WO2009137531A2 - Compositions et procédés se rapportant à l'action de faibles dosages de doxépine sur les récepteurs h1 et 5-ht2a - Google Patents

Compositions et procédés se rapportant à l'action de faibles dosages de doxépine sur les récepteurs h1 et 5-ht2a Download PDF

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WO2009137531A2
WO2009137531A2 PCT/US2009/042912 US2009042912W WO2009137531A2 WO 2009137531 A2 WO2009137531 A2 WO 2009137531A2 US 2009042912 W US2009042912 W US 2009042912W WO 2009137531 A2 WO2009137531 A2 WO 2009137531A2
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patient
doxepin
dosage
sleep
milligrams
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PCT/US2009/042912
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WO2009137531A3 (fr
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Robert Mansbach
Philip Jochelson
Roberta L. Rogowski
Susan E. Dube
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Somaxon Pharmaceuticals, Inc.
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Publication of WO2009137531A2 publication Critical patent/WO2009137531A2/fr
Publication of WO2009137531A3 publication Critical patent/WO2009137531A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin

Definitions

  • Doxepin is a tricyclic compound approved at dosages from 75 milligrams to 300 milligrams for the treatment of depression and anxiety.
  • Doxepin can be prescribed to psychoneurotic patients with depressive and/or anxiety reactions. Patients experiencing somatic disorders or alcoholism may also be administered doxepin to treat their secondary anxiety and/or depressive condition.
  • Doxepin may be used to treat psychotic depression, including involutional melancholia and manic-depressive illnesses.
  • anticholinergic side effects can include, for example, ataxia, dry throat, sore throat, xerostomia, an increase in body temperature, degradation of accommodation, diplopia, tachycardia, cessation of perspiration, urinary retention, diminished bowel movement, increased intraocular pressure, confusion, agitation, respiratory depression, disorientation, short-term memory loss, difficulty concentrating, incoherent speech, myoclonic jerking, increased sensitivity to sudden sounds, photophobia, difficulty engaging in logical thinking, visual disturbances, and/or hallucinations.
  • adrenergic side effects can include hypertension, tremor, tachycardia, palpitations, headache, sweating, and hyperglycemia.
  • An example of serotonergically mediated side effects would be the suppression of rapid eye movement (REM) sleep.
  • Sleep disorders affect a growing number of individuals each year.
  • Various medications are approved for the treatment of sleep disorders.
  • the patients afflicted with the disorders have diverse susceptibilities to side effects from the medications, as well as distinct sleep disorder needs.
  • many of these existing medications have undesirable side effects and/or fail to adequately treat certain aspects of the sleep disorders, and therefore fail to work effectively in certain patient populations. Improvements in sleep treatment methods are described herein.
  • Some embodiments relate to methods for selecting a sleep therapy for a patient, which methods can include, for example, evaluating whether the patient is in need of combined Hl receptor antagonism and 5-HT 2 A antagonism, and if so, administering or providing to the patient doxepin, a pharmaceutically acceptable salt or prodrug thereof in a dose of about 0.01 to about 10 mg.
  • Some embodiments relate to methods for selecting a sleep therapy for a patient, which methods can include, for example, identifying a patient in need of combined Hl receptor antagonism and 5-HT 2A antagonism, and administering or providing to the patient doxepin, a pharmaceutically acceptable salt or prodrug thereof in a dose of about 0.01 to about 10 mg.
  • Still some embodiments relate to methods of using doxepin including, for example, providing a patient with doxepin, a pharmaceutically-acceptable salt or a prodrug thereof in a daily dosage ranging from about 0.01 to about 10 milligrams; and providing the patient with information that the provided dosage of doxepin, the pharmaceutically- acceptable salt or the prodrug thereof acts on one, or preferably both of the Hl and 5-HT 2A receptors.
  • the providing information can also include providing the patient with information that the low dose doxepin is a selective Hl antagonist, that it binds to the Hl receptor while having clinically irrelevant or minimal binding to other receptors that are associated with adverse side effects.
  • the methods further can include identifying a patient in need of a lseep medication.
  • some embodiments relate to methods of treatment, comprising identifying a patient in need of a treatment comprising at least one antagonist selected from an Hl antagonist and a 5-HT 2A antagonist; and administering or providing to the patient doxepin, a pharmaceutically-acceptable salt or a prodrug thereof in a daily dosage ranging from about 0.01 to about 10 milligrams.
  • the pharmaceutically-acceptable salt can be, for example, the hydrochloride salt thereof.
  • the prodrug can be, for example, a prodrug ester, ester, amide or N-oxide.
  • the dosage can be, for example, about 0.1 to about 10 milligrams, or preferably, about 0.5 to about 6 or 9.9 milligrams.
  • patient can be one who does not suffer from depression.
  • patient can be one who suffers or is at risk of suffering from a sleep disorder.
  • the methods further can include, for example, identifying a patient who suffers or is at risk of suffering from a sleep disorder.
  • the sleep disorder can be insomnia, including maintenance insomnia or onset insomnia.
  • the methods can further include identifying a patient in need of minimizing at least one side effect, for example, withdrawal, tolerance, rebound insomnia, or an arousability defect.
  • the methods can further include identifying a patient in need of minimizing side effects of a treatment associated with anticholinergic activity or adrenergic activity.
  • the methods can further include identifying a patient in need of avoiding behavioral, neurological, cardiovascular, autonomic, endocrine, allergic, and/or gastrointestinal side effects of the treatment.
  • some methods can further include identifying a patient in need of avoiding side effects associated with administration of doxepin, a pharmaceutically-acceptable salt or a prodrug thereof in a daily dosage ranging above about 10 milligrams.
  • the patient can be in need of a medication that can increase the amount of time that patient spends in slow-wave sleep or the patient can be in need of a medication that decreases the amount of time required for the patient to fall asleep.
  • the method further can include providing the patient with at least one additional medication, for example, a compound that enhances gamma-aminobutyric acid (GABA) activity, a 5HT 2A antagonist, a melatonin agonist, an ion channel blocker, a serotonin-2 antagonist/reuptake inhibitor (SARIs), a 5HT IA agonist, a GABA-B agonist or an orexin receptor antagonist.
  • GABA gamma-aminobutyric acid
  • 5HT 2A antagonist for example, a compound that enhances gamma-aminobutyric acid (GABA) activity
  • 5HT 2A antagonist for example, a compound that enhances gamma-aminobutyric acid (GABA) activity
  • 5HT 2A antagonist for example, a compound that enhances gamma-aminobutyric acid (GABA) activity, a 5HT 2A antagonist, a melatonin agonist, an ion channel blocker,
  • the compound that enhances GABA activity can be, for example, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine or estazolam.
  • the 5HT 2 a antagonist can be, for example, ketanserin, risperidone, eplivanserin, pruvanserin, MDL 100907, APD 125 or AVE 8488.
  • the melatonin agonist can be, for example, melatonin, ramelteon and agomelatine.
  • the ion channel blocker can be, for example, lamotrigine, gabapentin or pregabalin.
  • the serotonin-2 antagonist/reuptake inhibitor (SARIs) can be, for example, Org 50081, ritanserin, nefazodone, serzone or trazodone.
  • the 5HTi A agonist can be, for example, repinotan, sarizotan, eptapirone, buspirone or MN- 305.
  • the orexin receptor antagonist can be, for example, orexin, a 1,3-biarylurea, SB- 334867-a, ACT-078573 or a benzamide derivative.
  • the at least one additional medication can be provided in its approved dosage, its clinical trial dosage, or a literature reported dosage, for example.
  • the at least one additional medication can be provided in a dosage less than its approved dosage, its clinical trial dosage, or a literature reported dosage, for example.
