Methods of treating acute stress disorder and posttraumatic stress disorder

Abstract

This invention relates to a method for treating post-traumatic stress disorder (PTSD) and acute stress disorder using a pharmaceutical composition comprising cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. Specifically, this invention relates to a method for treating PTSD or one or more symptoms thereof in individuals who have experienced a traumatic event less than or equal to about 9 years prior to the commencement of treatment. This invention also relates to a method for treating acute stress disorder or one or more symptoms thereof in individuals who have experienced a traumatic event less than or equal to about 1 month prior to the commencement of treatment.

Description

[Technical Field] This application relates to methods for treating acute stress syndrome, post-traumatic stress disorder, and related symptoms. Particular interest is focused on methods for administering pharmaceutical compositions containing cyclobenzaprine, amitriptyline, or pharmaceutically acceptable salts thereof to individuals who have experienced a traumatic event leading to PTSD or ASD less than or equal to approximately 9 years prior to the initiation of treatment. [Previous Technology] Post-traumatic stress disorder (PTSD) develops from exposure to a traumatic event and results in symptoms including sleep difficulties, nightmares, irritability, poor concentration, hypervigilance, and a persistent, exaggerated startle response. Individuals with PTSD have a higher risk of developing further mental illness and a greater risk of suicidal behavior. Acute stress syndrome (ASD) is a condition in itself, but it is often a precursor to PTSD. In the field of pharmacological treatment, treating ASD or PTSD has been consistently challenging. Studies evaluating the efficacy of tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SSRIs) in search of pharmacological therapies have been conducted; however, these drugs are generally ineffective. For example, in ASD or very early-stage PTSD, studies investigating the efficacy of the SSRI escitalopram (commonly used to treat depression) have shown that this treatment is no better than placebo in preventing the development of PTSD (Shalev et al., 2012). Another study evaluated the efficacy of the SSRI paroxetine as a treatment for PTSD (Tucker et al., 2001). Paroxetine has been reported to provide long-term PTSD relief (an average of 15 years since the individual's trauma). However, the efficacy of this treatment appears to be related to the amount of time elapsed since the patient experienced the trauma. Specifically, patients who experienced trauma more than 5 years prior to treatment showed greater improvement than those whose trauma was more recent. Therefore, there is a need to develop an effective drug treatment that can be provided to patients who have recently experienced trauma. Cyclobenzyl or 3-(5H-dibenzo[a,d]cyclohepten-5-yl)-N,N-dimethyl-1-propane was first approved by the U.S. Food and Drug Administration in 1977 for the treatment of acute muscle spasms of local origin (Katz and Dube, 1988). Subsequent studies have shown that it is an effective serotonergic-2A (5-HT2A) and α-adrenergic-1A (α1A) receptor antagonist, which can improve restorative sleep in neuropsychiatric disorders and fibromyalgia by antagonizing 5-HT2A and α1A receptors during sleep (Moldofsky et al., 2011; Moldofsky et al., 2015). Low-dose cyclobenzylamine is also believed to be effective in treating sleep disorders caused by, or exacerbated by, or associated with, myofibrodysplasia, chronic fatigue, chronic fatigue syndrome, sleep disorders, psychogenic pain syndrome, chronic pain syndrome (type II), medication use, autoimmune diseases, stress or anxiety, or other conditions caused or exacerbated by sleep disorders, and symptoms of such conditions and generalized anxiety disorder. See U.S. Patents 6,395,788, 6,358,944, and 9,918,948, which are incorporated herein by reference. Amitriptyline, or 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-N,N-dimethyl-1-propane, was first approved by the U.S. Food and Drug Administration for the treatment of depression. Amitriptyline is also approved for the prevention of migraines. [Summary of the Invention] The first aspect of this invention relates to a method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to about 9 years prior to the commencement of treatment. In some embodiments, the method includes administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof. The second aspect of the present invention relates to a method for treating acute stress syndrome (ASD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to one month prior to the commencement of treatment, the method comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention relates to a method for treating or preventing PTSD or ASD and related symptoms in an individual in need, the method comprising: a) administering to the individual daily a pharmaceutical composition comprising cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof; b) periodically assessing the efficacy of the treatment during treatment; c) suspending treatment when the efficacy diminishes; d) resuming treatment after a 4-week suspension; wherein steps (a) through (d) may be repeated one or more times. Another aspect of the present invention relates to a method for treating or preventing PTSD and related symptoms in an individual with such need, the method comprising: a) administering to the individual daily