Therapeutic agent for autism spectrum disorder
Combining oxytocin receptor agonists with AVP1aR antagonists addresses the limitations of high-dose oxytocin treatment for ASD, enhancing therapeutic efficacy and minimizing side effects.
Patent Information
- Application Number
- JP2024212409
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-07-25
- Filing Date
- 2024-12-05
- Publication Date
- 2026-02-05
AI Technical Summary
Existing treatments for autism spectrum disorder (ASD) face challenges such as reduced therapeutic effects and side effects from high doses of oxytocin administration, and the ineffectiveness of vasopressin 1a receptor (AVP1aR) antagonists like balovaptan.
Combining oxytocin receptor agonists with AVP1aR antagonists, such as SR49059, to enhance therapeutic efficacy and reduce side effects, particularly when high doses of oxytocin are administered.
The combination therapy effectively improves social behavior and reduces motor dysfunction, providing a robust treatment for ASD with minimized adverse effects.
Smart Images
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Abstract
Description
[Technical Field]
[0001] The present invention relates to a medicament for the treatment of autism spectrum disorder (ASD). [Background technology]
[0002] ASD is a type of developmental disorder whose core symptoms include impaired social communication, restricted interests, and repetitive behaviors. According to a 2023 report from the US Centers for Disease Control and Prevention, ASD affects 2.8% of the general population and severely limits the daily and social lives of individuals with ASD for many years, beginning in early childhood. The pathogenesis and etiology of ASD remain unclear, and there are no proven effective treatments, resulting in significant unmet medical needs worldwide.
[0003] On the other hand, oxytocin (CAS RN: 50-56-6) is a posterior pituitary hormone consisting of nine amino acids. Animal experiments have shown that intranasal administration of oxytocin improves social behavior and social cognitive function. Therefore, active efforts are being made around the world to develop drugs for treating ASD using oxytocin. For example, the present inventors have conducted multiple randomized placebo-controlled trials and demonstrated the effectiveness of oxytocin for treating core symptoms of ASD, such as impaired social communication (Non-Patent Document 1).
[0004] In addition, vasopressin (CAS RN: 113-79-1), a posterior pituitary hormone, is a peptide hormone structurally similar to oxytocin, and it is known that vasopressin and oxytocin have cross-binding affinities to their respective receptors (Non-Patent Document 2). Therefore, vasopressin, which is closely related to oxytocin, has also been investigated as a candidate treatment for ASD, but its effectiveness has not been confirmed. For example, clinical trials of balovaptan, a vasopressin 1a receptor (AVP1aR) antagonist, were conducted in patients with ASD, but it has been reported that phase 3 trials failed to demonstrate superiority over placebo in either children or adults (Non-Patent Documents 3 and 4). [Prior art documents] [Non-patent literature]
[0005] [Non-Patent Document 1] Yamasue, Peptides, 2024, vol.171, Article:171133. [Non-patent document 2] Song and Albers, Frontiers in Neuroendocrinology, 2018, vol.51, p.14-24. [Non-patent document 3] Jacob et al., Lancet Psychiatry, 2022, vol.9(3), p.199-210. [Non-patent document 4] Hollander et al., JAMA Psychiatry, 2022, vol.79(8), p.760-769. [Non-Patent Document 5] Uvnaes-Moberg et al., BMC Pregnancy and Childbirth, 2019, vol.19, Article:285. [Non-patent document 6] Kazdoba et al., Current Topics in Behavioral Neurosciences, 2016, vol.28, p.1-52.
Non-licensed Document 7
Non-licensed literature 9
Non-licensed literature 10
Non-licensed Document 11
Non-licensed Document 12
Non-licensed Document 13
Non-licensed Document 14
Non-licensed Document 15
Non-licensed Document 16
[0006] When oxytocin is administered to patients with ASD, there are issues such as the therapeutic effect being reduced by high doses or repeated administration, and side effects being observed.
