1, 3, 5 (10), 16-estratetraen-3-yl acetate for improving mental movement or cognitive performance

Abstract

The intranasal administration of 1, 3, 5 (10), 16-estratetraen-3-yl acetate may be used to improve mental motor and / or cognitive performance in mental fatigue subjects.

Description

Technical Field

[0001] This invention relates to improving psychomotor and / or cognitive performance in individuals with mental fatigue by intranasal administration of 1,3,5(10),16-estratetraen-3-ylacetate. Background Technology

[0002] Psychomotor and cognitive performance

[0003] 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 sensorimotor function) refers to an individual's ability to respond to stimuli in a coordinated, timely, and appropriate manner; while cognitive function (sometimes called cognition) refers to an individual's ability to think and reason about temporal and spatial relationships and symbols (such as words and numbers). In simple terms, psychomotor function (or psychomotor performance) is a responsiveness. In contrast, cognitive function (or cognition or cognitive performance) is a thinking ability.

[0004] As Wetherell explains, psychomotor performance and cognitive performance are not separate; they overlap in the degree to which stimuli require thought. Therefore, a simple reaction time test is often considered a psychomotor performance test, but if the stimuli are complex and require decision-making, the test leans more towards cognitive performance. Wetherell describes several automated performance tests used by the UK Defence Evaluation and Research Agency Chemical and Biological Defence Human Studies Group, noting that these tests are all in the public domain. He points out that these tests assess environmental stressors (primarily drugs, but also physical fatigue, sleep deprivation, and protective clothing).

[0005] Testing of psychomotor performance primarily employs automated testing. The Psychomotor Alertness Task (PVT) is a sustained attention and reaction time task used to measure the speed at which a subject reacts to a visual stimulus (light): the subject presses a button immediately upon the appearance of light. The light is pseudo-randomly turned on every few seconds for 5-10 minutes. The primary measure of this task is not assessing the subject's reaction time, but rather observing the number of times the button is not pressed when the light is on or when it is off. The purpose of the PVT is to measure sustained attention / alertness by calculating the number of attentional errors by the test subject and to provide a numerical measure of inattention / alertness.

[0006] Cogstate, a company based in New Haven, Connecticut, offers a variety of computer-implemented individual tests (which Cogstate calls "tasks") that can be combined into test suites, including detection tests (where cards are first shown face down, then flipped face up, and test subjects are required to react when the cards are face up), a variant of the PVT. The reaction time test in Example 4 is an automated psychomotor performance test.

[0007] Cognitive performance testing includes both human-rated and automated tests. Automated cognitive performance tests include, for example, IntegNeuro from Cogstate and BrainClinics Products from Radboud, Netherlands. TM The Cogstate test includes a recognition test (where cards are first shown face down, then flipped face up, and participants are asked to identify whether the front of the card is red or black); a one-card learning test (where cards are flipped face up one after another, with some cards being shown more than once, and participants are asked to identify whether the currently shown card is new or has been shown before); and a one-back test (where cards are flipped face up one after another, with some cards being shown twice consecutively, and participants are asked to identify whether the currently shown card is new or has just been shown).

[0008] The IntegNeuro™ system is a touchscreen computer that offers a range of tests, including: a timing test (circles light up for 1 to 12 seconds, then the subject is asked to estimate the duration of the light), a selection reaction time test (one of four circles is lit, and the subject is asked to touch the lit circle), a verbal interference test (words representing color names appear on the screen in different colors, and the subject is asked to point to the color of the displayed word, not the word itself), and a "spot the real word" test (a real word and a meaningless word are displayed, and the subject is asked to point to the real word). The time estimation test in Example 4 is an automated cognitive performance test.

[0009] Mental fatigue Mental fatigue (as opposed to physical or muscular fatigue, which refers to a temporary inability of muscles to function optimally) refers to a temporary inability to maintain a level of psychomotor and / or cognitive performance that is typical for a particular individual or normal or optimal for that individual or the general population. It can also be caused by prolonged cognitive activity (long periods of time engaged in tasks requiring thinking or mental labor), sleep deprivation (insufficient sleep), sleep interruption or sleep apnea (leading to sleep deprivation), or conditions related to these conditions (such as shift work sleep disorders and excessive daytime sleepiness).

[0010] Mental fatigue can also be caused by psychological conditions such as depression (e.g., major depressive disorder (MDD) and perinatal depression), as well as other disorders that typically present with or are associated with mental fatigue, such as attention deficit hyperactivity disorder (ADHD) and mild cognitive impairment. For example, according to Takeda et al, “Impact of depression on mental fatigue and attention in patients with multiplesclerosis”, J. Affect. Disord. Rep According to [reference needed], mental fatigue is closely associated with depression in patients with multiple sclerosis. However, according to Pan, et al., “Cognitive Impairment in Major Depressive Disorder”, [further details needed]. CNS Spectrums According to Polosan et al., 24, 22-29 (2019), "Most antidepressants have not been developed and / or evaluated for their ability to directly and independently improve cognitive deficits." This aligns with the statement, "Cognition—the core of major depressive disorder." L'Encephcde , 42(1, Suppl.1), 1S3-1S11 (2016), "Until recently, cognitive deficits were not considered a major phenotypic determinant of major depressive disorder." Pan et al. also reported that "...cognitive subdomains, such as learning and memory, executive function, processing speed, and attention and concentration, are significantly impaired during and between episodes in patients with MDD." Furthermore, depression is highly associated with sleep disorders (Murphy and Peterson, "Sleep Disturbances in Depression"), Sleep Med. Clinics , 10(1), 17-23 (2015)), which may lead to cognitive impairment in patients with major depressive disorder. Furthermore, Sommerfeldt et al., “Executive Attention Impairment in Adolescents with Major Depressive Disorder,” J. Clin. Child Adolesc. Psychol. , 45(1), 59-83 (2016), reported “attention deficit” in adolescents with MDD, characterized by, for example, longer reaction time compared to controls.

[0011] According to Rogers et al., “Fatigue in an adult attention deficithyperactivity 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).