a pharmaceutical composition comprising cyclobenzylamine, amitriptyline or a pharmaceutically acceptable salt thereof; b) discontinuing treatment after approximately 4 weeks; c) resuming treatment after approximately 4 weeks of discontinuation; wherein steps (a) to (c) may be repeated one or more times. Another aspect of the present invention is a method for determining a therapeutic dose of cyclobenzylamine or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from an individual suffering from PTSD or ASD; b) identifying the individual's CYP1A2, CYP2D6, and CYP3A4 genotypes to determine whether the patient has a high cyclobenzylamine metabolizer genotype; c) assessing the individual's medical history for smoking history or use of drugs that are inducers of CYP1A2, CYP2D6, or CYP3A4; wherein if the individual has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzylamine administered to the individual is greater than about 5 mg / day; wherein if the individual does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzylamine administered to the individual is about 5.6 mg / day or less. Another aspect of the present invention is a method for determining a therapeutic dose of amitriptyline or a pharmaceutically acceptable salt thereof for treating PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from an individual suffering from PTSD or ASD; b) identifying the individual's CYP1A2, CYP2D6, and CYP3A4 genotypes to determine whether the patient has a high amitriptyline metabolizer genotype; c) assessing the individual's medical history for smoking history or use of drugs that are inducers of CYP1A2, CYP2D6, or CYP3A4; wherein if the individual has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the individual is greater than about 11 mg / day; wherein if the individual does not have at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the individual is about 11.2 mg / day or less. Some embodiments of the present invention are: 1. The use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to about 9 years prior to initiating the treatment. 2. The use of a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating acute stress disorder (ASD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to 1 month prior to initiating the treatment. 3. The use as in Example 1 or 2, wherein the traumatic event is a standard A traumatic event. 4. The use as in any of Examples 1 to 3, wherein the medicament is administered once daily. 5. The use as in any of Examples 1 to 4, wherein the treatment lasts no more than 4 weeks. 6. As in Example 2 or any of Examples 3 to 5, wherein the treatment of ASD can reduce the development of PTSD and related symptoms in an individual. 7. As in any of Examples 1 to 6, wherein cyclobenprilin or amitriptyline is a free base. 8. As in any of Examples 1 to 6, wherein cyclobenprilin or amitriptyline is a pharmaceutically acceptable salt. 9. As in any of Examples 1 to 8, wherein the drug is prepared for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, non-intestinal, rectal, or vaginal administration. 10. As in Example 9, wherein the drug is prepared for sublingual administration. 11. As in any of Examples 1 to 10, wherein the drug contains an alkalizing agent. 12. As used in Example 11, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 13. As used in any of Examples 1 to 12, wherein the efficacy of the treatment increases as the time between the start of treatment and the traumatic event decreases. 14. As used in any of Examples 1 to 13, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 50 mg / day. 15. As used in Example 14, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.5 mg / day and about 30 mg / day. 16. As used in Example 15, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 1 mg / day and about 20 mg / day.17. As used in any of Examples 1 to 13, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 150 mg / day. 18. As used in Example 17, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 1.0 mg / day and about 90 mg / day. 19. As used in Example 18, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 3 mg / day and about 60 mg / day. 20. As used in Example 1 or 2, wherein the drug is administered sequentially or simultaneously with a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. 21. As used in Example 20, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 22. As used in Example 20, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or excipientan. 23. As used in Example 1 or 2, wherein the drug is administered in combination with a psychotherapeutic intervention during treatment. 24. As used in Example 1 or any of Examples 3 to 5 or 7 to 23, wherein at least one of the PTSD symptoms is eliminated or improved. 25. As used in Example 24, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 26. The use as described in Example 2 or any of Examples 3 to 23 of Example 2, wherein at least one of the ASD symptoms is eliminated or improved. 27. The use as described in Example 26, wherein the ASD symptoms are selected from the group consisting of: recurring symptoms, avoidance symptoms, awakening symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistent and exaggerated startle responses, feelings such as not knowing where you are, and feelings as if you are outside your body. 28. The use as described in Example 1, wherein the medication is administered during the rapid recovery phase, remission phase, or persistent phase of PTSD.29. The use of a pharmaceutical composition comprising cyclobenzyl, amitriptyline, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing PTSD, ASD, or one or more related symptoms in an individual in need, wherein the treatment comprises: a) administering the medicament to the individual daily; b) periodically assessing the efficacy of the treatment during the course of treatment; c) discontinuing the administration of the medicament when the efficacy diminishes; d) resuming the administration of the medicament after a 4-week suspension of treatment; wherein steps (a) to (d) may be repeated one or more times. 