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  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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  • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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Definitions

• the present invention provides methods of treating pathological conditions, such as spasticity and convulsions, the symptoms of which are alleviated by a modulation 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.
• a number of pathological states, diseases, and disorders are characterized by a profound aberration in the normal function of the central nervous system
• CNS CNS
• Such conditions include spasticity, strokes, spinal cord injuries, chronic neurodegenerative disorders and diseases such as Parkinson's and Huntington's diseases, Alzheimer's disease, and epilepsy.
• these states usually only respond to pharmacologic intervention with compounds or substances that possess significant activity at the level of the CNS.
• agents currently employed in the treatment of pathologies such as spasticity and convulsions display troubling side-effect profiles which limit their long-term clinical utility.
• these agents for example, are the benzodiazepines, which can cause impairment of cognition (impairment of memory-related performance, or "cognitive blunting"). See, for example,
• ANTIEPILEPTIC DRUGS Fourth Edition, (Levy et al, eds.), Raven Press, (1995).
• Two other clinically used agents are valproate and related therapeutically useful salts such as valproic acid hemisodium salt, which are hepatotoxic and teratogenic, and baclofen, which produces excessive muscle weakness and sedation.
• valproate and related therapeutically useful salts such as valproic acid hemisodium salt, which are hepatotoxic and teratogenic, and baclofen, which produces excessive muscle weakness and sedation.
• the present invention also provides a method of treatment comprising the step of administering, to a patient suffering from a pathology that is ameliorated by a modulation of CNS activity, a therapeutically effective amount of a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a composition selected from the aforementioned group of agents.
• the pharmaceutically acceptable amide of isovaleric acid is selected from the group consisting of isovaleramide, N-ethyl isovaleramide, N-methyl isovaleramide, NN-dimethyl isovaleramide, N-methyl, N-ethyl isovaleramide, ⁇ -(2-acetamido)isovaleramide ("N- isovaleryl glycinamide”), and N-isovaleryl GABA.
• the treated pathology is an affective mood disorder, convulsions, a central neuropathic pain syndrome, a headache, or a restlessness syndrome.
• the pathology is spasticity that is ameliorated by a centrally mediated decrease in muscle tone.
• the treated pathology is a cerebral insult, neurodegeneration, or the acquisition of epilepsy.
• the treated pathology is substance abuse, craving of substance, addiction, and withdrawal.
• a method of use is provided for an extract of Valerianaceae, cramp bark, black haw, or hops in a method of treating a symptom of spasticity, where the extract comprises at least one compound that is hydrolyzed in vivo to yield isovaleric acid or isovaleramide.
• 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.
• Figures la and lb depicts the structures of compounds, including isovaleramide, capable of inducing a modulation of the central nervous system.
• Figure 2 portrays the effect of isovaleramide (at 300 mg/kg, i.p.) on gross observational spasticity scores elicited 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 pre-treatment control values.
• Figure 3 illustrates a time-dependent reduction of the flexor reflex, an electrophysiological measure of spasticity, in the chronic spinalized rat.
• the effects of isovaleramide (300 mg/kg p.o.), baclofen (10 mg/kg s.c), and vehicle (water. 12 ml/kg p.o.) are shown at pre-treatment (time zero) and at 30, 60, 90, and 120 minutes post-admimstration. Isovaleramide caused a significant decrease in the magnitude of the flexor reflex, comparable to that observed with baclofen.
• Figure 4 shows a dose-response relationship for isovaleramide and baclofen, a known antispasticity agent.
• Isovaleramide and baclofen produced a similar dose- dependent reduction of the flexor reflex in the chronic spinalized rat.
• the responses from Figure 3 and response from additional doses were converted to a total-area- under-the-curve for the two-hour measurement. All drag-related groups were significantly different from the vehicle (p ⁇ 0.05, ANOVA).
• FIG. 5 shows that isovaleramide was effective in reducing in a dose- dependent manner the generalized seizure responses of fully kindled rats.
• Isovaleramide decreased the mean seizure score and the afterdischarge duration in amygdala-kindled rats, showing that it exerts anticonvulsant activity against both focal and secondarily generalized seizures.
• Figure 6 illustrates the antiepileptogenesis effect of a daily 500 mg/kg p.o. dose of isovaleramide compared to controls.
• Isovaleramide elicited a delay in the rate of increase in both seizure score and afterdischarge duration (not shown) which normally develop during electrical kindling in the amygdala- kindled rat.
• Isovaleric acid and its pharmaceutically acceptable salts can be administered in vivo to effect a modulation of CNS activity.
• amides such as isovaleramide
• alcohol esters such as ethyl isovalerate and glyceryl tr ⁇ sovalerate
• amides such as isovaleramide
• alcohol esters such as ethyl isovalerate and glyceryl tr ⁇ sovalerate
• a series of structurally related compounds also display similar properties. These agents modulate CNS activity by enhancing inhibitory (or decreasing excitatory) neurotransmission centrally, without complete suppression of all activity.
• a subject receiving such an agent is not overtly sedated, anesthetized, or paralyzed in the context, for example, of decreasing seizures (while causing little or no anesthesia), decreasing muscle tone (while causing little or no accompanying paralysis), eliciting a calmative effect (with little or no sedation), or ameliorating an ambulatory syndrome such as spasticity (with little or no accompanying weakness or flaccidity).
• a number of pathologies exemplified by affective mood disorders (i.e. bipolar disorder), headaches (chronic, cluster, migraine), restlessness syndromes, neuropathic pain, movement disorders, spasticity, convulsions, cerebral insult, neurodegeneration, and substance abuse have at least one symptom that is usefully alleviated by effecting a modulation of CNS activity. Accordingly, an individual who suffers from such a pathology may be treated with a therapy where, pursuant to the present invention, that individual receives a pharmaceutical formulation of isovaleramide, isovaleric acid, or a related compound.
• the inventors believe that the compounds of the present invention act via a GABAergic mechanism and, hence, 5 bear a pharmacological similarity to known drugs that are considered to enhance central GABAergic neurotransmission.
• the compounds of the present o invention are effective in treating pathological conditions, illustrated by those mentioned above, that are thought to arise from a defect in the regulation of inhibitory (GABA- and or glycine-related) neurotransmission.