[0012] 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 that occurs with age and the more severe dementia-like decline, and may further be associated with depression, as described below. MCI can include problems with memory, language, or judgment, but it is not a necessary precursor to dementia, as MCI can also occur in people with other mental illnesses (such as depression) or systemic diseases (such as diabetes or obesity). The Alzheimer's Association (https: / / www.alz.org / alzheimers-dementia / what-is-dementia / related_conditions / mild-cognitive-impairment) describes MCI as: "Mild cognitive impairment (MCI) is an early stage in which an individual experiences memory loss or other cognitive impairments (such as language or visual / spatial perception), but these individuals still retain the ability to independently perform most daily activities." They also note: "The cognitive changes caused by mild cognitive impairment are severe enough to be noticed by the affected person and their family and friends, but have not yet affected the individual's ability to perform daily activities. MCI can be caused by a variety of factors, and individuals with MCI may develop dementia, while others may not. For neurodegenerative diseases, if there are characteristic changes in the brain, MCI may be an early stage of the disease continuum (including Alzheimer's disease). The etiology of MCI is not fully understood. Experts believe that most cases—not all—are caused by brain changes occurring in the very early stages of Alzheimer's disease or other neurodegenerative diseases that lead to dementia."

[0013] When the underlying cause is a neurodegenerative disease rather than other factors, the risk factors most closely associated with MCI are aging, a family history of Alzheimer's disease or other dementias, and conditions that increase the risk of cardiovascular disease… Approximately 12% to 18% of people aged 60 or older have MCI. It is estimated that 10% to 15% of individuals with MCI develop dementia each year. About one-third of individuals with MCI due to Alzheimer's disease develop dementia within five years.

[0014] Tests for MCI include cognitive assessments such as the Mini-Cog (consisting of 3-word recall and clock drawing), the General Practitioner Cognitive Assessment Scale (GPCOG: the patient part assesses orientation, awareness, and memory; while the information part compares the patient's current and past functions), the Montreal Cognitive Assessment Scale (MoCA, a 1-page, 30-point test that assesses 8 cognitive domains through 13 tasks), or the Saint Louis University Mental State Examination Scale (SLUMS, a 30-point, 11-item scale that includes various cognitive assessments: task assessment attention, numerical calculation, immediate and delayed recall, animal naming, digit span, clock drawing, figure recognition / size discrimination, and immediate recall of facts in a passage). 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 between patients with mild cognitive impairment (MCI), cognitively healthy controls, and patients with mild to moderate Alzheimer's disease. Petersen et al., "Practice guideline updates summary: Mild cognitive impairment", Neurology The article 90(3), 126-135 (2018) discusses the diagnosis and treatment of MCI, but notes that despite the use of various medications, "there is no high-quality evidence to support the pharmacological treatment of MCI." MCI is also known to be associated with hypertension, depression, and other mental disorders. MCI is well-known to cause suffering for patients, and therefore may lead to mental fatigue resulting from this suffering.

[0015] Mental fatigue can also be caused by a combination of any of the above situations or conditions; for example, cramming before an exam may involve both prolonged cognitive activity and sleep deprivation; while anxiety and insomnia stemming from MCI may involve both sleep deprivation and MCI itself.

[0016] In any cognitive activity, the onset of mental fatigue is gradual, depending on individual cognitive abilities as well as other factors such as existing sleep deprivation and overall health. (Marcora et al., "Mental fatigue impairs physical performance in humans") J. Appl. Plysiol. , 106, 857-864 (2009) showed that mental fatigue reduces physical performance. Mental fatigue can manifest as somnolence, lethargy, or directed attention fatigue (the inability to maintain a high level of attention or alertness, such as when things are monotonous or boring). Among the many physical consequences of mental fatigue, deficits in attention / alertness and working memory are perhaps the most significant; these deficits, and the resulting errors in daily tasks, can lead to regrettable outcomes, from forgetting ingredients while cooking to missing a sentence while taking notes.

[0017] Decreased attention (lack of alertness) can extend to more critical areas, with potentially life-threatening consequences; car accidents and industrial disasters can be caused by inattention due to mental fatigue. The dangers of mental fatigue are particularly pronounced while driving; the American Academy of Sleep Medicine (AASM) reports in its Drowsy Driving Fact Sheet that one in five serious motor vehicle injuries is related to driver fatigue, with 80,000 drivers falling asleep at the wheel every day and 250,000 accidents related to fatigue annually, although the National Highway Traffic Safety Administration believes the number 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), Some of the detrimental effects of mental fatigue and sleep deprivation on psychomotor and cognitive performance are the same as those of intoxication.

[0018] Combating the effects of mental fatigue Several strategies are commonly used when attempting to combat the effects of mental fatigue. The AASM recommends non-pharmacological strategies including preventative sleep before sleep deprivation, naps, and combinations thereof. However, the only definitive and safe way to combat mental fatigue caused by sleep deprivation / 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 function recovery after acute total sleep deprivation is faster than that after prolonged partial sleep restriction.

[0019] The primary over-the-counter medication for combating the effects of mental fatigue is caffeine, which improves alertness, psychomotor function, and cognitive function, but does not reduce the number of errors during work. Prescription medications for combating the effects of mental fatigue include stimulants (such as amphetamines, dextroamphetamine, etc.) and eugeroics (awakening promoters, such as modafinil, armodafinil). For example, see Urban et al., “The Role of Eugeroics in the Treatment of Affective Disorders”. Psvchiatr. Pol. , 54(1),21-33 (2020). Caffeine is often used for short-term arousal when acute mental fatigue occurs; however, its effects diminish with regular use, high doses can cause jitteriness, and it takes time to reach its maximum effect. Amphetamines (as can caffeine) are addictive and can cause insomnia and mood swings; modafinil and armodafinil can cause nausea and dizziness. Both also take time to reach their maximum effect and are therefore usually taken preventively before mental fatigue begins. In the United States, amphetamines and modafinil / armodafinil are controlled substances.

[0020] Wesensten et al., “Maintaining alertness and performance during sleepdeprivation: modafinil versus caffeine”, Psychopharmacology (Berlin) , 159(3),238-247 (2002), used cognitive tests to measure arousal and attention levels, showing that prolonged sleep deprivation is a useful method for comparing the stimulant effects of caffeine and modafinil. However, in this study, the authors did not use polygraphic recording to assess brain alertness levels and drowsiness associated with mental fatigue.

[0021] There is a need to develop a formulation for improving psychomotor and / or cognitive performance in individuals with mental fatigue. This formulation should ideally be rapidly acting so that it can be administered when mental fatigue (or its effects on psychomotor and / or cognitive performance) occurs, without requiring prophylactic administration before anticipated mental fatigue. It should also have minimal side effects such as addictiveness, insomnia, mood instability, and irritability.

