Patent Publication Number: US-4322440-A

Title: Anticonvulsive compositions and method of treating convulsive disorders

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a group of pharmaceutically acceptable amino-carboxylic acids and their amide derivatives and to pharmaceutical uses for these compounds. More particularly the invention pertains to the use of these compounds as anti-convulsant, sedative and anxiolytic agents in mammals. 
     2. Description of the Prior Art 
     Certain induced, recurrent, generalized seizures in mammals can be prevented by the administration of glutamine (GLN). These seizures have been thought to be related to the depletion of brain glutamine and its product gamma-amino-butyric acid (GABA), which is known to be a major inhibitory neurotransmitter substance acting between the nerve cells in the brain. Decreased GABA in the brain causes seizures. A precursor of GABA is the amino acid glutamine. GABA itself cannot be used clinically to prevent seizures because it does not cross the blood-brain barrier and has serious side effects (hypotension, shock, mortality). Glutamine is metabolized too quickly to be pharmacologically effective. 
     Several investigators have indicated that the use of GABA agonists given systemically is not associated with a useful anti-convulsant effect. For example, Meldrum (in an article published in The Lancet, August 5, 1978, at p.304-306) teaches that diffuse activation of GABA receptors by GABA or a GABA agnoist given systemically does not provide a useful anti-convulsant effect. An article by Tsuchiya et.al., in Journal of the Physiological Society of Japan, 22,70-74 (1960) reports on the administration to mice of GABA and delta-amino valeric acid (DAVA) ten minutes before inducing convulsions by the application of electroconvulsive shock. The results reported by the authors demonstrate that DAVA is ineffective in preventing or inhibiting convulsions and after initial testing the compound was dropped from subsequent anticonvulsant trials as reported in the article. 
     It has now been unexpectedly discovered that DAVA&#39;s anticonvulsant activity is delayed after introduction and administration of DAVA and other related amino-carboxylic acids either as free amino acids or their amide derivatives can be used to prevent seizures in mammals or decrease the severity of convulsive episodes. 
     It has also been surprisingly found that these amino acid components are useful an anxiolytic agents in mammals. 
     Accordingly, it is an object of the present invention to provide a method of preventing seizures, and particularly epileptic seizures in mammals. 
     Another object of the present invention is to provide pharmaceutical dosage forms containing amino acid compositions which are analogs of glutamine, thus making more glutamine available for conversion to GABA. 
     Still another object of the present invention is to provide pharmaceutical formulations comprising an effective amount for inhibiting the onset of seizures of an amino acid composition in a solid or liquid dosage form. 
     A further object of the present invention is to provide an effective method of administering the anti-convulsant compositions disclosed herein. 
     A further aspect of the present invention is to provide effective sedative compositions. 
     These and other aspects of the invention will be apparent from the following description. 
     Convulsive disorders (e.g. epilepsy, seizures, fits, convulsions) have in common the occurrence of brief episodes. These episodes are associated with loss or disturbance of consciousness. Such episodes are usually but not always associated with characteristic body movements, and sometimes with autonomic hyperactivity. They are generally correlated with abnormal EEG discharges. The etiology of such disorders is varied and includes, e.g., genetic diseases, metabolic dysfunction, tumors and trauma. 
     The amino acids found to be useful as anti-convulsant and anxiolytic agents in the present invention may be generally described as aliphatic compounds in which the carboxylic acid and primary amine are separated by three or four units constituting a simple or substituted alkane, an ether or thioether, or an amide forming the backbone of a straight or branched chain molecule. The amine and carboxylic acid are either free acids or an amide and/or ester derivative of the acid. The amide and ester forms have been found to facilitate entry of the compound into the brain. 
     The active compositions of the present invention are represented by the following general formula: ##STR1## wherein 
     R 1  is H, ##STR2## 
     A is H, Ch 3 , CH 3  CH 2  --, HO--CH 2 , HO--CH 2  CH 2 , CH 3  OCH 2  -- HS--CH 2  --, HS--CH 2  CH 2  --, CH 3  SCH 2  --, 
     Y is C═O, HC--OH or, CH--A, 
     Z is CH--A, O, S; or NH only if Y is C═O, and 
     R 2  is --OH, --NH 2  or CH 3  --CH 2  --O--, 
     N is 0 or 1, and Y is CH--A when N═O; and 
     A+Y+Z include no more than one Oxygen or Sulfur atom 
     The preferred anti-convulsant of the present invention is DAVA or delta aminovaleric (5-aminopentanoic) acid of the formula: ##STR3## 
     Aside from its anxiolytic and anticonvulsant activity, DAVA and other compounds of the general formula have been found to posess sedative properties when administered in effective amounts for this purpose. 