• This regulation may occur by a direct or modulatory effect at CNS receptors or by impact on a metabolic pathway which heightens GABA or glycine levels 5 and/or which reduces levels of an excitatory neurotransmitter like glutamate. See
• the compounds of the present invention do not engender the disadvantageous side effects associated with conventional drug therapies in this area, such as the hepatotoxicity or teratogenicity that arises with valproate administration. 5
• SPASTICITY Spasticity may be "defined as an upper [i.e., CNS] motor neuron disorder characterized by a velocity-dependent increase in tonic stretch 0 reflexes (muscle tone) with exaggerated tendon jerks resulting from hyperexcitability of the stretch reflex.” Lance, Symposia synopsis in SPASTICITY - DISORDERED MOTOR CONTROL, Feldman et al. (eds.) (1980) (Symposia Specialists, distributed by Year Book Medical Publishers).
• spasticity Major disease states and conditions associated with spasticity include multiple sclerosis, cerebral palsy, stroke, trauma or injury to the spinal cord, and closed head trauma.
• the pathological states observed in spasticity are fundamentally different at the physiological level from the commonly experienced acute muscular aches, strains, and sprains that occur from a localized external insult to a particular muscle. i.e., outside of, or peripheral to, the CNS. These pathological states also are different from the relatively common involuntary spasms of smooth muscle, such as vascular spasms, bladder spasms, and bronchial spasms. Such non-spastic (non- CNS), peripheral or localized symptoms are commonly treated with so-called "antispasmodic” or "spasmolytic” agents. Such agents generally are not useful in treating spasticity.
• 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 alleviation of one or more symptoms of spasticity.
• "spasticity” refers to a heightened tone of skeletal muscle which is manifested by symptoms exemplified by but not limited to painful flexor or extensor spasms, increased or exaggerated deep tendon reflexes, hyperreflexia, loss of dexterity, muscular weakness, exaggerated tendon jerks, and clonus.
• antispasticity agent refers here to a composition that is useful for the symptomatic treatment of spasticity, as demonstrated by the alleviation of at least one of the following manifestations of spasticity: painful flexor or extensor spasms, increased or exaggerated deep tendon reflexes, hyperreflexia, loss of dexterity, muscular weakness, exaggerated tendon jerks, and clonus.
• spasticity refers here to the lessening of one or more symptoms of spasticity, including, but not limited to, painful flexor or extensor spasms, increased or exaggerated deep tendon reflexes, hyperreflexia, loss of dexterity, muscle weakness, exaggerated tendon jerks, and clonus.
• Spasticity is associated with multiple sclerosis, stroke, head trauma, spinal cord injuries, cerebral palsy, and other neurodegenerative diseases, disorders, and conditions.
• Spasticity is distinct from acute muscle spasms, which may be associated with a variety of conditions different from those leading to spasticity. These acute muscle spasm-causing conditions 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.
• agents used heretofore to treat spasticity associated with chronic neurological disorders have not been employed in treating acute muscle spasms, except for the benzodiazepines, such as diazepam (Nalium ® ), which are recognized also to have muscle-relaxant activity as well as anxiolytic and anticonvulsant properties.
• the present invention achieves a centrally mediated decrease in muscle tone which, in turn, addresses the particular symptoms of spasticity.
• CONVULSIVE DISORDERS Due to the widespread availability of reasonably predictive and experimentally accessible animal models of convulsant states, a number of clinically useful anticonvulsants have been prepared and developed.
• the present invention can be used to treat convulsive disorders such as epilepsy. That is, the pharmaceutical compositions of the invention display "anticonvulsant activity," which is evidenced by a reduction of the severity, number, and or duration of convulsions in animal models of epilepsy. Accordingly, the inventive pharmaceutical compositions should be useful in treating conditions including, but not limited to, simple partial seizures, complex partial seizures, generalized tonic-clonic seizures, secondarily generalized seizures, status epilepticus, and trauma-induced seizures, as occur following head injury or surgery.
• Epilepsy is a common disorder with many causes, and can be very difficult to treat, often requiring treatment for many years to keep seizures under control.
• the pharmaceutical compositions of the invention display "anticonvulsant activity," evidenced by a reduction of the severity, number, and/or duration of convulsions in animal models of epilepsy. Accordingly, the inventive pharmaceutical compositions should be useful in treating conditions including, but not limited to, simple partial seizures, complex partial seizures, secondarily generalized seizures, status epilepticus, and trauma-induced seizures, as occur following head injury or surgery.
• mood disorders are conditions ranging from depression to dysphoric mania, i.e., bipolar mood disorder, mania, schizoaffective disorder, traumatic brain injury- induced aggression, post-traumatic stress disorder, panic states, and behavioral dyscontrol syndromes.
• Affective mood disorders have been treated primarily prophylactically, with Uthium salts, since the 1950s in Europe and since the 1970s in the United States. Emrich et al. , /. Affective Disorders 8: 243-50 (1985). In recent years, alternatives to Uthium treatment have been under development, given the several problems with Uthium therapy.
• Valproate has a lower propensity towards depressed arousal and mentation, memory impairment, and cognitive blunting than is seen with the benzodiazepines.
• a pharmaceutical formulation according to the present invention is effective to this end, especially with respect to improved side effects.
• Valproic acid itself is teratogenic (Nau and Hendrickx, 1987). Some of the structural elements required for teratogenic activity in vivo are: a free carboxyl group (stable amides exhibit significantly lower teratogenicity, or to be non- teratogenic); substituents on C-2 larger than a methyl group, and a double or triple bond at C-4. Addition of a methyl group at C-3 to valproic acid reduces teratogenicity.
• NEUROPATHIC PAIN SYNDROMES 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 PAIN AND CENTRAL NERVOUS SYSTEM DISEASE
• a pharmaceutical formulation of the present invention wiU be appUed in similar fashion to ameUorate neuropathic pain.
• HEADACHES Headaches of the migraine type (Hering & Kuritzky, Cephalalgia 12: 81-84 (1992)), the cluster type (Hering & Kuritzky, loc. dt. 9: 195-98 (1989)) and the chronic type (Mathew & Sabiha, Headache 31: 71-74 (1991)) have been treated by the administration of valproate and other anticonvulsants.