[0022] The olfactory chemoreceptors, vomeronasal organ, and olfactory epithelium, as well as pherine Olfactory chemoreceptors are distributed in the olfactory epithelium, present in the mucosal lining of the medial and dorsal sides of the nasal septum and the recesses on the nasal dorsum, including the vomeronasal organ (“VNO”, also known as “Jacobson’s organ”). In particular, these receptors in the VNO are associated with pheromone reception in many non-human species (see often 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: AReview”, Ann. NY Acad. Sci. ,855:373-389 (1998). The axons of the neuroepithelial layer of the nasal chemoreceptors directly input to the hypothalamus and limbic amygdala of the brain, while their distal processes (cilia and microvilli) are the locations of the chemoreceptors. (See Stensaas et al., “Ultrastructure of the human vomeronasal organ”, 855:373-389 (1998).) J. Steroid Biochem. Mol. Biol. , 39(4):553-560 (1991), and Monti-Bloch, “Patchrecorded 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”, Abstract #200 for Seventeenth Annual Meeting of the Association for Chemoreception Sciences (AChemS XVII), Chem. Senses , 20(6): 745-746(1995).

[0023] Human-derived neurosteroids delivered to the nasal septum bind to cilia and microvilli on local chemoreceptors, triggering neural signals that transmit to the brain, thereby inducing 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). Pherine, a chemically modified naturally occurring human neurosteroid (a substance that binds to olfactory chemoreceptors in the nose), can induce potent physiological, pharmacological, and behavioral changes when delivered to these receptors via the nasal cavity through airborne transmission. This information is supported by several studies in human volunteers using functional magnetic resonance imaging and positron emission tomography, which have shown that pherine selectively activates brain regions (hypothalamus, limbic system, cingulate gyrus, anterior thalamus, and prefrontal cortex) where its physiological, pharmacological, and behavioral effects are integrated.

[0024] Studies of several pherines have shown that, because the compounds act directly on olfactory chemoreceptors that are directly connected to the brain, they can affect physiological markers (such as autonomic nervous system responses and EEG) within seconds to less than a minute after administration, and affect endocrine and neurotransmitter metabolism markers within about 10-15 minutes.

[0025] 1,3,5(10),16-estratetraen-3-ylacetate 1,3,5(10),16-estradiol-3-acetate (“estradiol-3-acetate”, “ETA”) and its synthesis are described, for example, in 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 various estradiols as compounds capable of altering hypothalamic or autonomic function by administration to the olfactory epithelium of a human subject. The patent discloses ETA and mentions it as a preferred compound near line 20 in column 8. It is an acetate of 1,3,5(10),16-estradiol-3-acetate, mentioned as a preferred compound in the same paragraph, and is compound E2 / N1 in the estradiol table (bottom of column 7, described as “known”). The patent broadly claims pharmaceutical compositions comprising estradiols (including ETA) in dosage forms suitable for nasal administration and discloses methods of using them by vomeronasal administration to alter hypothalamic or autonomic function.

[0026] ETA, administered at a dose of 60 pg to the vomeronasal organ, produced changes in mass receptor potentials (electroradiogram) compared to the control group (propylene glycol), with the magnitude of the changes being greater in men (Fig. 3A) than in women (Fig. 3B). Compared to the control group, ETA also showed increased vomeronasal electroradiogram integrals (Fig. 4A), decreased skin resistance (Fig. 4B), and increased skin temperature (Fig. 4C) in men. ETA also showed increased vomeronasal electroradiograms (Fig. 6A and 6B), increased α-cortical activity (Fig. 6E and 6F), and increased skin temperature (Fig. 6G and 6H) in both men and women, with more significant effects in men; it also reduced skin electrical activity in men (Fig. 6C), but had no effect on women (Fig. 6D). However, the patent does not describe any improvement in psychomotor or cognitive function, nor does it provide any relevant data.

[0027] Some 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”, Jennings-White et al., U.S. Patent No. 6,066,627, “Steroids as neurochemical initiators of change in human blood levels of LH”, Jennings-White et al., U.S. Patent No. 6,117,860, “Steroids as neurochemical stimulators of the VNO to treat paroxistic tachycardia”, and Berliner et al., U.S. Patent No. 6,331,534, “Steroids as neurochemical stimulators of the VNO to alleviate pain”, slightly expanded the disclosure of ETA, while also including many other different kinds of steroids.

[0028] Berliner et al., U.S. Patent No. 6544971, “Method of increasing alertness by administration of a vomeropherin, and vomeropherin-emitting alarm devices,” discloses a method for increasing individual alertness by administering estradiol with the following chemical formula via the vomeronasal route:

[0029] Wherein, R1 is hydrogen, C 1-4 Alkyl group, or -SO3H or its salt; R2 is hydrogen or methylene; R3 is absent, or it is either hydrogen or C. 1-4 Alkyl; one or two non-adjacent members of “a”, “b”, “c”, and “d” are optional double bonds; when R2 is hydrogen, “e” is a double bond or a 16α,7α-epoxide; when R2 is methylene, “e” is absent and “f” is a double bond. The patent also discloses an alarm device for detecting the presence of an alarm condition, and a dispenser for administering estradiol via the vomeronasal route. Preferred compounds are claimed to be ETA and 17-methylene-1,3,5(10),6,8-estradiol-3-ol.

[0030] US Patent No. 6,544,971 defines "alertness" as including wakefulness and responsiveness to external stimuli. It also defines "increasing individual alertness" as including one or both of arousing the individual and increasing their responsiveness to external stimuli; this effect may occur as sleep becomes lighter, but not fully awakened. Increased alertness refers to "increasing an individual's responsiveness to external stimuli, such as ringing, telephone ringing, fire, smoke, etc." The patent also defines an "alarm situation" related to the individual as a situation where the safety or health of the individual or others may be adversely affected by the individual's lack of responsiveness, or a situation requiring the individual to respond. Summary of the Invention

[0031] In a first aspect, the present invention is a method for improving psychomotor and / or cognitive performance in mentally fatigued individuals by intranasal administration of 1,3,5(10),16-estratetraen-3-ylacetate.

[0032] Mental fatigue can be caused by any reason, but notable causes include prolonged cognitive activity, sleep deprivation, sleep disruption, and conditions associated with these, such as shift work sleep disorders and excessive daytime sleepiness. It can also be caused by or associated with mental illnesses such as depression (including major depressive disorder and perinatal depression) and other conditions such as attention deficit hyperactivity disorder and mild cognitive impairment.

[0033] In other respects, the invention therefore includes: 1,3,5(10),16-estratetraen-3-ylacetate, for use by intranasal administration to improve psychomotor and / or cognitive performance in patients with mental fatigue; Pharmaceutical formulations and devices comprising 1,3,5(10),16-estratetraen-3-ylacetate for improving psychomotor and / or cognitive performance in mentally fatigued individuals via nasal administration; and Use of 1,3,5(10),16-estatetraen-3-ylacetate in the preparation of a medicament for improving psychomotor and / or cognitive performance in patients with mental fatigue via intranasal administration.