30. The use of a pharmaceutical composition comprising cyclobenzyl, amitriptyline, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing PTSD, ASD, or one or more related symptoms in an individual in need, wherein the treatment comprises: a) administering the medicament to the individual daily; b) discontinuing the administration after approximately 4 weeks; c) resuming the administration after a 4-week suspension of administration; wherein steps (a) to (c) may be repeated one or more times. 31. As in Example 29 or 30, wherein the treatment or prevention is for PTSD and the individual has experienced a traumatic event less than or equal to about 9 years prior to initiation of treatment. 32. As in Example 31, wherein the efficacy of the treatment is measured at least every about 2 weeks after the initiation of treatment. 33. As in Example 32, wherein the efficacy of the treatment is assessed based on an individual clinician-managed DSM-5 PTSD scale (CAPS-5) score. 34. As in any of Examples 29 to 33, wherein the cyclobenzyl or amitriptyline in the pharmaceutical composition is a free base of cyclobenzyl or amitriptyline. 35. As in any of Examples 29 to 33, wherein the cyclobenzyl or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable salt of cyclobenzyl or amitriptyline. 36. The use as described in any of Examples 29 to 35, wherein the drug is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, percutaneously, non-intestinally, rectally, or vaginally. 37. The use as described in Example 36, wherein the drug is administered sublingually. 38. The use as described in any of Examples 29 to 37, wherein the pharmaceutical composition comprises an alkalizing agent. 39. The use as described in Example 38, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 40. As used in any of Examples 29 to 39, wherein the efficacy of the treatment increases as the time between the start of the treatment and the traumatic event decreases.41. As used in any of Examples 29 to 40, wherein the amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof in the drug is between about 0.1 mg / day and about 50 mg / day. 42. As used in Example 41, wherein the amount of cyclobenzylamine, or a pharmaceutically acceptable salt thereof in the drug is between about 0.5 mg / day and about 30 mg / day. 43. As used in Example 42, wherein the amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof in the drug is between about 1 mg / day and about 20 mg / day. 44. As used in Examples 29 to 40, wherein the amount of amitriptyline, or a pharmaceutically acceptable salt thereof in the drug is between about 0.1 mg / day and about 150 mg / day. 45. As used in Example 44, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the drug is between about 1.0 mg / day and about 90 mg / day. 46. As used in Example 45, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the drug is between about 3 mg / day and about 60 mg / day. 47. As used in Examples 29 or 30, wherein the drug is administered sequentially or simultaneously with a combination of compounds selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. 48. As used in Example 47, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 49. As used in Example 47, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or excipientam. 50. As used in Example 29 or 30, wherein the drug is administered in combination with a psychotherapeutic intervention during treatment. 51. As used in any of Examples 29 to 50, wherein the treatment or prevention is for PTSD, and at least one of the symptoms of PTSD is eliminated or improved. 52. As used in Example 51, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 53. As used in Example 29 or 30, wherein the individual has experienced a standard A trauma. 54. As used in Example 53, wherein the standard A trauma resulted in ASD or its symptoms. 55. As used in Example 54, wherein at least one of the ASD symptoms is eliminated or improved. 56. As used in Example 55, wherein the ASD symptoms are selected from the group consisting of: recurring symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistently exaggerated startle responses, feelings such as not knowing where you are and feelings as if you are outside your body.57. A method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to about 9 years prior to the commencement of treatment, the method comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof. 58. A method for treating acute stress disorder (ASD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to 1 month prior to the commencement of treatment, the method comprising administering to the individual a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof. 59. The method of Example 57 or 58, wherein the traumatic event is a standard A traumatic event. 60. The method of any one of Examples 57 to 59, wherein the pharmaceutical composition is administered once daily. 61. The method of any one of Examples 57 to 60, wherein the treatment lasts for no more than 4 weeks. 