Methods to improve psychomotor or cognitive abilities

Abstract

Intranasal administration of 1,3,5(10),16-estratetraen-3-ylacetate is useful in improving the psychomotor and / or cognitive abilities of mentally fatigued individuals.

Description

Technical Field

[0001] The present invention relates to the improvement of psychomotor ability and / or cognitive ability of mentally fatigued individuals by intranasal administration of 1,3,5(10),16-estratetraen-3-yl acetate.

Background Art

[0002] Psychomotor ability and cognitive ability According to Wetherell, “Cognitive And Psychomotor Performance Tests and Experimental Design in Multiple Chemical Sensitivity” (Environ. Health Perspect., 105 (Suppl. 2), 495-503 (1997)), psychomotor function (sometimes called perceptual-motor function) refers to a person's ability to coordinate timely and appropriate responses to stimuli, while cognitive function (sometimes called cognition) refers to the ability to think about temporal and spatial relationships, as well as the ability to think and reason with symbols such as words and numbers. In general terms, psychomotor function (or psychomotor ability) is the ability to respond. In contrast, cognitive function (or cognition or cognitive ability) is the ability to think.

[0003] As explained by Wetherell, psychomotor and cognitive abilities are not discrete; they overlap to the extent that stimuli require thought. Therefore, while a simple reaction time test is typically considered a test of psychomotor ability, if the stimuli used are complex and require decisions about how to respond, the test becomes more of a test of cognitive ability. Wetherell describes several autocapsule tests used by the Chemical and Biological Defense Human Research Group at the UK's Defence Assessment Research Institute, all of which he notes are in the public domain. He points out that these tests are used to assess environmental stressors (primarily drugs, but also physical fatigue, sleep deprivation, and protective clothing).

[0004] Psychomotor ability tests are primarily automated tests. The psychomotor arousal task (PVT) is a sustained attention response time task that measures how quickly a subject reacts to a visual stimulus (light), in which the subject presses a button as soon as the light appears. The light flashes on and off in a pseudo-random manner every few seconds for 5-10 minutes. The main measurement of this task is not to evaluate the subject's reaction time itself, but to see how many times the button is not pressed when the light is on, or how many times the button is not pressed when the light is off. The purpose of the PVT is to measure sustained attention / arousal and to provide a numerical measure of attention / arousal deficits by counting the number of times the subject's attention is interrupted.

[0005] Cogstate, Inc., based in New Haven, Connecticut, USA, offers a variety of computer-implemented individual tests that can be assembled into a test battery (Cogstate calls them “tasks”), including a detection test, which is a version of the PVT (where a card is shown face down, then face up, and the subject is required to respond when the card is face up). The reaction time test in Example 4 is an automated psychomotor ability test.

[0006] Cognitive ability tests include both manually scored and automated tests. Examples of automated cognitive ability tests include tests from Cogstate and the IntegNeuro® system from BrainClinics Products (Nijmegen, The Netherlands). Cogstate tests include identification tests (cards are shown face down and then face up, and the subject must indicate whether the face on the card is red or black), one-card learning tests (a single card is shown multiple times during the test, with the cards successively turned face up, and the subject must indicate whether the shown card is new or previously shown), and one-back tests (several cards are shown twice in a row, with the cards successively turned face up, and the subject must indicate whether the shown card is new or immediately shown).

[0007] The IntegNeuro® system is a touchscreen computer that provides a series of tests, including a timing test (a circle lights up for 1 to 12 seconds, after which the subject must estimate the duration of the light), a selective reaction time test (one of four circles lights up, and the subject must touch the lit circle), a verbal interference test (words that are color names are displayed on the screen in different colors, and the subject must indicate the color on which the word appears, not the word itself), and a "spot the real word" test (where real words and nonsense words are shown, and the subject must indicate the real word). The time estimation test in Example 4 is an automated cognitive ability test.

[0008] Mental fatigue (In contrast to physical or muscular fatigue, which is a temporary physical inability in which muscles are unable to function optimally,) mental fatigue is a temporary inability to maintain the level of psychomotor and / or cognitive ability that is typical for a given individual, or otherwise normal or optimal for that individual or for people in general. It can also result from prolonged cognitive activity (excessively long activity on tasks requiring thinking or mental effort), sleep deprivation (a state of not having enough sleep), sleep disturbance or sleep apnea (resulting in sleep deprivation), or conditions related to these, such as shift work sleep disorder and excessive daytime sleepiness.

[0009] Mental fatigue can also arise from depressive disorders, such as major depressive disorder (MDD) and perinatal depression, as well as from other disorders in which mental fatigue is a typical symptom or is otherwise associated, such as attention deficit hyperactivity disorder and mild cognitive impairment. For example, according to Takeda et al., “Impact of depression on mental fatigue and attention in patients with multiple sclerosis” (J. Affect. Disord. Rep., 5, 100143 (2021)), mental fatigue is strongly correlated with depression in patients with multiple sclerosis. However, according to Pan et al., “Cognitive Impairment in Major Depressive Disorder” (CNS Spectrums, 24, 22-29 (2019)), “most antidepressants have not been developed and / or evaluated for their ability to directly and independently improve cognitive impairment.” According to Polosan et al., “Cognition—the core of major depressive disorder” (L'Encephale, 42(1, Suppl.1), 1S3-1S11 (2016)), “cognitive impairment has recently come to be recognized as a major phenotypic determinant.” Pan et al. also report that “...cognitive subdomains such as learning and memory, executive function, processing speed, and attention and concentration are significantly impaired during and between episodes in individuals with MDD.” Furthermore, depression is also highly associated with sleep disturbances (Murphy and Peterson, “Sleep Disturbances in Depression,” Sleep Med. Clinics, 10(1), 17-23 (2015)), which may contribute to cognitive impairment in major depressive disorder.Furthermore, Sommerfeldt et al., “Executive Attention Impairment in Adolescents with Major Depressive Disorder” (J. Clin. Child Adole sc. Psycho., 45(1), 59-83 (2016)), reported on “attention deficits” in adolescents with MDD, characterized, for example, by longer reaction times compared to controls.

[0010] According to Rogers et al., “Fatigue in an adult attention deficit hyperactivity disorder population: A trans-diagnostic approach” (Br.J.Clin.Psychol., 56(1), 33-52 (2017)), fatigue, including mental fatigue, is a common clinical feature of adult attention deficit hyperactivity disorder (ADHD).

