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(12) Patent Application Publication (10) Pub. No.: US 2011/00284.18 A1 Parker Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2011/00284.18 A1 Parker Et Al US 2011 002841 8A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/00284.18 A1 Parker et al. (43) Pub. Date: Feb. 3, 2011 (54) USE OF GABBA RECEPTOR ANTAGONISTS Publication Classification FOR THE TREATMENT OF EXCESSIVE SLEEPINESS AND DISORDERS ASSOCATED (51) Int. Cl. WITH EXCESSIVE SLEEPINESS A63L/7028 (2006.01) A 6LX 3/557 (2006.01) (75) Inventors: Kathy P. Parker, Rochester, NY A63L/335 (2006.01) (US); David B. Rye, Dunwoody, A63L/4355 (2006.01) GA (US); Andrew Jenkins, A63L/047 (2006.01) Decatur, GA (US) A6IP 25/00 (2006.01) Correspondence Address: (52) U.S. Cl. ........... 514/29: 514/220; 514/450, 514/291; FISH & RICHARDSON P.C. (AT) 5147738 P.O BOX 1022 Minneapolis, MN 55440-1022 (US) (57) ABSTRACT (73) Assignee: Emory University, Atlanta, GA GABA receptor mediated hypersomnia can be treated by (US) administering a GABA receptor antagonist (e.g., flumazenil; clarithromycin; picrotoxin; bicuculline; cicutoxin; and (21) Appl. No.: 12/922,044 oenanthotoxin). In some embodiments, the GABA receptor antagonist is flumazenil or clarithromycin. The GABA (22) PCT Filed: Mar. 12, 2009 receptor mediated hypersomnia includes shift work sleep disorder, obstructive sleep apnea/hypopnea syndrome, narco (86). PCT No.: PCT/USO9/37034 lepsy, excessive sleepiness, hypersomnia (e.g., idiopathic hypersomnia; recurrent hyperSonmia; endozepine related S371 (c)(1), recurrent stupor; and amphetamine resistant hyperSonmia), (2), (4) Date: Sep. 10, 2010 and excessive sleepiness associated with shift work sleep disorder, obstructive sleep apnea/hypopnea syndrome, and Related U.S. Application Data hypersomnia (e.g., idiopathic hypersomnia; recurrent hyper (60) Provisional application No. 61/036,047, filed on Mar. Somnia; endozepine related recurrent stupor; and amphet 12, 2008. amine resistant hypersomnia. AS-CSFm V m. m . & $8 SSFairgeri s CSF D- is M. GABA to MGABA a roy - es g f f , f 1 | a S. W 3fes ; : set 5 sec Patent Application Publication Feb. 3, 2011 Sheet 1 of 11 US 2011/0028418A1 Ssss Sr SS i.S.S.F ESS AS-CSF as A Flairaxei i0 iM GABA D to M. GABA R t i s \ w W FIG. 1 Patent Application Publication Feb. 3, 2011 Sheet 2 of 11 US 2011/0028418A1 O M Flumazeni g block by 1 M Flumazenil 12 mg Flumazenil (SL) block by 3 MFlumazenil O 2O 40 60 8O 1 OO 120 140 Time (minutes) FIG. 2 {otios Hypersonics m idor-hunan primates - 5 58- 99. -2&O, GABA Potentiation FIG. 3 Patent Application Publication Feb. 3, 2011 Sheet 3 of 11 US 2011/0028418A1 s SS : & SS 8 & 8. 3 & 8 : 8 8 & & 8 8 & 8 38: S : 8 s: 8 8 8 && & &8 8& & & SS : & .......... 8. Epoc Epoch 30 Segesis FIG. 4 ??----------------------------------------.?? ? ? 1 s a. 8 F gael Ko- it:25 -o- Epochs Epoch 3 Seconds FIG.S Patent Application Publication Feb. 3, 2011 Sheet 4 of 11 US 2011/0028418A1 FIG. 7 Patent Application Publication Feb. 3, 2011 Sheet 5 of 11 US 2011/0028418A1 Resissississise FIG. 8 Patent Application Publication Feb. 3, 2011 Sheet 6 of 11 US 2011/0028418A1 Sississifies S. FIG 10 S. M M M M M M M M & & S8: 8.8 SRS: FIG 11 Patent Application Publication Feb. 3, 2011 Sheet 7 of 11 US 2011/0028418A1 FIG. 13 Patent Application Publication Feb. 3, 2011 Sheet 8 of 11 US 2011/0028418A1 8 5 4 3. 28 s FIG. 14 Patent Application Publication Feb. 3, 2011 Sheet 9 of 11 US 2011/0028418A1 E 5 O 9:45 75 FIG. 16 3. 5 2 5. 5 3. f:3. F.G. 17 Patent Application Publication Feb. 3, 2011 Sheet 10 of 11 US 2011/0028418A1 is a tri S. S. S; Sr. fir. F.G. 18a. S is 33 FN & Firs SRS SE ES:S sis $3:3s ris Y i x S38 F. SS SS : SSS S F.G. 18b Patent Application Publication Feb. 3, 2011 Sheet 11 of 11 US 2011/0028418A1 o.1 B2y2s SACS " " " ( , GABA FIG. 19A or 1 (H102R)2y2s D s: CSFACSF O M GABA - - - - w R w w k F.G. 19B US 2011/002841 8 A1 Feb. 3, 2011 USE OF GABBA RECEPTOR ANTAGONSTS methods comprising administering to the Subject an effective FOR THE TREATMENT OF EXCESSIVE amount of a GABA receptor antagonist. In addition, pro SLEEPINESS AND DISORDERS ASSOCATED vided herein is a method of treating excessive sleepiness WITH EXCESSIVE SLEEPINESS associated with GABA receptor mediated hypersomnia in a Subject, comprising administering to the Subject an effective CROSS-REFERENCE TO RELATED amount of a GABA receptor antagonist. In some embodi APPLICATIONS ments, the GABA receptor mediated hypersomnia is 0001. This application claims priority under 35 U.S.C. selected from one or more of: shift work sleep disorder; S119 to U.S. Provisional Application Ser. No. 61/036,047, narcolepsy; obstructive sleep apnea/hypopnea syndrome; filed Mar. 12, 2008, incorporated by reference in its entirety REM behavior disorder; frontal nocturnal dystonia; restless herein. legs syndrome; nocturnal movement disorder, Kleine-Levin syndrome; Parkinson's disease; excessive sleepiness; hyper TECHNICAL FIELD Somnia; idiopathic hypersomnia; recurrent hypersomnia; endozepine related recurrent stupor; and amphetamine resis 0002 The present disclosure relates to the treatment