01(^**) (ii) a NS-difference is not significant.

Figure 4 shows that isovaleramide and a known anti-ankylosing drug, baclofen, cause similar reductions in flexor reflexes in chronically myelized rats. Here, the reaction values of fig. 3 are converted into the total area under the curve measured in two hours. The decrease in flexor reflex was significantly different in all the groups administered compared to the vehicle control group (P < 0.05, ANOVA)

Detailed description of the preferred embodiments

1. Overview

The inventors have discovered that isovaleric acid and its pharmaceutically acceptable salts, amines such as isovaleramide, alcohol esters such as ethyl isovalerate and beta-sitosteryl isovalerate, and the like can be administered in vivo to provide a mild depression of CNS function. That is, these drugs slightly inhibit CNS function by increasing inhibitory (or decreasing excitatory) central neurotransmitters, but do not completely inhibit all of their functions. Thus, according to the present invention, a subject receiving such a drug will not be completely sedated, anesthetized, or paralyzed, for example: reduced seizures (but not anesthetized), decreased muscle tone (but not paralysis), induction of sedation (but not sedation), or amelioration of a behavioral syndrome, such as rigidity (but not weakness or muscle relaxation).

At least one of a variety of pathological conditions such as affective psychosis, headache (chronic, cluster, migraine), hyperactivity syndrome, neuropathic pain, movement disorders, rigidity and convulsion can be alleviated by mild depression of the CNS. Thus, individuals suffering from such disorders are candidates for treatment in accordance with the present invention. The subject will be treated with a pharmaceutical formulation comprising isovaleramide, isovaleric acid, or a related compound.

It is believed that the compounds of the present invention function via the gabaergic mechanism. Thus, they have similar pharmacological properties to known drugs that potentiate central gabaergic neurotransmitters. Like many of the available drugs, such as barbital, benzodiazepine , gabapentin, 2-propylvalerate, vigabatrin, and haloperidol, the compounds of the present invention are effective in treating the above-mentioned pathological conditions, which are believed to occur in connection with deficiencies in the regulation of inhibitory neurotransmitters (GABA-related and/or glycine-related). This modulation may be a direct or indirect effect on CNS receptors, or an increase in GABA or glycine levels by affecting a metabolic pathway and/or a decrease in excitatory neurotransmitter glutamate levels. See Ruggero et al, ANTIEPILEPTIC DRUG (4 th edition), pages 581-88 (Raven Press 1995), nogardy, MEDICINAL CHEMISTRY: a BIOCHEMICAL APPROACH (2 nd edition), pp.225-39 (Oxford university Press, 1988); fonnum and Morselli, respecitvely, psychpharmacology: THE THE THIRD GENERATION OFPROGRESS, pages 173-82 and 183-95 (Raven Press 1987). Although the compounds of the present invention have similar pharmacological properties to those of the known drugs described above, it is surprising that the present invention does not have all of the side effects of the conventional drugs in the art, such as the hepatotoxicity that can occur when 2-propylvalerate is administered.

2. Typical disorders ameliorated by mild inhibition of CNS function

Tetanic: "rigidity is generally defined as an abnormality of an advanced (i.e., CNS) motor neuron characterized by a rate-dependent increase in the tonic stretch reflex (muscle tone) accompanied by hyperreflexia of the tendon due to sensitivity to the stretch reflex. "Lance, Symposia synopsis inSPASTICITY-DISORDERED MOTOR CONTROL, Feldman et al, (eds.) (1980). However, the tonic stretch reflex is but one of the many symptoms in motor dysfunction caused by higher-order neuronal damage in many neurological diseases, and therefore, such motor dysfunction varies with etiology and manifestation.

Many disease states are associated with spasticity, including multiple sclerosis, cerebral palsy, stroke, spinal cord trauma or injury, and closed brain trauma. "positive symptoms" that occur with rigidity are also: such as babinski reflex, painful flexor or extensor spasms, deep tendon reflex enhancement or hyperfunction, and clonus. There are also some "negative symptoms," including weakness, lassitude, lack of dexterity, and paralysis. These positive and negative signs and symptoms are collectively called "tingling paralysis" (tonic paresis) clinically. In addition, pain, impaired sleep and a variable loss of motor function in general are also associated with rigidity.

The pathological states manifested by rigidity are physiologically different from general acute muscle pain, strain injury and localized extrinsic injury resulting in a muscle sprain of a specific muscle, i.e. a muscle near or peripheral to the CNS. These pathological conditions are also different from the more common smooth muscle spasms, such as: vascular smooth muscle spasm, bladder smooth muscle spasm, bronchial smooth muscle spasm. These non-tonic (non-central nervous system), peripheral or local symptoms are usually treated with so-called "antispasmodics" or "spasmolytic" drugs, but these drugs generally do not work well for treating spasticity. "A medicament for THE treatment of Parkinson 'S disease, spasticity and acute muscle spasm" is described in Goodman AND GILMAN' S THE PHARMACOLOGICAL BASIS OFTHERAPEUTIC, 8 th edition. [ hereinafter referred to as GOODMAN AND GILMAN' S ], 463-484 pages (Pergamon Press (1990).

The pharmaceutical preparations employed according to the invention produce a centrally mediated reduction in muscle tone and can therefore be used for acute or chronic relief of one or more symptoms of rigidity. As used herein, "tonic" refers to an increase in skeletal muscle tone, which is manifested by, but not limited to, painful flexor or extensor spasms, deep tendon reflex enhancement or hyperactivity, hyperreflexia, loss of mobility, muscle weakness, tendon hyperreflexia, and clonus. The term "anti-ankylosing agent" as used herein refers to a composition useful for symptomatic treatment of spasticity, which has been shown to alleviate at least one of the following manifestations of ankylosis: painful flexor and extensor spasms, deep tendon reflex enhancement or hyperactivity, hyperreflexia, loss of mobility, muscle weakness, tendon hyperreflexia, and clonus. Accordingly, tonic "relief" herein refers to relief of one or more symptoms of rigidity, including but not limited to the following symptoms: painful flexor or extensor spasms, deep tendon reflex enhancement or hyperactivity, hyperreflexia, loss of mobility, muscle weakness, tendon hyperreflexia, and clonus.

Tetanic related diseases include: multiple sclerosis, stroke, brain trauma, spinal cord injury, cerebral palsy and other neurodegenerative diseases, abnormalities and conditions. Spasticity is distinct from acute muscle spasms, which may be associated with a variety of conditions other than the condition causing spasticity. Conditions that may cause acute muscle spasms include trauma, inflammation, anxiety, and/or pain.