• the compositions of the present invention also wiU aUeviate symptoms associated with each of the three headache types, without the adverse side effects of valproate and other anticonvulsant therapy.
• RESTLESSNESS SYNDROME The phrase "restlessness syndrome” denotes a somatic (non-mental) restlessness characterized by involuntary movement of the limbs, as weU as by a sense of physical (rather than mental) agitation, which is independent of mood and, hence, is distinguished from restlessness per se. See Sachdev et al., Austral. New Zealand J. Psychiatry 30: 38-53 (1996).
• the genus of restlessness syndromes can be observed in association with many organic and non-organic psychiatric illnesses.
• drug-induced restlessness (tardive, chronic, and withdrawal akathisias), such as drag-induced extrapyramidal symptoms, is one of the most common side effects of neuroleptic drug therapy.
• restlessness- syndrome rubric are also within the restlessness- syndrome rubric.
• Idiopathic restless leg syndrome foUows an autosomal dominant inheritance, with a variable clinical expression of symptoms.
• MOVEMENT DISORDERS Various agents with known effects on the 5 GABAergic system have been shown to decrease the dyskinetic movement characterizing movement disorders such as Parkinson's disease, Huntington's chorea, tardive dyskinesia, and stiff-man syndrome. This fact has highUghted a role for central GABAergic function in the control and modulation of CNS excitabiUty and movement. Lloyd & MorselU (1987), supra. A method of treatment according o to the present invention that can effect an altered level of CNS activity, presumably via a GABAergic mechanism, wiU alleviate one or more symptoms of a movement disorder.
• L5 and aspartate, as well as a variety of voltage-gated ion channels are thought to play a central role in mediating cell death after a variety of cerebral insults including, but not limited to, ischemia, trauma, seizure and hypoglycemia.
• cerebral insults including, but not limited to, ischemia, trauma, seizure and hypoglycemia.
• compounds or therapeutic strategies that decrease excitatory neurotransmission for example, glutamate antagonists, ion channel 0 blockers, and the like, elicit a neuroprotective effect in animal models of cerebral insults.
• GABA and glycine are the primary inhibitory neurotransmitters in the mammalian central nervous system and, therefore, it is expected that enhancement of inhibitory neurotransmission via GABA or glycine
• GABA/glycine reuptake inhibitors GABA/glycine metabolic inhibitors.
• GABA/glycine synthesis enhancers GABA/glycine receptor modulators, etc.
• antiepileptogenic refers to the idea of inhibiting the processes that underly the development of epilepsy.
• Anticonvulsant refers to the actual inhibition of seizures in an epileptic model.
• anticonvulsants that have been shown to delay the acquisition of seizures in animal models of kindling have been proposed to be antiepileptic versus anticonvulsant i.e., the compounds are neuroprotective and block the development of seizures rather than merely blocking the seizure once the disorder is in place (Antiepileptic Drags, Fourth Edition, Chapter 7., White, H.S. et al., Chapter 7, Experimental Selection, Quantification, and Evaluation of Antiepileptic Drugs (99-110) in Antiepilep ⁇ c Drugs, Fourth Edition edited by
• Seizure kindling models are characterized by giving a sub-seizure eliciting electrical or chemical stimulus (i.e., sub-threshold) over a period of time (Goddard et al., Exp. Neurol. 25: 295-330, (1969)).
• SUBSTANCE ABUSE/CRAVING Anticonvulsants such as cambamazepine, that have shown efficacy in kindled models of epilepsy, have also demonstrated efficacy in reducing the symptoms of affective mood disorders and substance abuse/craving in patients (Post, et al., Ann. N. Y. Acad. Sci. 537:292-308, (1988)); Post, et al., Epilepsia 25: 234-239, (1984)); Post, et al., Psychopharmacology 72: 189-196, (1981)) Ha ⁇ kas et al., 1989; Blumer et al., 1988).
• Anticonvulsants such as cambamazepine, that have shown efficacy in kindled models of epilepsy, have also demonstrated efficacy in reducing the symptoms of affective mood disorders and substance abuse/craving in patients (Post, et al., Ann. N. Y. Acad. Sci. 537:292-308, (1988)
• Post and Kopanda (1976) have demonstrated a pharmacologic (chemical) kindling model employing subconvulsive doses of cocaine as the stimulus.
• the progressive human response to high cocaine usage such as irritability, restlessness, hypervigilance, and paranoia may be a human equivalent of the kindling phenomenon observed in animals.
• Seizure kindling models are characterized by administration of a sub-seizure eliciting electrical or chemical stimulus (i.e., sub-threshold) over a period of time (Goddard et al.; 1969).
• a sub-seizure eliciting electrical or chemical stimulus i.e., sub-threshold
• the majority of initially non-convulsive animals that are exposed to such stimuli over a number of days eventually exhibit seizure activity to these stimuli, have a permanently lowered threshold, exhibit altered manifestations of normal behavior and therefore are considered
• a kindling phenomenon has been proposed to underlie the development of disorders such as certain types of epilepsy syndromes, substance abuse/craving and affective mood disorders such as bipolar (Post et al. 1981, 1984, 1988, supra: Ballenger, et al., Br. J. Psychiatry 133: 1-14, (1978));
• the pharmaceutical compositions of the invention display anticonvulsant activity and efficacy in animal models of kindling and, accordingly, the inventive pharmaceutical compositions should be useful in treating conditions associated with substance abuse/craving.
• valerian preparations include aqueous and hydroalcohoUc extracts, such as tinctures, intended for oral administration.
• ammoniated valerian tinctures were used hereinaUy in the EngUsh-speaking world since at least the beginning of the seventeenth century. Hobbs, HerbalGram No.
• valerian-epoxy-triesters (-ates) The most common and abundant of the valepotriates, valtrate and didrovaltrate, each contain two isovalerate moieties esterified to a "central" iridoid nucleus. Lin et al, Pharm. Res. 8: 1094-02 (1991).
• valerian extracts and other preparations have been determined to be the ester hydrolysis product, isovaleric acid.