[0007] A primary object of the present invention is to provide more effective drugs for treating ASD. [Means for solving the problem]
[0008] The present inventors discovered that when high doses of oxytocin are administered alone, social behavior is not improved and may even worsen, but when administered in combination with an AVP1aR antagonist, the improvement effect can be confirmed when high doses of oxytocin are administered and side effects can be reduced, leading to the completion of the present invention.
[0009] That is, the present invention is as follows. [1] A treatment for autism spectrum disorder that contains an oxytocin receptor agonist as its active ingredient and is administered in combination with a vasopressin 1a receptor antagonist. [2] The therapeutic agent according to [1], wherein the oxytocin receptor agonist is oxytocin. [3] The therapeutic agent according to [2], wherein the dose of oxytocin administered to an adult human is 30 IU or more. [4] The therapeutic agent according to any one of [1] to [3] above, wherein the vasopressin 1a receptor antagonist is SR49059. [5] A therapeutic agent for autism spectrum disorder, comprising an oxytocin receptor agonist as an active ingredient, wherein the oxytocin receptor agonist does not have agonism for the vasopressin 1a receptor. [6] The therapeutic agent according to [5] above, which is administered in combination with a vasopressin 1a receptor antagonist. [7] A pharmaceutical composition containing an oxytocin receptor agonist and a vasopressin 1a receptor antagonist as active ingredients, and used to treat autism spectrum disorder. [8] The pharmaceutical composition according to [7], wherein the oxytocin receptor agonist is oxytocin. [9] The pharmaceutical composition according to [8], wherein the dose of oxytocin administered to an adult human is 30 IU or more.
[10] The pharmaceutical composition according to any one of [7] to [9] above, wherein the vasopressin 1a receptor antagonist is SR49059. [Effects of the Invention]
[0010] The present invention can provide a therapeutic agent that is highly effective in improving the pathological condition of ASD. [Brief explanation of the drawings]
[0011] [Figure 1] FIG. 1 shows the results of examining the effects of administration of oxytocin and an AVP1aR antagonist on social behavior in mice based on dominance index. [Figure 2] FIG. 1 shows the results of examining the physical effects on the lower body of mice caused by administration of oxytocin and an AVP1aR antagonist. DETAILED DESCRIPTION OF THE INVENTION
[0012] <Therapeutic Agent According to the First Embodiment> The therapeutic agent according to the first embodiment is a therapeutic agent for ASD, and is characterized by containing an oxytocin receptor (OXTR) agonist (agonist) such as oxytocin as an active ingredient, and being administered in combination with an AVP1aR antagonist. When oxytocin is administered alone, increasing the dose of oxytocin reduces the effect on social behavior and may also cause motor dysfunction as a side effect. Because the therapeutic agent according to the first embodiment is administered in combination with an AVP1aR antagonist, it is possible to avoid the attenuation of the effect that occurs when a relatively high concentration of oxytocin is administered, thereby making the effectiveness of oxytocin robust and further relieving motor dysfunction.
[0013] The OXTR agonist, which is the active ingredient of the therapeutic agent according to the first embodiment, is not particularly limited as long as it is a substance that has OXTR agonism (a substance that binds to OXTR and activates the intracellular signaling pathway downstream of OXTR), similar to oxytocin. The OXTR agonist may be a peptide or a substance other than a peptide, such as a low-molecular-weight compound (a compound with a molecular weight of less than 500). In addition, the OXTR agonist, which is the active ingredient of the therapeutic agent according to the first embodiment, may be a prodrug of an OXTR agonist (a compound that is metabolized in the body to a compound with OXTR agonism) or a pharmacologically acceptable salt thereof.
[0014] The OXTR agonist, which is the active ingredient of the therapeutic agent according to the first embodiment, can be oxytocin or a known OXTR agonist described in Non-Patent Document 15 or 16. OXTR agonists can also be obtained by screening various libraries of peptides, small molecules, nucleic acids, etc. for substances that have OXTR agonism. Whether a substance has OXTR agonism can be experimentally determined using various methods described in Non-Patent Document 15, etc.
[0015] Oxytocin, which is the active ingredient of the therapeutic agent according to the first embodiment, may be a peptide preparation synthesized by a conventional method, or a purified peptide produced using a microorganism, etc. Furthermore, the active ingredient of the therapeutic agent according to the first embodiment may be appropriately selected from oxytocin preparations that have already been used in clinical trials.