[0011] Mental fatigue can also be caused by (or associated with) mild cognitive impairment (MCI). MCI is a stage between the expected decline in memory and thinking and the more severe decline of dementia, as described below, and may be further associated with depression. MCI may include problems with memory, language, or judgment, but is not a definitive precursor to dementia as it may be in people with other mental disorders (e.g., depression) or systemic disorders (e.g., diabetes or obesity). The Alzheimer's Association (https: / / www.alz.org / alzheimers-dementia / what-is-dementia / related_conditions / mild-cognitive-impairment) states that "mild cognitive impairment (MCI) is an early stage of memory loss or other cognitive impairment (such as language or visual / spatial cognition) in an individual who retains the ability to independently perform most activities of daily living." They also stated that "Mild Cognitive Impairment (MCI) involves cognitive changes that are significant enough to be noticed by the affected person, as well as family and friends, but do not affect the individual's ability to perform daily activities. MCI can develop for several reasons, and individuals living with MCI may or may not develop dementia. In the case of neurodegenerative diseases, MCI can be an early stage of a continuum of diseases, including Alzheimer's disease, where there are significant changes in the brain. The causes of MCI are not yet fully understood. Experts believe that many, though not all, cases are due to brain changes that occur in the very early stages of Alzheimer's disease or other neurodegenerative diseases that lead to dementia."

[0012] When the underlying cause is neurodegenerative disease and not another cause, the risk factors most strongly associated with MCI are age, a family history of Alzheimer's or another dementia, and conditions that increase the risk of cardiovascular disease. ... Approximately 12% to 18% of people over 60 live with MCI. An estimated 10% to 15% of individuals living with MCI will develop dementia each year. Approximately one-third of people living with MCI due to Alzheimer's disease will develop dementia within five years.

[0013] Cognitive assessments for MCI include the Mini-Cog (memory of three words and drawing a clock), the General Practitioner Cognitive Assessment (GPCOG: the patient section assesses orientation, recognition, and memory traits, while the information section compares the patient's current functioning to previous functioning), the Montreal Cognitive Assessment (MoCA: a one-page, 30-point test that assesses eight cognitive domains through 13 tasks), or the Saint Louis University Mental State Assessment (SLUMS: a 30-point, 11-item scale that includes various cognitive assessments; tasks assess attention, numerical calculation, immediate and delayed recall, animal naming, number span, clock drawing, shape recognition / size discrimination, and immediate recall of facts from a paragraph). Moreira et al., “Distinguishing mild cognitive impairment from healthy aging and Alzheimer's Disease: The contribution of the INECO Frontal Screening (IFS)” (PLoS ONE, 14(9), e0221873 (2019)), reported that IFS can distinguish MCI patients from cognitively healthy controls and patients with mild to moderate Alzheimer's disease. Petersen et al., “Practice guideline update summary: Mild cognitive impairment” (Neurology, 90(3), 126-135 (2018)), discuss the diagnosis and treatment of MCI, but caution that despite the use of many medications, “there is no high-quality evidence to support pharmacological treatment of MCI.” MCI is also known to be associated with hypertension, as well as depression and other mental disorders. MCI is well known to cause distress to those who suffer from it, and therefore, MCI can lead to mental fatigue resulting from that distress.

[0014] Mental fatigue can also result from any combination of the above situations or conditions. For example, late-night "cramming" for an exam may imply both prolonged cognitive activity and sleep deprivation, while worry and insomnia stemming from MCI may imply both sleep deprivation and MCI itself.

[0015] The onset of mental fatigue during any cognitive activity is gradual and depends on a person's cognitive abilities as well as other factors such as pre-existing sleep deprivation and overall health. Marcora et al., “Mental fatigue impairs physical performance in humans” (J. Appl. Physiol., 106, 857-864 (2009)), showed that mental fatigue can impair physical abilities. Mental fatigue can manifest as somnolence, lethargy, or sustained attention fatigue (the inability to maintain attention or vigilance that requires considerable effort, such as in a monotonous or boring state). Among the many physical consequences of mental fatigue, deficits in attention / vigilance and working memory are perhaps the most significant, and such deficits and resulting deviations in everyday routines can have unfortunate consequences, ranging from forgetting ingredients while cooking to overlooking sentences while taking notes.

[0016] While decreased attention span can extend to more critical areas where consequences may be life-threatening, car accidents and industrial accidents can be caused by inattention stemming from mental fatigue. The risks of mental fatigue are particularly evident while driving, with the American Academy of Sleep Medicine (AASM) reporting in its "Drowsy Driving Fact Sheet" that one-fifth of serious car accidents are related to driver fatigue, 80,000 drivers fall asleep at the wheel every day, and 250,000 accidents each year are related to fatigue, although the U.S. National Highway Traffic Safety Administration suggests the number of traffic accidents may be closer to 100,000. According to Williamson et al., “Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally prescribed levels of alcohol intoxication” (Occup. Environ. Med., 57(10), 649-655 (2000)), mental fatigue and sleep deprivation can have the same harmful effects on psychomotor and cognitive abilities as alcohol intoxication.

[0017] Coping with the effects of mental fatigue Several strategies are commonly employed to address the effects of mental fatigue. Non-pharmacological strategies recommended by the AASM include preventative sleep before sleep deprivation, naps, and combinations thereof. However, the only sure and safe way to counteract mental fatigue induced by sleep deprivation / sleep interruption is to increase nighttime sleep duration. According to Alhola et al., “Sleep deprivation: Impact on cognitive performance” (Neuropsychiatr. Dis. Treat., 3(5), 553-567 (2007)), cognitive recovery is achieved more rapidly after acute total sleep deprivation than after chronic partial sleep restriction.

[0018] The primary non-prescription drug used to counteract the effects of mental fatigue is caffeine, which improves alertness, psychomotor function, and cognitive function, but does not reduce the number of errors during performance. Prescription drugs used to counteract the effects of mental fatigue include stimulants such as amphetamines and dextroamphetamine, and eugerotics such as modafinil and almodafinil. See, for example, Urban et al., “The Role of Eugeroics in the Treatment of Affective Disorders” (Psychiatr.PoL, 54(1), 21-33 (2020)). Caffeine is often used for short periods to enhance alertness when experiencing acute mental fatigue; however, caffeine becomes less effective when taken routinely, can cause discomfort in large quantities, and takes time to achieve maximum effectiveness. Amphetamines are addictive (similar to caffeine) and tend to cause insomnia and emotional instability, while modafinil and almodafinil tend to cause nausea and vertigo, and both require some time to achieve maximum effectiveness, so they are usually taken preventively before mental fatigue begins. Both amphetamines and modafinil / almodafinil are controlled substances in the United States.

[0019] In their study Wesensten et al., “Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine” (Psychopharmacology (Berlin), 159(3), 238-247 (2002)), they demonstrated that prolonged sleep deprivation is a useful method for comparing the psychostimulant effects of caffeine and modafinil, using cognitive tests to measure arousal levels and attentional levels. However, in this study, the authors did not use polysomnography to assess brain arousal levels and somnolence associated with mental fatigue.

[0020] It is desirable to develop drugs to improve the psychomotor and / or cognitive abilities of mentally fatigued individuals. Such drugs should not need to be taken preventively before anticipated mental fatigue occurs, but rather should be fast-acting so that they can be administered when mental fatigue (or its effects on psychomotor and / or cognitive abilities) occurs. They should also have minimal side effects such as addiction, insomnia, emotional instability, and restlessness.