• Ammonium isovalerate and isovaleramide are produced in ammoniated tinctures. Balandrin et al, J. Toxicol-Toxin Rev. 14: 165 (1995).
• the stracmres of isovaleramide and related compounds are depicted in Figure 1.
• the chemicaUy labile valepotriates and other valerian-derived monoterpenoid-isovalerate esters, such as bornyl, lavandulyl, and ethyl isovalerates might be considered to act as "pro-drugs" and chemical precursors for isovaleric acid, its salts, and isovaleramide.
• Isovaleramide has been isolated from valerian plants, most probably as an isolation artifact foUowing treatment with ammonia. Buckova et al., Cesk. Farm. 26: 308 (1977); Chem. Abstr. 88: 86063z (1978); see also Bos et al. and Fuzzati et al., Phytochem. Anal. 7: 143, 76 (1996). More recently, isovaleramide was shown to exhibit low acute toxicity in vivo, no mutagenic potential, and cUnicaUy useful anxiolytic properties (U.S. patent No. 5,506,268; PCT appUcation WO 94/28,888). Methods for preparing isovaleramide are weU known.
• Extracts of medicinal plants that are useful for treating the symptoms of spasticity can be prepared by aqueous, hydroalcohoUc, or alcohoUc extraction, or by extraction with other suitable solvents using methods weU known to those skiUed in the art.
• useful extracts contain at least one of the foUowing: isovaleric acid, its salts or complexes, ethyl isovalerate, isovaleramide, N-ethyl isovaleramide, and their chemical precursors.
• Useful extracts also share the common property of releasing isovaleric acid and/or isovaleramide upon hydrolysis in vivo. Standard methods for preparing such extracts can be found in pre-1950 editions of the U.S.
• valerian rhizomes and roots as weU as those of closely related plants in the fa ⁇ tily Valerianaceae. As discussed by Hobbs (1989), supra, these include the common valerian plant, Valeriana officinalis L., as weU as the East Indian valerian, V. wallichii DC, and the bibUcal spikenard, Nardostachys jatamansi (Roxb.) DC.
• valerian rhizomes and roots other plants which have been used traditionaUy as sedative herbal medicines are known to contain, or to produce, isovaleric acid.
• hops Humulus lupulus L., fa-mily Moraceae, which is often used in herbal formulations in combination with valerian
• "cramp bark” or “guelder rose” Viburnum opulus L., family CaprifoUaceae
• black haw V. prumfoUum L., root bark. Hare et al., THE NA ⁇ ONAL STANDARD DISPENSATORY, pages 93, 94, 159, 160, 169, 256, 642, 692-694, 766, 767,
• hops As in the case of valerian rhizomes and roots, hops generate isovaleric acid from more chemicaUy complex precursors upon oxidation or enzymatic breakdown.
• PharmaceuticaUy acceptable salts of organic acids such as isovaleric acid
• isovaleric acid which have been approved by the U.S. Food and Drag Administration for commercial marketing
• sodium, potassium, lithium, zinc, aluminum, calciu , and magnesium salts include sodium, potassium, lithium, zinc, aluminum, calciu , and magnesium salts.
• Salts of isovaleric acid that are commerciaUy available in the United States include the ammonium, sodium, potassium, and zinc isovalerates.
• PharmaceuticaUy acceptable alcohols can form esters with isovaleric acid by methods that are weU known in the art.
• Such alcohols may contain more than one hydroxyl moiety, and are weU tolerated in vivo.
• 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, saUcyUc acid, saUgenin, saUcylamide, vanillin, p-hydroxycinnamic acid (p-coumaric acid), caffeic acid, feruUc acid, galUc acid, ellagic acid, quercetin, and eugenol.
• sugar alcohols such as dulcitol, mannitol, and sorbitol
• sugar acids such as gluconic and glucuronic acids
• glycerol the polyol inositol
• benzyl alcohol certain
• suitable alcohols include alkaloids and biogenic amines such as ephedrine, pseudoephedrine, phenylpropanolamine, tyramine, and dopamine, vitamins such as ascorbic acid (vitamin C), thiamine (vitamin Bl), riboflavin (vitamin B2), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), the tocopherols (vitamin E), choline, foUc acid, and pantothenic acid, monoterpenoid alcohols such as geraniol, nerol, and Unalool, naturaUy occurring triterpenoid alcohols such as ⁇ - and ⁇ -amyrins, lupeol, and oleanoUc and ursoUc acids, bile acids such as choUc acid, deoxychoUc acid, and taurochoUc acid, and common naturaUy occurring plant sterols (phytosterols) such
• esters of isovaleric acid that are commerciaUy available in the United States include the bornyl, ethyl, n-butyl, isoamyl, and geranyl isovalerates.
• Isovaleric acid, ammonium isovalerate, and the esters ethyl isovalerate, isoamyl isovalerate, 2-methylbutyl isovalerate, cinnamyl isovalerate, methyl isovalerate, bornyl isovalerate, isobornyl isovalerate, and menthyl isovalerate are approved by the FDA and are Usted in the Code of Federal Regulations as being acceptable flavoring agents which may be used in foods. 21 CFR ⁇ 172.515 (1991).
• Valerian (Valeriana of ⁇ nalis L.) rhizomes and roots and black haw (Viburnum prunifoliwn L.) bark are Usted as acceptable natural flavoring substances and natural adjuvants in 21 CFR ⁇ 172.510 (1991). Hops and "luputin” are Usted among substances that are generaUy recognized as safe (“GRAS"). 21 CFR ⁇ 182.20 (1991).
• esters of isovaleric acid are expected to be hydrolyzed t> ⁇ vt ' v ⁇ by ubiquitous esterase enzymes, thereby releasing isovaleric acid and the constituent alcohol.
• Particularly preferred among the isovalerate esters are glyceryl mono-, di-, and especiaUy tri-isovalerates (“triisovalerin”), isovaleryl sahcyUc acid or saUcylate (saUcyUc acid isovalerate), ethyl isovalerate, and ⁇ -sitosteryl isovalerate. See Figure 1.