62. The method of any of Examples 58 or 59 to 61, which is subordinate to Examples 58, wherein treating ASD reduces the development of PTSD and related symptoms in an individual. 63. The method of any of Examples 57 to 62, wherein cyclobenprilin or amitriptyline is administered as a free base. 64. The method of any of Examples 57 to 62, wherein cyclobenprilin or amitriptyline is administered as a pharmaceutically acceptable salt. 65. The method of any of Examples 57 to 64, wherein the pharmaceutical composition is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, percutaneously, non-intestinally, rectally, or vaginally. 66. The method of Example 65, wherein the pharmaceutical composition is administered sublingually. 67. The method of any of Examples 57 to 66, wherein the pharmaceutical composition contains an alkalizing agent. 68. The method of Example 67, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 69. The method of any one of Examples 57 to 68, wherein the efficacy of the treatment increases as the time between the initiation of the treatment and the traumatic event decreases. 70. The method of any one of Examples 57 to 69, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 50 mg / day. 71. The method of Example 70, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.5 mg / day and about 30 mg / day. 72. The method of Example 71, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 1 mg / day and about 20 mg / day.73. The method of any one of Examples 57 to 69, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 150 mg / day. 74. The method of Example 73, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 1.0 mg / day and about 90 mg / day. 75. The method of Example 74, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 3 mg / day and about 60 mg / day. 76. The method of Example 57 or 58, wherein the method further comprises sequentially administering cyclobenzylamine, amitriptyline or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, or concurrently thereof. 77. The method of Example 76, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 78. The method of Example 76, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or excipipram. 79. The method of Example 57 or 58, also including psychotherapeutic intervention during the treatment process. 80. The method of Example 57 or any of 59 to 61 or 63 to 79 of Example 57, wherein at least one of the PTSD symptoms is eliminated or improved. 81. The method of Example 80, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 82. The method of Example 58 or any of Examples 59 to 79 of Example 58, wherein at least one of the ASD symptoms is eliminated or improved. 83. The method of Example 82, wherein the ASD symptoms are selected from the group consisting of: recurring symptoms, avoidance symptoms, awakening symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistent and exaggerated startle responses, feelings such as not knowing where you are, and feelings as if you are outside your body. 84. The method of Example 57, wherein the treatment is administered during the rapid recovery phase, remission phase, or persistent phase of PTSD. 85. A method for treating or preventing PTSD, ASD, or one or more related symptoms in an individual in need, the method comprising: a) administering to the individual daily a pharmaceutical composition comprising cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof; b) periodically assessing the efficacy of the treatment during treatment; c) suspending treatment when the efficacy diminishes; d) resuming treatment after a 4-week suspension; wherein steps (a) through (d) may be repeated one or more times.86. A method for treating or preventing PTSD, ASD, or one or more related symptoms in an individual in need, the method comprising: a) administering to the individual daily a pharmaceutical composition comprising cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof; b) discontinuing treatment after approximately 4 weeks; c) resuming treatment after approximately 4 weeks of discontinuation; wherein steps (a) through (c) may be repeated one or more times. 87. The method of Example 85 or 86, wherein the treatment or prevention is for PTSD and the individual has experienced a traumatic event less than or equal to approximately 9 years prior to initiating treatment. 88. The method of Example 87, wherein the efficacy of the treatment is measured at least approximately every 2 weeks after the initiation of treatment. 89. The method of Example 88, wherein the efficacy of the treatment is assessed based on the individual's clinician-managed DSM-5 PTSD scale (CAPS-5) score. 90. The method of any one of Examples 85 to 89, wherein cyclobenzyl or amitriptyline is administered as a free base. 91. The method of any one of Examples 85 to 89, wherein cyclobenzyl or amitriptyline is administered as a pharmaceutically acceptable salt. 92. The method of any one of Examples 85 to 91, wherein the pharmaceutical composition is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, percutaneously, non-intestinally, rectally, or vaginally. 93. The method of Example 92, wherein the pharmaceutical composition is administered sublingually. 94. The method of any one of Examples 85 to 93, wherein the pharmaceutical composition contains an alkalizing agent. 95. The method of Example 94, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 96. The method of any one of Examples 85 to 95, wherein the efficacy of the treatment increases as the time between the initiation of the treatment and the traumatic event decreases. 