Drugs that are effective in treating muscle spasms do not work in the treatment of spasticity associated with chronic neurological diseases (chronic neurological diseases). This fact also accounts for the difference between a strong direct and acute muscle spasm. Cedarbaum&Schleifer (1990), supra. Accordingly, the heretofore available treatments for stiffness associated with chronic neurological conditions have not been used to treat acute muscle spasms, except for benzodiazepine  -type drugs, such as diazepam (Valium)^) It is believed to have not only a muscle relaxant effect, but also anxiolytic and analgesic properties. In contrast, the present invention achieves a centrally mediated reduction in muscle tone, which in turn may be directed to certain symptoms of spasticity.

Convulsive disorders: since animal models of convulsions that can be reasonably predicted and used in experiments are readily available, a number of effective anticonvulsants have been developed and developed clinically. For example: see Cereghino et al, "Introduction" in ANTIEPILEPTIC DRUGS, 4 th edition, pages 1-11 (ravenPress 1995). "seizures in many patients can be controlled by currently available antiepileptic drugs, but despite the use of optimal therapy, 25-30% of patients continue to seize, while many other patients experience unacceptable side effects". Dichter et al, Drug Therapy 334: 1583(1996).

Thus, many clinically used antiepileptic drugs have significant side effects including troublesome daytime sedation, muscle weakness, drug resistance, gingival hyperplasia, blood cachexia, and potentially fatal hepatotoxicity. When the medicine is used for the clinical treatment of children epilepsy, the side effects need to be paid attention to.

The invention can be used for treating convulsive diseases, such as epilepsy. That is, such pharmaceutical compositions of the present invention exhibit "anticonvulsant function" as evidenced by a reduction in severity, number, duration of convulsions in animal models of epilepsy. Accordingly, the pharmaceutical compositions of the present invention should be used to treat, but are not limited to, the following conditions, such as: simple focal seizures, complex focal seizures, status epilepticus, and trauma-induced seizures, such as occur following head trauma and surgery.

Epilepsy is a common disease, with many causes and difficult to control. Many years of treatment are often required to control their onset. "there is currently no satisfactory treatment for a significant proportion of epileptic patients. Clinical trials show that: even if patients have similar types of seizures, the mechanisms of action of the drugs used are the same, some patients respond differently to the drugs, and the frequency and severity of side effects are substantially different. Therefore, when epilepsy cannot be cured or a novel medicine with wide function and safe function is not discovered and developed, a plurality of medicines with different action mechanisms and side effects still need to be used in the treatment of epilepsy. "Dichter et al. (1996), supra.

Emotional mood disorder (affective mood disorder): the state changes in this disease can range from depression to anxiety mania, i.e.: mania, schizophrenia (schizoaffectivedissorder), traumatic brain injury-induced aggression, post-traumatic stress disorder, panic state, and behavioral disorders. Emotional mood psychosis is treated primarily by prophylactic use of lithium salts since the fifties of this century in europe and seventies of this century in the united states. Emrich et al, j.affactive Disorders 8: 243-50(1985). In recent years, because of the problems associated with lithium therapy, alternatives to lithium therapy have been developed. Newer therapies for treating affective psychosis as a replacement for lithium are treatment with anticonvulsant drugs such as carbamazepine, benzodiazepine , valproate and 2-propylvalerate. Bernasconi et al, ANTICONVULASTANS IN AFFECTIVE DISORDERS, pp 14-32 (Excerpt Medica 1984). Compared to benzodiazepine , 2-propylvalerate is less likely to cause arousal suppression, mental activity suppression, memory impairment and cognitive dulling.

Although 2-propylvalerate has been shown to be effective in many affective disorders, it was found to be hepatotoxic, mutagenic and gastro-intestinal upset when administered, requiring the search for new therapeutic drug therapies with fewer side effects. A pharmaceutical formulation according to the invention meets this need well, especially with respect to the improvement of side effects. For example: although valproamide and isovaleramide (see FIG. 1) are structurally similar, it is not expected that the 2-propylvalerate-related side effects, which would reduce the efficacy of the present invention in treating affective disorders, would occur.

Central neuropathic pain syndromes, such conditions, including "neuropathic pain", affect a considerable number of patients with brain or spinal disorders, such as: stroke, trauma, multiple sclerosis, and diabetes. Casey, PAIN AND CENTRAL NERVOUS SYSTEM DISEASE (Raven 1991). Many gabaergic compounds are effective in a variety of sedation models that can be used to identify candidate therapeutics for neuropathic pain. See Lloyd & Morselli, PSYCHOPHARMACOLOGY: THE THE THIRD GENERATION OFPROGRESS (Raven Press 1987). It has been widely demonstrated that a variety of pain states are treated with anticonvulsants such as 2-propylvalerate in the relevant vein. Swenlow, j.clin.neuropharmacol.7: 51 to 82 (1984). Thus a pharmaceutical formulation of the invention may also be used in a similar manner to ameliorate neuropathic pain.

Headache: migraine headaches in Headache (Hering & Kuritzky, Cephalalgia 12: 81-84 (1992), cluster pain (Hering & Kuritzky, loc. cit.9: 195-98(1989)) and chronic pain (Mathew & Sabiha, Headache 31: 71-74(1991)) can be treated with 2-propylvalerate the interaction with the GABAergic system is believed to play a major role in the etiology of these headaches and the associated 2-propylvalerate treatment.

Hyperactive syndrome: the term "hyperkinetic syndrome" as used herein refers to a physical (non-psychogenic) restlessness characterized by involuntary movements of the limbs and a feeling of physical (rather than mental) agitation which is independent of mood and therefore distinguishable from hyperkinetic itself. See, Sachdev et al, Austral.New Zealand J.Psychiatry 30: 38-53(1996).

True hyperactivity syndrome comprises a myriad of indications and is associated with a number of organic and non-organic psychiatric disorders. For example: drug-induced hyperactivity (tardive, chronic, withawal akathisia), like drug-induced extrapyramidal symptoms, is one of the most common side effects of anti-epileptic therapy. So-called "restless legs syndrome" and "sleep-related periodic leg movements", pathological conditions which may be related to head and/or spinal cord trauma and spinal cord injuries are also included in restless legs syndrome. Spontaneous restless legs syndrome is one kind of autosomal dominant hereditary disease with variable clinical expression.