• esters possess the advantage of having neutral to pleasant odors, in contrast to the extremely unpleasant odors of isovaleric acid and its salts, such as the ammonium, sodium, potassium, and zinc isovalerate salts.
• ethyl isovalerate is a Uquid
• the glycerylmono-, di-, and tri-isovalerates, isovaleryl saUcylate, and ⁇ -sitosteryl isovalerate are expected to be soUds at room temperature, thereby faciUtating their formulation into various standard sohd and Uquid oral dosage forms weU known in the an, such as tablets (e.g., uncoated tablets, enteric-coated tablets, and film-coated tablets), capsules, gelcaps, powders, concentrates (drops), etixirs, tinctures, and syrups.
• amides of isovaleric acid may be used in the inventive methods. These amides can be prepared by methods weU known in the art and may. See, for example, March, ADVANCED ORGANIC CHEMISTRY: REACTIONS, MECHANISMS, AND STRUCTURE, 4th ed. (John Wiley and Sons 1992).
• Preferred amides include N-ethyl isovaleramide, N-methyl isovaleramide, N,N-dimethyl isovaleramide, N-methyl ,N- ethyl isovaleramide, ⁇ -(2-acetamido)isovaleramide ("N-isovaleryl glycinamide”), and N-isovaleryl GABA. See. for example, Tanaka et al , J. Biol. Chem. 242: 2966 (1967).
• the present invention also is directed to compounds and methods of using compounds that, by virtue of their structural si ⁇ nlarity to isovaleramide, share similar pharmacological activities. These compounds generaUy share the common structure:
• FIG. la and lb The structures of these compounds are shown in Figures la and lb and include substituted isovaleramides such as 2-methylisovaleramide, 3- methyUsovaleramide, 2,2-dimethyUsovaleramide, 2,3-dimethyUsovaleramide.
• the present invention specificaUy includes each of the possible enantiomeric or diastereomeric forms of the compound.
• N,N-Diethyl isovaleramide (“Valyl”), although purported to possess C ⁇ S depressant (sedative) activity, recently has been shown to possess C ⁇ S stimulant (convulsant) properties; see U.S. patent No. 5,506,268 and PCT appUcation WO 94/28,888, supra.
• An amide of isovaleric acid with p-aminophenol also can be prepared using standard methods to provide a compound, "isovaleraminophen,” which is related stracturaUy to the drag acetaminophen (Tylenol ® ; see Figure 1). In a manner analogous to that of the isovalerate esters, these substituted amides should be hydrolyzed in vivo (in this case, via hepatic amidase enzymes), releasing isovaleramide or isovaleric acid.
• the present invention also is directed to certain sulfonamide, sulfamate, and carbamate compounds that, by virme of their stracmral si ⁇ nlarity to isovaleramide, share simUar pharmacological activities.
• Preferred sulfonamides and sulfamates include 2- methyl- 1-propyisulfonamide, 1-methylethyl sulfamate, and 2-methyl- 1 -propyl sulfamate.
• Preferred carbamates include isobutylcarbamate
• Certain of the compounds and preparations discussed above represent alternative forms for deUvering isovaleric acid or isovaleramide in vivo.
• the pharmacologicaUy active moiety corresponding to the alcohol portion may be expected to exert its own pharmacological effects.
• compounds such as "isovaleraminophen” would be expected to exhibit a "Tylenol ® -like” effect, similar to acetaminophen as weU as the effect expected from the isovaleric acid or isovaleramide moiety.
• Such novel chemical combinations of a previously known, pharmacologicaUy active alcohol, phenol, or primary or secondary amine with isovaleric acid faU within the scope of the present invention.
• the compounds of the present invention may be prepared using synthetic methods that are weU known in the art.
• many of the carboxyUc acid precursors of the amide compounds are commerciaUy available, for example from the Aldrich Chemical Co., MUwaukee, WI, and can be converted into the corresponding amide by preparation of the acid chloride with thionyl chloride or oxalyl chloride, foUowed by reaction with ammonia or an amine.
• the hydroxyl group first is protected using a suitable protecting group as described, for example, in Green, "Protective Groups in Organic Synthesis", WUey (1981), prior to preparation of the acid chloride.
• 2-hydroxy and 3-hydroxy isovaleramide are metaboUtes of isovaleramide in vivo, and can be isolated in high yield from the urine of a patient being treated with isovaleramide.
• the required acid can be prepared by straightforward methods of organic synthesis known to the skiUed chemist.
• carboxyUc acid esters may be deprotonated with a strong non-nucleophilic base, such as Uthium dusoropylamide, foUowed by alkylation with methyl iodide or methyl trifluoromethanesulfonate.
• the alkylated ester is hydrolyzed and converted to the amide by the methods described above.
• the individual enantiomers may be prepared from opticaUy active starting materials, or separated by traditional methods of resolution, such as fractional crystallization of salts with chiral amines, or by preparation of amides with chiral amides, chromatographic separation, and hydrolysis of the amides.
• the amides can be prepared by weU known methods of asymmetric synthesis, such as alkylation of an ester or amide of the acid prepared using a chiral auxiliary. See, for example, Evans et al, Tetrahedron, 44:5525 (1988) and Fadel et al. Asymmetry 1994:531.
• the present invention also is directed to pharmaceutical compositions containing the active compounds described above.
• the pharmaceutical compositions can contain a single active compound, or can contain combinations of two or more of the active compounds.
• the pharmaceutical formulations of the present invention can be prepared according to known methods to prepare pharmaceuticaUy useful compositions, whereby active agents are combined in a mixture with a pharmaceuticaUy acceptable carrier. For instance, see REMINGTON'S PHARMACEUTICAL SCIENCES and GOODMAN AND GILMAN'S, both cited above.
• a composition is said to be in a "pharmaceuticaUy acceptable carrier" if its administration can be tolerated by a recipient patient.
• Sterile phosphate-buffered saline is one example of a pharmaceuticaUy acceptable carrier.
• suitable carriers e.g. saline and Ringer's solutions
• skUled in the art. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, supra.
• the dosages of the antispasticity and anticonvulsant agents described herein wiU vary depending upon such factors as the patient's age, weight, height, sex, general medical condition, and previous medical history.
