Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Aldehyde doai
Reexamination Certificate
2002-03-01
2004-02-10
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Aldehyde doai
C514S702000, C514S704000
Reexamination Certificate
active
06689816
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel drug treatments for neuropsychiatric disorders, for example anxiety disorders, psychotic disorders, mood disorders and somatoform disorders. These treatments relieve symptoms of disorders characterized by repetitive, stereotyped, an unwanted, intrusive, or involuntary thoughts, perceptions, or behaviors. These include posttraumatic stress disorder, obsessive-compulsive disorder, somatization disorder, hypochondriasis, and body dysmorphic disorder. Contemporary drug therapy for these conditions is limited in efficacy, with many patients continuing to have symptoms despite treatment. Antidepressants, mood stabilizers, anti-anxiety drugs, and antipsychotic drugs all have been used to treat them. Even when they provide some relief, persistent intrusive, repetitive mental phenomena may remain as a distressing symptom. Thus, when a person with posttraumatic stress disorder is treated with an antidepressant, mood may improve while “flashbacks” of the traumatic event continue.
Clearly, there is a need for additional medications efficacious for the treatment of these disorders, and especially for medications that suppress or eliminate the recurrent unwanted, intrusive, or involuntary thoughts, perceptions and behaviors characteristic of those disorders. Such medications might also be used to reduce such symptoms when they occur as part of another psychiatric syndrome, such as depression or schizophrenia, or when they are incidental to a neurological disorder such as Tourette's syndrome or Huntington's disease.
I begin by reviewing the prototypical conditions for which the novel treatment is useful:
Posttraumatic Stress Disorder (PTSD)
Description of PTSD
Posttraumatic stress disorder is an immediate or delayed response to a catastrophic event, characterized by the following features:
“re-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders. Intrusive memories are spontaneous, unwanted, distressing recollections of the traumatic event. Repeated nightmares contain themes of the trauma or a highly accurate and detailed re-creation of the actual event(s). Flashbacks are dissociative states in which components of the event are relived, and the person feels as if he or she is experiencing the event for a few seconds for as long as days. Reactivity to trauma-related stimuli can involve intense emotional distress or physical symptoms similar to those of a panic attack, when the patient is exposed to sights, sounds, smells or events that were present during the traumatic event. Avoidance may include thoughts, feelings, situations or activities that are reminders of the trauma. Numbing may occur through amnesia, emotional detachment, restricted affect, or loss of interest in activities. Increased arousal may include insomnia, irritability, hypervigilance, increased startle response, or impaired concentration. This disorder can have pervasive effects on an individual's interpersonal behavior and all spheres of his or her life.” (Charney D S et al.: Neurobiological mechanisms of human anxiety. In Fogel B S, Schiffer R B, Rao S M: Neuropsychiatry. Baltimore: Williams & Wilkins, 1996, pp. 257-286).
Epidemiology of PTSD
Among American veterans of the Vietnam War, the lifetime prevalence rate of PTSD was estimated as 31% in men and 27% in women; current prevalence estimates were 15% and 8.5%, respectively. In a survey of female victims of crime, the lifetime prevalence of PTSD was 13% and the current prevalence 3%. Overall, PTSD affects 2% or more of the US population (Charney et al., supra). Among people with work-related injuries, the rate of PTSD may exceed one-third, or even one-half, if people with partial PTSD syndromes are included (Asmundson G J, et al.: Posttraumatic stress disorder and work-related injury. J Anxiety Disord, 12:57-69, January-February 1998). Manifestly, PTSD is a significant public health problem.
Complications and Comorbidity
There is a strong association between PTSD and substance abuse, especially alcoholism. (Coffey S F, et al.: Screening for PTSD in a substance abuse sample: psychometric properties of a modified version of the PTSD Symptom Scale Self-Report. J Trauma Stress, 11:393-9, April 1998). In addition, chronic PTSD can increase a person's long-term risk of a broad range of chronic diseases. Long-term follow up of men exposed to severe combat-related stress showed that PTSD significantly increased the risk of developing disorders of the circulatory, digestive, and respiratory systems as well as, infectious diseases, and neurological and psychiatric disorders other than PTSD (Boscarino J A: Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. Psychosom. Med., 59:605-14, November-December 1997).
Various studies over the past decade have identified risk factors for the development of PTSD following an acute traumatic event. These include lower intelligence, a less developed narrative of the traumatic event, a history of prior trauma, and a rapid heart rate at the time of post-trauma medical examination. If a person develops an acute stress disorder after a major traumatic event (i.e., immediately displays symptoms resembling those of PTSD), that individual is likely to continue having symptoms, and eventually warrant, a diagnosis of PTSD. These considerations imply that a population at high risk for PTSD can be identified. If there were a non-toxic drug that significantly and specifically reduced the symptoms of PTSD, it could be used in this high-risk population to prevent the development of PTSD.
Pathophysiology of PTSD
The pathophysiology of PTSD involves disturbances in brain systems involved with reaction to stress, including the hypothalamic-pituitary-adrenal axis, and systems involving norepinephrine, serotonin, endogenous opiates, and endogenous ligands for benzodiazepine receptors. PTSD involves overactivity of the noradrenergic arousal systems, with relative underactivity of the hypothalamic-pituitary-adrenal axis (Henry JP: Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl, 640:10-25, 1997). On the other hand, underactivity of endogenous opiate mechanisms may contribute to the symptoms of PTSD. (Baker D G, et al.: Cerebrospinal fluid and plasma beta-endorphin in combat veterans with post-traumatic stress disorder. Psychoneuroendocrinology, 22:517-29, October 1997)
Animal experiments suggest NMDA receptor-mediated processes are likely to be involved in the establishment of anxiety-like behavior following stressful events. The latter induce long-term potentiation (LTP) affecting connections within the amygdala, and between the amygdala and its efferents. A natural inference is that NMDA-receptor mediated processes are involved in the development of PTSD in humans (Adamec R: Transmitter systems involved in neural plasticity underlying increased anxiety and defense: implications for understanding anxiety following traumatic stress. Neuroscience and biobehavioral reviews 21(6):755-65, 1997). In a recent review, two Israeli investigators described a central role of NMDA receptors in posttraumatic stress disorder, as well as schizophrenia, alcoholism and major depression. They proposed that agents that modulate NMDA receptor function would be useful in treating all of these disorders (Heresco-Levy U, Javitt D C: The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur Neuropsychopharmacol May 1998;8(2):141-52). They did not, however, propose acamprosate in the treatment of PTSD, nor the combination of NMDA receptor and GABA-A receptor actions in the treatment of these disorders.
In a
Choate Hall & Stewart
Criares Theodore J.
Synchroneuron
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