The neurochemical basis of hyperactivity syndrome may involve the disappearance of gabaergic neurotransmitters. Supporting this speculation is: benzodiazepine , baclofen, 2-propylvalerate and gabapentin are effective in the treatment of restless legs syndrome, an important indicator of restless legs syndrome. See O' keefe, arch.lntern.med.156: 243-48 (1996); danek et al, NEUROLOGICALDISORDER: COARSE AND TREATMENT, pages 819-23 (Academic Press 1996); mellick & Mellick, Neurology 45 (suppl): 285-86(1995). In summary, the present invention provides a therapy with minimal side effects and effective treatment of hyperkinetic syndrome.

Movement disorder: a number of gabaergic drugs are known to alleviate motor disorders characterized by dyskinesias, for example: parkinson's disease, Huntington's disease, tardive dyskinesia and stiff person syndrome. This fact highlights the role of GABA in the regulation of excitation and movement of the CNS. Lloyd & Morselli (1987), supra. Similarly, one treatment within the scope of the present invention may be to reduce the level of CNS activity via a GABAergic mechanism, thereby alleviating one or more symptoms of the motor disorder.

3. Method for producing pharmaceutical preparations

The roots and rhizomes of valerian (common name: valerian; Valerianaceae) have been used in medical treatment since ancient times. The most commonly used preparations of valerian include aqueous and hydrated alcoholic extracts such as: tincture for oral administration. Furthermore, the tincture of Valeriana officinalis has been used in medicine in the English family of countries as early as at least the beginning of the seventeen-seven century. (Hobbs, Herbal Gram 21: 19-34 (1989)). In recent thirty years, the sedative and anticonvulsant properties of valerian preparations have been attributed primarily to the presence of chemically labile iridoid triester compounds (valeriane epoxytriesters).

The most common of the most abundant valerian triesters are the pentetate (valrate) and the isovalerate (dihydrovalrate), each containing two isovaleric acid moieties esterified with a "central" cycloalkene ester terpene nucleus. Lin et al, Pharm, Res.8: 1094-02(1991). These substances, which are not acid and heat resistant, cannot remain intact after oral ingestion into the stomach, but rather release two molecules of isovaleric acid per molecule of valerian triester. In addition, the aqueous extract of valerian rhizome and root retains its biological properties despite the fact that the valerian triesters are water insoluble. Bos et al, phytochem. 143-51(1996).

Common valerian extracts and other preparations, such as: water or hydrated alcohol extracts or tinctures, the major water-soluble active ingredient of which was identified as the ester hydrolysate isovaleric acid. Ammonium isovalerate and isovaleramide were produced in ammoniacal tincture. Balandrin et al j.toxicol.toxin rev.14: 165, (1995) isovaleramide and related compounds are shown in figure 1. Thus, easily decomposable valerian triesters and other valerian-derived monoterpene isovalerate esters such as: borneol isovalerate, lavender isovalerate and ethyl isovalerate can be used as a precursor drug and a chemical precursor of isovaleric acid and salts thereof and isovaleramide.

Isovaleramide is isolated from valerian plants and is more likely an artifact isolated after ammonia treatment. Buckova et al, cesk.farm.26: 308 (1977); chem.abstr.88: 86063z (1978); bos et al and Fuzzati et al, phytochem.anal.7: 143, 76(1996). Isovaleramide has recently been shown to have low acute toxicity, no mutagenic potential, and clinically useful anxiolytic properties in vivo. U.S. Pat. nos. 5,506,268; PCT application WO94/28,888. Methods for the preparation of isovaleramide are well known.

The extract of the medicinal plant effective in treating spasticity and convulsion can be prepared by extracting with water, mixed water and ethanol, or extracting with other suitable solvent by a method known to those skilled in the art. In the present invention, the effective extract contains at least one of the following components: isovaleric acid, its salts or complexes, ethyl isovalerate, isovaleramide, N-ethyl isovaleramide, and chemical precursors thereof. All effective extracts share a common feature: isovaleric acid and/or isovaleramide may be released after hydrolysis in vivo. Standard methods for the preparation of this extract are described in u.s.pharmacopotia (u.s.p.)1950, natrion fomula (N.F), and well known references such as: gennaro (Ed.), REMINGTON' S PHARACEUTIC SCIENCE, 18 th edition. Mack publishing Co. (1990), Tyler et al, PHARMACOGNOSY, 9 th edition (Lea and Febiger1988), Hare et al, THE NATIONAL STANDARD DISPENSATORY (Leabrothers 1905). Additional references are found in U.S. Pat. No. 5,506,268 and PCT application WO94/28,888.

Historically, natural isovaleric acid has been derived primarily from the rhizome and root of valerian, as well as those plants that have a close relationship to the valerian family. As noted by Hobbs (1989, supra), it includes the common Valerianaceae plant, Valeriana fauriei, and Valeriana fauriei, V.Wallichi DC, and the Indian, Calycosin, mentioned in the Bidens, Bidens spongia. In addition to the rhizome and root of valerian plants, other herbs traditionally used as sedatives or "antispasmodics" are known to contain or are convertible to isovaleric acid. These traditional herbs include hops (lupulus, Moraceae, often used in combination with valerian in herbal preparations), "viburnum bark" or "hydrangea" (Europe hydrangea, Caprifoliaceae), and "black hawthorn" (viburnum prunifolium, root bark). Hare et al, THENTATIONAL 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 et al, j.am.chem.soc.42: 1744 (1920); grier, pharm.j.pharm.68: 302 (1929); grier, chem.drug, (London) 110: 420 (1929); grieve, AMODERN HERBAL, pages 35-40, 265-276, 381, 382, 411-415, 744-746, 781, 782, and 824-830(Hafner 1959); holbert, j.am.pharm.assoc, sci.ed.35: 315 (1946); hoffmann, THE He RBAL HANDBOOK: a USER' SGUIDE TO MEDICAL HEALBALISM, pages 38, 39, 83, and 84 (Healingarms Press 1989).