[0016] The AVP1aR antagonist administered in combination with the therapeutic agent according to the first embodiment is not particularly limited as long as it has an antagonistic effect on AVP1aR. It may also be a prodrug (a compound that is metabolized in vivo to a compound with AVP1aR antagonistic effect) or a pharmacologically acceptable salt thereof. Examples of pharmacologically acceptable salts include salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as magnesium and calcium; salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid; and salts with organic acids such as acetic acid, citric acid, lactic acid, gluconic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, adipic acid, methanesulfonic acid, and benzenesulfonic acid. Examples of AVP1aR antagonists include SR49059 (CAS RN: 150375-75-0) and RG7314 (CAS RN: 1228088-30-9).
[0017] The therapeutic agent according to the first embodiment is administered in combination with an AVP1aR antagonist, meaning that the therapeutic agent is administered in such a manner that the period during which the OXTR agonist (e.g., oxytocin, the active ingredient of the therapeutic agent according to the first embodiment) exerts its therapeutic effect in the body of the administered animal and the period during which the administered AVP1aR antagonist exerts its therapeutic effect overlap at least partially. The therapeutic agent according to the first embodiment may be administered simultaneously with the AVP1aR antagonist, or the administration times may be delayed by several hours. For example, either the therapeutic agent according to the first embodiment or the AVP1aR antagonist may be administered once or twice a day, and the other may be administered, for example, every other day, once a week, or at longer intervals.
[0018] <Therapeutic Agent According to the Second Embodiment> A therapeutic agent according to a second embodiment is a therapeutic agent for ASD, characterized in that it contains as an active ingredient an OXTR agonist that does not have agonism for AVP1aR. By using an OXTR agonist that does not have agonism for AVP1aR as an active ingredient, it is possible to avoid the attenuation of effect due to AVP1aR agonism, as in the case of co-administration with an AVP1aR antagonist, and to robustly improve social behavior and social cognition via OXTR.
[0019] The OXTR agonist serving as the active ingredient of the therapeutic agent according to the second embodiment is not particularly limited as long as it is a substance that does not have agonism for AVP1aR but binds to OXTR and activates the intracellular signaling pathway downstream of OXTR in the same manner as oxytocin. The active ingredient of the therapeutic agent according to the second embodiment may be an OXTR agonist that does not bind to AVP1aR, or an OXTR agonist that has an antagonistic effect on AVP1aR. The OXTR agonist may be a peptide or a substance other than a peptide, such as a low-molecular-weight compound. Furthermore, the OXTR agonist serving as the active ingredient of the therapeutic agent according to the second embodiment may be a prodrug of an OXTR agonist that does not have agonism for AVP1aR (a compound that is metabolized in vivo to a compound that has OXTR agonism but does not have AVP1aR agonism), a pharmacologically acceptable salt thereof, or the like.
[0020] The OXTR agonist, which is the active ingredient of the therapeutic agent according to the second embodiment, can be a compound that does not have agonism for AVP1aR, selected from the known OXTR agonists described in Non-Patent Document 15 or 16. The OXTR agonist can also be obtained by screening various libraries of peptides, small molecules, nucleic acids, etc. for substances that have agonism for OXTR but not for AVP1aR. Whether a substance has agonism for OXTR and AVP1aR can be experimentally determined using various methods described in Non-Patent Document 15, etc.
[0021] The therapeutic agent according to the first embodiment and the therapeutic agent according to the second embodiment may be used as is, or may be used as a pharmaceutical composition containing other components. Examples of other components contained in the pharmaceutical composition include additives such as excipients, binders, lubricants, disintegrants, fluidizing agents, solvents, solubilizers, buffers, suspending agents, emulsifiers, isotonicity agents, stabilizers, preservatives, antioxidants, flavoring agents, and coloring agents. These additives can be appropriately selected from pharmaceutically acceptable substances used in pharmaceutical formulations.