  • Some embodiments relate to sleep treatment methods, which methods can include, for example, identifying a patient in need of pharmaceutical treatment of a sleep disorder while at the same time in need of avoiding an adverse side effect, for example, an anticholinergic effect, an adrenergic effect, sleep drug tolerance, sleep drug withdrawal, sleep drug rebound, adverse arousability effect, deficient restorative sleep; and treating said sleep disorder in said patient by administering doxepin, a pharmaceutically acceptable salt or prodrug thereof in a dosage between about 0.01 milligram and 10 milligrams.
  • an adverse side effect for example, an anticholinergic effect, an adrenergic effect, sleep drug tolerance, sleep drug withdrawal, sleep drug rebound, adverse arousability effect, deficient restorative sleep
  • doxepin a pharmaceutically acceptable salt or prodrug thereof in a dosage between about 0.01 milligram and 10 milligrams.
  • the pharmaceutically-acceptable salt can be, for example, the hydrochloride salt thereof.
  • the prodrug can be, for example, a prodrug ester, ester, amide or N-oxide.
  • the dosage can be, for example, about 0.1 to about 10 milligrams, or preferably, about 0.5 to about 6 or 9.9 milligrams.
  • the patient is one who does not suffer from depression.
  • the methods further can include informing the patient that doxepin, a pharmaceutically-acceptable salt or prodrug thereof selectively acts on at least one receptor, for example, an Hl receptor and a 5-HT 2A receptor.
  • the patient can be informed, for example, that doxepin, a pharmaceutically-acceptable salt or prodrug thereof selectively acts on an Hl receptor or both of an Hl receptor and a 5-HT 2A receptor.
  • doxepin is a selective Hl antagonist, that it binds to the Hl receptor while having clinically irrelevant or minimal binding to other receptors that are associated with adverse side effects.
  • Some embodiments relate to methods for selecting a drug to be administered to a patient in need of sleep therapy, which methods can include, for example, evaluating the importance of avoiding anticholinergic or adrenergic effects for that particular patient in conjunction with said sleep therapy; and selecting a therapy comprising 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof if avoiding anticholinergic or adrenergic effects is evaluated to be of sufficient importance.
  • Still some embodiments relate to methods for selecting a drug to be administered to a patient in need of sleep therapy, which methods can include, for example, identifying a patient in need of a sleep therapy while avoiding anticholinergic or adrenergic effects for that particular patient in conjunction with said sleep therapy; selecting a therapy that includes 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof if avoiding anticholinergic or adrenergic effects is evaluated to be of sufficient importance; and providing 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof to the patient.
  • Some embodiments relate to methods for selecting a doxepin therapy, which methods can include, for example, evaluating the importance of targeting an Hl receptor while avoiding or reducing side effects, such as for example, anticholinergic or adrenergic effects for that particular patient in conjunction with a doxepin therapy; and selecting a therapy comprising 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof if targeting the Hl receptor and avoiding or reducing side effects such as, for example, anticholinergic or adrenergic effects is evaluated to be of sufficient importance.
  • the pharmaceutically-acceptable salt can be, for example, the hydrochloride salt thereof.
  • the prodrug can be, for example, a prodrug ester, ester, amide or N-oxide.
  • the dosage can be, for example, about 0.1 to about 10 milligrams, or preferably, about 0.5 to about 6 or 9.9 milligrams.
  • the patient is one who does not suffer from depression.
  • some embodiments relate to methods for selecting a doxepin therapy, which methods can include, for example, identifying a patient having a sleep disorder in which it is desired to target an Hl receptor while avoiding or reducing anticholinergic or adrenergic effects for that particular patient in conjunction with a doxepin therapy; and administering a therapy to the patient comprising 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof.
  • some embodiments relate to methods of providing a doxepin therapy, which methods can include, for example, providing a patient with doxepin, a pharmaceutically acceptable salt or prodrug thereof in a daily dosage ranging from about 0.01 to about 10 milligrams; and informing the patient that doxepin, a pharmaceutically acceptable salt or prodrug thereof in the provided dosage acts on an Hl receptor while reducing or avoiding, side effects such as for example, anticholinergic or adrenergic effects exhibited by doxepin at higher dosages.
  • the pharmaceutically-acceptable salt can be, for example, the hydrochloride salt thereof.
  • the prodrug can be, for example, a prodrug ester, ester, amide or N-oxide.
  • the dosage can be, for example, about 0.1 to about 10 milligrams, or preferably, about 0.5 to about 6 or 9.9 milligrams.
  • the patient is one who does not suffer from depression.
  • the methods further can include informing the patient that doxepin, a pharmaceutically-acceptable salt or prodrug thereof acts on a 5-HT 2 A receptor.
  • Some embodiments relate to methods of providing a doxepin therapy, which methods can include, for example, selecting a patient in need of a sleep therapy; providing the patient with doxepin, a pharmaceutically acceptable salt or prodrug thereof in a daily dosage ranging from about 0.01 to about 10 milligrams; and providing the patient with information that doxepin, a pharmaceutically acceptable salt or prodrug thereof in the provided dosage acts on an Hl receptor while reducing or avoiding, side effects such as for example, anticholinergic or adrenergic effects exhibited by doxepin at higher dosages.
  • Some embodiments relate to methods for selecting a drug to be administered to a patient in need of sleep therapy, which methods can include, for example, evaluating the importance of reducing the duration of nighttime awakenings without significantly reducing arousability for that particular patient in conjunction with said sleep therapy; selecting a therapy that includes 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof if reducing the duration of nighttime awakenings without reducing arousability is evaluated to be of sufficient importance; and providing the patient with 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof.
  • the methods can further include identifying a patient in need of a sleep therapy without reducing arousability.
  • some embodiments relate to methods for treating insomnia while avoiding a significant reduction in arousability, which methods can include, for example, identifying a patient potentially in need of nighttime arousability without reducing the duration of nighttime awakenings; and providing 0.01 to 10 mg doxepin, a pharmaceutically acceptable salt or prodrug thereof to the identified patient.
  • the patient can be, for example, between the age of 18-64, over the age of 64, a law enforcement officer, a fire fighter, other emergency personnel, or the parent of a child. In some aspects of the various embodiments the patient can be in need of minimizing the interaction of the low-dose doxepin treatment with at least one other treatment.
  • FIG. 1 shows effects of doxepin on wake time after sleep onset in adult insomnia patients.
  • FIG. 2 shows effects of doxepin on wake time after sleep onset in elderly insomnia patients.
  • Embodiments described herein include improved methods of treating sleep, improved methods of selecting a sleep medication, and improved methods of selecting a doxepin sleep therapy.
  • doxepin binds with high affinity at both Hl and 5-HT2a receptors. It is also surprising that the high affinity of doxepin at 5-HT2a receptors is associated with potent functional antagonism at the cellular level.
  • 5-HT2a antagonists promote the expression of Stages 3 and 4 of sleep, often referred to as 'slow-wave' sleep, or 'restorative' sleep. Such slow wave sleep, particularly in the 0.5-3.5 Hz range, can provide deeper and more refreshing periods of sleep.
  • 5-HT2a antagonism represents a second mechanism by which doxepin promotes healthier sleep in insomnia patients. While Hl antagonism treats a disordered arousal system, 5-HT2a antagonism helps to selectively promote forms of sleep that are both refreshing and which contribute to longer periods of uninterrupted sleep. Furthermore, 5-HT2a antagonism facilitates the expression of restorative slow-wave sleep, resulting in associated improvements in sleep maintenance (WASO and WTDS), and including a decrease in the number of awakenings.
  • WASO and WTDS sleep maintenance
  • doxepin Low-dose doxepin increases the duration of stages 2, 3 and 4 of sleep without suppressing Rapid Eye Movement (REM) sleep. Because doxepin exerts both Hl and 5-HT2a blocking action, doxepin may provide additional benefits beyond a selective 5-HT2a antagonist by facilitating sleep onset, reducing hyperarousal and preventing early morning awakenings. That understanding and recognition permits improved treatment of sleep disorders including more precise prescribing of doxepin as a sleep drug, and more precise treatment of various patient populations.