In those herbal preparations containing valerian roots and rhizomes, isovaleric acid is produced from precursors of hops, which are more complex in chemical structure, by oxidation or enzymatic hydrolysis. Millspaugh, AMERICAN MEDICINALPLANTS, AN ILLUSTRATED AND DESCRIPTIVE GUIDE TO THEAMERICAN PLANTS USED AS HOMOPATHIC REMEDIES, pages622-626(Dover 1974); hare et al, THE Nationol STANDARDDISPENSATORY, pages 766-767(Lea Brothers 1905); grier, chem.drug, (London) 110: 420 (1929); grieve, A MODERN HERBAL, pages 411-415(Hafner 1959); stevens, chem.rev.67: 19 (1967); duke, CRCHANDBOOK OF medical HERBS, page 557(CRC Press 1985).

Pharmaceutically acceptable organic acid salts, e.g., isovalerate salts, including its sodium, potassium, lithium, zinc, aluminum, calcium or magnesium salts, approved by the U.S. food and drug administration for commercial marketing. Remington pharmaceutical science, version 18, page 1445 (Mark Publishing Co. 1990). Isovalerate salts available on the us market include ammonium, sodium, potassium and zinc salts of isovalerate.

The pharmaceutically acceptable alcohol can be esterified with isovaleric acid, which is derived from the corresponding isovaleric acid chloride or isovaleric anhydride, using methods known in the art. For example, see March, advanced organic chemistry: reaction mechanisms and structures (John Wiley and Sons 1992) 4 th edition. Such alcohols contain at least one hydroxyl group or one phenolic moiety and are well tolerated in vivo. Alcohols suitable for use herein 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 acid and glucuronic acid, glycerol, polyalcohol inositol, benzyl alcohol, certain phenols such as phenol, salicylic acid, saligenin, salicylamide, vanillin, p-hydroxystyrene carboxylic acid (p-coumaric acid), caffeic acid, ferulic acid, gallic acid, ellagic acid, quercetone and eugenol. Other useful alcohols include alkaloids and biogenic amines, such as ephedrine, pseudoephedrine, methamphetamine hydrochloride, tyramine, dopamine, vitamins such as ascorbic acid (VitC), thiamine (VitB)₁) Riboflavin (VitB)₂) Pyridoxine (VitB)₆) Cobalamin (VitB)₁₂) Tocopherols (VitE), choline, folic acid and pantothenic acid, monoterpene alcohols such as geraniol, nerol and linalool, naturally occurring triterpene alcohols such as α -and β -amyrin, lupeol, oleanolic acid and ursolic acid, bile acids such as cholic acid, deoxycholic acid and taurocholic acid, and generally naturally occurring phytosterols (phytosterols) such as β -sitosterol, stigmasterol, campesterol, brassicasterol. Tyler et al, PHARMACOGNOSY, 9 th edition (Lea and Fabiger 1988). The identification of other compounds which are well tolerated by the body and which contain hydroxyl or phenolic groups, such as these, is readily accomplished by those skilled in the art by reference to commonly used references such as "MERCD index" and "Remington pharmaceutical sciences" version 18 (Mack Publishing Co. 1990). Can be traded in the United statesCommercially available isovalerate esters include bornyl, ethyl, n-butyl, isoamyl and geranyl isovalerate.

Isovaleric acid, ammonium isovalerate and esters thereof such as ethyl isovalerate, isoamyl isovalerate, 2-methylbutyl isovalerate, styryl isovalerate, methyl isovalerate, bornyl isovalerate, isobornyl isovalerate and menthyl isovalerate, and other isovalerate esters have been listed by FAD as useful flavorings for food products in Code of Federal Regulation 21 CFR 172.515 (1991). The rhizomes and roots of valerian (valerian carthami) and the bark of black hawthorn (viburnum prunifolium) are listed in 21 CFR § 172.510(1991) as useful natural flavorings and natural additives. Hops and "lupulin" are listed in generally recognized as safe ("GRAS") 21 CFR § 182.20 (1991).

In general, isovalerate is expected to hydrolyze in vivo by the action of ubiquitous esterases, releasing isovalerate and the alcohols or phenols that make up it. Particularly preferred among the isovalerate esters are isovalerate monoglycerides, diglycerides, especially isovalerate triglycerides ("trisisovalerin"), isovalerylsalicylate or salicylate (isovalerate salicylate), ethyl isovalerate and beta-sitosterol isovalerate. See fig. 1. In vivo, these isovaleric acid esters can be hydrolyzed to release isovaleric acid and glycerol, salicylic acid (an analgesic, anti-inflammatory, antipyretic), ethanol (ethanol or commonly called "alcohol", a central depressant), and beta-sitosterol (a harmless phytosterol), respectively. Except for the ethyl isovalerate, these esters are non-volatile or slightly volatile, thus reducing the unpleasant odor. Moreover, unlike the particularly unpleasant taste of isovaleric acid and its salts, such as ammonium, sodium, potassium and zinc salts, these esters are tasteless or odorous in the neat state. Furthermore, although ethyl isovalerate is liquid at room temperature, glycerol mono-, di-and triesters of isovalerate, isovalerylsalicylate, and beta-sitosterol isovalerate are all solid at room temperature. This allows them to be formulated into a variety of standard solid, liquid dosage forms known in the art, such as tablets (e.g., uncoated tablets, enteric-coated tablets, and film-coated tablets), capsules, gelcaps, powders, concentrates (drops), elixirs, tinctures, and syrups.

In addition to isovaleramide, a variety of substituted amides of isovaleric acid can be prepared by methods well known in the art. For example: see March, advanced organic chemistry: reactions, mechanisms and structures [ 4 th edition John Wiley and Sons 1992). Preferred amides include N-ethyl isovaleramide, N-methyl isovaleramide, N-dimethyl isovaleramide, N-methyl, N-ethyl isovaleramide, N-isovaleryl GABA, and N-isovaleryl glycine. For example Tanaka et al, journal of biology and chemistry, 242: 2966(1967). Although N, N-diethylisovaleramide ("Valyl") is said to have a central inhibitory effect (sedation), recent studies have shown it to be characterized by a central excitation (convulsion-causing) as described in the aforementioned U.S. Pat. No. 5,506,268 and PCT application WO94/28,888. An amide of isovaleric acid and p-aminophenol can also be prepared by standard methods, and this compound, called "isovalerylaminophenol", is structurally related to the drug acetaminophen (Tylenol)^(ii) a See fig. 1) are similar. Like isovalerate, these substituted amides also undergo hydrolysis in vivo (referred to herein as hepatic amidase) to release isovaleramide or isovalerate.