[0034] 1,3,5(10),16-estratetraen-3-ylacetate has particular efficacy in improving psychomotor and / or cognitive performance in this group of individuals; and is expected to offer the following advantages compared to conventional stimulants: (1) Rapid onset of action: because the compound is delivered directly and locally to the olfactory chemoreceptors in the nose and then takes effect; (2) No local nasal or systemic side effects or toxicity: because the dose used is extremely low (nanograms to micrograms) and the route of administration is local, it means no or low systemic absorption; and (3) No side effects seen with other commonly used drugs such as caffeine, amphetamines, modafinil / armodafinil: for the same reason as (2) above.

[0035] The preferred embodiments of the present invention are defined by the technical features in the specification and the claims submitted in this application, and also include corresponding pharmaceutical compositions, apparatus, methods and uses of the said compound. Detailed Implementation

[0036] definition: "person" or "persons" refers to human beings; "man" or "men" refers to male human beings; "woman" or "women" refers to female human beings; there is no intention to restrict age.

[0037] "Nasal administration" or "intranasal administration" refers to the delivery of medication to the olfactory chemoreceptors in a person's nose. In a clinical setting, this can be achieved to some extent using a specially designed probe that delivers ETA primarily to the VNO (such a probe, also designed to measure effects on vomeronasal tissue, is described in Monti-Bloch, U.S. Patent No. 5,303,703, "Combined neuroepithelial sample delivery electrode device and methods of using the same"). However, nasal administration preferably involves delivery into the nasal cavity via a conventional nasal spray device, directed in a manner that directs the ETA generally toward the primary and secondary sites of the olfactory chemoreceptors in the olfactory epithelium of the nasal cavity, including the nasal dorsum recess and the VNO. See, for example, U.S. Provisional Patent Application SN 63 / 631,389, filed April 8, 2024, entitled "Intranasal Drug Delivery System".

[0038] "Effective dose" refers to the amount of ETA that, when administered to the olfactory chemoreceptors of a mentally fatigued person, is sufficient to improve the psychomotor and / or cognitive performance of that person, but is insufficient to produce a systemic effect through absorption into the circulation.

[0039] "Improving" the psychomotor and / or cognitive performance of individuals experiencing mental fatigue includes at least one of the following: Improving psychomotor performance, that is, by increasing or enhancing psychomotor performance compared to when ETA is not administered intranasally, thereby improving a person's ability to coordinate timely and appropriate responses to stimuli; and Improving cognitive performance means enhancing or increasing cognitive performance compared to when ETA is not administered intranasally, thereby improving a person's ability to think and reason about time and space relationships and symbols (such as words and numbers).

[0040] Because mentally fatigued individuals experience a decline in psychomotor and / or cognitive performance, i.e., they suffer from psychomotor and / or cognitive performance deficits, "improving" psychomotor and / or cognitive performance includes reducing these deficits.

[0041] "Psychomotor performance" and "cognitive performance," as well as the tests used to measure them, have been described in the "Psychomotor and Cognitive Performance" section of the background art.

[0042] Mental fatigue and its effects on psychomotor and / or cognitive performance have been described in the "Mental Fatigue" section of the background art.

[0043] "Pharmaceutically acceptable excipients" refer to excipients that can be used in the preparation of pharmaceutical formulations and are generally safe, non-toxic, and suitable. These excipients can be solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous.

[0044] 1,3,5(10),16-estratetraen-3-ylacetate and its preparation 1,3,5(10),16-estratetraen-3-ylacetate is a compound having the following structural formula: .

[0045] It is readily prepared by esterification of 1,3,5(10),16-estratetraen-3-ol, by, for example, the method described in paragraph

[0037] below.

[0046] The preparation of ETA is described in Examples 1 and 2 of U.S. Patent No. 5783571, starting with readily available commercially available steroid estrone (3-hydroxy-1,3,5(10)-estradiol-17-one, available from several suppliers, such as Sigma-Aldrich Company LLC), as shown in the following reaction scheme: .

[0047] According to the synthesis description in Examples 1 and 2 of US Patent No. 5783571: First, estrone (270 g, 1.00 mol) and 4-toluenesulfonylhydrazone (232.8 g, 1.25 mol) were heated under reflux in anhydrous methanol (2.5 L) for 20 hours. The mixture was transferred to an Erlenmeyer flask and cooled. The resulting crystalline estrone 4-toluenesulfonylhydrazone was filtered and washed with methanol (300 mL). Further products were obtained by sequentially evaporating the filtrate to 2 L, 800 mL, and 400 mL, crystallizing the estrone 4-toluenesulfonylhydrazone each time. The overall yield was 433.5 g (99%).

[0048] 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. The mixture was mechanically stirred while n-butyllithium (800 mL, 2.5 M hexane solution, 2.00 mol) was added via a double-ended syringe. The mixture was stirred at room temperature for 3 days. Ice (250 g) was added, followed by a saturated aqueous solution of ammonium chloride (500 mL). The phases were mixed by stirring and then allowed to settle. The aqueous phase was removed by suction using a PTFE tube and extracted with diethyl ether (500 mL). Both organic phases were washed sequentially with the same batch of saturated aqueous solution of sodium bicarbonate (500 mL) followed by a wash with saturated aqueous solution of sodium chloride (500 mL). The organic layer was dried (MgSO4) and evaporated under vacuum to give crude 1,3,5(10),16-estradiol-3-ol 2. The sample was rapidly filtered through silica gel 60 (500 g, 230-400 mesh) and eluted with ethyl acetate / hexane (1:3, 2.5 L). The filtrate was evaporated under vacuum to give crystalline 1,3,5(10),16-estradiol-3-ol. It 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-estradiol-3-ol (88.9 g, 70%).

[0049] In the third step, acetic anhydride (0.25 mL) was added to a solution of 1,3,5(10),16-estradiol (254 mg, 1.00 mmol) in ether (10 mL), followed by pyridine (0.25 mL). The mixture was stirred at room temperature for 16 hours. The mixture was poured into ice / water and extracted with ether (2 × 20 mL). The organic extract was washed successively with water, saturated copper sulfate solution, water, and saturated sodium chloride solution, dried (MgSO4), and evaporated under vacuum to give crude 1,3,5(10),16-estradiol-3-yl acetate. It was purified by rapid chromatography on silica gel 60 (17.5 g, 230-400 mesh) and eluted with 10%-12% ethyl acetate / hexane to give pure 1,3,5(10),16-estradiol-3-yl acetate (192 mg, 65%).

[0050] Those skilled in the art, taking into account the technology and the contents of this disclosure (including the aforementioned patents), will not have difficulty preparing an ETA.