  • REM Rapid Eye Movement
  • Doxepin is a tricyclic compound that has been approved as an antidepressant. Given the fact that all tricyclic antidepressant drugs (and even many non- tricyclic antidepressant drugs) suppress REM sleep, it is surprising that it has now been found that low dose doxepin does not decrease the time spent in REM sleep. At the higher, approved antidepressant doses (75 mg - 300 mg), doxepin and other tricyclic compounds inhibit the reuptake of norepinephrine and serotonin in the brain. The resulting increase in adrenergic (norepinephrine) and serotonergic stimulation is believed responsible for REM suppression, which may contribute to antidepressant effects.
  • low dose doxepin has little if any impact on REM sleep. As discussed more fully herein and without being limited thereto, it is believed that this is due to the selectivity of low dose doxepin, which is believed to be mainly restricted to acting on the Hl and 5-HT 2a receptors, thus producing little effect on REM sleep (Seifritz E, Contribution of Sleep Physiology to Depressive Pathophysiology, Neuropsychopharmacology 25 (S5): .S85-S87; which is incorporated herein by reference in its entirety).
  • doxepin acts as a selective Hl and 5-HT2a antagonist, other arousal systems (e.g. GABA, norepinephrine and acetylcholine) remain unaffected. In other words, an individual can have taken doxepin for sleep and can be awakened without any significant impairment.
  • Histamine release in the central nervous system is associated with arousal. Histamine release differs across the sleep wake cycle being generally lower at times of sleep and higher just before and during waking hours.
  • doxepin is believed to blunt excessive histamine activity during sleep periods, thus allowing normal sleep, yet this antagonism effect can be easily overwhelmed during waking hour when histamine levels are high. Thus doxepin can enhance normal sleep activity during the sleep period, but does not impair arousal mechanisms during waking hours.
  • some embodiments herein relate to the surprising discovery that low dose doxepin may not impair arousability.
  • a primary measure of arousability is the number of awakenings after sleep onset (NAASO).
  • WASO sleep maintenance
  • NAASO arousability
  • some embodiments relate to methods treating insomnia or improving sleep, while not impairing arousability.
  • certain populations of patients can be selected, for example, patients that need to be able to wake up and function, but who also need to be able to fall back asleep. Examples of such patients can include elderly, emergency personnel, parents of small children, and the like.
  • doxepin is both a highly selective histamine Hl (Hl) antagonist and also a 5- HT 2A antagonist when used at low doses.
  • Hl histamine Hl
  • 5-HT 2A antagonist a 5-HT 2A antagonist
  • Some embodiments disclosed herein relate to the surprising discovery that low-dose doxepin is a selective histamine Hl (Hl) antagonist, while its binding at other sites associated with adverse side effects observed at high doses (e.g., muscarinic and alpha- 1- adrenergic) is not clinically meaningful, thereby minimizing adverse side effects at the low dose.
  • Hl histamine Hl
  • This is particularly surprising in view of the fact that higher dose doxepin produces various adverse side effects.
  • the recognition that low-dose doxepin is effective as a sleep medication, while at the same time is a selective Hl antagonist can be useful in administering or prescribing doxepin as a sleep aid, particularly when prescribing it to certain patients or patient populations.
  • doxepin in particular low dose doxepin
  • the human 5-HT 2 A binding and functional data described herein are particularly surprising in view of previous binding data in non human animals.
  • a medication that can bind to and antagonize the 5-HT 2A receptor can be useful as sleep medication because of its ability to promote restorative forms of sleep.
  • Hl antagonism can facilitate onset and maintenance of sleep
  • the addition of 5-HT2a antagonism further can enhance the efficacy of doxepin to produce continuous restful and restorative sleep. This combination of activities allows for the effective treatment of patients suffering from difficulties in both onset and maintenance of sleep, as well as undesirable early morning awakenings.
  • embodiments of the present invention relate to providing a patient with a low dosage of doxepin, prodrugs, and pharmaceutically-acceptable salts of the same. It is now established that a low dosage of doxepin, prodrugs, and pharmaceutically- acceptable salts acts on the Hl receptor and/or the 5-HT 2A receptor, while, in some embodiments, reducing or avoiding the adverse side effects associated with higher dosages of doxepin, prodrugs, and pharmaceutically-acceptable salts of the same.
  • Physicians can now select a patient or prescribe low dose doxepin to a patient in need of a sleep medication on the basis of these previously unrecognized properties of low dose doxepin, and can prescribe doxepin to those patients for whom these newly-recognized properties are most suited.
  • doxepin can be used to treat patient populations and disease conditions with greater precision and selectivity.
  • a sleep medication that targets the Hl (selectively) or the 5-HT 2A receptors individually can be desirable. For example, a physician may seek to administer one or the other to a particular patient according the specific needs and condition of the patient.
  • a medication that can target both types of receptors can be even more desirable for some patients, and a physician can take advantage of knowing that a medication can target both receptors to more precisely prescribe the medication to those for whom it is best suited.
  • a patient in need of sleep medication that targets both an Hl and a 5-HT 2A receptor can use doxepin and benefit from the "dual" action of doxepin.
  • the patient can benefit from the sleep induction and sleep maintenance benefits of doxepin, without next day sedation.
  • doxepin or one of the other compounds listed herein as a therapy to treat a patient in particular need of the benefits of the low dose therapy.
  • low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same can effectively act on the Hl receptor and/or the 5-HT 2A receptor, which may explain the preserved efficacy of, for example, treating a sleep disorder using doxepin, even at lower dosages.
  • the low dosages may sufficiently reduce anticholinergic and/or adrenergic activity to reduce adverse side effects as compared to higher dosages.
  • compositions described herein can effectively improve sleep maintenance due to the action of low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same on the 5-HT 2A receptor.
  • the improved sleep maintenance can, in some embodiments, be characterized as longer total sleep time. In other embodiments, it can be characterized by greater sleep efficiency or fewer nocturnal awakenings.
  • the low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same can be administered to treat a condition related to the Hl receptor.
  • the condition can be a sleep disorder.
  • the low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same can be administered to treat a condition related to the 5-HT 2 A receptor.
  • the condition is a sleep disorder.
  • the low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same can be administered to treat a condition related to the Hl receptor and the 5-HT 2A receptor.
  • the condition can be a sleep disorder.
  • doxepin can act as a selective Hl antagonist at low doses, as well as interact with the 5-HT 2A receptor, permits a physician to better treat a sleep disorder due to, for example, the complementary action of low dose doxepin on those receptors.
  • a sleep disorder can be, in some embodiments, insomnia.
  • the insomnia can be non-chronic (transient) insomnia, while in other embodiments, the insomnia can be chronic insomnia.
  • the non-chronic insomnia may be a transient insomnia.
  • the insomnia is a maintenance insomnia.
  • the insomnia is an onset insomnia. The insomnia may be attributable to the concurrent use of other medications.
  • the insomnia is a primary insomnia, while in other embodiments, the insomnia is a secondary insomnia, that is, an insomnia attributable to another condition, such as depression or chronic fatigue syndrome.
  • Examples of causes of an insomnia may be extrinsic or intrinsic and include, but are not limited to environmental sleep disorders as defined by the International Classification of Sleep Disorders (ICSD) such as inadequate sleep hygiene, altitude insomnia or adjustment sleep disorder (e.g., bereavement). Also, short-term insomnia may also be caused by disturbances such as shift-work sleep disorder.
  • ISD International Classification of Sleep Disorders
  • sleep disorders such as inadequate sleep hygiene, altitude insomnia or adjustment sleep disorder (e.g., bereavement).
  • short-term insomnia may also be caused by disturbances such as shift-work sleep disorder.
  • Doxepin is currently approved for the treatment of depression and anxiety in daily dosages ranging from 75 milligrams to 300 milligrams.