The compounds or formulations discussed above represent alternative delivery forms of isovaleric acid or isovaleramide in vivo. In some instances, such as isovalerylsalicylate and ethyl isovalerate, the pharmacologically active moiety corresponding to the alcohol or phenol is expected to exert its own pharmacological effect. For example: compounds of the class of "isovalerylaminophenols" may exhibit the expected effect of "Tylenol" in addition to isovaleric acid or isovaleramide moieties^The effect is similar. Novel chemical combinations of alcohols, phenols or primary, secondary amines and isovaleric acid known to have pharmacological activity as such are also included within the scope of the present invention.

The pharmaceutical preparations of the invention can be prepared by known methods to give pharmaceutical compositions, whereby the active ingredient is mixed in a mixture with a pharmaceutically acceptable carrier. For example: see, e.g., Lemington's pharmaceutical sciences, and GOODMAN AND GILMAN, supra. A composition is said to be in a "pharmaceutically acceptable carrier" provided that the patient receiving the drug is resistant to the use of the carrier. Sterile phosphate buffered saline is an example of such a pharmaceutically acceptable carrier. Other suitable carriers (e.g., saline solution and ringer's solution) are well known to those skilled in the art. See, for example, Remington pharmaceutical sciences, cited above.

In general, the dosages of the antiferronic and anticonvulsant agents described herein will vary depending upon factors such as the age, weight, height, sex, general condition of the patient and their previous medical history. When used for therapeutic purposes, the compounds of the present invention and a pharmaceutically acceptable carrier are administered in a therapeutically effective amount to a subject in need of such treatment. The combination of the above active ingredients and carrier is considered to be administered in a therapeutically effective amount if the dosage used is physiologically significant. A drug is physiologically significant if its presence results in a detectable physiological change in the patient receiving the drug. In the present invention, for example, an anti-ankylosing agent is physiologically significant when its presence results in tonic remission. An anticonvulsant is also physiologically significant if its presence results in a reduction in the severity, number or duration of convulsions.

Isovaleramide and related compounds may be administered orally using solid oral dosage forms such as enteric tablets, caplets, gelcaps or capsules or liquid oral dosage forms such as syrups or elixirs. When used as an anti-ankylosing agent, the labeled dose of isovaleramide and related compounds should be in the range of 1000mg per dose, preferably 600mg per dose, of 300-. A preferred unit solid oral dosage form contains about 200-350mg per tablet or capsule, typically in an amount of 1-20mg/kg body weight, 1-2 tablets at a time, up to 4 times a day. The active ingredient composition may also be in the form of a liquid preparation, such that 1-2 spoons are administered per dose. Also, correspondingly reduced doses of chewable tablets for paediatric use and liquid oral dosage forms may be used. These compounds can also be added to food or beverages in the form of drops for oral administration (the drops are derived from concentrated preparations). In addition, compounds like isovaleramide may be added to chewing gum to facilitate oral transport and absorption.

Alternatively, isovaleramide and related compounds may be administered by injection or other systemic routes, for example transdermally or transmucosally, for example nasally, buccally or rectally by suppository. Oral administration is however more convenient and is therefore preferred.

In the case of oral administration of the anticonvulsant composition, the dosage level of the active ingredient is in the range of 100-1000mg per dose, preferably 200-600mg per dose or 1-20mg/kg body weight.

In addition to being useful in humans, isovaleramide and related compounds may also be useful as an anticonvulsant or an anticonvulsant in animals such as cats, dogs, birds, horses, cattle, ferrets, poultry, and fish. In these embodiments of use the active compounds can be administered by injection or other systemic routes, such as transdermal or transmucosal administration (e.g., rectal administration via suppositories), or orally, by addition to food or beverages. The indicated dose of isovaleramide and/or related compounds as an anti-ankylosing agent for these animals is about 1-1000mg/kg body weight, depending on the route of administration of the animal species. The preferred oral dosage is about 200-600mg/kg body weight.

When isovaleramide and/or related compounds are used as anticonvulsants in animals, the indicated oral dosage per kilogram of body weight is in the range of about 1-1000mg/kg, depending on the animal species and route of administration. The preferred oral dosage range is about 100-600mg/kg body weight.

The present invention thus encompasses a number of pharmaceutical compositions comprising isovaleramide, isovaleric acid and/or its pharmaceutically acceptable salts, substituted amides and alcohol esters as active ingredients suitable for oral, parenteral, transdermal, transmucosal: the medicine is administered in nasal cavity, oral cavity and rectum. Although these compounds may be concomitant by-products of certain pharmaceutical formulations outside the scope of the present invention, a common feature of these formulations is that isovaleramide, isovaleric acid, and/or pharmaceutically acceptable salts, substituted amides, and alcohol esters thereof are present in a standardized dosage. That is, these pharmaceutical preparations contain at least one of these compounds in an amount that is a predetermined chemically-defined amount and that can be accurately determined to enable the determination of the amount of a particular composition required to achieve the dosage levels described herein.

It is further understood that isovaleramide and/or its corresponding compounds may be used in combination with other pharmaceutically active ingredients.

4. Demonstration of treatment-related Activity

As discussed above, the appropriateness and effectiveness of a given pharmaceutical formulation in ameliorating a disease can be demonstrated by using animal models such as, but not limited to, the models described below.

a) Mutant rigid mice

The mutant rigid mouse is a homozygous mouse and suffers from autosomal recessive genetic disease-rigid inheritance. The mouse is normal at birth, and has symptoms of coarse tremor, abnormal gait, stiff skeletal muscle and abnormal righting reflex at 2-3 weeks of age. But no structural change was found. Specifically, the entire central nervous system of the mouse lacks glycine receptors. Drugs that bind GABA or increase GABA synthesis, such as 2-propylvalerate and benzodiazepine , are effective in ameliorating certain symptoms of spasticity in this animal model as well as in humans.

The mutant tonic mice can be evaluated for rigidity using electrophysiological evaluation, similar to the EMG recordings described below. It can also be roughly measured by measuring the alignment. When placed in a dorsal position, this mouse exhibited a righting reflex delay. Any righting over 1 second is considered abnormal. Most normal mice cannot even be placed in a dorsal position. Assessment of tremor can be subjectively classified as "none," "mild," "moderate," or "severe" by grasping the tail of the mouse. The mobility was evaluated by placing the mouse on a glass object with smooth grooves and ridges and lifting the glass object 12 inches from the table and then slowly tilting it to a nearly vertical position. Normal mice may climb around the object for 1 minute or more before falling and standing. Rigid mice often remain stiff in one place and fall quickly to back on the ground. Chai et al, proc.soc.exptl.biol.med.109: 491(1962).