97. The method of any one of Examples 85 to 96, wherein the amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 50 mg / day. 98. The method of Example 97, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.5 mg / day and about 30 mg / day. 99. The method of Example 98, wherein the amount of cyclobenzylpropionate, amitriptyline, or a pharmaceutically acceptable salt thereof administered is between about 1 mg / day and about 20 mg / day. 100. The method of any one of Examples 85 to 96, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 150 mg / day.101. The method of Example 100, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 1.0 mg / day and about 90 mg / day. 102. The method of Example 101, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 3 mg / day and about 60 mg / day. 103. The method of any one of Examples 85 to 102, wherein the method further comprises sequentially administering cyclobenzulin, amitriptyline or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, or concurrently thereof. 104. The method of Example 103, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 105. The method of Example 103, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or exipram. 106. The method of Example 85 or 86, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the treatment process. 107. The method of any one of Examples 85 to 106, wherein the treatment or prevention is a treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved. 108. The method of Example 107, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 109. The method of Example 85 or 86, wherein the individual has experienced a standard A trauma. 110. The method of Example 109, wherein the standard A trauma resulted in ASD or its symptoms. 111. The method of Example 110, wherein at least one of the ASD symptoms is eliminated or improved. 112. The method of Example 111, wherein the ASD symptoms are selected from the group consisting of: recurring symptoms, avoidance symptoms, arousal symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistent and exaggerated startle responses, feelings such as not knowing where you are and feelings as if you are outside your body.113. A method for determining a therapeutic dose of cyclobenprilin or a pharmaceutically acceptable salt thereof for the treatment of PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from an individual suffering from PTSD or ASD; b) identifying the individual's CYP1A2, CYP2D6, and CYP3A4 genotypes to determine whether the patient has a high cyclobenprilin metabolizer genotype; c) assessing the individual's medical history for smoking history or use of drugs that induce CYP3A4; wherein if the individual meets at least one of the criteria identified in step (b) or (c), the dose of cyclobenprilin administered to the individual is greater than about 5 mg / day; wherein if the individual does not meet at least one of the criteria identified in step (b) or (c), the dose of cyclobenprilin administered to the individual is about 5.6 mg / day or less. 114. A method for determining a therapeutic dose of amitriptyline or a pharmaceutically acceptable salt thereof for the treatment of PTSD or ASD, the method comprising: a) obtaining a suitable cell or tissue sample from an individual suffering from PTSD or ASD; b) identifying the individual's CYP1A2, CYP2D6, and CYP3A4 genotypes to determine whether the patient has a high amitriptyline metabolizer genotype; c) assessing the individual's medical history for smoking history or use of drugs that induce CYP3A4; wherein if the individual meets at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the individual is greater than about 11 mg / day; wherein if the individual does not meet at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the individual is about 11.2 mg / day or less. 115. The method of Example 113 or 114, wherein the drugs used as inducers of CYP3A4 are selected from carbamazepine, phenytoin, phenobarbital, and nevirapine. 116. The method of Example 113 or 114, wherein the treatment is for PTSD and the individual has experienced a traumatic event less than or equal to about 9 years prior to initiating the treatment. 117. The method of Example 113 or 114, wherein the cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition. 118. The method of Example 117, wherein the pharmaceutical composition comprises a free base of cyclobenzylamine or amitriptyline. 119. The method of Example 117, wherein the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzylamine or amitriptyline. 120. The method of any one of Examples 117 to 119, wherein the pharmaceutical composition is administered sublingually, via the buccal mucosa, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, via the nose, as a film, percutaneously, non-intestinally, via the rectum, or via the vagina.121. The method of Example 120, wherein the pharmaceutical composition is administered sublingually. 122. The method of any one of Examples 117 to 121, wherein the pharmaceutical composition comprises an alkalizing agent. 123. The method of Example 122, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 124. The method of any one of Examples 113 to 123, wherein the cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof, and a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are administered sequentially or simultaneously. 125. The method of Example 124, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 126. The method of Example 124, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or excipipram. 127. The method of any one of Examples 117 to 126, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during the treatment process. 