  • Embodiments of the present invention relate to administering low dosages of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same.
  • the low dosage can, in some embodiments, be between about 0.0001 milligram and 10 milligrams. In some embodiments, the dosage can be, for example, about 0.001, 0.01, 0.1, 0.5, 1, 3, 6, 9, or 10 milligrams.
  • the dosage can be about 0.5 milligrams. In one aspect, the dosage can be about 1 milligram. In one aspect, the dosage can be about 3 milligrams. In one aspect, the dosage can be about 6 milligrams.
  • Low dosages of doxepin, a doxepin prodrug, or a pharmaceutically- acceptable salt of the same can be effective in the treatment of sleep disorders.
  • hypnotic drugs There are numerous limitations of the currently available hypnotic drugs and there is no one drug that can address all three components of insomnia efficacy (onset, maintenance and duration) with a clean safety profile. Side effects of hypnotics can include: residual sedation, lethargy, disorientation, impaired psychomotor function including light headedness and falls, amnesia, headaches, agitation, nightmares, dry mouth, dependence, withdrawal syndrome and rebound insomnia. The side effects are often worse in elderly patients. These drugs may be also subject to the additional problems of addictive potential and tolerance.
  • the limitations of the currently available hypnotics is reflected in that current medical guidelines recommend and emphasize the use of non drug treatment options as first line therapy.
  • low dose doxepin has the ability to strongly bind to and antagonize both the Hl and the 5-HT 2a receptors, it can be effectively used in combination with many existing hypnotic medications, including in some cases, to avoid the limitations of those medications.
  • some embodiments can include methods comprising administering doxepin, prodrugs or salts of the same in combination with other insomnia or sleep medications, for example, one or more of a compound that modulates GABA activity (e.g., enhances the activity and facilitates GABA transmission, a GABA-B agonist, a 5-HT modulator (e.g., a 5-HTIA agonist, a 5-HT 2 A antagonist, a 5-HT 2 A inverse agonist, etc.), a melatonin agonist, an ion channel modulator (e.g., blocker) a serotonin-2 antagonist/reuptake inhibitor (SARIs), an orexin receptor antagonist, an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin- 1 drug, and the like.
  • a compound that modulates GABA activity e.g., enhances the activity and facilitates
  • the methods can include the use of one or more of alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HYl 0275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San Diego
  • Compounds which enhance GABA activity for use in the compositions and methods of the present invention include, but are not limited to, alprazolam, bromazepam, chlorodiazepoxide, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam, Zolpidem, zaleplon, zopiclone, eszopiclone, gabaxadol, estazolam (Prosom) vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals) and indiplon.
  • Melatonin receptor agonists for use in the compositions and methods of the present invention include, but are not limited to, melatonin (e.g., Circadin®), ramelteon (ROZEREM ® , Takeda Pharmaceuticals, Japan), agomelatine, PD-6735 (Phase II Discovery) and VEC- 162 (Vanda Pharmaceuticals, Rockville, MD).
  • Preferred melatonin receptor agonists are those that are selective for MTj and/or MT 2 receptors, in comparison to MT 3 receptors.
  • 5-HT2a receptor antagonists preferably include, but are not limited to, any sleep-enhancing 5-HT2a antagonist or reverse agonist, which in particular embodiments may include eplivanserin (Sanofi-Aventis, France), volinanserin (Sanofi-Aventis, France), ketanserin, risperidone, pruvanserin (Eli Lilly), HY 10275 (Eli Lilly), MDL 100907 (Sanofi- Aventis, France), APD 125 (Arena Pharmaceuticals, San Diego, CA), ITI-722 (Intra-Cellular Therapies) or AVE 8488 (Sanofi-Aventis, France), [0051] 5-HTla receptor agonists preferably include, but are not limited to, repinotan, sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San Diego, CA).
  • Serotonin-2 antagonists/reuptake inhibitors include, but are not limited to, Org 50081 (Organon, The Netherlands), ritanserin, nefazodone, serzone and trazodone.
  • Orexin receptor antagonists include, but are not limited to, 1, 3- biarylureas, SB-334867-A (GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), ACT- 078573 (Actelion, Switzerland) and benzamide derivatives, such as those disclosed in U.S. Patent No. 7,078,565, the contents of which are incorporated herein by reference.
  • GABA-B agonists include, but are not limited to, ( -)baclofen ( ⁇ -(4- chloro-phenyl)- ⁇ -aminobutyric acid) ("Baclofen”)
  • doxepin drugs that may be combined with doxepin include gabapentinoids (alpha2 delta ligands), neurokinin- 1 drugs (casopitant (GlaxoSmithKline), histamine antagonist compounds (HYl 0275 Eli Lilly) and ion channel modulators (e.g., gabapentin, pregabalin, lamotrigine).
  • gabapentinoids alpha2 delta ligands
  • neurokinin- 1 drugs casopitant (GlaxoSmithKline)
  • histamine antagonist compounds HYl 0275 Eli Lilly
  • ion channel modulators e.g., gabapentin, pregabalin, lamotrigine.
  • one or more compounds from the classes mentioned herein, including the drugs that are specifically mentioned can be specifically excluded from one or more embodiments of the embodiments described herein.
  • one or more of the drugs alone in any combination or number can be specifically excluded from certain embodiments.
  • the methods using the combination compositions can include mixtures of the combined drugs, as well as two or more separate compositions of the drugs, which individual compositions can be, for example, coadministered together to a patient.
  • the dosages of these drugs can be the same as or lower than the approved dosage for the drug, the clinical or literature test dosage or the dosage used for the drug as a monotherapy.
  • Ramelteon ((S)- N-[2-(l,6,7,8-tetrahydro-2 H-indeno-[5,4- b]furan-8- yl)ethyl]propionamide) can be used in any dosage, but preferably can be used in a dosage of about 0.5 milligrams to about 20 milligrams. More preferably, about 4, 8 or 16 milligrams can be used, for example. Even more preferably, the dosage of Ramelteon can be less than about 4 mg, about 8 mg, or about 16 mg, for example between about 0.001 and about 3.9 mg.
  • Eszopiclone also can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 10 milligrams.
  • the dosage can be about 1 , 2, or 3 milligrams.
  • the dosage of Eszopiclone can be less than about 1 mg, about 2 mg, or about 3 mg, for example between about 0.001 and about 0.9 mg.
  • Zolpidem N,N,6-trimethyl-2-p-tolylimidazo[l,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1)
  • the dosage can be about 0.1 to about 20 milligrams.
  • the dosage can be about 6.25- milligrams, about 12.5 milligrams or a dosage that is a factor thereof, for example.
  • the dosage of Zolpidem can be less than about 6.25 mg or about 12.5 mg, for example between about 0.0001 and about 5, or between about 0.0001 and about 6 mg.
  • the dosage may be between about 0.001 and about 19.9 milligrams, about 0.001 and about 12.4 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 6.24 milligrams, or about 0.001 and about 4.9 milligrams. It is worth noting that Zolpidem (not just Zolpidem but all the GABAs)is known to have various undesirable side effects. Use of the low doses described herein when in combination with a doxepin compound provides efficacy as a sleep medication with reduced side effects.
  • zaleplon N- [3- (3- cyantopryazolo[l,5-a]pyrimidin-7- yl)phenyl]-N -ethylacetamide
  • the dosage can be between about 0.1 and about 20 milligrams, about 0.001 and about 19.9 milligrams, about 0.001 and about 12.4 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 6.24 milligrams, or about 0.001 and about 4.9 milligrams.
  • the dosage can be about 5, about 10 or about 20 milligrams, for example.
  • the dosage of zaleplon can be less than 5 mg, 10 mg, or 20 mg, for example between about 0.01 and 4.9 mg.
  • Gabaxadol (7-tetra hydroisoxazolo[5, 4-c]pyridin-3-ol) can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 40 milligrams.