(b) Acute/chronic spinal cord transection rat and acute brain-removing rat

There are many models of stiffness, including acute-deceased rats, acute/chronic spinal cord transected rats, and chronic spinal cord injured rats. Acute models, while of well-established value in elucidating the mechanisms of development of rigidity, are criticized because they are acute. Often experimental animals will die from rigidity or complete recovery. Rigidity occurs immediately upon intervention, unlike human rigidity, which is manifested in most humans as tardive paralysis initially, with rigidity seizures occurring weeks or months later. Some models of slower-progressing injury or spinal cord transection are also indeed indicative of delayed postoperative paralysis. After approximately four weeks of injury/transection, a transition from muscle weakness to a variable degree of rigidity occurs. Although all these models have their own particular disadvantages and do not truly represent human spasticity, they provide much information about spasticity. These models also provide a variety of methods that can be used to test various treatment modalities that result in similar treatments being used for human testing. Many of these models also employ animals of different species, such as cats, dogs, and primates. Barcol, diazepam, and tizanidine were effective on many of the rigidity parameters in these models, (EMG recordings, H-reflexes, H/M ratios, single or multiple synaptic reflexes, clonus, hyperreflexia, etc.).

(c) Early observation of rat Irwin assay

The method is based on the description of Irwin, psychopharmacogenogia 13: 222-57(1968). Can be used to measure the physiological, behavioral and toxic effects of test substances and to label a range of doses that can be used in subsequent tests. The typical method is as follows: rats (three groups) were observed after administration of the test substance and compared with the control group to which the vehicle was administered. Changes in behavior, neurotoxic symptoms, pupil diameter and rectal temperature were recorded using a standardized observation table derived from Irwin. The table contains the following items: death number, sedation, excitement, aggression, Straub tail, roll, convulsion, tremor, eyeball protrusion, salivation, lacrimation, erections, defecation, fear, traction, touch responsiveness, loss of righting reflex, sleep, motor discoordination, muscle tone, stereotypy, shaking head, catalepsy, grasping, ptosis, respiration, corneal reflex, analgesia, gait abnormalities, forepaw stepping, loss of balance, cephalic twitch, rectal temperature, and pupil diameter. Observations were made 15, 30, 60, 120, 180 minutes after administration of the test substance, and also after 24 hours. The test substance is usually administered intraperitoneally. (i.p.)

(d) Rotarod test in rats and mice

This is a neurological deficit test using the method described by Dunham et al, j.am.pharm.assoc.46: 208-09(1957). Rats or mice were placed on a rod rotating at 8 revolutions per minute, the number of animals falling from the rod in three minutes was counted and the number of falls was recorded (maximum 3 minutes). One group of ten rats was tested with the eye. Test compounds were administered intraperitoneally 60 minutes prior to the test. Diazepam, a benzodiazepine  drug, was administered intraperitoneally at 8mg/kg body weight as a reference test. A vehicle-administered control group was also included in this study.

(e) Anticonvulsant activity

There are many in vivo models that involve different kinds of seizures and behavioral effects that are associated with clinically different forms of epilepsy. It is therefore prudent to detect effects in many animal models, as it may be simplistic to assume that the mechanisms of all forms of seizure activity are the same.

A useful model is the Frings-derived seizure sensitive mouse, a model of reflex epilepsy. In the test, a single mouse was placed in a round pleckstrin glass chamber and exposed to a 110 db, 11kHz sound stimulus for 20 seconds, and animals that did not exhibit straightening of hindlimb tone were considered protected. In addition, seizure scores per mouse can be recorded as: (1) running for less than 10 seconds; (2) run longer than 10 seconds; (3) limb and/or tentacle clonus; (4) extension of the upper limb/contraction of the hind limb; and (5) straightening of hind limbs.

The mean seizure score for each group of rats in the dose-response test was calculated. Mice were tested for impaired movement (toxicity) at each dose by placing them on a rotating rod. Tests on detecting motion impairment on rotating rods include: mice were placed on rods 1 inch in diameter at 6 revolutions per minute for 3 minutes. If the mouse falls 3 times from the rotating rod within 3 minutes, this is considered a toxic reaction.

(f) Antimanic activity

To assess the possible use of the compounds for the treatment of affective mood psychosis, an amphetamine-induced hypermotility rat model was used. This process, in addition to being an assay to measure both classical and non-classical antipsychotic activity, also acts as a simple manic model in animals Costall et al, Brain res.123: 89-111(1977).

(g) Neurogenic inflammation of meninges

Neurogenic inflammation within the meninges is thought to constitute an event in migraine pathology, Lee et al, brit.j.pharmacol.116: 1661-67(1995). Detecting leakage of radiolabeled bovine serum albumin following blockade of epidural trigeminal stimulation by the test compound.

(h) Analgesic Properties

There are a number of whole-body animal tests that identify analgesic properties, such as tumbling, hot plate, tail twitching, arthralgia, paw pressure tests and the neuropathic pain model of Bennet or chung, Albe-Fessard et al, 13 ADVANCES IN PAIN RESEARCH AND THERAPY, 11-27(Raven Press 1990).

(i) Therapeutic benefits associated with movement disorders and hyperactivity syndrome

Some animal models are available for studying dyskinesias and hyperkinetic syndromes, for example: drug-induced akathisia, 5-hydroxytryptamine syndrome, unilateral substantia nigra impairment-induced rotation. Lloyd & Morselli (1987), supra. In addition, individual reports on the specific efficacy of compounds in humans also support these indications. Mellick & Mellick (1995) supra; olson et al, am.j.med.102: 60-66(1997).

The therapeutic efficacy of isovaleramide, isovaleric acid, and related compounds in the various assays described above, coupled with their general lack of toxicity, make the compounds of the present invention ideal for the treatment of the diseases described above. These diseases include: ankylosis and convulsions/seizures. With this background in mind, the present invention will be more readily understood by reference to the following examples, which are included to illustrate the invention, but are not intended to limit the invention thereto.