[0051] Preparation and administration ETA can be administered nasally via any suitable route designed to bring it into contact with the nasal olfactory chemoreceptors. Routes of administration include, but are not limited to, topical nasal dressings (e.g., creams or gels for the skin or preferably for intranasal use), nasal sprays, nasal powder sprays, nasal aerosols, etc. Pharmaceutical formulations are typically designed for mucosal administration or transdermal preparations. Suitable formulations for each method of administration can be found, for example, Remington: The Science and Practice of Pharmacy , 20th ed., A. Gennaro, ed., Lippincott Williams & Wilkins, Philadelphia, Pennsylvania, USA, 2003. Typical preferred formulations are aqueous solutions for nasal sprays containing ETA and water, and often also containing one or more other pharmaceutically acceptable excipients to increase the solubility of the ETA, such as alcohols and glycols (e.g., ethanol and propylene glycol). Suitable delivery devices for these formulations are metered-dose nasal spray pumps, commonly used for intranasal delivery of steroids used to treat allergies and asthma. Such pumps are manufactured by several manufacturers. The liquid volume should allow for efficient delivery of the formulation without exceeding the nasal retention volume, causing excessive fluid reflux into the sinuses or dripping from the nose; a volume of 50 μL has been found convenient, although larger or smaller volumes are also acceptable. Exemplary formulations include those discussed in paragraph

[0057] below; those skilled in the art, considering the technology and the content of this disclosure, will not have difficulty preparing suitable formulations and delivery systems for nasal administration of ETA.

[0052] When administered in the form of a nasal spray of the type described above, the effective dose of an intranasally administered ETA is approximately 400-6000 nanograms per dose, for example, 1000-4000 nanograms per dose, or approximately 1600-3200 nanograms per dose (or half the dose to each nostril, assuming the compound is administered to both nostrils); male doses are typically in the lower part of the given range, for example, 1000-2500 nanograms per dose, or approximately 1600 nanograms per dose; while female doses are typically in the higher part of the given range, for example, 2500-4000 nanograms per dose, or approximately 3200 nanograms per dose. It is expected that no more than a few percent of this intranasal spray dose actually reaches the nasal olfactory chemoreceptors, and therefore the effective dose may be even lower when essentially only administered to the nasal olfactory chemoreceptors. Doses may vary with other intranasal administration methods, depending on the administration method; those skilled in the art, considering this technology and the content of this disclosure, will not have difficulty determining an appropriate dose range for a given administration method / formulation / delivery system. These doses, both nasal / intranasal and directly acting on the nasal olfactory chemoreceptors, are all well below any level that would cause systemic effects, except for those mediated by the nasal olfactory chemoreceptors.

[0053] The initial physiological response to nasal administration of ETA occurs very rapidly, typically within one minute of administration; and improvements in psychomotor and cognitive performance are usually observed within 15 minutes of administration, for example, within 5 minutes. Due to the rapid onset of action and safety of nasal ETA, it is expected that ETA can be administered as needed upon experiencing mental fatigue, such as immediately when a person experiencing mental fatigue feels drowsy or exhibits symptoms of drowsiness (e.g., excessive yawning, eye closing, nodding, etc.) or experiences a decline in psychomotor or cognitive performance, to improve psychomotor and cognitive performance in these situations. It is also expected that ETA can be administered prophylactically to improve or at least prevent a normal decline in psychomotor and / or cognitive performance in individuals experiencing mental fatigue or those at risk of experiencing mental fatigue. Therefore, for example, a firefighter whose work schedule may require him or her to be on standby for 72 consecutive hours, although he / she may sleep when he / she is not actually needed at night, but when he / she is awakened at night and called to fight a fire, may be given an ETA to improve psychomotor and / or cognitive performance; or a pilot of a night flight who flies the aircraft during the afternoon takeoff phase, rests during the night cruise phase of the flight, but then flies the aircraft again the following morning for approach and landing, may be given an ETA to improve psychomotor and / or cognitive performance when transitioning from rest to performing approach and landing.

[0054] It is also anticipated that ETAs can be administered as scheduled during waking hours (e.g., during shift work) or at night or during similar activities (e.g., for the entire crew of a night flight), for example, 2–8 times, 3–5 times, or 4 times during that waking or activity period, to minimize the decline in psychomotor and / or cognitive performance caused by prolonged fatigue (e.g., over weeks or months). This scheduled dosing can be on a uniform schedule, for example, at 10 pm, midnight, 2 a.m., and 4 am (4 times / day for night shift workers, such as nurses); or on a non-uniform schedule where the dosing frequency is based on the circadian rhythm of mental fatigue, whether in the general population or in individuals receiving treatment. Thus, for example, the maximum dose can be selected when mental fatigue (or the decline in psychomotor and / or cognitive performance) is most severe or anticipated to be most severe. Of course, even with scheduled dosing, ETAs can be administered as needed if mental fatigue (or the decline in psychomotor and / or cognitive performance) is still felt.

[0055] Similarly, for individuals who need to improve psychomotor and / or cognitive performance deficits associated with depression (such as major depressive disorder and postpartum depression) and other disorders (such as attention deficit hyperactivity disorder, “long COVID”, shift work sleep disorder, excessive daytime sleepiness, or mild cognitive impairment), administration may be on demand (when a decline in psychomotor and / or cognitive performance is felt), preventative (to prevent or mitigate the effects of such decline), or scheduled in patients with these disorders.

[0056] Example Example 1: Electrophysiological study of ETA ETA induces inward currents in isolated human olfactory chemosensory neuron membranes and causes electrotonic depolarization of the olfactory chemosensory epithelium of the nasal septum: this is the first event in chemical transduction in peripheral receptors. The amplitude of this response increases with increasing compound concentration. In vitro, it exhibits no agonist or antagonist activity against rat estrogen, androgen, progesterone, and glucocorticoid receptors.

[0057] Example 2: Preclinical Studies of ETA When tested in the Ames reversion mutation assay and in vivo bone marrow micronucleus assay, the genotoxicity assays showed no evidence of ETA’s potential to cause mutations or chromosome breaks.

[0058] Administration of ETA (1 mg / day, intravenously) to rats of both sexes for 7 days did not result in death, adverse symptoms, or behavioral changes, and no macroscopic or microscopic changes were observed in any of the studied organs. Administration of ETA (600 μg / kg intravenously, 900 μg / kg intranasally) to male rats for 7 days did not result in death, adverse symptoms, or behavioral changes, and showed rapid absorption, metabolism, and excretion.