     In administering DAVA and the other compositions of the inventin it has been found desirable to reduce their acidity by buffering them to between about pH 4.0 to about pH 6.8. Preferably the present compositions are buffered to pH 4.5. This buffering action can be achieved by co-administering DAVA or the other active agents with a pharmaceutically acceptable organic or inorganic buffering agent. Illustrative buffering agents for the present invention include calcium citrate, calcium carbonate, aluminum hydroxide, sodium bicarbonate, magnesium oxide, magnesium carbonate and sodium carbonate. 
     In considering the substituents of the general formula described above it has been noted that only a single oxygen or sulfur atom is present in A, Y and Z. The preferred constituent of the R 1  group is hydrogen although acetyl ##STR4## is also desirable at this position. Besides the R 1  groups shown to be useful in the general formula, acyl groups derived from other simple metabolizable organic acids such as, citric, or butyric acid have been found useful. 
     As constituent A of the general formula hydrogen is the preferred moiety. However, compounds in which A is a CH 2  --OH group have been found to perform almost as well as those which contain the H moiety. 
     In addition to the moieties enumerated in the general A formula set forth above, anxiolytic and anticonvulsant activity has also been found in compounds of the general formula wherein the A constituent is selected from groups having homologous side chains with 3 or 4 carbons in a straight or branched chain configuration. Representative of this class of constituents is 5-amino-4 hydroxy octanoic acid. 
     The preferred constituents of the Y and Z groups is CH 2 , which is especially preferred. As to the Z groups, it should be noted that NH may only be present at this position when the Y constituent is &gt;C═O. 
     Hydroxy (--OH) is the especially preferred constituent at the R 2  position in the general formula for the present pharmaceutical compounds, although amino (--NH 2 ) is also a preferred R 2  constituent. Compounds in which other esters and amides (e.g. peptides) are constituent R 2  have shown some anticonvulsant activity, but are not believed to offer any particular benefit or advantage over those in the general formula. 
     In addition to DAVA, the preferred compound of the present invention, 5-amino-4-oxo-pentanoic acid, 2-aminoethoxy acetic acid, 2-aminoethylthio acetic acid, and 5-amino-4-hydroxy pentanoic acid, also display anticonvulsant and anxiolytic properties in animals. 
     Although principal use of the compounds of the invention is anticipated to be as oral or parenterally administered pharmaceutical agents for prevention, inhibition or arrest of epileptic discharges in humans, the desirable sedative properties of DAVA are also of great significance. This is particularly true in view of the relatively non-toxic nature of the present compounds and the fact that they may be synthesized at relatively low cost. 
     The compositions of the present invention are preferably administered via the oral route, although parenteral administration by subcutaneous, intramuscular annd intravenous injection is also effective. The oral dose may take the form of a tablet, capsule, pill, beadlet or other solid dosage unit. The active ingredients may be compounded in the desired oral form in combination with inert ingredients including fillers such as talc, lactose, starch, bentonite and diatomaceous earth; lubricants and food flavorings. 
     Liquid oral doses in the form of solutions, and suspensions are also contemplated by the invention. For parenteral administration the compounds of the invention are preferably dissolved in distilled water, isotonic saline solution or any other pharmaceutically acceptable carrier liquid. 
     Several of the (4-) and (5-) amino carboxylic acid compounds in this series are commercially available. They include among others, 5-aminopentanoic acid, 5-aminolevulinic acid, and glycylglycine, all available from Sigma Chemical Company, St. Louis, Mo. 
     The other compounds of the general formula can be directly prepared by conventional synthetic procedures or using processes described in the literature. Thus, 2-aminoethoxy-acetic acid may be prepared according to the synthesis taught in Acadamie des Sciences, Paris. Comptes Rendus Hebdomadaires des Seances (Compt. Rend.) 234, 1980 (1952), CA 47,2761e. 5-amino-hexanoic acid can be synthesized by the method in Ricerca Scientifica 1, IIA, 312 (1961), CA57,9658h. 5-amino-4-hydroxy-pentanoic acid is prepared by reduction of 5-aminoevulinic acid using the procedure taught in Biochemical Biophysical Research Communications 39, 135 (1970); and 4-amino-5-hydroxy-pentanoic acid, synthesized by the method in Biochemica Biophysica Acta 8, 287 (1952), CA 47, 4843d. Other compounds of the invention such as 2-acetoxy-1-propylamine, 1-acetoxy-2-propylamine, 2-acetoxy-1-butylamine, 1 acetoxy-2 butylamine and 2-amino-ethylthio-acetic acid are prepared by adaptation of the method for preparing 2-amino ethoxyacetic acid (taught in the Compt. Rend. article referred to above) by substituting, respectively, in the synthesis of each of the above amino acids: 1-amino-2-propanol, 2-amino-1-propanol, 1-amino-2-butanol, 2-amino-1-butanol and 2-amino-ethylthiol. 
     It is to be understood that where an amino acid compound described in the art is identical with one of the above specified named compounds, but has been known by another name by reason of isomerization or production in accompaniment with other compounds, the identification of such substances by the name set forth above is intended to identify the same compound under all other designations. 