128. The method of any one of Examples 113 to 127, wherein at least one of the PTSD symptoms is eliminated or improved. 129. The method of Example 128, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 130. The method of any one of Examples 113 to 127, wherein at least one of the ASD symptoms is eliminated or improved. 131. The method of Example 130, wherein the ASD symptoms are selected from the group consisting of: re-experienced symptoms, avoidance symptoms, arousal symptoms, difficulty sleeping, nightmares, irritability, inattention, hypervigilance, persistently exaggerated startle responses, such as feelings of not knowing where you are and feelings of being outside your body. 132. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof, for the treatment of post-traumatic stress disorder (PTSD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to about 9 years prior to initiation of treatment. 133. A pharmaceutical composition comprising a therapeutically effective amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof, for the treatment of acute stress disorder (ASD) or one or more symptoms thereof in an individual who has experienced a traumatic event less than or equal to 1 month prior to initiation of treatment.134. A pharmaceutical composition of Example 132 or 133, wherein the traumatic event is a standard A traumatic event. 135. A pharmaceutical composition of any one of Examples 132 to 134, wherein the drug is administered once daily. 136. A pharmaceutical composition of any one of Examples 132 to 135, wherein the treatment lasts no more than 4 weeks. 137. A pharmaceutical composition of Example 133 or any one of Examples 134 to 136, which is subordinate to Example 133, wherein treatment of ASD reduces the development of PTSD and related symptoms in an individual. 138. A pharmaceutical composition of any one of Examples 132 to 137, wherein cyclobenzylamine or amitriptyline is a free base. 139. A pharmaceutical composition of any one of Examples 132 to 137, wherein cyclobenzylamine or amitriptyline is a pharmaceutically acceptable salt thereof. 140. A pharmaceutical composition of any one of Examples 132 to 139, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, non-intestinal, rectal, or vaginal administration. 141. A pharmaceutical composition of Example 140, wherein the pharmaceutical composition is formulated for sublingual administration. 142. A pharmaceutical composition of any one of Examples 132 to 141, wherein the pharmaceutical composition comprises an alkalizing agent. 143. A pharmaceutical composition of Example 142, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 144. A pharmaceutical composition of any one of Examples 132 to 143, wherein the efficacy of the treatment increases as the time between the initiation of the treatment and the traumatic event decreases. 145. A pharmaceutical composition of any one of Examples 132 to 144, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 50 mg / day. 146. A pharmaceutical composition of Example 145, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 0.5 mg / day and about 30 mg / day. 147. A pharmaceutical composition of Example 146, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof administered is between about 1 mg / day and about 20 mg / day. 148. A pharmaceutical composition of any one of Examples 132 to 144, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 0.1 mg / day and about 150 mg / day. 149. A pharmaceutical composition of Example 148, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 1.0 mg / day and about 90 mg / day.150. The pharmaceutical composition of Example 149, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof administered is between about 3 mg / day and about 60 mg / day. 151. The pharmaceutical composition of Example 132 or 133, wherein a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors is administered sequentially or simultaneously with the pharmaceutical composition. 152. The pharmaceutical composition of Example 151, wherein the α-1-adrenergic receptor antagonist is pipeprazole. 153. The pharmaceutical composition of Example 151, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or exipram. 154. The pharmaceutical composition of Example 132 or 133, wherein the pharmaceutical composition is intended to be administered in combination with a psychotherapeutic intervention during treatment. 155. The pharmaceutical composition of Example 132 or any of Examples 134 to 136 or 138 to 154 thereof, wherein at least one of the PTSD symptoms is eliminated or improved. 156. The use of Example 155, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 157. The use of Example 133 or any of Examples 134 to 154 thereof, wherein at least one of the ASD symptoms is eliminated or improved. 