Use of Serotonin 5-HT1A Receptor Agonists to Treat Diseases Associated with Sudden Unexpected Death in Epilepsy

Abstract

The present application concerns the treatment and prevention of diseases associated with an increased risk of sudden unexpected death in epilepsy, such as Fragile X syndrome, by administering a selective 5-HT1A receptor agonist

Claims

1-11. (canceled)

12. A method of treatment or prevention of a disease associated with Sudden Unexpected Death in Epilepsy (SUDEP) selected from the group consisting of Fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome, Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, and diseases associated with the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5, or DEPDC5 gene dysfunction, the method comprising administering a therapeutically effective amount of a selective 5-HT.sub.1A receptor agonist to a patient suffering from the disease.

13. The method of claim 12, wherein said patient exhibits a FRM1 gene dysfunction.

14. The method of claim 12, wherein said patient suffers from a disease selected from the group consisting of Fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, and Ohtahara syndrome.

15. The method of claim 12, wherein the 5-HT.sub.1A receptor agonist is a biased 5-HT.sub.1A receptor agonist.

16. The method of claim 12, wherein the 5-HT.sub.1A receptor agonist is a compound of formula (I): ##STR00008## wherein: X represents a halogen atom; and Z represents a —(CH.sub.2—Y).sub.n—Ar group, wherein: n is 0 or 1; Y is selected from the group consisting of —CH.sub.2—, —NH—, —S— or —O—; and Ar represents a 5 to 10 membered aryl or heteroaryl ring optionally substituted by one or more C1-C6 alkyl groups; or a pharmaceutically acceptable salt or ester thereof.

17. The method of claim 16, wherein the compound of formula (I) is NLX-101 (also known as F-15599) having formula (IA): ##STR00009## or a pharmaceutically acceptable salt or ester thereof.

18. The method of claim 16, wherein the compound of formula (I) is a compound of formula (II): ##STR00010## wherein: X is F or Cl; Y is selected from the group consisting of —CH.sub.2—, —NH—, —S— or —O—; and Ar is chosen from phenyl and N-containing 6-membered monocyclic heteroaryl groups, optionally substituted by one or more C1-C6 alkyl groups; or a pharmaceutically acceptable salt or ester thereof.

19. The method of claim 18, wherein the compound of formula (I) is one of the following: ##STR00011## a pharmaceutically acceptable salt or ester thereof.

20. The method of claim 12, wherein the selective 5-HT.sub.1A receptor agonist is administered at a dose in a range of about 0.1 mg/day to about and 10 mg/day in a human patient.

21. A method of treatment or prevention of seizures comprising administering a therapeutically effective amount of a selective 5-HT.sub.1A receptor agonist in a patient suffering from a disease where SUDEP occurs.

22. The method of claim 21, wherein said patient exhibits a FRM1 gene dysfunction.

23. The method of claim 21, wherein said patient suffers from a disease selected from the group consisting in Fragile X syndrome, Rett syndrome, Dravet syndrome, Guillain-Barré syndrome, Ohtahara syndrome and Angelman syndrome, myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome and diseases associated with the FMR1, SCN1A, SCN1B, SCN8A, SCN2A, GNB5, KCNA1, CDKL5 and DEPDC5 gene dysfunction.

24. The method of claim 21, wherein said patient suffers from a disease selected from the group consisting of Fragile X syndrome, Dravet syndrome, Guillain-Barré syndrome, and Ohtahara syndrome.

25. The method of claim 21, wherein the 5-HT.sub.1A receptor agonist is a biased 5-HT.sub.1A receptor agonist.

26. The method of claim 21, wherein the selective 5-HT.sub.1A receptor agonist is administered at a dose in a range of about 0.1 mg/day to about and 10 mg/day in a human patient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0085] The invention will be described in connection with the attached drawings:

[0086] FIG. 1 illustrates the lack of anti-seizure activity of NLX-101 in two models of seizures in wild-type mice.

[0087] FIG. 2 illustrates the dose-dependent reduction by NLX-101 of tonic-clonic seizures (TCS) and death rate in FRM1 transgenic mice (ns: not significant; *** p<0.001, **** p<0.0001, Log-rank (Mantel-Cox) test).

[0088] The invention will be further understood by reference to the following illustrative examples:

EXAMPLES

Methods

[0089] Seizures Induced by Corneal Electrical Stimulation (CES) in Wild-Type Mice

[0090] Experiments were carried out in accordance with the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (https://panache.ninds.nih.gov/TestDescription/Test6HZ). The CES test was carried out using wild-type male CF-1 mice. Seizures were induced by a low frequency (6 Hz, 0.2 msec rectangular pulse), long-duration (3 sec), 44 mA current (double the current producing seizures in 97% of animals) delivered through corneal electrodes (Barton M E, Klein B D, Wolf H H, White H S. Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy. Epilepsy Res. 2001; 47:217-27). A drop of 0.5% tetracaine hydrochloride in 0.9% saline (anesthetic/electrolyte) solution was applied to the eyes just prior to the placement of corneal electrodes. The seizure in mice is characterized by an initial momentary stun followed immediately by jaw clonus, forelimb clonus, twitching of the vibrissae, and “Straub tail”. Animals not displaying this behavior within the one-minute observation period are considered “protected” from seizures.