     When used as anticonvulsant agents in mammals, the present compositions are administered at a dosage level of from about 0.03 to about 50 mmol of active ingredient per kilogram of body weight. For parenteral administration the compounds of the invention are desirably administered in a 1.5 M solution in isotonic (normal) saline. The daily effective dosage, or the dosage required to prevent or inhibit convulsions from a particular disease or stimulus depends upon the condition being treated, the individual characteristics of each mammal being treated and the nature of the physical or chemical stimulus inducing or responsible for the convulsive activity. Thus, the exact dose required to alleviate convulsions attributable to a particular disorder or stimulus will vary from one patient to another. The anxiolytic properties of the present compounds are evident in the same dosage ranges employed for anticonvulsant treatment. Sedative properties of the present agents are apparent at approximately twice the anti-convulsant dosages, i.e., dosages of between about 0.06 and 100 mmol active ingredient per kilogram of body weight are sedative dosages. 
     Solid pharmaceutical dosage forms such as pills, capsules, and tablets may contain from 5 to about 750 milligrams of active ingredient. Preferably from about 50 to about 500 milligrams of active ingredient is incorporated in each solid dosage form together with the required amount of buffering compound to bring the pH of the dosage unit to about 4.5. 
     The liquid dosage forms of the present invention are preferably administered in the form of a solution or suspension in a pharmaceutically acceptable vehicle, preferably distilled water. Liquid dosages containing from about 5-100 milligrams of active ingredient per cubic centimeter of vehicle have been found to be useful in administering these agents to mammals. The preferred concentration within this range will depend upon the age and weight of the subject being treated. 
     It is also contemplated that the anti-convulsant agents of the invention may be administered in the form of rectal suppositories. Suitable suppository dosage forms may be prepared by incorporating the active agent into a shapeable base material. Among the suppository bases that can be used to prepare suppositories according to the present invention are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. Rectal suppositories for adults are tapered at one end, usually weigh about 2-4 grams and may contain from about 5 to about 500 milligrams of active ingredient. Preferably such suppositories are made from one or more bases having a melting point that will enable them to melt or dissolve slowly upon retention in the rectal cavity. 
     The anticonvulsant activity of the instant aminocarboxylic acid compounds was measured against seizures produced in female DBA/2J mice using: L-methionine-RS-sulfoximine (MSO), 100 mg/Kg injected subcutaneously (SC), pentylenetetrazole (PTZ), 65 mg/Kg, SC or electroconvulsive shock (ECS), 18 mA at 380 V for 0.1 sec. These are standard test conditions which produce convulsions in 90-100% of saline injected (control) animals. 
     In testing representative compounds of the invention for anti-convulsant activity Glycylglycine (Glygly), Glycine (Gly), Glutamine (Gln), 5-amino-valeric acid (DAVA) and 5-amino-levulinic acid (DALA) were administered to the DBA/2J animals SC at 15 mmol/kg body weight or orally at 30 mmol/kg of body weight. The active ingredients were injected or administered 45 minutes after MSO injection or 60 minutes before PTZ or ECS administration. Saline injected controls were treated in parallel with those animals receiving an active dose. In some instances glygly injected animals and saline controls were given ECS after 180 minutes. 
     An important aspect of the present invention involves administration of the active anti-convulsant substantially prior to the application or onset of the convulsive stimulus or attack. Generally the active agent should be administered from at least 30 minutes to 4 hours or more before application or onset of the seizure stimuli whose inhibition is sought. The interval between administration of the agent and observation of its anticonvulsant effect is believed to be attributable to the fact that the mode of action of these agents is to spare glutamine, a GABA precursor, thus making more Glutamine available for the production of GABA. During this latency, the glutamine which has been spared must travel to the pre-synaptic terminals of the neurons where it is metabolized to GABA. Glutamine also plays an important role in other metabolic processes in the brain. Thus, the mechanism of action of the active compounds in the present invention is believed to be different than for prior art anticonvulsant agents which directly affect the ability of the synapses to transmit neural impulses. 
     For administration via the parenteral route in mice, the acid compounds of the invention were injected subcutaneously, in isotonic saline solution, at a dose of 15 mmol/KG body weight. Anti-convulsant activity against seizures produced by MSO or PTZ was determined by measuring the difference in time to onset of seizures between experimentally treated animals and saline injected control animals. The effectiveness against ECS seizures was measured on a four point scale with seizure severity being scored as follows: Seizure with full extension and death, 3; seizure with full extension, 2; clonic seizure without tonic extension, 1; no seizure, 0. 
    