• a compound of the present invention and a pharmaceutically acceptable carrier are administered to a subject in need of such treatment in a therapeuticaUy effective amount.
• the combination of active agent and carrier is said to be administered in a "therapeuticaUy effective amount" if the amount administered is physiologicaUy significant.
• An agent is physiologicaUy significant if its presence results in a detectable change in the physiology of a recipient patient.
• an antispasticity agent is physiologicaUy significant if the presence of the agent results in the aUeviation of one or more symptoms of spasticity, whtie an anticonvulsant agent is physiologicaUy significant if the presence of the agent results in the reduction of the severity, number, or duration of convulsions.
• a compound is physiologicaUy significant if, upon administration to a patient, it can aUeviate or reduce a clinicaUy recognized symptom of that pathology.
• Isovaleramide and related compounds can be administered oraUy using soUd oral dosage forms such as enteric-coated tablets, caplets, gelcaps, or capsules, or via Uquid oral dosage forms such as syrups or elixirs.
• soUd oral dosage forms such as enteric-coated tablets, caplets, gelcaps, or capsules
• Uquid oral dosage forms such as syrups or elixirs.
• the indicated dosage of isovaleramide and related compounds as antispasticity agents is on the order of 50-
• Unit soUd oral dosage forms preferably contain about 50-800 mg per tablet or capsule, which typicaUy would be taken 1-2 at a time for a maximum of four times per day, at a dosage of 1-20 mg/kg body weight.
• Liquid formulations can also be employed with active ingredient compositions so as to provide 1-2 teaspoonfuls per dose.
• corresponding reduced dosage pediatric chewable and Uquid oral dosage forms also can be administered. These compounds also can be added to foods and beverages in the form of drops (with a dropper from a "concentrate" preparation) for oral administration.
• compounds such as isovaleramide may be formulated into chewing gum to facilitate oral deUvery and absorption.
• isovaleramide and related compounds can be administered by injection or other systemic routes, such as IV, transdermai or transmucosal a ⁇ ninistration, for example, nasaUy, buccaUy, or rectaUy, via suppositories. Oral administration is much more convenient, however, and therefore is preferred.
• the dosage level of active ingredients is on the order of 50-1200 mg per dose or 1-20 mg/kg body weight.
• isovaleramide and related compounds can be used, for example, as antispasticity agents or anticonvulsant agents, in animals such as cats, dogs, birds, horses, cattle, mink, poultry, and fish.
• the active compound may be administered by injection or other systemic routes, such as transdermal or transmucosal administration (for example, rectal administration via suppositories), or oraUy by addition to food or drink.
• transdermal or transmucosal administration for example, rectal administration via suppositories
• oraUy by addition to food or drink.
• the indicated oral dosage of isovaleramide and/or related compounds per kUogram of body weight of such animals is about 50-1200 mg/kg, depending upon the species of animal and the route of administration.
• the indicated oral dosage of isovaleramide and/or related compounds per kUogram body weight as anticonvulsant agents for animals is in the range of about 50-1200 mg/kg, depending upon the species of animal and the route of administration.
• the present invention thus contemplates a variety of pharmaceutical compositions containing the active compounds described above (including isovaleramide, isovaleric acid, and/or its pharmaceuticaUy acceptable salts, substituted amides, alcohol esters, sulfonamide. sulfamate, and carbamate analogs) as active ingredients that are suitable for oral, IN, parenteral, transdermal, transmucosal, intranasal, buccal, or rectal administration.
• active compounds described above including isovaleramide, isovaleric acid, and/or its pharmaceuticaUy acceptable salts, substituted amides, alcohol esters, sulfonamide. sulfamate, and carbamate analogs
• the common feature of the present formulations is that isovaleramide, isovaleric acid, and/or its pharmaceuticaUy acceptable salts, substituted amides, alcohol esters, and sulfonate, sulfamate, and carbamate analogs, are present in a standardized amount. That is, the pharmaceutical formulations contain a predetermined, chemicaUy defined, and quantifiable amount of at least one of such compounds to enable the determination of the quantity 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 pharmaceuticaUy active ingredients.
• the mutant spastic mouse is a homozygous mouse that carries an autosomal recessive trait of genetic spasticity.
• the mouse is normal at birth, and then the mouse develops a coarse tremor, abnormal gait, skeletal muscle rigidity, and abnormal righting reflexes at two to three weeks of age. No structural abnormaUties have been found. Rather, the mouse has a deficit of glycine receptors throughout the central nervous system.
• Drags that either potentiate the binding or synthesis of GABA, such as valproate and the benzodiazepines, are effective compounds to ameUorate some of the symptoms of spasticity in this model, as weU as in humans.
• the assessment of spasticity in the mutant spastic mouse can be performed by electrophysiological assessment simUar to the EMG recordings described below.
• Tremor can be evaluated by holding mice by their taUs and rating the tremor subjectively by "absent,” “sUght,” “moderate,” or “severe.”
• FlexibiUty is assessed by placing the mouse on a glass object with smoothly rounded grooves and rims. The glass object is tifted about 12 inches above the table and slowly tilted until almost vertical.
• spasticity There are several models of spasticity including the acute decerebrate rat, the acute or chronic spinaUy transected rat, and the chronicaUy spinal cord-lesioned rat.
• This method is based on that described by Irwin, Psychopharmacologia 13: 222-57 (1968). It is used to detect physiological, behavioral, and toxic effects of a test substance, and indicates a range of dosages that can be used for later experiments.
• TypicaUy rats (three per group) are administered the test substance and are then observed in comparison with a control group given vehicle. Behavioral modifications, symptoms of neurotoxicity, pupU diameter, and rectal temperature are recorded according to a standardized observation grid derived from that of Irwin.
• the grid contains the foUowing items: mortaUty, sedation, excitation, aggressiveness, Straub tati.
• test substance can be administered intraperitoneaUy (i.p.) subcutaneously (s.c.) or oraUy (p.o.).
• One useful model is provided by the Frings audiogenic seizure-susceptible mouse, a model of reflex epUepsy.
• individual mice are placed into a round Plexiglas chamber and exposed to a sound stimulus of UO decibels, 11 kHz, for 20 seconds. Animals not displaying tonic hindlimb extensions were considered protected.