[0091] Testing for anti-seizure activity in the CES model was performed with 4 male mice/dose/time point. Six doses of NLX-101 (0.02, 0.06, 0.5, 1 and 2 mg/kg i.p.) and two timepoints (30 and 120 min after drug administration) were tested.

[0092] Seizures Induced in the Maximal Electroshock Seizure (MES) Test

[0093] Experiments were carried out in accordance with the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (https://panache.ninds.nih.gov/TestDescription/TestMES). The MES test was carried out using wild-type male mice. MES is a model for generalized tonic-clonic seizures and provides an indication of a compound's ability to prevent seizure spread when all neuronal circuits in the brain are maximally active (White H S, Johnson M, Wolf H H, Kupferberg H J. The early identification of anticonvulsant activity: role of the maximal electroshock and subcutaneous pentylenetetrazol seizure models. Ital J Neurol sci. 1995; 16:73-7). These seizures are highly reproducible and are electrophysiologically consistent with human seizures. Seizures were induced by a high frequency (60 Hz) of alternating current at 50 mA over a short duration (0.2 sec) delivered through corneal electrodes. Prior to stimulation, corneas were irrigated with 0.5% tetracaine hydrochloride for local anesthesia and 0.9% saline to improve electrical conductivity. Seizures induced by MES are characterized by tonic extension of forelimbs and hindlimbs that is followed by brief episodes of clonic activity of the forelimbs and hindlimbs. An animal is considered “protected” from MES-induced seizures upon abolition of the hindlimb tonic extensor component of the seizure. Testing for anti-seizure activity in the MES model was performed with 4 male mice/dose/time point. Six doses of NLX-101 (0.02, 0.06, 0.5, 1 and 2 mg/kg i.p.) and two timepoints (30 and 120 min after drug administration) were tested.

[0094] Audiogenic Tonic-Clonic Seizures (TCS) in FMR1 Transgenic Mice

[0095] FMR1 knock-out (KO) mice were bred and weaned at postnatal day 21 (P21), and all mice were tested between P21 to P23. NLX-101 was administered at doses of 0.6, 1.2, 1.8 and 2.4 mg/kg i.p. Control FMR1 KO mice received saline. NLX-101 or saline was injected 10 min before subjecting the mice to the auditory stimulus.

[0096] To differentiate each mouse for post-hoc video analysis, mice were color coded prior to drug or saline administration. Mice (up to 4/cage) were then put in a cage with a lid; after 10 min, a speaker was placed on top of the lid, and the cage placed in a sound attenuation booth (Gretch-Ken Inc., OR); the auditory stimulus was a continuously alternating up and down frequency modulated sweep with frequencies between 2-8 kHz, presented at an intensity between 105-110 dB for 15 min. The procedure lasted a total of 20 min starting with 5 min of habituation (without a sound stimulus). The full 20-min procedure was video recorded for off-line analysis.

[0097] The typical behavior of FMR1 knock-out mice subjected to loud audio stimulus includes tonic-clonic seizures (TCS: the mouse lays on the cage bottom with hindlimb extension), and death by respiratory arrest (manifested by a deep respiratory gasp and relaxation of pinna).

[0098] The latency time (from the stimulus onset) to the occurrence of TCS and death were recorded with a stopwatch (precision: 1 sec). Survival analysis was used to analyze the probability of TCS or death by log-rank test.

[0099] The results are illustrated in FIGS. 1 and 2:

[0100] In wild-type mice, NLX-101, over a wide range of doses (0.02 to 2 mg/kg i.p.) and at 30- and 120-min post-injection, did not affect the occurrence of seizures in the maximal electroshock seizures (MES) test (left panel). In the corneal electrical stimulation (CES) seizure test (right panel), NLX-101 reduced seizure occurrence in only 1 out of 4 mice at the highest dose tested, and at only one time point (30 min post injection). The minimal activity of NLX-101 in the MES and CES tests suggest that it does not possess anti-seizure activity (FIG. 1).

[0101] In contrast, NLX-101 dose-dependently reduced the percentage of FMR1 knock-out mice displaying tonic-clonic seizures, with significant effects at 1.8 and 2.4 mg/kg (left panels). NLX-101 also dose-dependently reduced the number of FMR1 knock-out mice that died, with significant effects at doses of 1.2, 1.8 and 2.4 mg/kg (right panels). Each experimental groups consisted of 14 or 16 mice (half of which were males, half were females). These data indicate that NLX-101 displays robust anti-seizure and anti-SUDEP activity in FMR1 knock-out mice (FIG. 2).