  • the dosage can be between about 0.5 and about 20 milligrams, about 10 and about 15 milligrams, about 0.001 and about 39.9 milligrams, about 0.001 and about 19.9 milligrams, about 0.001 and about 12.4 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 6.24 milligrams, or about 0.001 and about 4.9 milligrams for example.
  • VEC-162 can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 150 milligrams.
  • the dosage can be about 10, about 20, about 50 or about 100 milligrams, for example.
  • the dosage can be between about 0.001 and about 149.9 milligrams, about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of VEC-162 can be about 0.001 to about 9 mg.
  • Indiplon (N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[l ,5-»]pyrimidin- 7-yl]phenyl]acetamide) can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 10 milligrams.
  • the dosage can be about 5 or about 10 milligrams, for example.
  • the dosage can be between about 0.001 and about 9.9 milligrams or about 0.001 and about 4.9 milligrams. Even more preferably, the dosage of indiplon can be about 0.001 to about 4.9 mg.
  • MDL 100907 (Sanof ⁇ -A vent ' s) can be used in any suitable dosage.
  • the dosage can be about 0.5 to about 100 milligrams, preferably from about 1 to about 50 milligrams.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of MDL 100907 can be about 0.001 to about 0.5 mg.
  • APD 125 (Arena Pharmaceuticals) can be used in any suitable dosage.
  • the dosage can be about 1 to about 160 milligrams, preferably about 5 to about 80 milligrams, or more preferably about 10 to about 40 milligrams.
  • the dosage can between about 0.001 and about 159.9 milligrams, about 0.001 and about 79.9 milligrams, about 0.001 and about 39.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of ADP125 can be about 0.001 to about 5 mg.
  • AVE 8488 can be used in any suitable dosage.
  • the dosage can be about 0.5 to about 100 milligrams, preferably from about 1 to about 50 milligrams.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of AVE 8488 can be about 0.001 to about 1 mg.
  • MN-305 (MediciNova) can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 50 milligrams, preferably from about 0.5 to about 10 milligrams or 1-6 milligrams.
  • the dosage can between about 0.001 and about 49.9 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 5.9 milligrams, about 0.001 and about 4.9, about 0.001 and about 3.9, about 0.001 and about 2.9 or about 0.001 and about 1.9 milligrams.
  • the dosage of MN-305 can be about 1 mg, about 3 mg or about 6 mg. Even more preferably, the dosage of MN-305 can be about 0.001 to about 0.5 mg.
  • ORG 50081 (Organon; Akzo Novel) can be used in any suitable dosage.
  • the dosage can be about 0.5 to about 100 milligrams, preferably from about 1 to about 50 milligrams.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of ORG 50081 can be about 0.001 to about 1 mg.
  • ACT-078573 (Actelion) can be used in any suitable dosage.
  • the dosage can be about 0.5 to about 100 milligrams, preferably from about 1 to about 50 milligrams.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of ACT-078573 can be about 0.001 to about 1 mg.
  • Baclofen (( -)baclofen ( ⁇ -(4-chloro-phenyl)- ⁇ -aminobutyric acid) can be used in any suitable dosage.
  • the dosage can be about 1 mg to about 100 mg, preferably from, about 5 to about 40 mg.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 39.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams.
  • the dosage of baclofen can be about 0.001 to about 1 mg.
  • Eplivanserin can be used in any suitable dosage.
  • the dosage can be about 0.1 mg to about 20 mg.
  • the dosage can between about 0.001 and about 19.9 milligrams, about 0.001 and about 9.9 milligrams, or about 0.001 and about 4.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 5 mg.
  • Pruvanserin (Eli Lilly) can be used in any suitable dosage.
  • the dosage can be about 0.1 mg to about 50 mg.
  • the dosage can between about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 10 mg.
  • ACT-078573 (Actelion; GlaxoSmithKline) can be used in any suitable dosage.
  • the dosage can be about 100 mg to about 1200 mg.
  • the dosage can between about 0.001 and about 1199.9 milligrams, about 0.001 and about 999.9 milligrams, about 0.001 and about 499.9 milligrams, or about 0.001 and about 9.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 100 mg.
  • EVT 201 can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 30 mg.
  • the dosage can between about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, or about 0.001 and about 9.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 1 mg.
  • Volinanserin can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 20 mg.
  • the dosage can between about 0.001 and about 19.9 milligrams, about 0.001 and about 9.9 milligrams, or about 0.001 and about 4.9 milligrams, or about 0.001 and about 1.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 2 mg.
  • HY 10275 (Eli Lilly) can be used in any suitable dosage.
  • the dosage can be about 0.1 to about 50 milligrams, preferably from about 0.5 to about 10 milligrams or 1-6 milligrams.
  • the dosage of HY10275 can be about 1 mg, about 3 mg or about 6 mg.
  • the dosage can between about 0.001 and about 49.9 milligrams, about 0.001 and about 19.9 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 4.9 milligrams, about 0.001 and about 3.9 milligrams, about 0.001 and about 2.9 milligrams, about 0.001 and about 1.9 milligrams, or about 0.001 and about 0.9 milligrams. Even more preferably, the dosage of HY10275 can be about 0.001 to about 1 mg.
  • PD-6735 (6-chloro-(beta)-methyl melatonin; Phase II Discovery) can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 150 mg.
  • the dosage can between about 0.001 and about 149.9 milligrams, about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, or about 0.001 and about 19.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 20 mg.
  • ITI-722 can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 500 mg.
  • the dosage can between about 0.001 and about 499.9 milligrams, about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, or about 0.001 and about 9.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 100 mg.
  • GW649868 (GlaxoSmithKline) can be used in any suitable dosage.
  • the dosage can be about 6.25-milligrams, 12.5 milligrams or a dosage that is a factor thereof, for example.
  • the dosage can between about 0.001 and about 19.9 milligrams, about 0.001 and about 6.24 milligrams, about 0.001 and about 12.4 milligrams, or about 0.001 and about 4.9 milligrams.
  • the dosage of GW649868 can be less than 6.25 mg or 12.5 mg, for example between about 0.001 and 5 mg.
  • Casopitant can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 500 mg.
  • the dosage can between about 0.001 and about 499.9 milligrams, about 0.001 and about 99.9 milligrams, about 0.001 and about 49.9 milligrams, or about 0.001 and about 9.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 100 mg.
  • Circadin® (H. Lundbeck AIS) can be used in any suitable dosage.
  • the dosage can be about 0.01 mg to about 30 mg.
  • the dosage can between about 0.001 and about 29.9 milligrams, about 0.001 and about 9.9 milligrams, about 0.001 and about 4.9 milligrams, or about 0.001 and about 1.9 milligrams. Even more preferably the dosage can be about 0.001 mg to about 2 mg.
  • doxepin for use in the methods described herein can be obtained from any suitable source or made by any suitable method. As mentioned, doxepin is approved and available in higher doses (75-300 milligrams) for the treatment of depression and anxiety.
  • Doxepin HCl is available commercially and may be obtained in capsule form from a number of sources. Doxepin is marketed under the commercial name SINEQU AN® and in generic form, and can be obtained in the United States generally from pharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg dosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can be obtained from Plantex Ltd. Chemical Industries (Hakadar Street, Industrial Zone, P.O.
  • doxepin is commercially available from PharmacyRx (NZ) (2820 1 st Avenue, Castlegar, B.C., Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg.
  • Doxepin HCl is available in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg and in a lOmg/ml liquid concentrate from CVS Online Pharmacy Store (CVS.com).
  • doxepin (l l-(3-dimethylaminopropylidene) -6,11 - dihydrodibenzo(b,e)oxepin) can be prepared according to the method taught in U.S. Patent No. 3,438,981, which is incorporated herein by reference in its entirety. An example preparation is described below in Example 1.
  • each of the references discussed above is incorporated by reference in its entirety.
  • teachings of one or more of the references can be included or combined with instant methods or embodiments, while in other aspects the teachings of one or more of the references can be specifically excluded from the methods and embodiments described herein.