[0021] The olfactory chemosensory receptors of the nose, the vomeronasal organ and olfactory epithelium, and ferrin Nasal olfactory chemosensory receptors are distributed in the olfactory epithelium and are located in the inner mucosal layer of the medial and dorsal nasal septa, as well as in the dorsal nasal recess, including the vomeronasal organ (also known as Jacobson's organ or "VNO"). In particular, these receptors in the VNO are associated with pheromone reception in many non-human species (see, for reviews, Monti-Bloch et al., “Effect of putative pheromones on the electrical activity of the human vomeronasal organ and olfactory epithelium” J.Steroid Biochem.Mol.Biol.,39(4):573-582(1991) and Monti-Bloch et al., “The Human Vomeronasal System: A Review” Ann.NY Acad.Sci.,855:373-389(1998)).The axons of the neuroepithelium of nasal chemosensory receptors have direct input to the hypothalamus and limbic amygdala in the brain, but the distal processes (cilia and microvilli) are the sites where chemosensory receptors are located (Stensaas et al., “Ultrastructure of the human vomeronasal organ” J.Steroid Biochem. Mol.Biol.,39(4):553-560(1991), and Monti-Bloch, “Patch recorded isolated adult human vomeronasal cells are electrically excitable and respond to skin steroidal substances: androsta-4,16-dien-3-one and "estra-1,3,5(10),16-tetraen-3-ol" (Adult human vomeronasal cells isolated by patch recording are electrically excitable and respond to the cutaneous steroids: androsta-4,16-dien-3-one and estra-1,3,5(10),16-tetraen-3-ol) See Abstract #200 for the Seventeenth Annual Meeting of the Association for Chemoreception Sciences (AChemS XVII), Chem. Senses, 20(6):745-746 (1995).

[0022] Human-derived neurosteroids delivered to the nasal septum bind to cilia and microvilli on local chemosensory receptors, inducing neural signals that reach the brain and trigger physiological and behavioral changes (Monti et al., “Effect of Putative Pheromones On the Electrical Activity of the Human Vomeronasal Organ and Olfactory Epithelium” J.Steroid Biochem.Molec.Biol.,39(4B),573-582(1991), and Grosser et al., “Behavioral and electrophysiological effects of androstadienone, a human pheromone” Psychoneuroendocrinology,2000,25:289-299). Ferrin, a naturally occurring, chemically modified human neurosteroid (a substance that binds to olfactory chemosensory receptors in the nose), can induce strong physiological, pharmacological, and behavioral changes when delivered to these receptors via the nasal cavity through the air. This information is supported by several studies in human volunteers using functional magnetic resonance imaging and positron emission tomography, which show that ferrin selectively activates brain regions (hypothalamus, limbic system, cingulate gyrus, anterior thalamus, and prefrontal cortex) where its physiological, pharmacological, and behavioral effects are integrated.

[0023] Several studies using ferrin have shown that because the compound acts directly on olfactory chemosensory receptors in the nose that are directly connected to the brain, administration of the compound affects physiological markers (e.g., autonomic nervous system responses and EEG) within seconds to less than a minute, and affects endocrine and neurotransmitter metabolite markers within about 10 to 15 minutes.

[0024] 1,3,5(10),16-Estratetraene-3-Ilacetate 1,3,5(10),16-Estratetraenylacetate ("Estratetraenylacetate", "ETA") and its synthesis are described, for example, by Berliner et al., U.S. Patent No. 5,783,571, "Method of altering hypothalamic function by nasal administration of estrene steroids." This patent describes the use of several estrans as compounds that can alter hypothalamic or autonomic nervous system function by administration to the olfactory epithelium of human subjects. ETA is disclosed in this patent and is mentioned as a preferred compound around line 20 of column 8. It is the acetate ester of 1,3,5(10),16-Estratetraenylacetate, which is mentioned as a preferred compound in the same paragraph and is compound E2 / N 1 in the chart of estrans ("Known" at the end of column 7). This patent generally claims a pharmaceutical composition containing estran with ETA in a dosage form suitable for intranasal administration, and discloses a method for altering hypothalamic or autonomic nervous system function by vomeronasal administration.

[0025] ETA administered intravenously at a dose of 60 pg resulted in changes in mass receptor potential (electrovomerogram) that were higher in amplitude in men (Figure 3A) than in women (Figure 3B) compared to the control (propylene glycol). ETA was also shown to result in an increase in integrated electrovomerogram (Figure 4A), a decrease in skin resistance (Figure 4B), and an increase in skin temperature (Figure 4C) in men compared to the control. ETA also resulted in an increase in electrovomerogram (Figures 6A and 6B), an increase in α-cortical activity (Figures 6E and 6F), and an increase in skin temperature (Figures 6G and 6H) in both men and women, with the effect being more pronounced in men, while it resulted in a decrease in skin electrical activity in men (Figure 6C) but not in women (Figure 6D). However, this patent does not describe or provide any relevant data on improvements in psychomotor or cognitive function.

[0026] Several subsequent patents, such as Jennings-White et al., U.S. Patent No. 6,057,439, "Steroids as neurochemical stimulators of the VNO to alleviate symptoms of PMS and anxiety" (Steroids act as neurochemical stimulants of the VNO to alleviate symptoms of premenstrual syndrome (PMS) and anxiety), Jennings-White et al., U.S. Patent No. 6,066,627, "Steroids as neurochemical initiators of change of human blood levels of LH" (Steroids play a role as neurochemical causative factors that cause changes in human blood LH levels), Jennings-White et al., U.S. Patent No. 6,117,860, "Steroids as neurochemical stimulator of the VNO to treat paroxistic tachycardia" (Treatment of paroxysmal tachycardia with steroids as neurochemical stimulants of the vomeronasal organ (VNO)), and Berliner et al., U.S. Patent No. 6,331,534, "Steroids as neurochemical stimulators of the VNO to alleviate pain" (Steroids act as neurochemical stimulants of the VNO to relieve pain), disclose slightly more about ETA but also include many other steroids of different classes.

[0027] Berliner et al.'s U.S. Patent No. 6,544,971, "Method of increasing alertness by administration of a vomeropherin, and vomeropherin-emitting alarm devices" (Method of improving alertness by administering vomeropherin and vomeropherin-emitting alarm devices) discloses a method of enhancing an individual's alertness by administering an estrane of the following formula into the vomeronasal cavity:

Chemical formula

[0028] U.S. Patent No. 6,544,971 defines "arousal" as including responsiveness to the waking state and external stimuli. It also defines "enhancing an individual's arousal" as including either or both of awakening that individual and enhancing that individual's responsiveness to external stimuli, and this effect can occur without complete awakening but by brightening the sleep state. An increase in arousal is said to mean "enhancing that individual's responsiveness to external stimuli such as the ringing of a bell, the ringing of a telephone, a fire, smoke, etc.". This patent also defines "alarm condition" regarding an individual as something where the safety or health of that individual or others may be adversely affected by the lack of response by that individual, or something for which the individual is desired to respond. SUMMARY OF THE INVENTION

[0029] In a first aspect, the present invention is a method for improving the psychomotor ability and / or cognitive ability of a mentally fatigued individual by the nasal administration of 1,3,5(10),16-estratetraen-3-yl acetate.