[0059] Example 3: Pilot Human Clinical Study of ETA In pilot trials in healthy volunteers of both sexes, intranasal administration of ETA was well tolerated and induced a strong response. Intranasal administration of the compound caused significant changes in heart rate and respiratory rate, but did not alter the duration of the QTc interval on electrocardiograms. ETA significantly increased the frequency of electrical skin activity events (measured as skin conductance, indicating increased sympathomimetic activity), but had no significant effect on body temperature or the α and β bands of electroencephalograms.

[0060] Example 4: Study on the efficacy of ETA on men with mental fatigue This study employed a computerized reaction time and time estimation test (RTTET), developed by the testing laboratory. The psychomotor performance test (reaction time test) involves the subject pressing a control lever each time he or she perceives a visual stimulus (flash), thus allowing for the measurement of reaction time to the visual stimulus. The flashes are emitted at fixed intervals of 10 seconds (isochronous stimuli) or random intervals (random stimuli). The cognitive performance test (time estimation test) involves the subject observing three sets of flashes emitted at fixed intervals of 10 seconds, and after the third set, they press the control lever at the same interval (i.e., estimate the 10-second flash interval).

[0061] During the testing, subjects need to maintain a sufficient level of attention to avoid errors during the reaction time test (missing the flash, delayed reaction); and they need to concentrate to estimate the duration of the time interval between stimuli in the time estimation test, as they will need to use this information in their responses. A sequence in the RTTET lasts 20 minutes, and each test consists of four sequences, with 10-20 minute intervals between sequences. Tests are conducted at 6 pm (control), 9 pm, midnight, and 3 am, therefore each test consists of four sessions. Subjects are not allowed to sleep between tests.

[0062] This study was designed as a double-blind, placebo-controlled, three-way crossover study using 10 healthy male volunteers. Inclusion criteria included: good prior health, regular nighttime sleep patterns (regular bedtime and average sleep duration of 8 hours), and no use of any psychotropic medications for at least 2 months. Exclusion criteria included: caffeine allergy or tolerance, and any sleep disturbances, attention deficits, or memory impairments. Participants were tested every 8 days.

[0063] The test compound ETA was administered intranasally: 1600 ng ETA (50 μL of an aqueous solution containing 16 μg / mL ETA, 2% propylene glycol, and 2% ethanol per nostril via a Valois nasal spray pump); while the control compound caffeine was administered orally: 400 mg tablets. An intranasal placebo (using the same pump and solution, but without ETA) and an oral placebo (lactose tablets) were also used concurrently.

[0064] Testing began at 5 p.m. each night. Upon arrival at the lab, subjects were fitted with electrodes for polysomnography (EEG, EEG, EMG) according to the guidelines outlined in *A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects*, edited by Rechtschaffen and Kales, NIH Publication No. 204, U.S. Government Printing Office, 1968. All subjects received an oral and intranasal dose of either placebo or the active ingredient—ETA or caffeine (as appropriate)—one hour before each test, and an intranasal dose 10 minutes before and 40 minutes after each test. In the control group, all doses were placebo; in the ETA group, all oral doses were placebo, with intranasal doses containing ETA 10 minutes before and 40 minutes after the start of the 9 p.m., midnight, and 3 a.m. tests, and the remainder being placebo; in the caffeine group, all intranasal doses were placebo, with an oral dose containing caffeine 1 hour before the start of the 9 p.m. test, and the remainder being placebo. The timing of administration was chosen to ensure maximum efficacy of ETA and caffeine.

[0065] No serious adverse events occurred; the most common mild adverse events were fatigue experienced by most subjects after completing the study test, and sneezing in one subject after nasal administration. All subjects tolerated the ETA nasal spray well.

[0066] During the testing period, subjects experienced polyphasic physiological signals of drowsiness or stage I or stage II sleep approximately halfway through the night. In all three uncontrolled tests, caffeine significantly reduced reaction time and the number of errors in isochronous and random stimulus reaction time tests (p<0.005 and p<0.001, respectively, compared to placebo), with this effect being more significant in random stimulus tests; while it improved time estimation tests, this effect was only statistically significant in midnight tests 4 hours after caffeine administration (p<0.001).

[0067] In all three uncontrolled tests, ETA significantly reduced reaction time and the number of errors in both isochronous and random stimulus reaction time tests (p<0.001 and p<0.0001, respectively, compared to placebo), with this effect being more significant in random stimulus tests; it also significantly improved time estimation tests at both midnight and 3 am (p<0.01). Compared to caffeine and placebo, ETA caused less variability in isochronous and random reaction time tests; and although the effect of ETA was similar to that of caffeine in the 9 pm test (when subjects were relatively unfatigued), its effect was significantly superior to that of caffeine in the midnight and 3 am tests (when subjects were fatigued) (p<0.001 and p<0.0001, respectively, for isochronous and random tests, compared to caffeine). Furthermore, ETA significantly improved time estimation tests at both midnight and 3 am (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 performance in patients with mental fatigue.

[0069] Example 5—Improvement of psychomotor and / or cognitive performance in mental fatigue associated with shift work sleep disorders by ETA According to Jang, “Work-Fitness Evaluation for Shift Work Disorder,” Int. J. Environ. Res. Public Health, 18(3), 1294 (2021), shift work sleep disorder (Shift Work Disorder, in DSM-5 Classified as a circadian rhythm sleep disorder (307.45), it is characterized by insomnia and excessive sleepiness associated with shift work, and is one of the most common health problems among shift workers. As described by Valentino et al., “Modafinil in the treatment of excessive daytime sleepiness,” Cleve. Clin. J. Med., 74(8), 561-571 (2007), modafinil was approved for the treatment of excessive daytime sleepiness associated with shift work sleep disorder. This approval is partly based on the finding that ETA directly improves psychomotor and cognitive performance in subjects with mental fatigue, and with similar efficacy to caffeine and modafinil, and that ETA will similarly improve psychomotor and cognitive performance in those with mental fatigue associated with shift work sleep disorder.

[0070] In subjects experiencing psychomotor and / or cognitive decline due to mental fatigue associated with shift work sleep disorders, an effective dose of ETA was administered intranasally as described in Example 4. Psychomotor and cognitive performance improved in this group of subjects.

[0071] Example 6—Improvement of psychomotor and / or cognitive performance by ETA in mental fatigue associated with excessive daytime sleepiness As Valentino et al. stated, modafinil is also approved for the treatment of excessive daytime sleepiness associated with narcolepsy and as adjunctive therapy for patients with obstructive sleep apnea syndrome who still experience daytime sleepiness despite optimal treatment with continuous positive airway pressure. This approval is partly based on the finding that ETA directly improves psychomotor and cognitive performance in subjects with mental fatigue, with efficacy similar to caffeine and modafinil; ETA will similarly improve psychomotor and cognitive performance in individuals with mental fatigue associated with excessive daytime sleepiness.