  • the dosages used or the patient population that is treated (e.g., age, health/disease profile, etc.) in a reference can be excluded or included from the methods and embodiments described herein.
  • the methods and other embodiments described herein can utilize any suitable pharmaceutically-acceptable salt or prodrug of doxepin. Therefore, substitution of salts and prodrugs is specifically contemplated in the various embodiments, even though, only doxepin may be specifically mentioned.
  • the pharmaceutically-acceptable salts and prodrugs can be made by any suitable method.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, dislyate, estolate, esylate, ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate
  • prodrug refers to a chemical entity that is rapidly transformed in vivo to yield an active drug, such as for example doxepin, by hydrolysis in blood or inside tissues.
  • active drug such as for example doxepin
  • pro-drug groups can be found in, for example, T. Higuchi and V. Stella, in "Pro-drugs as Novel Delivery Systems,” Vol. 14, A.C.S. Symposium Series, American Chemical Society (1975); H. Bundgaard, “Design of Prodrugs,” Elsevier Science, 1985; and “Bioreversible Carriers in Drug Design: Theory and Application,” edited by E. B. Roche, Pergamon Press: New York, 14-21 (1987), each of which is hereby incorporated by reference in its entirety.
  • prodrug amide is a prodrug amide.
  • Prodrug amides can hydrolyze under physiological conditions to afford a free amine, such as desmethyldoxepin, and a carboxylic acid (Hellberg, et al, "The Hydrolysis of the Prostaglandin Analog Prodrug Bimatoprost to 17-Phenyl-trinor PGF2 by Human and Rabbit Ocular Tissue", 2003,19(2), 97-103), which is incorporated herein by reference in its entirety. Patients
  • a low dosage of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same can be administered or provided to a patient.
  • the patient can be suffering from a sleep disorder.
  • the sleep disorder is insomnia.
  • the insomnia can be chronic insomnia, while in others, the insomnia is non-chronic insomnia.
  • the insomnia may be maintenance insomnia.
  • the insomnia may be onset insomnia.
  • the insomnia may be a primary or a secondary insomnia.
  • the non-chronic insomnia can be a short term or transient insomnia.
  • the patient can be suffering from an adverse side effect associated with a sleep medication.
  • the side effect can be an anticholinergic side effect, an adrenergic side effect, sleep drug withdrawal, sleep drug tolerance, sleep drug rebound, or any other adverse effect.
  • the patient can be suffering from a sleep condition that includes a deficiency in restorative sleep or a deficiency associated with arousability.
  • the patient can be suffering from an Hl associated condition or Hl receptor associated sleep disorder.
  • the patient can be in need of treatment comprising an Hl antagonist.
  • the patient can be suffering from a 5-HT 2A receptor associated condition or a 5-HT 2A receptor associated sleep disorder.
  • the patient can be in need of treatment comprising a 5-HT 2A antagonist.
  • the patient can be suffering from an Hl associated condition and a 5-HT 2A associated condition or sleep disorder.
  • the patient can be in need of treatment comprising an Hl antagonist and a 5-HT 2 A antagonist.
  • the patient may or may not be identified based on one of these characteristics.
  • methods of the present invention include identifying a patient suffering from at least one adverse side effect of a drug used to treat insomnia (e.g., GABA-A modulators or trazodone.
  • a drug used to treat insomnia e.g., GABA-A modulators or trazodone.
  • the drug also can be any other medication, including other sleep medications such as those listed elsewhere herein.
  • methods of the present invention include identifying a patient who is particularly susceptible to at least one anticholinergic and/or adrenergic side effect or susceptible to any other adverse effect associated with a sleep medication (tolerance, rebound, withdrawal, night arousal, etc.)-
  • methods of the present invention include identifying a patient suffering from insomnia who is in need of treatment and who wishes to minimize anticholinergic and/or adrenergic side effects. The patient may wish to minimize the withdrawal effects following treatment with an alternate sleep agent.
  • the patient may be informed, orally or in writing, that the low dosage of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same acts selectively on the Hl receptor.
  • the patient may be informed that the low dosage acts selectively on the Hl receptor by informing the patient that the low dosage treats a specific Hl condition while reducing the probability of experiencing and/or the severity of at least one side effect.
  • informing the patient that the low dosage acts selectively on the Hl receptor is informing the patient that the low dosage treats insomnia while reducing the probability of experiencing anticholinergic side effects.
  • the patient may be informed that the low dosage of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same acts with high potency at the 5- HT 2A receptor.
  • the patient may be informed that the low dosage acts with potency, for example, high potency at the 5-HT 2A receptor by informing the patient that the low dosage treats a specific 5-HT 2A condition while reducing the probability of experiencing and/or the severity of at least one side effect.
  • informing the patient that the low dosage acts with high potency at the 5-HT 2A receptor is informing the patient that the low dosage treats insomnia while reducing the probability of experiencing anticholinergic side effects.
  • the patient may be informed that the low dosage of doxepin, a doxepin prodrug, or a pharmaceutically-acceptable salt of the same acts selectively on the Hl receptor and the 5-HT 2A receptor.
  • the patient may be informed that the low dosage acts selectively on the Hl receptor and the 5-HT 2 A receptor by informing the patient that the low dosage treats a specific Hl and 5-HT 2A condition while reducing the probability of experiencing and/or the severity of at least one side effect.
  • informing the patient that the low dosage acts selectively on the Hl receptor and the 5-HT 2A receptor is informing the patient that the low dosage treats insomnia while reducing the probability of experiencing anticholinergic side effects.
  • the selected dosage level can depend upon, for example, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. It will be understood, however, that the specific dose level for any particular patient can depend upon a variety of factors including the genetic makeup, body weight, general health, diet, time and route of administration, combination with other drugs and the particular condition being treated, and its severity.
  • low dosages are dosages between 0.0001 and 10 milligrams. In other embodiments, low dosages are dosages between 0.001, 0.1, or 1.0 milligrams and 10 milligrams. In still other embodiments, low dosages are between 0.01 milligrams and 4.0, and 9.9 milligrams. In some embodiments, low dosages can be as low as about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08 or 0.09 milligrams.
  • low dosages can be as low as about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 milligrams. Therapy at each of the doses described in this paragraph as well as ranges between these doses, are particularly contemplated. These relatively low doses between 0.01 milligrams up to, for example, 2, 3, 4, 5, and 10 milligrams, have reduced anticholinergic side effects and are surprisingly effective.
  • Doxepin, a pharmaceutically-acceptable salt or a prodrug thereof can be prescribed or administered at a constant dose, or the dosage can change as a function of treatment time.
  • dosages may increase or decrease with time in a step-wise or continuous manner.
  • the dosage may vary depending on the effect of the dosage on an Hl receptor-related condition and the occurrence of adverse side effects.
  • the dosage may vary depending on the effect of the dosage on a 5-HT 2A receptor-related condition and the occurrence of adverse side effects.
  • the dosage may vary depending on the effect of the dosage on a condition related to both an Hl receptor and a 5-HT 2A receptor and the occurrence of adverse side effects.
  • the patient may be instructed to continue to lower the dosage until an anticholinergic side effect, such as dry mouth, is reduced to an acceptable level.
  • the patient may be instructed to continue to lower the dosage until the dosage is no longer effective and then slightly increase the dosage.
  • doxepin, a pharmaceutically-acceptable salt or a prodrug thereof can be prescribed or administered at a specific dosage per day.
  • the patient can be instructed to take a low dosage of doxepin, a pharmaceutically-acceptable salt or a prodrug thereof when he or she experiences one or more symptoms related to a condition related to an Hl receptor and/or a 5-HT 2A receptor.
  • the patient may be instructed to take a low dosage of doxepin, a pharmaceutically-acceptable salt or a prodrug thereof when he is experiencing insomnia.