[0030] Mental fatigue can arise from a variety of causes, but notable causes include prolonged cognitive activity, sleep deprivation, sleep disturbance, and related conditions such as shift work sleep disorder and excessive daytime sleepiness. It can also arise from or be related to psychological conditions such as depressive disorders (including major depressive disorder and perinatal depression) as well as other disorders such as attention deficit hyperactivity disorder and mild cognitive impairment.

[0031] Therefore, in other embodiments, the present invention includes: 1,3,5(10),16-Estratiotetraen-3-ylacetate, administered intranasally, to improve psychomotor and / or cognitive abilities in mentally fatigued individuals. Pharmaceutical formulations and devices containing 1,3,5(10),16-estratetraen-3-ylacetate for improving psychomotor and / or cognitive abilities in mentally fatigued individuals via intranasal administration, and, Use of 1,3,5(10),16-estratetraen-3-ylacetate in the manufacture of a drug for improving psychomotor and / or cognitive abilities in mentally fatigued individuals via intranasal administration.

[0032] 1,3,5(10),16-Estratiotetraen-3-ylacetate is expected to have the following advantages over conventional stimulants, particularly useful in improving the psychomotor and / or cognitive abilities of such individuals: (1) Rapid onset of effect due to direct local delivery of the compound to olfactory chemosensory receptors in the nose and the resulting action. (2) The dose used is very low (nanograms to low micrograms), and due to the local administration route, there are no local nasal and systemic adverse effects or toxicity, i.e., low or no systemic uptake, and (3) For the same reasons as in (2) above, the absence of side effects seen with caffeine, amphetamines, and other commonly used medications such as modafinil / almodafinil.

[0033] Preferred embodiments of the present invention are characterized by the features of the specification and the claims of this application at the time of filing, as well as by corresponding pharmaceutical compositions, devices, methods and uses of the compound.

[0034] Detailed explanation Definition: "Individual" or "Individual(plural)" refers to a human being; "Male" or "Male(plural)" refers to a male human being; and "Female" or "Female(plural)" refers to a female human being; no age limitation is intended.

[0035] "Nasal administration" or "intranasal administration" refers to administration to human nasal olfactory chemosensory receptors. In clinical contexts, this can be achieved to some extent by using probes specifically designed to deliver ETA to the VNO only (such probes designed to measure effects on vomeronasal tissue are also described in Monti-Bloch's U.S. Patent No. 5,303,703, “Combined neuroepithelial sample delivery electrode device and methods of using the same”). However, preferably, nasal administration involves administering the ETA into the nasal cavity via a conventional nasal spray device in a manner that directs the ETA largely to primary and secondary sites of olfactory chemosensory receptors in the olfactory epithelium of the nasal cavity, including the dorsal nasal recess and VNO. See, for example, U.S. Provisional Patent Application SN63 / 631,389, filed April 8, 2024, titled “Intranasal Drug Delivery System.”

[0036] "Effective dose" refers to the amount of ETA administered to the nasal olfactory chemosensory receptors of a mentally fatigued individual that is sufficient to improve the individual's psychomotor and / or cognitive abilities, but is insufficient to have a systemic effect through absorption into the circulation.

[0037] To “improve” psychomotor and / or cognitive abilities in mentally fatigued individuals, To improve psychomotor function by increasing or enhancing psychomotor function compared to an individual's psychomotor function without intranasal administration of ETA, i.e., to improve a person's ability to coordinate a timely and appropriate response to a stimulus, and This includes improving cognitive abilities by increasing or enhancing cognitive abilities compared to an individual's abilities without intranasal administration of ETA, namely, improving the ability to think and judge in relation to temporal and spatial relationships, as well as symbols such as words and numbers. Psychomotor and / or cognitive abilities are diminished in mentally fatigued individuals; that is, mentally fatigued individuals suffer from deficits in psychomotor and / or cognitive abilities, so “improving” psychomotor and / or cognitive abilities includes reducing these deficits.

[0038] "Psychomotor abilities" and "cognitive abilities," as well as the tests used to measure them, are described in the "Psychomotor and Cognitive Abilities" section of the background information.

[0039] "Mental fatigue" and its effects on psychomotor and / or cognitive abilities are described in the "Mental Fatigue" section of the background information.

[0040] "Pharmacologically acceptable excipients" generally refer to excipients that are safe, non-toxic, and useful in preparing a desirable pharmaceutical formulation. These excipients may be solids, liquids, semi-solids, or, in the case of aerosol compositions, gases. 1,3,5(10),16-Estratetraen-3-yl acetate and its preparation

[0041] 1,3,5(10),16-Estratetraene-3-ylacetate is a compound of the following formula: [ka] It can be easily prepared by esterification of 1,3,5(10),16-estratetraen-3-ol by the method described in paragraph

[0037] below.

[0042] The preparation of ETA is described in Examples 1 and 2 of U.S. Patent No. 5,783,571 and starts with readily available steroid estrone (3-hydroxy-1,3,5(10)-estratrien-17-one, available from many suppliers such as Sigma-Aldrich Company LLC), as shown in the reaction scheme below: [ka]

[0043] From the synthesis description in Examples 1 and 2 of U.S. Patent No. 5,783,571: In the first step, estrone (270 g, 1.00 mol) and 4-toluenesulfonyl hydrazide (232.8 g, 1.25 mol) in anhydrous methanol (2.5 L) were heated under reflux for 20 hours. The mixture was transferred to an Erlenmeyer flask and cooled. The formed crystalline estrone 4-toluenesulfonyl hydrazone 1 was filtered off under suction and washed with methanol (300 mL). Further products were obtained by sequentially evaporating the filtrate to 2 L, 800 mL, and 400 mL, crystallizing estrone 4-toluenesulfonyl hydrazone each time. The total yield was 433.5 g (99%).

[0044] In the second step, estrone-4-toluenesulfonylhydrazone (219.0 g, 500 mmol) in anhydrous tetrahydrofuran (8.0 L) was cooled in a sodium chloride / ice bath. While mechanically stirring the mixture, n-butyllithium (800 mL, 2.00 mol, 2.5 M solution in hexane) was added using a double-ended needle. The mixture was stirred at room temperature for 3 days. After adding ice (250 g), saturated ammonium chloride aqueous solution (500 mL) was added. The phases were mixed by stirring and then allowed to stand. The aqueous phase was removed by suction using a PTFE tube and extracted with ether (500 mL). The two organic phases were sequentially washed with saturated sodium bicarbonate aqueous solution (500 mL) from the same batch, followed by washing with saturated sodium chloride aqueous solution (500 mL). The organic layer was dried (MgSO4) and evaporated under vacuum to obtain crude 1,3,5(10),16-estratetraen-3-ol II. This was subjected to flash filtration with silica gel 60 (500 g, 230-400 mesh) eluted with ethyl acetate / hexane (1:3, 2.5 L). The filtrate was evaporated under vacuum to obtain 1,3,5(10),16-estratetraen-3-ol as a crystalline substance. This was recrystallized from methanol / water (4:1, 375 mL) and washed with methanol / water (4:1, 100 mL). Further recrystallization from ethyl acetate / hexane (1:7) yielded pure 1,3,5(10),16-estratetraen-3-ol (88.9 g, 70%).