    
     EXAMPLE I 
     5-amino-4-hydroxypentanoic acid was prepared according to the following procedure: 
     222 mg NaBH 4  was dissolved in 30 ml 0.1 M NaHCO 3 . 5 ml of this solution (1000 μmoles of NaBH 4 ) was added to 250 μmoles (32.8 mg) of δ-amino-levulinic acid (5-amino-4-oxo-pentanoic acid) in 5 ml of water. The mixture was stirred at room temperature for about 20 hours. The excess NaBH 4  is destroyed by adding HCl dropwise until the pH is 2. ##STR5## 
     EXAMPLE II 
     γamino-δ-hydroxy valeric acid (4-amino-5-hydroxypentanoic acid) was prepared according to the following procedure: 
     353 mg of γ-L-glutamylglycine was added to 5 ml absolute ethanol containing 0.11 N HCl (dry gas) and the mixture stirred for a half hour at room temperature. The alcohol was then removed under vacuum and the ethyl ester of the dipeptide was dried under vacuum with P 2  O 5 . 174 mg of this product was finely emulsified in 10 ml of N-ethylmorpholine containing 180 mg of lithium aluminum hydride. The mixture was stirred for 8 hrs. under an atmosphere of dry nitrogen at 50° C. The excess hydride was destroyed with a drop of water and the precipitate filtered and washed with ether to remove the morpholine. The precipitate contains almost all of the diol, a yield of about 31%. The precipitate was subjected to Soxhlet extraction for 24 hours with dry ether after acidification with a drop of concentrated H 2  SO 4 . This removes the residual N-ethylmorpholine. The peptide diol remaining in the precipitate is hydrolyzed with 6 N HCl at 110° C. for 24 hours in a sealed tube. The residual HCl is evaporated, the solution desalted and the 4-amino-5-hydroxypentanoic acid isolated by [paper] chromatography. ##STR6## 
     EXAMPLE III 
     5-Aminohexanoic Acid was prepared by combining 0.5 g 2-methylcyclopentanone and 9.5 ml 2 N NaOH in sufficient ethanol to give a homogeneous solution. The mixture was cooled to 0° C., 0.9 g of benzene sulfohydroxamic acid (C 6  H 5  SO 2  NHOH) was added, and the mixture stored overnight in the refrigerator. Thereafter the mixture was concentrated in vacuo and extracted with ether. The post-extraction residue is brought to between pH 5-6 with 2 N HCl and extracted with chloroform to give an oil bp. 70°-80° C. (4 mm), 7-8% yield. This product N-hydroxy-6-methyl-2-piperidone, is reduced with hydrogen over 10% palladium-charcoal to a lactam, 6-methyl-2-piperidone (mp. 79°-80° C.). The lactam is hydrolyzed with aqueous Ba(OH) 2  to yield 5-amino-hexanoic acid. ##STR7## 
     EXAMPLE IV 
     2-aminoethoxy-acetic acid was prepared by dissolving 35 g of ethanolamine in 100 ml anhydrous dioxane. 11.5 g sodium metal was slowly added in small portions with stirring and heated until fully dissolved. To this solution 63 g of monochloroacetic acid was added dropwise while cooling the mixture. The mixture was then refluxed for 2 hours to precipitate sodium chloride which is filtered off. The dioxane is removed by evaporation. The product, 3-morpholone, is extracted with boiling benzene. Colorless, needle-shaped crystals are obtained which are crystallized in anhydrous ether (mp. 105° C.). An additional quantity of crystals can be obtained by washing the sodium chloride precipitate with boiling ethanol. The total yield is 70%. The lactam is easily hydrolyzed to 2-aminoethoxy acetic acid with aqueous Ba(OH) 2  which is easily crystallized (mp. 182° C.). ##STR8## Substitution of other amino alcohols or amino-ethanethiols can be used to obtain the 4- and 5-methyl substituted compounds or the analogous thio ethers. 2-acetoxy-1-propylamine, 1-acetoxy-2-propylamine, 2-acetoxy-1-butylamine, 1-acetoxy-2-butylamine and 2-amino-ethylthioacetic acid are prepared by adaptation of the method for preparing 2-amino ethoxyacetic acid (taught above) by substituting, respectively, in the synthesis of each of the above amino acids: 1-amino-2-propanol, 2-amino-1-propanol, 1-amino-2-butanol, 2-amino-1-butanol, and 2-amino-ethylthiol. 
     The following examples illustrate the anti-convulsive, sedative and anxiolytic qualities and the method of administration and compositions of the present invention: 
     EXAMPLE V 
     Female DBA/2J mice were injected with normal saline solution, the volume of solution (ml) being equal to 0.01 times the body weight in grams. Either 60 or 180 min. later the animals were attached by ear clips to a conventional laboratory electroshock apparatus which delivered 18 mA at 380 V for 0.1 sec. (constructed according to the principle of Behavioral Research Methods &amp; Instruments, Vol. 4, p. 313, 1972). The severity of seizures was scored using a system where 0 is no seizure, 1 is a clonic seizure, 2 is a seizure with extension, and 3 is a seizure with extension and death. 
     