• the seizure score for each mouse can be recorded as: (1) running for less than 10 seconds; (2) running for greater than 10 seconds; (3) clonic activity of limbs and/or vibrissae; (4) foreUmb extensio-t-yhindUmb flexion; and (5) hindlimb extension.
• the average seizure score can be calculated for each group of mice employed in the dose-response study. At each dose, mice are also tested on a rotarod for testing of motor impairment (toxicity). Testing for motor impairment on the rotarod involves placing a mouse for a three-minute trial period on a one-inch diameter rod rotating at six revolutions per minute. If the mouse Ms off of the rotating rod three times within the three-minute time period, it is considered a toxic response.
• the amphetamine-induced hyperactivity model in rats can be used to assess the possible use of compounds in the treatment of affective mood disorders. In addition to being a test for classical and atypical antipsychotic activity, this procedure has also been proposed as a simple animal model of manic behavior. CostaU et al., Brain Res. 123: 89-111 (1977).
• Anticonvulsants such as cambamazepine, that have shown efficacy in kindled models of epUepsy, have also demonstrated efficacy in reducing the symptoms of affective mood disorders and substance abuse/craving in patients (Post, /. CUn. Psychiatry 50: 45-47, (1989), Halikas, et al., Lancet 18: 623- 624, (1989); Blumer et al., Compr. Psychiatry 29: 108-122, (1988)).
• antiepileptogenic refers to the idea of inhibiting the processes that underly the development of epUepsy thereby providing a "neuroprotective" effect.
• Anticonvulsant refers to the acutal inhibition of seizures in an epileptic model. Several models of kindling are useful. The amygdala-kindled rat is such a model (Tober, C, Eur. J.
• Seizure kindling models are characterized by giving a sub-seizure eliciting electrical or chemical stimulus (i.e., sub-threshold) over a period of time (Goddard et al.; 1969).
• Acute cerebral insults such as status epilepticus, traumatic injury and stroke induce damage to selective neuronal populations in the hippocampus (Matsuyama, et al., J. Cereb. Blood Flow Metab. 13: 229-234, (1993));
• Stroke in humans is a highly variable clinical condition, dependent upon pre-existing disease in a patient, the site and severity of the stroke, the type of stroke (ischemic or hemorrhagic), and the time from onset to presentation for treatment.
• a number of animal models of stroke have been developed over the past several years to aid in our understanding of die pathophysiological mechanisms of neuronal injury and to allow for the evaluation of potential neuroprotective agents (Ginsberg et al, Stroke 20: 1627-1642, 1989; Hunter et al, Trends. Pharmacol Sci. 16: 123-128, 1996).
• a major goal of these animal models has been to reduce the biological variability, by controlling or eliminating the variables mentioned above, to facUitate data analysis and interpretation. In doing so, however, these animal models do not perfectly mimic the human condition.
• the subject decided to consume a preparation of valerian that was noted for its sleep-aid properties.
• the valerian product "Baldriparan stark N,” consists of tablets manufactured in Germany that contain extracts of valerian root, hops, and lemon balm.
• the coated, pressed tablets each contain 95 milUgrams of a dried 70% (v/v) ethanol extract of valerian root, 15 milligrams of a dried 45% (m/m) methanol extract of hops, and 85 milligrams of a dried water extract of lemon balm.
• valerian preparation not only facihtated the onset of sleep and improved the quatity of sleep for the subject, but it was also noticed that the painful extensor spasms were aUeviated.
• the subject noted that upon awakening during the night to use the bathroom, she did not experience the painful extensor spasms upon getting out of bed nor the usual stiff-leg sensation.
• the subject continues to consume the same valerian product for the aUeviation of these symptoms on an as- needed basis (prn or pro re natd) and continues to experience reUef.
• the subject Upon taking the same German-made preparation of valerian described in Example 1, the subject noted considerable improvement in the quaUty of sleep as weU as a significant reduction in night-time extensor spasms. This subject continues to consume the preparation on an as-needed (prn) basis for the aUeviation of the symptoms described above.
• Example 3 Isovaleramide Antispasticity Tests (1) Assessment of Spasticity in Chronic SpinaUy Transected Rats
• mice male albino Holtzman-derived rats (Harlan Sprague-Dawley Laboratories) weighing 270-530 grams were used as subjects. The animals were housed independently and had continuous access to food and water throughout the experiments.
• a commercial antibiotic cream was appUed to any part of the skin that showed signs of decubitus lesions. Within approximately two weeks, aU animals regained bladder control and were no longer given antibiotic treatment. Advokat, Brain Res. 684: 8 (1995). Assessment of spasticity was performed before and after drag treatment such that each animal served as its own control.
• Initial assessment of spasticity was- performed by the subjective scoring method of rating the resulting spasticity response eUcited with an innocuous stimulus, i.e., a metal probe, that 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 aU four trials) to four (a maximum, tonic-clonic reaction elicited in aU four trials).
• the spasticity scores had essentiaUy returned to baseline values. No overt behavioral toxicity or motor impairment was observed at this dose.
• the rats were alert and able to grasp with their non-paralyzed front paws as were the control, untreated rats.
• the polysynaptic flexor- reflex responses to test stimuli which activate high-threshold afferents, were recorded as EMG activity from the ipsUateral hamstring muscle.
• Supramaximal electric shocks were appUed to the hindpaw, and recording electrodes were placed in the biceps femoris semitendinosus muscle. Five sets of stimuti were made at each time point.
• the flexor reflex was recorded, in both the pre-drag and the post-drug periods, every 30 minutes once a stable baseline response was achieved. See Hao etal., Eur. J. Pharmacol 191: 407 (1990).
• the responses were determined in spinalized rats by observing the flexor-reflex response (Figure 3) before treatment and at each of 30, 60, 90, and 120 minutes foUowing administration of isovaleramide (300 mg/kg p.o.), baclofen (10 mg/kg s.c.) and vehicle (water, 12 ml/kg p.o.), respectively.
• Isovaleramide was shown to reduce the magnitude of the flexor-reflex responses, at aU time points in a chronic spinaUzed rat with Malawiar efficacy to baclofen, the positive control.