  • Doxepin, a pharmaceutically-acceptable salt or a prodrug thereof can be administered alone or in combination with other substances, such as for example, other insomnia or sleep medications, or with other medications that treat a primary illness, including the medications or classes of medications described elsewhere herein.
  • doxepin, prodrugs or salts of the same can be used or administered with alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol, vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam, ketanserin, risperidone, eplivanserin, volinanserin (Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis, France), HYl 0275 (Eli Lilly), APD 125
  • compositions as described herein can include doxepin, a pharmaceutically-acceptable salt or a prodrug thereof in a unit dosage form.
  • Unit dosage form can refer to a product form in which pre-measured dosages of the drug are packaged, in contrast to bulk preparations. Examples of unit dosage forms are described herein, but several non limiting examples, include, a pill, a tablet, a capsule, a gel cap, a small liquid drug, an ampoule, a fast melt formulation, and the like.
  • the salts and prodrugs alone or in combination can be included and administered as a composition. Methods of use can include the step of administering a therapeutically-effective amount of the compound or composition to a patient in need thereof by any suitable route or method of delivery, including those described herein.
  • doxepin, a pharmaceutically acceptable salt of doxepin or prodrug of doxepin can be administered using any suitable route or method of delivery.
  • doxepin, pharmaceutically acceptable salts, and/or prodrugs of the same can be administered alone or in combination with other substances, such as for example, other insomnia or sleep medications, or with other medications that treat a primary illness.
  • Doxepin, a pharmaceutically-acceptable salt or a prodrug thereof alone or in combination can be included and administered as a composition.
  • Suitable routes of administration include oral, buccal, sublingual, transdermal, rectal, topical, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the compounds can be formulated as pills, tablets, powders, granules, dragees, capsules, liquids, sprays, gels, syrups, slurries, suspensions and the like, in bulk or unit dosage forms, for oral ingestion by a patient to be treated.
  • the compounds can be formulated readily, for example, by combining the active compound with any suitable pharmaceutically acceptable carrier or excipient.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with a pharmaceutical composition as described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are listed below.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the formulation can be in form suitable for bolus administration, for example.
  • Oral administration can be accomplished using fast-melt formulations, for example.
  • the formulations can be included in pre-measured ampules or syringes, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take any suitable form, for example, tablets or lozenges.
  • the compounds may be formulated for administration to the epidermis as ointments, gels, creams, pastes, salves, gels, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • any of the compounds and compositions described herein can also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • any of the compounds and compositions described herein also can be formulated as a fast-melt preparation.
  • the compounds and compositions can also be formulated and administered as a drip, a suppository, a salve, an ointment, an absorbable material such a transdermal patch, or the like.
  • sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in the incorporated materials in Remington: The Science and Practice of Pharmacy (20 th ed, Lippincott Williams & Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety.
  • compositions and formulations disclosed herein also can include one or more pharmaceutically acceptable carrier materials or excipients.
  • Such compositions can be prepared for storage and for subsequent administration.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in the incorporated material of Remington: The Science and Practice of Pharmacy (2003).
  • carrier material or “excipient” herein can mean any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • suitable excipients for soft gelatin capsules include vegetable oils, waxes, fats, semisolid and liquid polyols.
  • suitable excipients for the preparation of solutions and syrups include, without limitation, water, polyols, sucrose, invert sugar and glucose.
  • Suitable excipients for injectable solutions include, without limitation, water, alcohols, polyols, glycerol, and vegetable oils.
  • the pharmaceutical compositions can additionally include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers, coating agents, or antioxidants.
  • Sterile compositions for injection can be formulated according to conventional pharmaceutical practice as described in the incorporated material in Remington: The Science and Practice of Pharmacy (2003).
  • dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired.
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compound can also be made in microencapsulated form.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • absorption enhancing preparations for example, liposomes), can be utilized.
  • compositions and formulations can include any other agents that provide improved transfer, delivery, tolerance, and the like.
  • These compositions and formulations can include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LipofectinTM), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.
  • any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. "Pharmaceutical excipient development: the need for preclinical guidance.” Regul. Toxicol. Pharmacol. 32(2):210-8 (2000), Charman WN “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.” J Pharm Sci .89(8):967-78 (2000), Powell et al. "Compendium of excipients for parenteral formulations" PDA J Pharm Sci Technol. 52:238- 311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.
  • a Grignard compound was prepared in the conventional manner from 4.8 g (0.2 gram-atom) magnesium in 100 ml ether and 30 g (34 ml) (3-chloropropyl)- tertbutyl-ether and 16.40 grams (0.078 mol) 6,l l-dihydrodibenzo-[b,e]-oxepine-l l-one dissolved in 100 ml ether were added in dropwise fashion so that the contents of the flask boiled lightly. The mixture was heated for 1 hour with agitation in a reflux condenser to complete the reaction and then it was decomposed with ammonium chloride solution.
  • the (3-chloropropyl)-tertbutyl ether was thereafter obtained in the following manner: 19 g (0.2 mol) l-chloropropanol-(3), 50 ml liquid isobutylene and 0.5 ml concentrated sulfuric acid were permitted to stand for 24 hours in an autoclave, then poured into excess sodium bicarbonate solution and extracted with ether. The ether solution was dried with calcium chloride and distilled. 23.6 grams of (3-chloropropyl)-tertbutylether having a boiling point of 150-156 0 C (78% of theory) were recovered.
  • the separated, aqueous-acid components were then made alkaline with dilute caustic soda solution, and the oil thereby separated was taken up in ether.
  • the ether residue after distillation in a high vacuum, produced 4.1 g (73.5% of theory) of 1 l-(3-dimethylamino- propylidene)- 6,11-dihydrodibenzo- [b,e]-oxe ⁇ ine, having a B.P.0.1 147-15O 0 C.
  • the melting point of the hydrochloride was 182-184 0 C (recrystallized from isopropanol).
  • a randomized, double blind, placebo controlled, parallel group study was designed to assess the efficacy and safety of two doses of doxepin, 3 mg and 6 mg, in adult patients with primary insomnia and sleep maintenance difficulties.
  • Subjects were females and males, 18 to 64 years of age inclusive, with at least a 3 -month history of primary insomnia (as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), who reported experiencing >60 minutes of Wake After Sleep Onset (WASO), >20 minutes of Latency to Sleep Onset (LSO), and ⁇ 6.5 hours of Total Sleep Time (TST) on at least 4 of 7 consecutive nights prior to PSG Screening.
  • WASO Wake After Sleep Onset
  • LSO Latency to Sleep Onset
  • TST Total Sleep Time
  • the overall duration of the study for each subject was approximately two months including the Initial Screening Period, PSG Screening Period, Baseline, 35 day Double blind Treatment Period, 2-day Discontinuation Period, and Final Study Day
  • the primary efficacy variable was WASO on Night 1. Additional efficacy variables obtained during each PSG recording night during the Double blind Treatment Period were Wake Time During Sleep (WTDS), TST, Sleep Efficiency (SE) overall, SE by third of the night, SE in the last quarter of the night, SE by hour of the night, Latency to Persistent Sleep (LPS), latency to Stage 2 sleep, Number of Awakenings After Sleep Onset (NAASO), NAASO by hour of the night, Total Wake Time (TWT), TWT by hour of the night, Wake Time After Sleep (WTAS), and sleep architecture (including percentage and minutes of Stage 1, 2, and 3-4 sleep; percentage and minutes of rapid eye movement [REM] and non-REM sleep; and latency to REM sleep).
  • WTDS Wake Time During Sleep
  • SE Sleep Efficiency
  • AEs adverse events
  • ECGs 12-lead electrocardiograms
  • Hangover/residual effects were determined based on test scores from the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), and Visual Analog Scale (VAS) for sleepiness, all obtained within 1 hour of waking.
