Promoting sleep using AT1 receptor blockers
View Patent ↗The present invention relates to the use of an Angiotensin II type 1 (AT1) receptor blocker for promoting sleep and/or the treatment of insomnia. It is based, at least in part, on the results of experiments performed using a validated rat model of stress-induced insomnia in which candesartan was found to ameliorate sleep disturbances induced by stress. Further, it was observed that this effect seems to be caused by blockade of AT1 receptors located in several brain regions that are key components of the neural circuitry activated during insomnia. In contrast to currently marketed treatments for insomnia, the AT1 receptor blocker was found to restore normal sleep without inhibiting REM sleep and/or inducing atypical wave components in the EEG.
1. A method for treating primary insomnia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an AT1 receptor blocker that promotes sleep, wherein the therapeutically effective amount is at least about 50% lower than a dosage of the AT1 receptor blocker for treating hypertension, wherein the AT1 receptor blocker is selected from the group consisting of azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, and combinations thereof.
2. The method of claim 1 , further comprising administering to the subject a second sleep-promoting agent.
3. The method of claim 2 , wherein the second sleep-promoting agent is an H1 antagonist.
4. The method of claim 3 , wherein the H1 antagonist is selected from the group consisting of diphenhydramine hydrochloride, doxepin, doxylamine succinate, orphenadrine, bromodiphenhydramine, and dimenhydrinate.
5. The method of claim 2 , wherein the second sleep-promoting agent is selected from the group consisting of H3 agonists, immepip, imetit, methimepip, immethridine, R-alpha-methylhistamine, 4-benzyl-1H-imidazole-based H3 receptor agonists, and H3B agonists.
6. The method of claim 2 , wherein the second sleep-promoting agent is a GABA A ligand with alpha-3 or alpha-2/alpha-3 agonist activity.
7. The method of claim 2 , wherein the second sleep-promoting agent is selected from the group consisting of zolpidem, zaleplon, and eszopiclone.
8. The method of claim 2 , wherein the second sleep-promoting agent is a benzodiazepine.
9. The method of claim 8 , wherein the benzodiazepine is selected from the group consisting of diazepam, clonazepam, lorazepam, and alprazolam.
10. The method of claim 2 , wherein the second sleep-promoting agent is a corticotropin releasing hormone antagonist.
11. The method of claim 1 , further comprising administering to the subject a melatonin receptor agonist.
12. The method of claim 11 , wherein the melatonin receptor agonist is selected from the group consisting of ramelteon, agomelatine, tasimelteon, TIK-301, and melatonin.
13. The method of claim 1 , further comprising administering to the subject a homeopathic sleep aid.
14. The method of claim 13 , wherein the homeopathic sleep aid is selected from the group consisting of tryptophan, L-tryptophan, lavender, chamomile, valerian root, passionflower, lemon balm, inositol, magnesium, humulus lupus, hops extract, St. John's wort, and melatonin.
15. The method of claim 11 , wherein the melatonin receptor agonist is administered to the subject in a therapeutically effective amount that is lower than a dosage of the melatonin receptor agonist when the melatonin receptor agonist is the only sleep-promoting agent administered to the subject.
16. The method of claim 1 , wherein the method promotes sleep in the subject through at least one of: decreasing sleep latency, increasing non-rapid eye movement (NREM) sleep, increasing rapid eye movement (REM) sleep, and not inducing atypical wave components in electroencephalogram (EEG).