[0022] Examples of excipients include sugars such as lactose, glucose, and D-mannitol; celluloses such as starch and crystalline cellulose; sugar alcohols such as erythritol, sorbitol, and xylitol; dicalcium phosphate, calcium carbonate, and kaolin. Examples of binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol. Examples of lubricants include stearic acid, calcium stearate, talc, sucrose fatty acid esters, and polyethylene glycol. Examples of disintegrants include crospovidone (cross-linked polyvinylpyrrolidone), low-substituted hydroxypropyl cellulose, starch, alginic acid, and sodium alginate. Examples of fluidizers include silicic acid, silicic anhydride, aluminum silicate, calcium silicate, magnesium aluminometasilicate compounds, aluminum oxide, aluminum hydroxide, magnesium oxide, and magnesium hydroxide. Examples of solvents include purified water and physiological saline. Examples of solubilizers include dextran, polyvinylpyrrolidone, sodium benzoate, ethylenediamine, salicylic acid amide, nicotinic acid amide, and polyoxyethylene hydrogenated castor oil derivatives. Examples of buffers include sodium citrate hydrate, sodium acetate hydrate, sodium bicarbonate, trometamol, boric acid, borax, sodium hydrogen phosphate hydrate, and sodium dihydrogen phosphate. Examples of suspending or emulsifying agents include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glycerin monostearate, polyvinyl alcohol, polyvinylpyrrolidone, celluloses such as sodium carboxymethylcellulose, polysorbates, and polyoxyethylene hydrogenated castor oil. Examples of isotonic agents include sugars such as lactose, glucose, and D-mannitol, sodium chloride, potassium chloride, glycerin, propylene glycol, polyethylene glycol, and urea.Examples of stabilizers include polyethylene glycol, dextran sodium sulfate, and sodium sulfite. Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, chlorocresol, dehydroacetic acid, and sorbic acid. Examples of antioxidants include sulfites and ascorbic acid. Examples of flavoring agents include sweeteners and fragrances commonly used in the pharmaceutical and food fields. Examples of coloring agents include coloring agents commonly used in the pharmaceutical and food fields.
[0023] Pharmaceutical compositions containing the therapeutic agent according to the first embodiment can be formulated by conventional methods using oxytocin as the active ingredient and the various additives described above as needed for the formulation, into solid preparations such as powders, granules, capsules, tablets, chewable tablets, and sustained-release preparations, liquid preparations such as solutions and syrups, injections, sprays, patches, ointments, etc. The therapeutic agent according to the first embodiment is preferably an orally administrable solid preparation or injection.
[0024] The pharmaceutical composition containing the therapeutic agent according to the first embodiment and the pharmaceutical composition containing the therapeutic agent according to the second embodiment may contain an active ingredient other than oxytocin. For example, the pharmaceutical composition containing the therapeutic agent according to the first embodiment may contain oxytocin and an AVP1aR antagonist. Furthermore, it may contain, together with the active ingredient OXTR agonist, a medicinal ingredient administered for another therapy performed in combination with ASD treatment. The pharmaceutical composition containing the therapeutic agent according to the second embodiment may contain an OXTR agonist and an AVP1aR antagonist. Furthermore, it may contain, together with the OXTR agonist, a medicinal ingredient administered for another therapy performed in combination with ASD treatment.
[0025] The therapeutic agent according to the first embodiment, the therapeutic agent according to the second embodiment, and pharmaceutical compositions containing them can be administered to humans or non-human animals to improve various pathological conditions caused by ASD in the animals, particularly impairments in social communication, restricted interests, and repetitive behavioral patterns. The animal in question is not particularly limited and may be a human or a non-human animal. Non-human animals include mammals such as cows, pigs, horses, sheep, goats, monkeys, dogs, cats, rabbits, mice, rats, hamsters, and guinea pigs, as well as birds such as chickens, quails, and ducks.