[0045] In the third step, 1,3,5(10),16-estratetraen-3-ol (254 mg, 1.00 mmol) in ether (10 mL) is mixed with acetic anhydride (0.25 mL), followed by pyridine (0.25 mL), and the mixture is stirred at room temperature for 16 hours. The mixture is poured over ice / water and extracted with ether (2 × 20 mL). The organic extract is washed with water, saturated copper sulfate aqueous solution, water, and saturated sodium chloride aqueous solution, dried (MgSO4), and evaporated under vacuum to obtain crude 1,3,5(10),16-estratetraen-3-yl acetate. This is purified by flash chromatography of silica gel 60 (17.5 g, 230-400 mesh) eluted with 10%-12% ethyl acetate / hexane to obtain pure 1,3,5(10),16-estratetraen-3-yl acetate (192 mg, 65%).

[0046] Those skilled in the art will find it easy to prepare an ETA, considering the technology and the present disclosure (including the aforementioned patents).

[0047] Formulation and administration ETA may be administered nasally by any suitable route designed to bring the ETA into contact with olfactory chemosensory receptors in the nose. Routes of administration include, but are not limited to, topical nasal application (e.g., dermal or preferably intranasal cream or gel), nasal spray, nasal powder spray, nasal aerosol, and the like. Pharmaceutical formulations are generally a type of drug designed to be administered via mucous membranes or transdermal preparations. Formulations suitable for each of these administration methods are described, for example, in Remington: The Science and Practice of Pharmacy, 20th ed., A. Gennaro, ed., Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, USA, 2003. A typical preferred formulation is an aqueous solution for nasal spray, containing ETA and water, and typically also containing one or more other pharmaceutically acceptable excipients to enhance the solubility of the ETA, such as alcohols and glycols (e.g., ethanol and propylene glycol). A suitable delivery device for these formulations is a metered-dose nasal spray pump, commonly used for intranasal delivery of steroids for allergies and asthma. Such pumps are manufactured by numerous manufacturers. The liquid volume should be such that an excess amount does not reflux into the sinuses or drip from the nose, and that the formulation is delivered efficiently without exceeding the volume that can be held in the nose. A volume of 50 pL has been found to be well-suited, but slightly larger or smaller volumes are also satisfactory. Exemplary formulations are discussed in the following paragraph

[0057] , and those skilled in the art will have no difficulty in preparing suitable formulations and delivery systems of ETA for intranasal administration, taking into account their art and this disclosure.

[0048] The effective dose of ETA administered intranasally, when administered with the above-described type of nasal spray formulation, is approximately 400–6000 nanograms per dose, e.g., 1000–4000 nanograms per dose, e.g., approximately 1600–3200 nanograms per dose (or half per nostril, assuming the compound is administered into both nostrils). The male dose is typically in the lower end of that range, e.g., 1000–2500 nanograms per dose, e.g., approximately 1600 nanograms per dose, and the female dose is typically in the upper end of that range, e.g., 2500–4000 nanograms per dose, e.g., approximately 3200 nanograms per dose. Since it is expected that less than a few percent of this intranasal spray dose actually reaches the nasal olfactory chemosensory receptors, the effective dose when administered essentially only to the nasal olfactory chemosensory receptors can be considerably lower. Doses for other methods of intranasal administration may vary depending on the method. Those skilled in the art will find it no difficulty in preparing to determine an appropriate dose range for a given method of administration / formulation / delivery system, given the art and this disclosure. These doses are far lower than any level that would cause systemic effects other than those mediated directly to the nasal / intranasal olfactory chemosensory receptors, or those mediated via the nasal olfactory chemosensory receptors.

[0049] The initial physiological response to intranasal administration of ETA is very rapid, typically occurring within one minute of administration, and improvements in psychomotor and cognitive abilities are typically seen within 15 minutes of administration, for example, within 5 minutes. Due to the rapid onset of action and safety of intranasally administered ETA, it is expected that ETA may be administered as needed to improve psychomotor and cognitive abilities in situations where mental fatigue is detected, for example, when a mentally fatigued individual immediately detects drowsiness or symptoms of drowsiness (e.g., excessive yawning, closing eyes, nodding head), or when a decline in psychomotor or cognitive abilities is detected. It is also expected that ETA may be administered prophylactically to improve or at least prevent a normal decline in psychomotor and / or cognitive abilities in individuals who are mentally fatigued or at risk of mental fatigue. Therefore, for example, a firefighter whose work schedule may require them to perform 72 hours continuously, even though they are permitted to sleep at night when it is not actually necessary, may be given ETA to improve their psychomotor and / or cognitive abilities when they are awake at night and called in to respond to a fire, or a night flight pilot who flies the aircraft between afternoon takeoffs and rests during the overnight cruising portion of the flight, but then flies the aircraft again the following morning when it approaches and lands, may be given ETA to improve their psychomotor and / or cognitive abilities when they rise from rest to perform the approach and landing.

[0050] Furthermore, ETA may be administered on a scheduled basis, for example, 2 to 8 times, 3 to 5 times, or 4 times, throughout periods of wakefulness (such as during a work shift) or throughout a night or similar period of activity (such as a crew member on an overnight flight), to minimize the decline in psychomotor and / or cognitive abilities from chronic fatigue, such as over several weeks or months. This scheduled administration may be on a regular schedule, e.g., 10 p.m., midnight, 2 a.m., and 4 a.m. (for four doses / day for night shift workers such as nurses), or the frequency of administration may be on an irregular schedule based on the circadian rhythm of mental fatigue in either the general population or the individual being treated. Therefore, for example, administration may be selected to maximize the dose when the onset of mental fatigue (or decline in psychomotor and / or cognitive abilities) is at its peak or is expected to be at its peak. Of course, if mental fatigue (or decline in psychomotor and / or cognitive abilities) still persists even after scheduled administration has been given, ETA may be administered as needed.