  • DSST Digit Symbol Substitution Test
  • SCT Symbol Copying Test
  • VAS Visual Analog Scale
  • the least-squares (LS) mean WASO on Night 1 was statistically significantly decreased following administration of doxepin 3 mg (by 26.0 minutes) and 6 mg (by 30.8 minutes) compared with the placebo group. Additionally, the LS mean WASO was statistically significantly decreased for the doxepin 3 mg and 6 mg groups at Night 15 (by 17.3 and 18.6 minutes, respectively) and Night 29 (by 15.7 and 22.3 minutes). Similar results for WASO were observed for the average of Nights 1, 15, and 29 as well as for the means of the paired study nights (Nights 1 and 2; Nights 15 and 16; and Nights 29 and 30)(Figure 1)
  • doxepin was safe and well-tolerated (Table 1). Patients taking doxepin 3 and 6 mg did not spontaneously report the well-documented anticholinergic and other adverse effects that are commonly associated with doxepin use at higher doses. See, for example, Roth et al., J Clin Psych, 1982; 43:366-368 and Hajak et al., Nocturnal Melatonin Secretion and Sleep after Doxepin Administration in Chronic Primary Insomnia, Pharmacopsychiatry 29: 187-192, (1996), each of which is hereby incorporated by reference in its entirety.
  • insomnia patients may suffer from overactivity in histamine-mediated arousal systems
  • blockade of Hl receptors in the cortex and thalamus can represent a specifically targeted approach for mitigating this imbalance without disrupting other key functions (e.g., motor control).
  • This histamine antagonist method of promoting sleep differs from hypnotic agents that target the GABA receptor complex.
  • Some differences from GABA agonist approaches to insomnia include: 1) Doxepin is essentially inactive at benzodiazepine recognition sites; 2) Histamine activity fluctuates over the circadian cycle and can be greatest in the latter part of the night and early morning where it facilitates the natural transition from sleep to waking; and 3) Sleep-enhancement involves antagonism of histamine and has the effect of preventing sleep-disturbing arousal at times of natural vulnerability such as in the middle of the night and early morning. Additionally, unlike GABA, which has simultaneous effects on many systems, low doses of doxepin selectively affect histamine.
  • doxepin does not interfere with those effects. Therefore, treatment of insomnia with low doses of doxepin represents a highly directed therapy for dysfunctional arousal systems without impairing the other systems that promote wakefulness, as well as intact cognitive and psychomotor function.
  • doxepin 3 and 6 mg produced improvement in PSG-defined and patient-reported sleep maintenance and duration endpoints that persisted throughout the night (including the final third-of-the-night) in adults with primary insomnia. Effects on sleep onset and early morning awakenings also were observed at the higher of these low doses. In terms of safety, the AE profile was comparable to placebo, there were no reported anticholinergic effects, there were no significant hangover/next-day residual effects, and sleep stages were essentially preserved.
  • Subjects were females and males, 65 years of age or older, with at least a 3-month history of primary insomnia (as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), who reported experiencing at least 60 minutes of Wake After Sleep Onset (WASO), at least 30 minutes of Latency to Sleep Onset (LSO), and no more than 6.5 hours of Total Sleep Time (TST) on at least 4 of 7 consecutive nights prior to PSG Screening.
  • WASO Wake After Sleep Onset
  • LSO Latency to Sleep Onset
  • TST Total Sleep Time
  • WTDS Wake Time During Sleep
  • TST 240 minutes and ⁇ 390 minutes
  • LPS Latency to Persistent Sleep
  • the overall duration of the study was approximately 4 months for each subject, including the Initial Screening Period, PSG Screening Period, 85-day Double-blind Treatment Period, and Final Study Day.
  • the primary efficacy variable was WASO on Night 1. Additional objective efficacy variables assessed on each PSG recording night during the Double-blind Treatment Period were WASO (Night 15, Night 29, Night 57, and Night 85); WTDS; TST; Sleep Efficiency (SE) overall, by third of the night, the last quarter of the night, and hour of the night; LPS; Latency to Stage 2 Sleep; Number of Awakenings After Sleep Onset (NAASO) overall and by hour; Total Wake Time (TWT) overall and by hour; Wake Time After Sleep (WTAS); and sleep architecture (including percentage and minutes of Stage 1, 2, and 3-4 sleep; percentage and minutes of rapid eye movement [REM] and non-REM sleep; and Latency to REM Sleep).
  • AEs adverse events
  • ECGs 12-lead electrocardiograms
  • Hangover/residual effects were determined based on test scores from the Digit Symbol Substitution Test (DSST), Symbol Copying Test (SCT), and Visual Analog Scale (VAS) for sleepiness.
  • DSST Digit Symbol Substitution Test
  • SCT Symbol Copying Test
  • VAS Visual Analog Scale
  • mean WASO on Night 1 was statistically significantly decreased following administration of doxepin 1 mg and 3 mg compared with placebo.
  • the least-squares (LS) mean WASO was shorter for the doxepin 1 mg and 3 mg groups by 17.8 minutes and 33.8 minutes, respectively, compared with the placebo group. Additionally, in the doxepin 3 mg group the LS mean WASO was statistically significantly decreased compared with placebo at each assessment through 85 nights of treatment ( Figure 2).
  • HEK-293 cells were used and serotonin was used as the stimulus.
  • the reaction product was intracellular [Ca 2+ ], which was detected using fluorimetry. Jerman et al., "Pharmacological characterization of human 5-HT 2 receptor subtypes,” Eur. J. Pharmacol, 414:23-30 (2001), which is incorporated herein by reference in its entirety.
  • Ketanserin and ritanserin were tested concurrently with doxepin as reference compounds. Compounds were tested at several concentrations (for IC 50 value determination), and the data were compared with historical values (for ketanserin). The assay was rendered valid if the results for ketanserin were comparable to historical values.
  • IC50 values concentration causing a half-maximal inhibition of the control specific agonist response
  • concentration-response curves generated with mean replicate values using Hill equation curve fitting
  • Y D + [(A - D)/(l + (C/C 50 ) nH )]
  • Y specific response
  • D minimum specific response
  • A maximum specific response
  • C compound concentration
  • C 50 IC 50
  • nH slope factor
  • NAASO Placebo 136 48) 132 (55) 126 (50) 119 (53) DXP 1 mg 144 (46) 143 (64) 149* (59) 149 ** (66) DXP 3 mg 133 (43) 140 (62) 133 (52) 129 (56)
  • *P-value comparing each active treatment versus placebo is determined from a repeated- measures ANOVA model with terms for sequence, patient within sequence, treatment, and period using Dunnett's test.
  • P-values reflect comparison of active dose with placebo using Dunnett's test.

Abstract

Des modes de réalisation de la présente invention portent sur des procédés et des compositions améliorés se rapportant à l'utilisation de la doxépine à faible dose.
PCT/US2009/042912 2008-05-06 2009-05-05 Compositions et procédés se rapportant à l'action de faibles dosages de doxépine sur les récepteurs h1 et 5-ht2a WO2009137531A2 (fr)

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CN102949360A (zh) * 2011-08-10 2013-03-06 瑟维尔实验室 用于阿戈美拉汀颊腔给药的固体药用组合物

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US20050171160A1 (en) * 2003-12-10 2005-08-04 Edgar Dale M. Doxepin analogs and methods of use thereof
US20050239838A1 (en) * 2004-04-23 2005-10-27 Dale Edgar Methods of treating sleep disorders
US20050256165A1 (en) * 2003-12-10 2005-11-17 Edgar Dale M Doxepin analogs and methods of use thereof

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US20050171160A1 (en) * 2003-12-10 2005-08-04 Edgar Dale M. Doxepin analogs and methods of use thereof
US20050256165A1 (en) * 2003-12-10 2005-11-17 Edgar Dale M Doxepin analogs and methods of use thereof
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CN102949360A (zh) * 2011-08-10 2013-03-06 瑟维尔实验室 用于阿戈美拉汀颊腔给药的固体药用组合物

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