158. As used in Example 157, wherein the ASD symptoms are selected from the group consisting of: re-experienced symptoms, avoidance symptoms, awakening symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistent and exaggerated startle responses, feelings such as not knowing where you are and feelings as if you are outside your body. 159. As used in Example 132, wherein the medication is administered during the rapid recovery phase, remission phase, or persistent phase of PTSD. 160. A pharmaceutical composition comprising cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of PTSD, ASD, or one or more related symptoms in an individual in need, wherein the treatment comprises: a) administering the medication to the individual daily; b) periodically assessing the effectiveness of the treatment during treatment; c) discontinuing the administration of the medication when the effectiveness diminishes; d) resuming the administration of the medication after a 4-week suspension of treatment; wherein steps (a) through (d) may be repeated one or more times.161. A pharmaceutical composition comprising cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of PTSD, ASD, or one or more related symptoms in an individual in need, wherein the treatment comprises: a) administering the medication to the individual daily; b) discontinuing administration after approximately 4 weeks; c) resuming administration after approximately 4 weeks of discontinuation; wherein steps (a) through (c) may be repeated one or more times. 162. The pharmaceutical composition of Example 160 or 161, wherein the treatment or prevention is for PTSD and the individual has experienced a traumatic event less than or equal to approximately 9 years prior to initiating the treatment. 163. The pharmaceutical composition of Example 162, wherein the efficacy of the treatment is determined at least approximately every 2 weeks after the initiation of treatment. 164. The pharmaceutical composition of Example 163, wherein the efficacy of the treatment is assessed based on the individual's clinician-managed DSM-5 PTSD scale (CAPS-5) score. 165. A pharmaceutical composition of any one of Examples 160 to 164, wherein the cyclobenzyl or amitriptyline in the pharmaceutical composition is a free base of cyclobenzyl or amitriptyline. 166. A pharmaceutical composition of any one of Examples 160 to 164, wherein the cyclobenzyl or amitriptyline in the pharmaceutical composition is a pharmaceutically acceptable cyclobenzyl or amitriptyline salt. 167. A pharmaceutical composition of any one of Examples 160 to 166, wherein the drug is administered sublingually, buccally, orally, as a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, as a film, percutaneously, non-intestinally, rectally, or vaginally. 168. A pharmaceutical composition of Example 167, wherein the drug is administered sublingually. 169. A pharmaceutical composition of any one of Examples 160 to 168, wherein the pharmaceutical composition comprises an alkalizing agent. 170. The pharmaceutical composition of Example 169, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 171. The pharmaceutical composition of any one of Examples 160 to 170, wherein the efficacy of the treatment increases as the time between the initiation of the treatment and the traumatic event decreases. 172. The pharmaceutical composition of any one of Examples 160 to 171, wherein the amount of cyclobenzylamine, amitriptyline, or a pharmaceutically acceptable salt thereof in the drug is between about 0.1 mg / day and about 50 mg / day. 173. The pharmaceutical composition of Example 172, wherein the amount of cyclobenzylamine or a pharmaceutically acceptable salt thereof in the medicament is between about 0.5 mg / day and about 30 mg / day.174. A pharmaceutical composition of Example 173, wherein the amount of cyclobenzylpropionate, amitriptyline, or a pharmaceutically acceptable salt thereof in the composition is between about 1 mg / day and about 20 mg / day. 175. A pharmaceutical composition of Examples 160 to 171, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the composition is between about 0.1 mg / day and about 150 mg / day. 176. A pharmaceutical composition of Example 175, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the composition is between about 1.0 mg / day and about 90 mg / day. 177. A pharmaceutical composition of Example 176, wherein the amount of amitriptyline or a pharmaceutically acceptable salt thereof in the composition is between about 3 mg / day and about 60 mg / day. 178. The pharmaceutical composition of Example 160 or 161, wherein the pharmaceutical composition is administered sequentially or simultaneously with a compound selected from the group consisting of α-1-adrenergic receptor antagonists, β-adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. 179. The pharmaceutical composition of Example 178, wherein the α-1-adrenergic receptor antagonist is piperazoxin. 180. The pharmaceutical composition of Example 178, wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram, or exipram. 181. The pharmaceutical composition of Example 160 or 161, wherein the pharmaceutical composition is administered in combination with a psychotherapeutic intervention during treatment. 182. A pharmaceutical composition of any one of Examples 160 to 181, wherein the treatment or prevention is a treatment or prevention of PTSD, and at least one of the symptoms of PTSD is eliminated or improved. 183. A pharmaceutical composition of Example 182, wherein the PTSD symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses. 184. A composition of Example 160 or 161, wherein the individual has experienced a standard A trauma. 185. A pharmaceutical composition of Example 184, wherein the standard A trauma resulted in ASD or its symptoms. 186. A pharmaceutical composition of Example 185, wherein at least one of the ASD symptoms is eliminated or improved. 187. The pharmaceutical composition of Example 186, wherein the ASD symptoms are selected from the group consisting of: re-experienced symptoms, avoidance symptoms, awakening symptoms, sleep difficulties, nightmares, irritability, inattention, hypervigilance, persistent and exaggerated startle responses, such as feeling not knowing where you are and feeling as if you are outside your body.