[0026] The dosage of the therapeutic agent according to the first embodiment, the therapeutic agent according to the second embodiment, and the pharmaceutical composition containing them is determined appropriately taking into consideration the age, sex, and weight of the ASD patient to be administered, the severity of the pathology caused by ASD, the presence or absence of other diseases other than ASD, the administration route, dosage form, etc. For example, the therapeutic agent according to the first embodiment, the therapeutic agent according to the second embodiment, and the pharmaceutical composition containing them can be administered once or in divided doses to a human adult at a dose of 6 IU (international units) or more per day in terms of oxytocin.
[0027] In order to enhance the combined effect with an AVP1aR antagonist, the dosage of the therapeutic agent according to the first embodiment and a pharmaceutical composition containing the same is preferably a high dosage of an OXTR agonist such as oxytocin, and is preferably 30 IU or more in oxytocin equivalent (Non-Patent Document 5) or more per day for a human adult, more preferably 48 IU or more, even more preferably 72 IU or more, and even more preferably 96 IU or more. The dosage of the therapeutic agent according to the first embodiment and a pharmaceutical composition containing the same is preferably 240 IU or less in oxytocin equivalent, more preferably 192 IU or less, and even more preferably 120 IU or less.
[0028] In order to achieve a higher therapeutic effect, the dosage of the therapeutic agent according to the second embodiment and the pharmaceutical composition containing the same is preferably a high dosage of the OXTR agonist, and is preferably 30 IU or more in oxytocin equivalent (Non-Patent Document 5) or more per day for a human adult, more preferably 48 IU or more, even more preferably 72 IU or more, and even more preferably 96 IU or more. The dosage of the therapeutic agent according to the second embodiment and the pharmaceutical composition containing the same is preferably 240 IU or less in oxytocin equivalent, more preferably 192 IU or less, and even more preferably 120 IU or less. [Example]
[0029] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to the following examples.
[0030] [Example 1] Using the IntelliCage, a fully automated group behavioral measurement system that is excellent for objectively observing natural social interactions in animals, we compared the effects of oxytocin alone and its combination with an AVP1aR antagonist (SR49059) on social behavior.
[0031] <Reagents> Oxytocin (4084-v, Peptide Institute) and SR49059 (Sigma-Aldrich) were used. Oxytocin was dissolved in saline to a concentration of 200 μg / mL and then diluted with saline to the respective concentrations tested. SR49059 was dissolved in 10% DMSO and saline to a concentration of 500 μg / mL and then diluted with saline to the respective concentrations tested.
[0032] <Animal> Thirty-six male wild-type C57BL / 6 mice (Jackson Laboratory Japan) were used.
[0033] <Drug administration> Drug administration was performed 60 minutes before the start of the drinking period. When oxytocin was administered concomitantly with SR49059, SR49059 was administered 15 minutes before oxytocin administration. Saline was administered twice to the control group. All mice were removed from the IntelliCage device immediately before administration. Once all mice were administered, they were promptly returned to the IntelliCage. Administration was intraperitoneal, with the concentration adjusted to 250 μL per mouse. Nine mice were used per group in all experiments. To ensure uniform dominance levels during saline administration, the group composition varied between experiments. Prior to the study of oxytocin administration alone or in combination with SR49059, a treatment-free period of at least five days was allowed. Furthermore, all mice received saline 2–4 days before drug administration to allow for acclimation to the administration procedure. Each administration experiment was conducted at least two weeks apart.
[0034] <Social behavior assessment> Dominance was evaluated as an index of social behavior. Dominance is a type of social behavior observed within groups of social animal species, including rodents, and is widely used to examine whether ASD model mice exhibit deviant social behavior (Non-Patent Document 6). The present inventors have already established a method for evaluating dominance based on the results of a competitive task using a group-rearing, fully automated mouse behavioral testing device (IntelliCage, Non-Patent Document 7) (Non-Patent Documents 8 and 9), and this was carried out according to the protocol reported in previous studies.
[0035] It has been reported that FMR1 KO mice (Non-Patent Document 10), Mecp2 KO mice (Non-Patent Document 11), Shank 3 KO mice (Non-Patent Document 12), Gabrb3 KO mice (Non-Patent Document 11), and Dvl1 KO mice (Non-Patent Documents 13 and 14), which are widely known as ASD model mice, all have reduced dominance indices compared to wild-type mice.