[0072] In subjects experiencing psychomotor and / or cognitive decline due to mental fatigue associated with excessive daytime sleepiness, a therapeutically effective dose of ETA was administered intranasally as described in Example 4. Psychomotor and cognitive performance improved in this group of subjects.

[0073] Example 7—Improvement of psychomotor and / or cognitive performance of ETA in mental fatigue associated with depression (such as major depressive disorder and perinatal depression). "Reaction time is one of the performance aspects described in Example 4 above, and both caffeine and ETA can improve reaction time. Iranpouret 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) indicate that caffeine alleviates depressive symptoms as measured by the PHQ-9 test, a nine-item patient health questionnaire developed by Pfizer to assess depressive symptoms. The test asks for each of the nine items: “How often in the past two weeks have you been bothered by any of the following problems?” Answers are scored from 0 (“never at all”) to 3 (“almost every day”); the total score is between 0 and 27. One of the questions in the test is about “whether you have difficulty concentrating on tasks such as reading a newspaper or watching television?” 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 improved reaction time and cognitive performance.

[0074] Medical literature generally suggests a negative correlation between caffeine and depression; in other words, caffeine reduces depression. An article by Bao et al., "Caffeine Is Negatively Associated with Depression in Patients Aged 20 and Older,"... Front. Psych. The study, 13:1037579 (2022), concluded that "these results suggest that people may consume some caffeine to reduce depression." Bao et al. also noted that "several epidemiological studies have found that caffeine use has a protective effect against cognitive impairment / decline…" and pointed out that "further research is needed to test the exact causal relationship between these factors," because "there is a complex association between caffeine intake and the risk of depression." However, the article explains that due to structural similarity, caffeine can competitively bind to adenosine A1 receptors (ADORA1) and adenosine A2A receptors (ADORA2A), thereby affecting neural networks in the brain. Lopez-Cruz et al., "Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression," Front. Pharmacol. Similar conclusions were reached in 9, 526 (2018). Although there is no specific explanation for its mechanism of action, it is believed that ETA indirectly activates the ADORA2A receptor through neural circuits connected to nasal olfactory chemosensory neurons in the nasal olfactory epithelium.

[0075] Based in part on the following findings: ETA directly improves psychomotor and cognitive performance in subjects with mental fatigue, with effects similar to caffeine and modafinil, and its hypothetical mechanism of action, ETA will similarly improve psychomotor and cognitive performance in individuals with mental fatigue associated with depression, such as MDD and perinatal depression.

[0076] In subjects experiencing psychomotor and / or cognitive decline due to mental fatigue associated with depression (such as MDD or perinatal depression), an effective amount of ETA was administered nasally to the olfactory epithelium as described in Example 4. Psychomotor and cognitive performance improved in this group of subjects.

[0077] Example 8—Effects of ETA supplementation on psychomotor and / or cognitive performance in subjects already taking antidepressants and suffering from depression-related mental fatigue. Liu et al., “Low dose of caffeine enhances the efficacy ofantidepressants in major depressive disorder and the underlying neuralsubstrates”, Mol. Nutr . Food Res. Studies 61, 8 (2017) have shown that caffeine supplementation can enhance the efficacy of commonly used antidepressants. In subjects taking escitalopram, Liu et al. reported that "prolonged supplementation with low doses of caffeine (60 mg) produces a rapid antidepressant effect by reducing depression scores. Furthermore, low doses of caffeine can improve cognitive performance in depressed patients. However, caffeine does not affect sleep." Assessment indicators of attention, concentration, and working memory include sustained attention tasks, i.e., target detection using tapping. Szopa et al., "Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice," Naunyn-Schmiedeber. Arch. Pharmacol. ,389, 211-221 (2016) reported a similar enhancing effect of caffeine on the antidepressant-like activity of six typical antidepressants (including imipramine, desipramine, fluoxetine, paroxetine, escitalopram, and reboxetine) in the rat forced swimming test, a behavioral test widely used to assess 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) also showed that modafinil improved overall depression scores, remission rates and fatigue when used as adjunctive therapy for acute depressive episodes in unipolar and bipolar depression.

[0078] This finding is partly based on the following findings: ETA directly improves psychomotor and cognitive performance in subjects with mental fatigue, with effects similar to caffeine and modafinil, and its hypothetical mechanism of action; when ETA is added to antidepressant treatment, ETA similarly improves psychomotor and cognitive performance in individuals with mental fatigue associated with depression (such as MDD and perinatal depression).

[0079] In subjects experiencing psychomotor and / or cognitive decline associated with MDD and who were already receiving escitalopram treatment, an effective dose of ETA was administered intranasally as supplemental or adjunctive therapy, as described in Example 4. The ETA was administered separately from antidepressant treatment and before, during, or shortly after situations requiring attention and concentration. The reduction in depression scores exceeded the efficacy of escitalopram alone. Psychomotor and cognitive performance improved in this group of subjects.

[0080] Example 9—Antidepressive therapy with supplemental administration of ETA and Itruvone Itruvone (INN, pregn-4-en-20-yn-3-one) is being developed for the treatment of MDD and is an investigational product not approved by the Food and Drug Administration. The preparation of this compound and its experimental use in the treatment of MDD are described, for example, in Monti U.S. Patent No. 10322138, “Treatment of Depressive Disorders.” Itruvone and ETA are believed to share a common mechanism of action: activation of olfactory chemosensory neurons in the nasal mucosa, followed by activation of specific hypothalamic circuits in the brain, without cerebral or systemic uptake. In subjects with major depressive disorder receiving Itruvone treatment, ETA was administered to the olfactory epithelium as described in Example 4. The reduction in depression scores exceeded the effect of Itruvone alone. Cognitive function and psychomotor performance improved in this group of subjects. Because Itruvone is also administered to the olfactory epithelium in the form of a spray or aerosol, ETA and Itruvone can be administered separately but at similar times, or co-formulated for simultaneous intranasal administration.

[0081] Example 10—Improvement of psychomotor and / or cognitive performance by ETA in subjects with mental fatigue associated with perinatal depression Perinatal depression (PPD, also known as postpartum depression; depression in...) DSM-5 In China, this condition is coded as "perinatal episodes," such as perinatal major depressive disorder (MDD), which is one of the most common perinatal complications, affecting approximately 8-26% of perinatal women annually; Wang et al., "Coffee and caffeine intake and depression inpostpartum women: A cross-sectional study from the National Health and Nutrition Examination Survey 2007-2018", Front. Psychol. A report in 14:1134522 (2023) stated that coffee intake is negatively correlated with perinatal depression. This is partly based on the following findings: ETA directly improves psychomotor and cognitive performance in subjects with mental fatigue, with effects similar to caffeine and modafinil, and its hypothetical mechanism of action, suggesting that ETA will similarly improve psychomotor and cognitive performance in individuals with mental fatigue associated with perinatal depression.