Example 1

Relief and MULTIPLE USING A valerian preparation

The symptoms of stiffness associated with sclerosis

A human female subject, age 42, with one or more symptoms of multiple sclerosis, experiencing considerable stress and having difficulty falling asleep at night and delayed onset of sleep, is often disturbed by stressful dreams and regular wakefulness even after falling asleep. Subjects also frequently experience nocturnal extensor painful cramps in the lower limbs that frequently occur, which also often wake her from sleep. The next day, these painful extensor spasms result in deep muscle pain (bruising) with muscle/joint stiffness.

The subject decided to use a valerian preparation known for its property of aiding sleep. The valerian product, "Baldriparan Stark N", is a tablet, produced in Germany, containing valerian root, hops and melissa extract. The coated compressed tablets each contained 95mg of dried 70% (v/v) ethanol extract of valerian root, 15mg of dried 45% (m/m) methanol extract of hops, and 85mg of dried aqueous extract of melissa. Surprisingly: the valerian preparations not only promote sleep onset and improve sleep quality in subjects, but also have been noted to relieve painful extensor spasms. The subjects noted that when they woken up to their restrooms, painful extensor spasms no longer appeared when they came out of bed, and the sensation of stiff legs also disappeared in normal times. To alleviate these symptoms, patients continued to take the same valerian product on an as needed basis (p.r.n., if necessary) and sustained relief was achieved.

Example 2

Relieving spinal cord using valerian preparations

Traumatic-related ankylosis

One human male subject, 38 years old, had rigidity symptoms (hyperreflexia, tendon reflexes, and extensor spasms) that developed with early spinal cord trauma. All of these symptoms interrupt the patient's sleep and reduce their sleep quality. When the same valerian preparation produced in germany as in example 1 was taken, the subjects noted a significant improvement in sleep quality in addition to a significant reduction in nocturnal extensor spasms. The subject continues to take the preparation as necessary (prn) to alleviate the symptoms.

Example 3

Isovaleramide straightening resistance test

(1) Evaluation of Chronic spinal cord crossing rat stiffness

In these studies, rats weighing between 270-530 grams of male albinism from Holtzman (Harlan Sprague-Dawley Laboratories) were used as subjects. These animals were housed individually throughout the test period and were given continuous food and water. All experimental procedures were checked and approved by the animal care and use committee. The animals were anesthetized with a mixture of isoflurane and oxygen at a flow rate of 4L/min, then the rats were placed in a brain stereometric frame and maintained under anesthesia, a contractible incision of the perispinal muscles was made and laminectomy was performed between T6-T9, a piece of spinal cord tissue of about 1-2mm in size was removed by aspiration and filled with gel foam to reduce bleeding, and then the incisions were sutured layer by layer.

After the transection was completed, the rats were placed in a room where the ambient temperature was raised to about 80 ° F by a heater in order to maintain the body temperature. The next morning after surgery, the lower half of the myelinated rat was cleaned and its artificial urinary tract was maintained by bladder pressurization. The test was performed 21-28 days after the operation. To prevent bladder infections, 0.25ml of the antibiotic Sulfatrim pediatric suspension was administered orally to these rats for the first two weeks. Commercial antibiotic ointment was applied to any decubitus skin. Within about two weeks, all animals regained the ability to control the bladder and were no longer given antibiotic therapy. Advokat, Brain Res.684: 8(1995). Robust assessments were performed both before and after dosing so that each animal served as its own control.

The method is used for grading the tonic reaction induced by the harmless stimulus, namely, a metal probe is used for pricking four specific parts of the lower abdomen. Each of these four trials was evaluated on a scale from 0 to 4, with 0 being the absence of tonic response in all four trials and 4 being the strongest, tonic clonic response induced in all four trials. All tetanic scores, including pre-and post-dose, were converted to percentages representing tetanic, such that the score 0/4 equals 0%, 1/4 equals 25%, and so on. These raw scores or normalized scores were analyzed using a one-way reproduced measures (ANOVA).

As shown in FIG. 2, isovaleramide administered intraperitoneally at a dose of 300mg/kg was effective at reducing the severity score (45-65%) 15, 30, 60 and 120 minutes after administration. By the next day, 1440 minutes (24 hours), the robust score returned to essentially baseline levels. No apparent behavioral toxicity or motor impairment was observed at this dose. Like those of the non-dosed control rats, these rats were conscious and able to be grasped with the nonparallel forepaw.

Referring to fig. 3, to test the high threshold afferent stimulation, the polysynaptic flexor reflex response was recorded as the ipsilateral hair generator EMG activity. The animal was used with a super-strong electric shock in the hindpaw and the recording electrode was placed on the biceps femoris semitendinosus muscle. Five groups of stimuli were performed at each time point. Flexor reflexes were recorded every 30 minutes before and after dosing once a stable baseline was obtained. See Hao et al, eur.j.pharmacol.191: 407(1990).

Thus, the response in spinal cord rats was determined by observing the flexor reflex response (FIG. 3) before the treatment and 30, 60, 90 and 120 minutes after administration of isovaleramide (300, 600, 1200mg/kg, oral), baclofen (10mg/kg, subcutaneous) and vehicle (water, 12ml/kg, oral), respectively.

Isovaleramide at all doses was shown to reduce the flexor reflex response and tonic intensity in chronically myelized rats at all time points. In this model, neither baclofen nor isovaleramide caused a change in the H/M reflectance.

In fig. 4, the reaction of fig. 3 is converted into a form of the total area under the curve, covering the entire 2-hour measurement period. All drug-treated groups were significantly different from the vehicle group according to one-way anova (P < 0.05). There was no significant difference in the sum of the reduction in flexor reflex over two hours between drug-treated groups. (paired multiple comparison, Student-Newman-Keuls method).

(2) Early observation of rat Irwin assay

Isovaleramide induced no difference from the saline injected control group when administered intraperitoneally to rats at a dose of 256 mg/kg. At 512mg/kg, mild sedation appeared at 60-120 min, contraction was lost at 120 min (observed only in 1/3 rats), and a decrease in muscle tone was also observed at 60-120 min. At 1024mg/kg, overt sedation was observed up to 30 minutes, moderate sedation at 120 minutes, and mild by 180 minutes. A fear decline was also observed at this dose for 30 minutes and 1/3 rats at 120 minutes. Decreased responsiveness to touch for 120 minutes, decreased muscle tone for 180 minutes, mild hypothermia for 120 minutes, and abnormal gait (rolling) at 60-80 minutes. Loss of grip and righting reflex also occurred in 1/3 rats at 15 minutes of this dose.