[0036] This experiment used two IntelliCages, each with 18 mice. Briefly, the IntelliCage is a home-cage behavioral monitoring device with operant chambers installed in the four corners of the cage. Mice could only drink water in these chambers, but only one mouse could enter each chamber at a time. Each mouse's entry into and exit from the chamber was individually identified using RFID (Radio Frequency Identification) technology, and the time, date, and date of each mouse's visit to each chamber were automatically recorded. A door was installed inside the chamber to restrict access to the nozzle of the water bottle, and the experimenter could freely design the door opening and closing rules.
[0037] In the IntelliCage competition task, mice were given a 20-hour water restriction period, with access to water only between 1 and 4 hours after the onset of the dark period. A red light and a buzzer (Tokyo Devices) signaled the start of the water period. During the water period, mice could drink from the nozzle of a water bottle in the chamber. However, after 200 ms, the door closed, forcing the mice to exit the chamber and re-enter one of the other chambers before they could drink again. (Mice cannot remain in the same chamber continuously, so they must repeatedly drink, exit, and re-enter another chamber.) Therefore, immediately after the start of the water period, all mice in the cage competed for one of the four water holes. Competition was particularly intense during the first 5 minutes, and dominance was assessed based on the time spent occupying the water hole (reward location) during this period. Specifically, the standardized value of the time spent occupying the water trough during these five minutes was used as the dominance index, and individuals with a high value were defined as dominant, and individuals with a low value were defined as subordinate.
[0038] The oxytocin doses tested were 200 ng / mouse and 5000 ng / mouse. Four doses of SR49059 were tested: 0, 1, 2.5, and 5 mg / kg. The experimental design for the six conditions is as follows:
[0039] Condition 1: After restricting water intake for 5 days or more, saline was administered intraperitoneally. Four days later, the experimental day was designated as the day of the experiment. On the experimental day, 200 ng of oxytocin or saline was administered intraperitoneally 60 minutes before the start of the water intake period (n=9). Condition 2: After five or more days of water restriction, saline was administered intraperitoneally. Two days later, the experimental day was designated the day of the experiment. On the experimental day, 1 mg / kg SR49059 or saline was administered intraperitoneally 75 minutes before the start of the water-allowed drinking period, followed by 200 ng oxytocin or saline intraperitoneally 60 minutes before the start of the water-allowed drinking period (n=9). Condition 3: After five or more days of water restriction, saline was administered intraperitoneally. Four days later, the experimental day was designated as the day of the experiment. On the experimental day, 5000 ng of oxytocin or saline was administered intraperitoneally 60 minutes before the start of the water-restricted period (n=9). Condition 4: After five or more days of water restriction, saline was administered intraperitoneally. Two days later, the experimental day was designated the day of the experiment. On the experimental day, 1.0 mg / kg SR49059 or saline was administered intraperitoneally 75 minutes before the start of the water-allowed drinking period, followed by 5000 ng oxytocin or saline intraperitoneally 60 minutes before the start of the water-allowed drinking period (n=9). Condition 5: After five or more days of water deprivation, saline was administered intraperitoneally. Two days later, the experimental day was designated the day of the experiment. On the experimental day, 2.5 mg / kg SR49059 or saline was administered intraperitoneally 75 minutes before the start of the water-allowed period, followed by 5000 mg oxytocin or saline intraperitoneally 60 minutes before the start of the water-allowed period (n=9). Condition 6: After five or more days of water restriction, saline was administered intraperitoneally. Two days later, the experimental day was designated the day of the experiment. On the experimental day, 5.0 mg / kg SR49059 or saline was administered intraperitoneally 75 minutes before the start of the water-allowed drinking period, followed by 5000 mg oxytocin or saline intraperitoneally 60 minutes before the start of the water-allowed drinking period (n=9).