         ______________________________________                                    
             RATING SCALE  Total                                          
             0    1      2      3    No.                                  
______________________________________                                    
Saline   60 min.   1      7    15   3    26                               
Saline  180 min.   0      3    5    2    10                               
______________________________________                                    
 
    
     A second group of animals were injected subcutaneously with a delta-amino acid of the invention, at a dose of 15 mmoles/kg using a 1.5 M solution in normal saline. These mice were also tested at 60 or 180 minutes using the electroconvulsive shock apparatus. The following results were recorded: 
     
         ______________________________________                                    
SCORE                                                                     
                                      Fisher&#39;s                            
            Total                     Exact                               
Time        No.     0     1   2   3   Probability                         
______________________________________                                    
5-Amino-                                                                  
pentanoic                                                                 
       60 min.  25      17  4   4   0   0.00000202                        
Acid                                                                      
Amino-                                                                    
levulinic                                                                 
       60 min.  10      6   2   2   0   0.00131                           
Acid                                                                      
Glycyl-                                                                   
glycine                                                                   
       180 min. 10      6   2   1   1   0.0108                            
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     Application of Fisher&#39;s Exact Probability test to the results confirmed that the lessened seizure incidence in the treated animals was a statistically valid observation and not a chance occurrence. 
     EXAMPLE VI 
     Two groups of DBA/2J female mice were injected subcutaneously with saline (0.01 ml×body weight in grams) or an active compound of the invention (15 mmol/kg of body weight). After 60 min. the animals were injected subcutaneously with the chemical convulsant pentylenetetrazol at a dose of 65 mg/kg body weight. The incidence of seizure activity was observed and recorded for each animal with the following results. Severity was scored by the presence or absence of seizures and the time to onset (latency). 
     