[0051] Similarly, for individuals who require improvement in psychomotor and / or cognitive deficits associated with depressive disorders (such as major depressive disorder and postpartum depression), as well as other disorders such as attention deficit hyperactivity disorder, "long COVID," shift work sleep disorder, excessive daytime sleepiness, or mild cognitive impairment, these drugs may be administered to individuals with these disorders as needed (when a decline in psychomotor and / or cognitive function is perceived), prophylactically (to prevent or mitigate the effects of such decline), or at the scheduled standard. [Examples]

[0052] Example 1: Electrophysiological testing using ETA

[0053] ETA induced inward currents in the membranes of isolated human nasal olfactory chemosensory neurons and electrotonic depolarization of the nasal septal olfactory chemosensory epithelium, i.e., the initial event of chemosensation at peripheral receptors. The amplitude of this response increased with increasing concentration of the compound. In vitro, there was no agonist or antagonist activity against rat estrogen, androgen, progestin, and glucocorticoid receptors.

[0054] Example 2: Preclinical trials using ETA

[0055] Genotoxicity studies, including the Ames reverse mutagenesis assay and in vivo micronucleus assay, did not show evidence of mutagenicity or chromosomal aberration-inducing ability of ETA.

[0056] Administration of ETA (1 mg / day intravenously) to male and female rats did not cause death, adverse symptoms, or behavioral changes for 7 days, and no macroscopic or microscopic changes were observed in any organs tested. Administration of ETA (600 pg / kg intravenously, 900 pg / kg intranasally) to male rats did not cause death, adverse symptoms, or behavioral changes for 7 days, and showed rapid absorption, metabolism, and excretion.

[0057] Example 3 - Pilot human clinical trial using ETA

[0058] In a pilot study using healthy male and female volunteers, intranasal administration of ETA was well-tolerated and induced a strong response. Intranasal administration of the compound induced significant changes in heart rate and respiratory rate, but did not alter the duration of the QTc interval on the electrocardiogram. ETA significantly increased the frequency of skin electrical activity events (measured as skin conductance, indicating increased sympathetic-mimicking activity), but did not significantly affect body temperature or the alpha and beta frequency bands on the electroencephalogram.

[0059] Example 4 - Efficacy trial of ETA in mentally exhausted men

[0060] The test was a computer-based reaction time and time estimation test (RTTET) developed by the laboratory. The psychomotor test (reaction time test) consisted of the subject pressing a lever each time they perceived a visual stimulus (flash), allowing for the measurement of reaction time to the visual stimulus. Flashes were delivered at fixed intervals of 10 seconds (isochronous stimuli) or at random intervals (stochastic stimuli). The cognitive ability test (time estimation test) consisted of the subject observing a series of three flashes delivered at fixed intervals of 10 seconds, and at the end of the third series, the subject had to press down the lever at the same interval (i.e., the step of estimating the 10-second interval between flashes).

[0061] During the test, participants were required to maintain an appropriate level of attention to avoid errors in the reaction time test (missed flashes, delayed responses) and to use the information obtained in their responses, thus paying attention to estimating the duration of the time intervals between stimuli in the time estimation test. One sequence of the RTTET lasted 20 minutes, and each test consisted of four sequences with intervals of 10-20 minutes between them. The tests were conducted at 6 p.m. (control), 9 p.m., midnight, and 3 a.m., so that each session consisted of four tests. Participants were not allowed to sleep during the tests.

[0062] The study design was a double-blind, placebo-controlled, three-way crossover trial using 10 healthy male volunteers. Inclusion criteria included a good health history, a regular nighttime sleep pattern with a consistent daily bedtime and an average duration of 8 hours, and no prior use of any psychiatric medications for at least two months. Exclusion criteria included caffeine hypersensitivity or tolerance, and any sleep, attention, or memory impairment. Participants were tested at 8-day intervals.

[0063] The following test compound, ETA, was administered intranasally: 1600 ng of ETA (a 50 pL aqueous solution containing 16 pg / mL of ETA, 2% propylene glycol, and 2% ethanol, administered once per nostril using a Valois intranasal spray pump). As a control compound, caffeine was administered orally as a 400 mg tablet. Intranasal placebo (using the same pump and solution, excluding ETA) and oral placebo (lactose tablet) were also used.

[0064] Each nighttime trial began at 5 p.m. Participants arrived in the laboratory and had electrodes (electroencephalogram, electrooculogram, electromyogram) attached for polysomnography recording of sleep, according to the criteria of "A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects" (Rechtshaffen and Kales, eds., NIH Publication No. 204, US Government Printing Office, 1968). All participants received an oral dose and an intranasal dose of either placebo or the active ingredient (ETA or caffeine) one hour before the start of each trial, and an intranasal dose 10 minutes before and 40 minutes after the start of each trial. In the control session, all doses were placebo. In the ETA session, all oral doses were placebo, and intranasal doses were given 10 minutes before and 40 minutes after the start of the trials at 9 p.m., 12 a.m., and 3 a.m., with ETA included in the trials and the remainder being placebo. In the caffeine sessions, all intranasal doses were placebo, while the oral dose administered one hour before the 9 p.m. session began included caffeine, with the remainder being placebo. The timing of administration was chosen to ensure maximum efficacy of the ETA and caffeine.

[0065] There were no serious adverse events. The most frequent mild adverse events were physical fatigue at the completion of the study session in the majority of subjects, and sneezing after nasal administration in one subject. ETA nasal spray was well-tolerated in all subjects.

[0066] During the study, subjects exhibited drowsiness or polyphenomena of stage 1 or 2 sleep almost midnight. The effect of caffeine was to significantly reduce both reaction time and error count in both isochronic and stochastic reaction time tests (p<0.005 and p<0.001 compared to placebo) in all three uncontrolled studies, with the effect being more pronounced in stochastic stimuli. It improved time estimation tests, but the effect was statistically significant (p<0.001) only in the midnight study four hours after caffeine administration.

[0067] The effect of ETA was to significantly reduce both reaction time and error rate in both isochronous and stochastic reaction time tests in all three uncontrolled studies (p<0.001 and p<0.0001 compared to placebo), with the effect being more pronounced in stochastic stimuli. It significantly improved time estimation tests (p<0.01) in both midnight and 3 a.m. studies. Compared to caffeine and placebo, ETA showed less variability in both isochronous and stochastic reaction time tests. The effect of ETA was similar to that of caffeine in the 9 p.m. study (when subjects were relatively unfatigued), but the effect of ETA was significantly better than that of caffeine in the midnight and 3 a.m. studies (when subjects were fatigued) (p<0.001 and p<0.0001 compared to caffeine for isochronous and stochastic tests, respectively). ETA also significantly improved time estimation tests in both midnight and 3 a.m. studies (p<0.01 compared to caffeine).

[0068] These data demonstrate the safety and efficacy of intranasal administration of 1,3,5(10),16-estratetraen-3-ylacetate in improving psychomotor and / or cognitive abilities in mentally fatigued individuals.