[0082] For subjects experiencing psychomotor and / or cognitive decline associated with perinatal depression, a therapeutically effective amount of ETA was administered to the olfactory epithelium as described in Example 4. ETA was administered separately from any other antidepressant treatment, either sequentially or sequentially with these other medications. Subjects were assessed, and depression scores decreased. Psychomotor and cognitive performance improved in this group of subjects.

[0083] Example 11—Improvement of psychomotor and / or cognitive performance by ETA in mental fatigue associated with attention deficit hyperactivity disorder Caffeine is known to be associated with improved cognition and attention in subjects 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), Given that caffeine has been used to treat this condition, modulating the ADORA2A receptor may be a novel and compelling new therapeutic strategy for controlling ADHD. Similarly, Heacock et al. reported in U.S. Patent No. 8845621, “Pharmaceutical Formulations of Modafinil,” that modafinil significantly improved attention and ADHD symptoms at specific doses. This was partly based on the finding that ETA directly improved psychomotor and / or cognitive performance in subjects with mental fatigue, with effects similar to caffeine and modafinil, and that ETA would similarly improve psychomotor and cognitive performance in individuals with ADHD-related mental fatigue.

[0084] In subjects experiencing ADHD-related psychomotor and / or cognitive decline, an effective dose of ETA was administered intranasally as described in Example 4. Psychomotor and cognitive performance improved in this group of subjects.

[0085] Example 12—Improvement of psychomotor and / or cognitive performance by ETA in mental fatigue associated with mild cognitive impairment Part of the findings are based on the following: ETA directly improves psychomotor and / or cognitive performance in subjects with mental fatigue, with effects similar to caffeine and modafinil. ETA will similarly improve psychomotor and cognitive performance in individuals with MCI-related mental fatigue.

[0086] In subjects experiencing psychomotor and / or cognitive decline associated with mild cognitive impairment, an effective dose of ETA was administered intranasally, as described in Example 4. Psychomotor and cognitive performance improved in this group of subjects.

Claims

1. 1,3,5(10),16-estratetraen-3-ylacetate is administered intranasally to improve psychomotor or cognitive performance in patients with mental fatigue.

2. The 1,3,5(10),16-estatetraen-3-ylacetate used in claim 1, wherein the mentally fatigued person is male.

3. The 1,3,5(10),16-estatetraen-3-ylacetate used in claim 1, wherein the mentally fatigued person is female.

4. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 1 to 3, wherein the nasal administration comprises administration to nasal olfactory chemoreceptors.

5. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 1 to 4, wherein the improved performance is psychomotor performance.

6. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 1 to 4, wherein the improved performance is cognitive performance.

7. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 1 to 4, wherein the improved performance is psychomotor and cognitive performance.

8. The 1,3,5(10),16-estratetraen-3-ylacetate used according to any one of claims 1 to 7, wherein, Improvements in psychomotor or cognitive performance were observed within about 1 hour, preferably about 15 minutes, and more preferably about 5 minutes, following administration of 1,3,5(10),16-estatetraen-3-ylacetate.

9. The 1,3,5(10),16-estatetraen-3-yl acetate used in any one of claims 1 to 8, wherein the 1,3,5(10),16-estatetraen-3-yl acetate is administered in the form of a pharmaceutical preparation.

10. The 1,3,5(10),16-estatetraen-3-ylacetate used in claim 9, wherein the pharmaceutical formulation is a nasal spray.

11. The 1,3,5(10),16-estatetraen-3-yl acetate used in claim 10, wherein the nasal spray comprises an aqueous solution of the 1,3,5(10),16-estatetraen-3-yl acetate.

12. The 1,3,5(10),16-estatetraen-3-yl acetate used in claim 11, wherein the nasal spray comprises about 16 μg / mL of 1,3,5(10),16-estatetraen-3-yl acetate, about 2% propylene glycol and about 2% ethanol.

13. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 10-12, wherein, Each administration of the nasal spray contains about 0.5-6 micrograms of 1,3,5(10),16-estatetraen-3-ylacetate, preferably about 1-4 micrograms per administration, and more preferably about 1.6-3.2 micrograms per administration.

14. The 1,3,5(10),16-estatetraen-3-yl acetate used in any one of claims 1-13, wherein the 1,3,5(10),16-estatetraen-3-yl acetate is administered when psychomotor or cognitive performance begins to decline.

15. The 1,3,5(10),16-estatetraen-3-yl acetate used in any one of claims 1-13, wherein the 1,3,5(10),16-estatetraen-3-yl acetate is administered according to a schedule throughout the day.

16. The 1,3,5(10),16-estatetraen-3-yl acetate ester used according to claim 15, wherein the 1,3,5(10),16-estatetraen-3-yl acetate ester is administered 2-8 times daily, preferably 3-5 times daily, and more preferably 4 times daily.

17. The 1,3,5(10),16-estatetraen-3-yl acetate used according to claim 15 or 16, wherein the 1,3,5(10),16-estatetraen-3-yl acetate is administered at a fixed schedule.

18. The 1,3,5(10),16-estatetraen-3-yl acetate used in any one of claims 1-17, wherein the 1,3,5(10),16-estatetraen-3-yl acetate is administered according to a schedule based on the diurnal rhythm of mental fatigue episodes in a population or in persons receiving the 1,3,5(10),16-estatetraen-3-yl acetate.

19. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with prolonged cognitive activity.

20. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with sleep deprivation or sleep disorder.

21. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with shift work sleep disorders.

22. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with excessive daytime sleepiness.

23. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with depression.

24. The 1,3,5(10),16-estatetraen-3-ylacetate used in claim 23 further comprises an effective amount of an antidepressant.

25. The 1,3,5(10),16-estratetraen-3-ylacetate used in claim 24, wherein the antidepressant is Itruvone.

26. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 23-25, wherein the depression is major depressive disorder.

27. The 1,3,5(10),16-estratetraen-3-ylacetate used in any one of claims 23-25, wherein the depression is perinatal depression.

28. The 1,3,5(10),16-estatetraen-3-ylacetate used in any one of claims 1-18, wherein the mental fatigue is associated with attention deficit hyperactivity disorder.

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

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