         ______________________________________                                    
               #Animals  #Animals  Average                                
         Total Without   With      Latency                                
         No.   Seiz.     Seiz.     Time                                   
______________________________________                                    
Saline     20      0         20       5.6 min.                            
5-Amino-                                                                  
pentanoic acid                                                            
           20      6         14      10.7                                 
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     As determined by Fisher&#39;s exact probability test (two-tailed), the probability that the six animals without seizures was due to random chance was 0.0202. The probability that the delay of seizures in the drug treated animals was due to random chance, was evaluated by the students T-test and was determined to be P&lt;0.0001. This confirms that the results are valid and not chance observations. 
     EXAMPLE VII 
     A group of DBA/2J female mice were given a 1.5 M aqueous solution of 5 aminopentanoic acid by stomach tube at a dose of 30 mmoles/kg. of body weight. A group of control animals were given an equivalent volume of water (0.02 ml/g) by the same route. Seventy-five minutes after administration of the active or control dose, electroconvulsive shock (18 mA, 380 V, 0.1 sec.) was administered, and the animals observed for evidence of seizures. The following results were recorded: 
     
         ______________________________________                                    
                         Number with Seizures                             
         Total Without   &amp; Severity                                       
         No.   Seizures  1       2     3                                  
______________________________________                                    
Water      19       2        5     9     3                                
5-Amino-                                                                  
pentanoic Acid                                                            
           16      10        3     0     3                                
______________________________________                                    
 
    
     The probability that the observed freedom from seizures was due to chance alone was examined using Fisher&#39;s Exact Probability test (two-tailed) and it was found that p=0.00328. This is evidence of a statistically valid observation. 
     TABLE I 
     Seizure incidence and latency to onset in mice receiving various test agents (subcutaneous administration) 45 min. after administration of L-Methionine-RS-Sulfoximine (MSO, 100 mg/Kg). 
     Effect of glycine, glycylglycine, and δ-amino-valeric acid (15 mmoles/kg, S.C.) given 45 min. after L-methionine-RS-Sulfoximine (MSO, 100 mg/kg, S.C.). N=total number of animals. Probability of freedom from seizures by chance alone, determined by Fisher&#39;s exact probability test (two-tailed): a,=0.0144; b,=0.00787. Significance of the difference in seizure onset time measured by the t-test (two-tailed): c, p&lt;0.0001; d, p&lt;0.003; e, p&lt;0.00005, f, p&lt;0.002. 
     
         ______________________________________                                    
               Without  With   Latency to                                 
Treatment                                                                 
         N     Seizures Seizures                                          
                               Seizure Onset (min.)                       
______________________________________                                    
Saline   20    0        20     248 ± 7.5                               
Gly       4    0        4      158 ± 21.0 c                            
Glygly   14    5 a      2      164 ± 0 d                               
                        7      354 ± 29.9 e                            
DAVA     12    5 b      7      338 ± 36.5 f                            
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     TABLE II 
     Effect of various substances on seizure incidence and severity from electro-convulsive seizures (ECS; 18 mA, 380 V, 0.1 sec). 0, No Seizure; 1, Clonic Seizure; 2, Clonic Seizure and Tonic Extension; 3, Death in Tonic Extension. a, Significant by Fisher&#39;s Exact Probability test at P=0.00000202; b, P=0.00131; c Severity of Seizures is significantly different from saline controls (chi square analysis), P&lt;0.03; d, Fisher&#39;s Exact Probability=0.0108. 
     