(3) Rotary rod test in rats and Frings mice

Isovaleramide was administered 60 minutes prior to the test at 128, 256 and 512mg/kg (i.p.) doses, and did not significantly affect the performance of rats in the rotarod test. See table 1. In contrast, stabilization reduces performance in its rotarod test in a dose-dependent manner.

TABLE 1

Effect of Isovaleramide and diazepam in rat rotarod test

Dosage of isovaleramide (mg/kg)a	Number of rats droppedb	Drop time (seconds)
					Mean ± standard deviation	t value	Difference from control (%)
		0	5	135.5±18.0				-	-
128	6				134.5±20.7c	0.036	-1％
		256	7	98.4±23.3c				1.261	-27％
512	7				115.9±20.5c	0.717	-14％
Stabilization ofa(mg/kg)
		4	9	55.8±20.6d	2.909	-59％
8	10+e						16.3±6.4f	6.222	-88％

^aIsovaleramide and diazepam administered 60 min before rotarod test

^bOne group of ten rats

^cNo significant differences according to Student' st test

^dP is less than 0.01 by Student's st test

^eFisher's Exact test shows that P is less than 0.05

^fP is less than 0.001 by Student' st test

Isovaleramide did not significantly affect performance when given intraperitoneally at a dose of 150mg/kg to Frings mice 15 minutes prior to rotarod testing. In contrast, doses of 300mg/kg, 600mg/kg and 1000mg/kg (i.p.) resulted in a decrease in the performance of the rotating rods of 1/8, 4/8, 8/8, respectively, in the subject Frings mice.

Example 4

Frings mice sensitive to audiogenic seizures

Anticonvulsant activity in models of epilepsy

The results of Table 2 confirmIsovaleramide has anticonvulsant activity in this animal model of epilepsy. Isovaleramide also exhibits accelerated onset and relatively reduced duration. Its anticonvulsant activity was observed as early as 15 minutes after administration, but was significantly reduced after 2 hours. All quantitative studies were therefore performed at 15 minutes. At this time point, there is no half effective amount of tonic Extension (ED)₅₀) Is injected intraperitoneally at 126 mg/kg. In addition, a dose-dependent decrease in seizure scores was also observed at this time point. At doses significantly higher than the anticonvulsant activity (> 300mg/kg), isovaleramide treated animals showed behavioral toxicity characterized by an inability to maintain equilibrium on rotating rods. No significant toxicity was observed at doses below 300 mg/kg. Half the Toxic Dose (TD) for the rotarod test₅₀) Is used for intraperitoneal injection at 513 mg/kg. Thus, the protection index (TD) can be calculated₅₀/ED₅₀) About 4.2.

Thus, despite its lower relative potency in animal models, isovaleramide exhibits a better separation of active toxicity. Isovaleramide has an unexpected efficacy as an anticonvulsant in the Frings mouse reflex epilepsy model susceptible to auditory seizures, based on the structure activity relationship of the amide and its corresponding acid. The activity pattern of isovaleramide is similar to that of the broad-spectrum anticonvulsant, sodium 2-propylvalerate. It has been suggested in the foregoing literature that compounds structurally similar to isovalerate and isovalerate appear to increase GABA levels throughout the CNS. This function is also primarily responsible for the anticonvulsant activity of 2-propylvalerate, although other mechanisms have been proposed. On the other hand, isovaleric acid has not been shown to have anticonvulsant activity, although it has been reported to induce mild increases in GABA levels in mouse brain. See, for example, Loscher et al, Neuropharmacology 24: 427 (1985); keane et al, loc.cit.22: 875 (1983); keane et al, pharmacol. res. commun.17: 547(1985).

TABLE 2

Isovaleramide paraauditory epilepsy after intraperitoneal administration

Effect of seizure sensitive mice

Dosage of isovaleramide (mg/kg, administered intraperitoneally)	Seizure score ± standard error	Number protected in eight mice testeda	Number of mice tested exhibiting toxicityb
				75	4.4±0.6	1	0
112.5	4.0±0.6	2	0
				150	2.0±0.6	6	0
300	1.0±0	8	1
				600	-		4
1000	-		8
				Protective action ED50：126mg/kg(98.8-168b)
TD50：531mg/kg(372-711b)

^aMeasured at 15 minutes

^b95% confidence interval

In general, the prior literature teaching on the structural and activity relationships of compounds similar to 2-propylvalerate does not claim the use of simple, unsubstituted compounds such as isovaleramide. Isovaleramide therefore exhibits a similar efficacy profile to 2-propylvalerate in an audiogenic seizure sensitive mouse model, with a similar separation of efficacy and toxicity measured by rotarod performance, a very surprising result. These observations show that isovaleramide is also effective as a broad spectrum anticonvulsant. Isovaleramide is known to be relatively devoid of toxicity in mutagenesis and cytotoxicity assays. In another aspect, see U.S. Pat. No. 5,506,268 and PCT application WO94/28,888, the hepatotoxic triggering pattern of 2-propylvalerate has been noted for a long time. See, for example, Loscher et al, Neuropharmacology 24: 427(1985).

While the foregoing indicates a particularly preferred embodiment, it is to be understood that the invention is not so limited. Those of ordinary skill in the art will recognize that numerous modifications may be made to the disclosed embodiments, and that such modifications are intended to be included within the scope of the present invention, which is defined in the following claims.

All publications and patent applications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications mentioned herein are incorporated by reference in their entirety.

Claims (8)

1. Use of a compound selected from isovaleric acid, its pharmaceutically acceptable salts, isovaleramide and ammonium isovalerate in the preparation of a pharmaceutical formulation for the treatment of headache.

2. The use of claim 1, wherein the medicament is for the treatment of chronic headache.

3. The use of claim 1, wherein the medicament is for the treatment of cluster headache.

4. The use of claim 1, wherein the medicament is for the treatment of migraine.

5. Use according to any one of claims 1 to 4, wherein the compound is isovaleramide.

6. The use of any one of claims 1-4, wherein the compound is a pharmaceutically acceptable salt of isovaleric acid.

7. Use of an extract of a plant of the family Valerianaceae (Valerianaceae), bark of England (cramp bark), Crataegus oxyacantha or Humulus lupulus (Humulus lupulus), wherein said extract contains at least one compound which generates isovaleric acid upon hydrolysis in vivo, for the preparation of a pharmaceutical preparation for the treatment of headache.

8. The use of claim 8, wherein the headache is selected from the group consisting of chronic headache, cluster headache and migraine.