• isovaleramide Administered i.p. in the rat, isovaleramide induced no changes from saline- injected controls at doses up to 256 mg/kg. At 512 mg/kg, sUght sedation from 60 to 120 minutes, loss of traction (observed in only one of three rats) at 120 minutes, and decreased muscle tone from 60 to 120 minutes were observed. At 1024 mg/kg, marked sedation up to 30 minutes was observed, becoming moderate up to 120 minutes, then stight at 180 minutes. Decreased fear also was observed at this dose up to 30 minutes and in one of three rats up to 120 minutes.
• Isovaleramide administered at doses up to 512 mg/kg (i.p.) 15 minutes before a test on the rotarod in the Frings mouse, did not affect performance significantiy. In contrast, doses of 300 mg/kg, 600 mg/kg, and 1000 mg/kg (i.p.) decreased rotarod performance in 1/8, 4/8, and 8/8 of Frings mice tested, respectively.
• Isovaleramide also displayed a quick onset and a relatively short duration of action. Anticonvulsant activity was noted as early as 15 minutes, but decreased substantiaUy by two hours. AU quantitative studies therefore were conducted at 15 minutes. At this time point, the median effective dose (EDso) for protection against tonic extension was 126 mg/kg, i.p. In addition, a dose-dependent reduction in seizure score was observed at this time point. At doses markedly higher than those providing anticonvulsant activity ( > 300 mg/kg), animals treated with isovaleramide displayed behavioral toxicity that was characterized by their inability to maintain their balance on the rotarod. No notable toxicity was observed at doses less than 300 mg/kg.
• the median toxic dose (TDso) for rotarod impairment was 531 mg/kg, i.p.
• the calculated protective index (TDso/EDso) was about 4.2. Therefore, despite the relatively low potency of isovaleramide in this model, it stiU displayed a relatively good separation between activity and toxicity.
• Isovaleramide thus had a surprising and unexpected efficacy, based on existing structure-activity relationships for amides and their corresponding acids, as an anticonvulsant in the Frings audiogenic seizure-susceptible mouse model of reflex epUepsy.
• the activity profile of isovaleramide is similar to that of the broad- spectrum anticonvulsant, sodium valproate.
• Isovaleramide was evaluated for its ability to block the expression of amygdala-kindled seizures in fully kindled rats. Isovaleramide was evaluated for its ability to block the kindled motor seizure (seizure scores of 4 and 5) and limbic behavioral seizures (seizure score between 1-3) as well as to affect changes in afterdischarge duration.
• Adult, male Sprague-Dawley rats weighing at least 230 gr were implanted with a teflon-coated bipolar electrode sterotaxically placed in the anterior basolateral nucleus of the amygdala under ketamine and xylazine anesthesia.
• the electrode was implanted at the following coordinates with Bregma as zero: AP-2.2 mm, ML-4.7 mm, DV-8.7 mm.
• animals were kindled to Stage 5 behavioral seizures using a stimulus consisting of a 50 Hz, 1 sec train of 1 ms biphasic 150 uA pulses that were delivered once daily until 10 consecutive stage 5 seizures were evoked.
• Testing of isovaleramide was initiated after a one-week, stimulus-free period.
• rats displaying a stage 5 seizure were divided into multiple treatment groups (i.e. vehicle control and isovaleramide treatment).
• Seizure score was classified according to Racine (Electroencephalogr. CUn. Neurophysiol. 32:281-294, (1972): stage 0: no abnormal behavior; stage 1: mouth or facial movements; stage 2: mouth or facial movements and head nodding; stage 3: stage 2 and forelimb clonus; stage 4: stage 3 and rearing; stage 5: stage 4 and falling.
• a score of 2-3 represents a focal seizure while a score of 4-5 represents secondarily generalized seizures.
• Afterdischarge duration was the total duration of the amygdala electroencephalogram spikes with an amplitude of at least twice the amplitude of the prestimulus recording and a frequency greater than 1/sec.
• Isovaleramide was effective in reducing in a dose-dependent manner the generalized seizure responses of fully kindled rats. Isovaleramide decreased the mean seizure score and the afterdischarge duration showing that it exerts anticonvulsant activity against both focal( seizure score 1-3) and secondarily generalized seizures (seizure score 4-5).
• 230 gr were implanted with a teflon-coated bipolar electrode sterotaxically placed in the anterior basolateral nucleus of the amygdala under ketamine and xylazine anesthesia.
• the electrode was implanted at the following coordinates with Bregma as zero: AP-2.2 mm, ML-4.7 mm, DN-8.7 mm.
• mice were stimulated at a suprathreshold current of 300 uA for 1 second daily (i.e, except weekends) until all control animals exhibited 7 consecutive stage 5 seizures (Racine, 1972). After 11 treatment days, all animals were permitted a 7-day drag- and stimulus-free period. Animals were then challenged with 300 uA once daily starting at day 18 until all animals displayed 5 consecutive stage 5 seizures. Seizure score and afterdischarge duration were recorded after each stimulation. Seizure score was classified according to Racine scale(1972): stage 0, no abnormal behavior; stage 1, mouth or facial movements; stage 2, mouth or facial movements and head nodding; stage 3, stage 2 and forelimb clonus; stage 4, stage 3 and rearing; stage 5, stage 4 and falling.
• a score of 2-3 represents a focal seizure while a score of 4-5 represents secondarily generalized seizures.
• Afterdischarge duration was the total duration of the amygdala electroencephalogram spikes with an amplitude of at least twice the amplitude of the prestimulus recording and a frequency greater than 1/sec.
• the results demonstrate the antiepiletogenic effect of a daily 500 mg/kg p.o. dose of isovaleramide, which delayed the increases in both seizure score and afterdischarge duration which normally develop during electrical kindling in the amygdala-kindled rat.
• isovaleramide at this dose elicited a delay in the acquisition of seizure development, over time, the rats eventually developed full stage 5 seizures.
• isovaleramide has a quick onset of action with a relatively short biological half-life. A greater antiepileptogenic effect may have occurred if the dosing schedule had been maximized for longer exposure.

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