         ______________________________________                                    
              No          Seizures and                                    
       Time   Seizures (n)                                                
                          Severity (n)                                    
Treatment                                                                 
         To ECS   0           1   2   3    Total                          
______________________________________                                    
Saline   60 min   1           7   15  3    26                             
DAVA     60 min   17 a        4   4   0    25                             
DALA     60 min   6 b         2   2   0    10                             
GABA     60 min   3           1   5   1    10                             
Gly      60 min   1           0   3   0     4                             
Glygly   60 min   1           1   3   5c   10                             
Glygly   180 min  6 d         2   1   1    10                             
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     TABLE III 
     Effect of subcutaneous DAVA (15 mmol/kg) on incidence and latency of seizures from pentylenetetrazole (PTZ, 65 mg/Kg) administered 60 min later. a, Significant by Fisher&#39;s Exact Probability; P=0.0202; b, Significant by t-test at P&lt;0.0001. 
     
         ______________________________________                                    
        No                     Latency Time                               
Treatment                                                                 
        Seizures (n)                                                      
                    Seizures (n)                                          
                               to Seizures (min)                          
______________________________________                                    
Saline  0           20          5.6 ± 0.42                             
DAVA    6 a         14         10.7 ± 1.21 b                           
______________________________________                                    
 
    
     DISCUSSION OF TABLES I-III 
     Glygly had a bimodal effect on the latency of convulsions following MSO (Table 1). The shorter onset time was the same as that seen in the Gly treated animals while the longer latency time was equal to that seen with DAVA. Gln appeared to have no effect on the seizure latency when given 45 min. after MSO. When Gln was injected after seizures had begun, however, it appeared to abort the convulsions for about 30 min. Glygly had no effect on seizures induced by ECS given 60 min. later but was significantly effective when ECS was administered after 180 min. (Table 2). The effect produced by Gly did not differ from that produced by saline at either 60 or 180 minutes. Both DAVA and DALA substantially reduced the convulsive response to electric shock. Seventeen of the 25 animals treated with DAVA and 6 of the 10 mice treated with DALA had no seizure while only one of the 26 saline controls did not have a convulsion (Table 2). The effect of GABA as an anticonvulsant was not statistically significant. In another series of animals, it was observed that 6 of 20 mice receiving DAVA (15 mmol/kg of body weight--subcutaneously) were completely protected against PTZ induced convulsions. The seizure latency time was almost doubled in the remaining 14 animals (Table 3). 
     EXAMPLE VIII 
     The following test was performed to illustrate the oral administration of the anticonvulsive agent DAVA. Two groups of mice were given either an aqueous solution containing 30 mmol/kg of body weight of DAVA (buffered to pH 4.5) or an equal volume of distilled water via the oral route. 75 minutes after ingestion of the active or control dose the animals were given electroconvulsive shock using the same apparatus as in Example V (18 MA at 380 V for 0.1 sec.) and observed for seizure behavior. 
     
         ______________________________________                                    
            No. of                                                        
            Animals       No Animals                                      
Treatment   With Seizures Free of Seizures                                
______________________________________                                    
Water       17             2                                              
DAVA         6            10                                              
______________________________________                                    
 
    
     Statistical analysis by Fisher&#39;s Exact Probability Test of the results yields P=0.00328. 
     It has also been observed that mice injected subcutanteously with 5-aminopentanoic acid or 5-aminolevulinic acid at 15 mmoles/kg behave as if sedated. The animals display considerably less spontaneous movement around the cage than saline injected control mice. When subjected to noxious stimuli (for example, when the ear clips are attached to the mice before ECS is administered, or when nudged with a blunt probe) the 5-aminopentanoic acid or 5-aminolevulinic acid treated mice show less resistive activity. In addition to being a standard test for anti-convulsant activity, protection against pentylenetetrazole seizures is a standard screening procedure for identifying potential anxiolytic agents. The fact that compounds of the present invention (e.g., 5-aminopentanoic acid) are effective against pentylenetetrazole seizures, indicates that these compounds have significant utility as anxiolytic agents. This observation is confirmed by past experience with prior art anticonvulsant agents, which indicates that many of them have dual roles as anxiolytics and sedatives (e.g., diazepam is a sedative, an anxiolytic and an anticonvulsant; phenobarbitol is a sedative, an anxiolytic, and an anticonvulsant). Thus, it is not unusual that the same activity has been identified for the compounds described here.