[0040] In human clinical trials, a dose of 30 IU (50.1 μg) of oxytocin is considered to be the boundary between low and high doses of oxytocin (Non-Patent Document 5). Assuming a human adult male weighing 65 kg, 30 IU of oxytocin corresponds to a dose of approximately 770 ng per kg of body weight (Non-Patent Document 5). When converted to human equivalent doses (HEDs), 200 ng / mouse and 5000 ng / mouse correspond to 530 ng / kg HEDs and 13,214 ng / kg HEDs, respectively, since the average mouse weight is approximately 0.03 kg. In other words, 200 ng / mouse corresponds to a low dose of oxytocin in humans, and 5000 ng / mouse corresponds to a high dose of oxytocin in humans.
[0041] The results of the dominance index obtained under each experimental condition are shown in Figure 1. In the figure, the "Experimental group" refers to the group administered oxytocin alone or in combination with an AVP1aR antagonist, and the "Control group" refers to the group administered saline. As shown in the results of Condition 1, low-dose oxytocin administration (200 ng / mouse) tended to increase dominance (effect size 0.32) (Experiment 1). On the other hand, as shown in the results of Condition 3, high-dose oxytocin administration (5000 ng / mouse) did not exhibit the same tendency to increase dominance as low-dose oxytocin administration and even showed a decrease in dominance compared to saline-administered mice (effect size 0.74). However, when an AVP1aR antagonist was administered at 2.5 or 5.0 mg / kg, the decrease in dominance induced by high-dose oxytocin was dose-dependently abolished. Specifically, when an AVP1aR antagonist (1 mg / kg) was co-administered, a decrease in dominance due to high-dose oxytocin administration (effect size 0.97) was observed (condition 4), but when higher concentrations of an AVP1aR antagonist (2.5 mg / kg and 5.0 mg / kg) were co-administered, the decrease in dominance due to high-dose oxytocin disappeared (effect sizes 0.19 and 0.00) (conditions 5 and 6).
[0042] <Physical impact assessment> To examine whether drug administration had any physical effects, mice were placed in transparent cages after drug administration, and images were recorded using a camera and analyzed. As indicators, the time (time elapsed since administration) and number of times the hind legs were stretched backward were counted.
[0043] The oxytocin doses tested were 400, 2000, 3000, 4000, 5000, 10000, and 50000 ng / mouse, and the SR49059 doses tested were 0, 0.5, 1.0, and 5.0 mg / kg.
[0044] Figure 2 shows the results of the evaluation of the groups administered oxytocin alone or in combination with SR49059. In the high-dose oxytocin group, limited hind leg motor dysfunction was observed between 10 and 15 minutes after administration, characterized by a tendency to lower the hips and extend the hind legs backward. This hind leg motor dysfunction was robustly observed at doses of 5000 ng / mouse and was eliminated by concomitant administration of an AVP1aR antagonist at 0.5 mg / kg or higher. These results confirmed that the motor dysfunction induced by high-dose oxytocin administration could be resolved by concomitant administration of an AVP1aR antagonist.
Claims
1. A therapeutic agent for autism spectrum disorder, containing an oxytocin receptor agonist as an active ingredient and administered in combination with a vasopressin 1a receptor antagonist.
2. The method of claim 1, wherein the oxytocin receptor agonist is oxytocin.
3. 3. The method of claim 2, wherein the dose of oxytocin administered to an adult human is 30 IU or more.
4. The therapeutic agent according to any one of claims 1 to 3, wherein the vasopressin 1a receptor antagonist is SR49059.
5. A therapeutic agent for autism spectrum disorder, comprising an oxytocin receptor agonist as an active ingredient, the oxytocin receptor agonist having no agonism for vasopressin 1a receptors.
6. The therapeutic agent according to claim 5 , which is administered in combination with a vasopressin 1a receptor antagonist.
7. A pharmaceutical composition for treating autism spectrum disorder, comprising an oxytocin receptor agonist and a vasopressin 1a receptor antagonist as active ingredients.
8. The pharmaceutical composition of claim 7, wherein the oxytocin receptor agonist is oxytocin.
9. 9. The pharmaceutical composition according to claim 8, wherein the dosage of oxytocin for an adult human is 30 IU or more.
10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the vasopressin 1a receptor antagonist is SR49059.