Implementation Method

Claims

1. The use of a eutectic of cyclobenzaprine HCl and mannitol for the manufacture of a medicine for treating post-traumatic stress disorder (PTSD) or one or more related symptoms in an individual who has experienced a traumatic event, wherein the time between the traumatic event and the commencement of the treatment is no more than about 9 years, wherein the eutectic comprises 75% ± 2% cyclobenzaprine HCl (by weight) and 25% ± 2% β-mannitol (by weight), and wherein the one or more PTSD-related symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle response.

2. As requested in item 1, wherein the traumatic event is a DSM-5 A traumatic event.

3. As requested in item 1, wherein the drug is prepared for once-daily administration.

4. As requested in item 1, wherein the treatment lasts no more than 4 weeks.

5. As claimed in claim 1, wherein the drug is prepared for sublingual, buccal, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, rectal, or vaginal administration.

6. As requested in claim 5, wherein the drug is prepared for sublingual administration.

7. As claimed in claim 6, wherein the drug is formulated into a film dosage form.

8. As claimed in claim 1, wherein the drug further comprises an alkalizing agent.

9. As claimed in item 8, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate.

10. As claimed in claim 1, wherein the drug is formulated to be delivered in doses between 0.1 mg / day and 50 mg / day, between 0.5 mg / day and 30 mg / day, between 1 mg / day and 20 mg / day, between 0.1 mg / day and 10 mg / day, or between 0.1 mg / day and 5 mg / day.

11. As claimed in claim 10, wherein the drug is formulated for administration of 5.6 mg / day or 2.8 mg / day of cyclobenzyl HCl.

12. Use of a eutectic of cyclobenzulin HCl and mannitol for the manufacture of a medicine for treating PTSD or one or more related symptoms in an individual who has experienced a traumatic event, wherein the time between the traumatic event and the commencement of the treatment is no more than about 9 years, wherein the eutectic comprises 75% ± 2% cyclobenzulin HCl (by weight) and 25% ± 2% β-mannitol (by weight), and wherein the one or more PTSD-related symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses, wherein the treatment includes: (a) Administer the drug to the individual once daily; (b) periodically assess the efficacy of the treatment during drug administration; (c) discontinue drug administration when the efficacy diminishes; (d) resume drug administration after a 4-week suspension; steps (a) through (d) may be repeated once or more.

13. Use of a eutectic of cyclobenzulin HCl and mannitol for the manufacture of a medicine for treating PTSD or one or more related symptoms in an individual who has experienced a traumatic event, wherein the time between the traumatic event and the commencement of the treatment is no more than about 9 years, wherein the eutectic comprises 75% ± 2% cyclobenzulin HCl (by weight) and 25% ± 2% β-mannitol (by weight), and wherein the one or more PTSD-related symptoms are selected from the group consisting of: intrusive symptoms, avoidance symptoms, cognitive and emotional symptoms, arousal and reactive symptoms, difficulty falling asleep, irritability, inattention, hypervigilance, and persistently exaggerated startle responses, wherein the treatment includes: (a) Administer the drug to the individual once a day; (b) Discontinue the drug administration after approximately 4 weeks; (c) Resume the drug administration after approximately 4 weeks of discontinuation; Steps (a) through (c) may be repeated once or more.

14. As claimed in claim 12 or 13, wherein the drug is prepared for administration of cyclobenzyl HCl at doses of 5.6 mg / day or 2.8 mg / day.

15. As claimed in claims 12 or 13, wherein the drug further comprises an alkalizing agent.

16. As claimed in claim 15, wherein the alkalizing agent is selected from the group consisting of: potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate.

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