of tant hypersomnia. In some embodiments, the GABA recep excessive sleepiness and promotion of wakefulness in a Sub tor mediated hypersomnia is a result of the production of ject. In particular, a method of treating hypersomnia (e.g., endogenous Somnogenic compounds in a Subject, e.g., exces GABA receptor mediated hypersomnia) using a GABA sive amounts of Somnogenic compounds. In some embodi receptor antagonist Such as flumazenil (formulated, for ments, the GABA receptor antagonist can be a negative example, for I.V., transdermal, transmucosal, Sublingual, or allosteric modulator. In some embodiments, the GABA Subdermal administration) is disclosed. receptor antagonist is selected from the group consisting of flumazenil; clarithromycin; picrotoxin; bicuculline; cicu BACKGROUND toxin; and oenanthotoxin. In some embodiments, the method 0003. There are two main categories of hypersomnia: pri includes administering an I.V., transdermal, transmucosal, mary hypersomnia (sometimes called idiopathic hyperSom sublingual, or subdermal formulation of the GABA receptor nia) and recurrent hypersomnia (sometimes called idiopathic antagonist to the Subject. recurrent hypersomnia). Both are characterized by similar 0008 Also provided herein is a method of treating exces signs and symptoms and differ only in the frequency and sive sleepiness in a Subject. The method comprises the steps regularity with which the symptoms occur. of determining whether the subject has an endogenously pro 0004 Primary hypersomnia is characterized by excessive duced somnogenic compound in a CSF sample of the Subject, daytime sleepiness over a long period of time. The symptoms e.g., an excessive amount of the Somnogenic compound; and are presentall, or nearly all, of the time. Recurring hyperSom administering to the Subject an effective amount of a GABA nia involves periods of excessive daytime sleepiness that can receptor antagonist, e.g., flumazenil. The step of determining last from one to many days, and recur over the course of a year whether the Subject has an endogenously produced somno or more. The primary difference between this and primary genic compound, including an excessive amount of the Som hypersomnia is that persons experiencing recurring hyper nogenic compound, includes the steps of: a) measuring the somnia will have prolonged periods where they do not exhibit potentiation of GABA receptors contacted with the CSF any signs of hypersomnia, whereas persons experiencing pri sample of the Subject in a whole cell patch clamp assay, mary hypersomnia are affected by it nearly all the time. Idio wherein the cells express benzodiazepine sensitive receptors; pathic hypersomnia is much like narcolepsy, except there is b) measuring the potentiation of GABA receptors contacted no cataplexy, no sleep paralysis, and no rapid eye movement with the CSF sample of the subject in a whole cell patch when the victim first falls asleep. clamp assay, wherein the cells express benzodiazepine insen 0005 Various treatments including prescription drugs sitive receptors; and c) comparing the response of step a) to have been used to treat hypersomnia without significant suc the response of step b), wherein a persistence of potentiation cess, and no substantial body of evidence Supports the effec in step b) to within +25% of the step a) response is indicative tiveness of any of these treatments. Stimulants are not gener of an endogenously produced somnogenic compound in the ally recommended to treat hypersomnia as they treat the CSF sample of the subject. In some embodiments, the som symptoms but not the base problem. There is a need for more nogenic compound is a non-classical benzodiazepine. In effective treatments of hypersomnia, especially using admin Some embodiments, the Somnogenic compound binds to a site istration routes that allow for better drug delivery and patient on the GABA receptor, e.g., an allosteric site. In some compliance. embodiments, the site on the GABA receptor is other than the benzodiazepine binding site. SUMMARY 0009. A method of treating excessive sleepiness of a sub 0006. The inventors have discovered that many patients ject endogenously producing a Somnogenic compound, e.g., that Suffer from excessive sleepiness or disorders associated an excessive amount of a Somnogenic compound, is also with excessive sleepiness have one or more endogenous Sub provided herein, the method comprising administering to the stances present, typically in excess, in their CSF that act as Subject an effective amount of a GABA receptor antagonist, positive allosteric modulators of the GABA receptor, poten e.g., flumazenil. Further described herein is a method of tiating the effect of GABA on the receptor. Treatment of such determining whether a subject will benefit from treatment patients with a GABA receptor antagonist thus can provide with a GABA receptor antagonist, e.g., flumazenil, wherein a method to treat the disorders, in particular the symptoms of the benefit is a reduction in excessive sleepiness, the method excessive sleepiness associated with the disorders.
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