[0069] Example 5 - Improvement of psychomotor and / or cognitive abilities by ETA in mental fatigue associated with shift work sleep disorder

[0070] According to Jang's “Work-Fitness Evaluation for Shift Work Disorder,” (Int. J. Environ. Res. Public Health, 18(3), 1294 (2021)), shift work sleep disorder (classified as a circadian rhythmic sleep disorder in DSM-5, 307.45) is characterized by insomnia and excessive daytime sleepiness associated with shift work and is one of the most common health problems among shift workers. Modafinil is approved for the treatment of excessive daytime sleepiness associated with shift work sleep disorder, as described by Valentino et al., “Modafinil in the treatment of excessive daytime sleepiness,” (Cleve. Clin. J. Med., 74(8), 561-571 (2007)). Based in part on the finding that ETA directly improves psychomotor and cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, ETA similarly improves psychomotor and cognitive abilities in individuals with mental fatigue associated with shift work sleep disorder.

[0071] In subjects experiencing impaired psychomotor and / or cognitive function in mental fatigue associated with shift work sleep disorder, a therapeutically effective dose of ETA is administered intranasally, as described in Example 4. Psychomotor and cognitive function improve in this group of subjects.

[0072] Example 6 - Improvement of psychomotor and / or cognitive abilities by ETA in mental fatigue associated with excessive daytime sleepiness

[0073] As described by Valentino et al., modafinil is also approved for the treatment of excessive daytime sleepiness associated with narcolepsy and as an adjunctive treatment in patients with obstructive sleep apnea syndrome who experience persistent daytime sleepiness despite optimal treatment with continuous positive airway pressure. Partly based on the finding that ETA directly improves psychomotor and cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, ETA similarly improves psychomotor and cognitive abilities in people with mental fatigue associated with excessive daytime sleepiness.

[0074] In subjects experiencing impaired psychomotor and / or cognitive function due to mental fatigue associated with excessive daytime sleepiness, a therapeutically effective dose of ETA is administered intranasally as described in Example 4. Psychomotor and cognitive function improve in this group of subjects.

[0075] Example 7 - Improvement of psychomotor and / or cognitive abilities by ETA in mental fatigue associated with depressive disorders such as major depressive disorder and perinatal depression.

[0076] Reaction time is one of the ability profiles described in Example 4 above, as it is improved by both caffeine and ETA. Iranpour et al., “Inverse Association Between Caffeine Intake and Depressive Symptoms in US Adults: Data from National Health and Nutrition Examination Survey (NHANES) 2005-2006” (Psych.Res., 271, 732-739 (2019)), show that caffeine reduces depressive symptoms as measured by the PHQ-9 test, a nine-item patient health questionnaire developed by Pfizer for assessing depressive symptoms. The test asks, for each of the nine items, “How often have you experienced any of the following problems in the last two weeks?” and the responses are scored from 0 (“never”) to 3 (“almost every day”), resulting in a total score between 0 and 27. One of the questions on that test asks, "Do you have trouble concentrating on things like reading the newspaper or watching TV?" Similarly, Paech et al., “Caffeine administration at night during extended wakefulness effectively mitigates performance impairment but not subjective assessments of fatigue and sleepiness” (Pharmacol. Biochem. Behavior, 145, 27-32 (2016)), showed that caffeine improves both reaction time and cognitive ability.

[0077] Medical literature generally agrees that caffeine is negatively associated with depression, or in other words, that caffeine can alleviate depression. Bao et al.'s paper, “Caffeine Is Negatively Associated with Depression in Patients Aged 20 and Older,” (Front.Psych., 13:1037579 (2022)) concludes that “these results suggest that people may be able to alleviate depression by consuming some caffeine.” Bao et al. also state that “several epidemiological studies have found that caffeine use has a protective effect against cognitive impairment / decline…” and that “further research is needed to investigate the exact causal relationship between these factors,” which they attribute to “a complex association between caffeine intake and the risk of depression.” However, the paper explains that caffeine, due to its similar structure, may compete with adenosine to bind to adenosine A1 receptors (ADORA1) and adenosine A2A receptors (ADORA2A), potentially affecting neural networks in the brain. Similar conclusions can be drawn, as described in Lopez-Cruz et al., “Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression” (Front.Pharmacol., 9, 526 (2018)). Without being constrained by a specific explanation of its mechanism of action, ETAs are thought to indirectly activate ADORA2A receptors via neural circuits linked to nasal olfactory chemosensory neurons in the olfactory epithelium.

[0078] Based in part on the finding that ETA directly improves psychomotor and cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, and its presumed mechanism of action, ETA similarly improves psychomotor and cognitive abilities in individuals with mental fatigue associated with depressive disorders (such as MDD and perinatal depression).

[0079] In subjects experiencing impaired psychomotor and / or cognitive function in mental fatigue associated with depressive disorders such as MDD or perinatal depression, a therapeutically effective dose of ETA is administered intranasally to the olfactory epithelium as described in Example 4. Psychomotor and cognitive function improve in this group of subjects.

[0080] Example 8 - Improvement of psychomotor and / or cognitive abilities with ETA supplementation in subjects with mental fatigue associated with depressive disorder who are already taking antidepressants.

[0081] Liu et al., “Low dose of caffeine enhances the efficacy of antidepressants in major depressive disorder and the underlying neural substrates” (Mol. Nutr. Food Res., 61, 8 (2017)), showed that caffeine supplementation enhances the efficacy of common antidepressants. Regarding subjects taking escitalopram, Liu et al. reported that “chronic supplementation with low-dose caffeine (60 mg) resulted in a rapid antidepressant effect by reducing depression scores. Furthermore, low-dose caffeine improved cognitive abilities in depressed patients. However, caffeine did not affect sleep.” Attention, concentration, and working memory assessment metrics included sustained attention tasks, i.e., target detection using tapping. Szopa et al., “Caffeine enhances the antidepressant-like activity of common antidepressant drugs in forced swim test in mice” (Naunyn-Schmiedeber.Arch.Pharmacol.,389,211-221(2016)), reported a similar enhancement of the antidepressant-like activity of six common antidepressants, including imipramine, desipramine, fluoxetine, paroxetine, escitalopram, and reboxetine, by caffeine in the forced swim test in mice, a behavioral test widely used to evaluate the antidepressant properties of drugs.Alexander et al., “Modafinil augmentation therapy in unipolar and bipolar depression: A systematic review and meta-analysis of randomized controlled trials” (J. Clin. Psych., 74(11), 1101-1107 (2013)), similarly showed that modafinil improves overall depression scores, remission rates, and fatigue when used as adjunctive therapy for acute depressive episodes in both unipolar and bipolar disorders.

[0082] Based in part on the finding that ETA directly improves psychomotor and cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, and its presumed mechanism of action, ETA, when added to antidepressant treatment, similarly improves psychomotor and cognitive abilities in humans with mental fatigue associated with depressive disorders (such as MDD and perinatal depression).

[0083] In subjects with MDD who are already receiving escitalopram treatment and experiencing impaired psychomotor and / or cognitive function in relation to mental fatigue, an effective therapeutic dose of ETA is administered intranasally as supplemental or additional therapy, as described in Example 4. ETA is administered separately from antidepressant treatment, sequentially or in temporal proximity to situations requiring attention and concentration. Depression scores are lower than those with escitalopram alone. Psychomotor and cognitive function improve in subjects in this group.

[0084] Example 9 - Addition of ETA with iturvon antidepressant therapy

[0085] Itorvon (INN, preg-4-en-20-in-3-one) is an investigational product under development for the treatment of major depressive disorder (MDD) and is not yet approved by the Food and Drug Administration. The preparation and experimental treatment of MDD with this compound are described, for example, in Monti's U.S. Patent No. 10322138, “Treatment of Depressive Disorders.” Both itorvon and ETA are thought to have a common mechanism of action in that they activate olfactory chemosensory neurons in the nasal mucosa, and then activate specific hypothalamic circuits in the brain without uptake into the brain or systemically. In subjects receiving itorvon treatment for major depressive disorder, ETA is administered intranasally as described in Example 4. Depression scores are lower than with itorvon alone. Cognitive function and psychomotor abilities improve in this group of subjects. Since itorvon is also administered intranasally in the form of a spray or aerosol, ETA and itorvon may be administered separately, but may be administered in close proximity in time, or may be co-formulated for simultaneous intranasal administration.

[0086] Example 10 - Improvement of psychomotor and / or cognitive abilities by ETA in subjects with mental fatigue associated with perinatal depression

[0087] Perinatal depression (PPD, also known as postpartum depression, is the DSM-5 code for depressive states with a perinatal onset, such as major depressive disorder with a perinatal onset) is one of the most common perinatal complications, affecting approximately 8-26% of women in the perinatal period each year. A negative association between coffee intake and perinatal depression was reported by Wang et al. in "Coffee and caffeine intake and depression in postpartum women: A cross-sectional study from the National Health and Nutrition Examination Survey 2007-2018" (Front.Psychol., 14:1134522 (2023)). Based in part on the finding that ETA directly improves psychomotor and cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, and its presumed mechanism of action, ETA similarly improves psychomotor and cognitive abilities in subjects with mental fatigue associated with perinatal depression.

[0088] In subjects experiencing psychomotor and / or cognitive impairments associated with perinatal depression, a therapeutically effective dose of ETA is administered intraocularly as described in Example 4. ETA is administered separately from any other antidepressant therapy, either sequentially or in temporal proximity to such other medications. Depression scores decrease upon assessment of the subjects. Psychomotor and cognitive abilities improve in this group of subjects.

[0089] Example 11 - Improvement of psychomotor and / or cognitive abilities by ETA in mental fatigue associated with attention deficit hyperactivity disorder.

[0090] Caffeine is known to be associated with improved cognition and attention in individuals with ADHD symptoms. According to Cunha et al., “Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders” (Curr. Pharm. Des., 14(15), 1512-1524 (2008)), manipulation of the ADORA2A receptor, considering the use of caffeine administration to treat this condition, could be a novel and compelling new therapeutic strategy for managing ADHD. Similarly, Heacock et al., U.S. Patent No. 8845621, “Pharmaceutical Formulations of Modafinil,” reported that a specific dose of modafinil significantly improved attention and significantly improved ADHD symptoms. Based in part on the finding that ETA directly improves psychomotor and / or cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, ETA similarly improves psychomotor and cognitive abilities in individuals with ADHD-related mental fatigue.

[0091] In subjects experiencing impaired psychomotor and / or cognitive abilities associated with ADHD, administer a therapeutically effective dose of ETA intranasally as described in Example 4. Psychomotor and cognitive abilities improve in this group of subjects.

[0092] Example 12 - Improvement of psychomotor and / or cognitive abilities by ETA in mental fatigue associated with mild cognitive impairment

[0093] Based in part on the finding that ETA directly improves psychomotor and / or cognitive abilities in mentally fatigued subjects with similar efficacy to caffeine and modafinil, ETA similarly improves psychomotor and cognitive abilities in individuals with mental fatigue associated with MCI.

[0094] In subjects experiencing reduced psychomotor and / or cognitive abilities associated with mild cognitive impairment, a therapeutically effective dose of ETA is administered intranasally, as described in Example 4. Psychomotor and cognitive abilities improve in this group of subjects.

Claims

1. 1,3,5(10),16-estratetraen-3-ylacetate, for use in improving the psychomotor or cognitive abilities of mentally fatigued individuals via intranasal administration.

2. The 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 1, wherein the individual is male.

3. 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 1, wherein the individual is female.

4. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 3, wherein the nasal administration includes administration to nasal olfactory chemosensory receptors.

5. 1,3,5(10),16-estratetraene-3-ylacetate for use according to any one of claims 1 to 4, wherein the improved ability is psychomotor ability.

6. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 4, wherein the improved ability is cognitive ability.

7. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 4, wherein the improved ability is both psychomotor ability and cognitive ability.

8. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 7, wherein the improvement in psychomotor or cognitive ability is observed within about one hour, preferably within about 15 minutes, more preferably within about 5 minutes, of administration of 1,3,5(10),16-estratetraen-3-ylacetate.

9. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 8, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered in a pharmaceutical formulation.

10. The 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 9, wherein the pharmaceutical preparation is a nasal spray.

11. The nasal spray comprises an aqueous solution of 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 10.

12. The nasal spray comprises approximately 16 pg / mL of 1,3,5(10),16-estratetraen-3-yl acetate, approximately 2% propylene glycol, and approximately 2% ethanol, for use according to claim 11.

13. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 10 to 12, wherein the nasal spray contains about 0.5 to 6 micrograms per dose, preferably about 1 to 4 micrograms per dose, and more preferably about 1.6 to 3.2 micrograms per dose.

14. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 13, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered at the onset of a decline in psychomotor function or cognitive function.

15. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 13, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered on a schedule throughout the day.

16. 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 15, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered 2 to 8 times per day, preferably 3 to 5 times per day, more preferably 4 times per day.

17. 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 15 or 16, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered on a regular schedule.

18. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 17, wherein 1,3,5(10),16-estratetraen-3-ylacetate is administered in a circadian rhythm-based schedule for episodes of mental fatigue in a group or in an individual receiving 1,3,5(10),16-estratetraen-3-ylacetate.

19. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is related to long-term cognitive activity.

20. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is related to sleep deprivation or sleep disturbance.

21. 1,3,5(10),16-estratetraene-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is related to shift work sleep disorder.

22. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is related to excessive daytime sleepiness.

23. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is associated with a depressive disorder.

24. 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 23, further comprising administering an effective amount of antidepressant.

25. 1,3,5(10),16-estratetraen-3-ylacetate for use according to claim 24, wherein the antidepressant is itorvon.

26. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 23 to 25, wherein the depressive disorder is major depressive disorder.

27. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 23 to 25, wherein the depressive disorder is perinatal depression.

28. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is related to attention deficit hyperactivity disorder.

29. 1,3,5(10),16-estratetraen-3-ylacetate for use according to any one of claims 1 to 18, wherein the mental fatigue is associated with mild cognitive impairment.

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