Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-02
2001-04-17
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S652000
Reexamination Certificate
active
06218395
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to medicine and more particularly to the administration of pharmaceuticals to relieve anxiety disorders and adjustment disorders with anxiety.
BACKGROUND OF THE INVENTION
Anxiety disorders are common, and they pose discomfort and health risks to the person who suffers with symptoms, his family and his co-workers.
The term “anxiety disorders” refers here to the group of conditions which are long-standing and persistent. They are listed under this term in the Diagnostic and Statistical Manual of Psychiatry, Fourth Edition. The presently accepted names of such anxiety disorders are: Generalized Anxiety Disorder, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, Panic Disorder, Agoraphobia, Specific Phobia, Social Phobia, Anxiety Disorder Due to General Medical Condition, Substance-Induced Anxiety Disorder, and Anxiety Disorder Not Otherwise Specified. These “anxiety disorders” are different from ordinary “reactive anxiety” which occurs in the normal course of life, for example, due to the stress of moving from one house to another. Such reactive anxiety disorders, without medication, decrease with time, e.g., in one to four weeks.
The term “adjustment disorders with anxiety” refers to conditions listed under this term in the cited Diagnostic and Statistical Manual of Psychiatry, which include the expression of anxiety. These conditions are: Adjustment Disorder with Anxiety, Adjustment Disorder with Mixed Anxiety and Depressed Mood, and Adjustment Disorder with Mixed Disturbance of Emotions and Conduct, in which the emotional symptoms include anxiety.
The term “centrally-acting beta-blockers” as used herein encompasses medications that enter the central nervous system by passage from the bloodstream across the blood-brain barrier, and there block beta-adrenergic receptors. This blockade of beta-adrenergic receptors may provide reliable therapeutic benefits for anxiety disorders, for example, the use of the beta-blocker betaxolol, as described in U.S. Pat. No. 5,798,393 (Swartz 1998). Not all beta-blockers are “centrally-acting beta-blockers” since some do not cross the blood-brain barrier, i.e., atenolol and nadolol.
The medications which have been identified as centrally-acting beta-blockers are: acebutolol,betaxolol, bisopropolol, bopindolol, carvedilol, metoprolol, oxprenolol, propranolol, and timolol. Those beta-blockers include, for each, its racemic mixture, its optical isomer, its immediate-release and sustained-release preparation. Generally, beta-blockers are not recognized by psychiatrists as a medication to treat anxiety disorders.
The term “serotonin-enhancer”, as used herein, means medications that increase or prolong serotonergic neurotransmission. For example, they act as a counteraction, an agonist of serotonin at serotonin receptor sites; by preventing the degradation of serotonin, by increasing the formation of serotonin, by preventing the removal of serotonin from the sites (i.e., the synaptic cleft) of the serotonin-reuptake inhibitor (SRI), by prolonging the actions or effects of serotonin, or by diminishing influences that inhibit serotonin release (Lakoski and Aghajanian 1985). Serotonin agonists include buspirone (BuSpar™) gepirone, and ipsapirone. Serotonin precursors, which increase its formation, include L-tryptophan and 5-hydroxytryptophan (5-HTP). Serotonin reuptake inhibitors (SRI) include chlorimipramine (also known as clomipramine and chlorimipramine), citalopram, fluoxetine (Prozac™), fluvoxamine, paroxetine, sertraline, venlafaxine, lamotrigine, and carbamazepine. Agents which diminish influences that inhibit serotonin release include presynaptic serotonin antagonists, which include ritanserin, ketanserin, risperidone, mirtazepine, nefazodone, trazodone, olanzapine, clozapine, serazepine, methysergide, mianserin, and flibaserin. Each agent includes its racemic mixture, optical isomer, immediate-release preparation and sustained-release preparation.
Separately, several centrally-acting beta-blockers and several serotonin enhancers have been identified as providing benefits in the mitigation of anxiety and in the treatment of anxiety disorders.
Benefits in the mitigation of anxiety and in the treatment of anxiety disorders have been reported for several centrally-acting beta blockers (e.g. Swartz 1998; Meibach et al 1987) and several serotonin enhancers (Michaelson et al 1998; Ballenger et al 1998).
SUMMARY OF THE INVENTION
As a combination of two different and complementary actions to mitigate anxiety disorders, the administration of a beta-blocker together with a serotonin-enhancer is believed to be more effective than either medication used alone. If they are administered together, they provide a synergistic effect—their combination provides a beneficial effect which is greater than would be expected on a dosage basis. The reason for this greater-than-additive effect is that somatic anxiety and psychic anxiety each provoke and exacerbate the other, and the mitigation of both together augments the mitigation of each. In the mitigation of anxiety, a beta-blocker primarily mitigates somatic anxiety, and this variably leads to a secondary mitigation of psychic anxiety. In the mitigation of anxiety, a serotonin-enhancer primarily mitigates psychic anxiety, and this leads to a secondary mitigation of somatic anxiety. Moreover, because the side effects of serotonin-enhancers include the symptoms of somatic anxiety, beta-blockers mitigate the side effects of serotonin-enharcers.
DETAILED DESCRIPTION OF THE INVENTION
Anxiety disorders are common; without including Adjustment Disorders, their 12-month prevalence is about 13% (Kessler et al 1994). Their recognition and treatment is urgent, not only because of psychological suffering but because anxiety can lead to sudden death, cardiac injury, or suicide (Kawachi et al, 1994a,1194b; Ketterer, 1997; taker et al 1992; Fawcett et al 1987; Chance et al 1994). A basic use of serotonin-enhancers is the mitigation of anxiety disorders, of mild to mild-to-moderate severity, in patients for whom symptoms are primarily psychic anxiety, e.g., persistent worry, doubt, dread, repetitive thoughts or obsessionalism, repetitive behavior or compulsiveness, mental concentration difficulty, and mood instability. In persistent, or more severe, cases somatic anxiety symptoms develop and add to the difficulty of achieving relief. Somatic anxiety symptoms include agitation, restlessness, jumpiness, edginess, hyperalertness, initial insomnia, vivid dreams, chest tightness, palpitations, irritable bowels, dyspepsia, headaches, dyspnea, and panic attacks. Somatic anxiety symptoms provoke and exacerbate psychic anxiety symptoms, and vice-versa, which produces a “positive feedback” cycle. In the natural progression of anxiety disorders, in time and in severity, psychic anxiety irritates somatic anxiety, which irritates more psychic anxiety, which irritates more somatic anxiety, and so forth. Several symptoms result from a combination of somatic anxiety and psychic anxiety, such as mind-blanking, irritability, argumentativeness, nightmares, and aggressive or violent behavior. Further, somatic anxiety symptoms are the same symptoms which are common side effects of serotonin-enhancers, and somatic anxiety symptoms and these side effects can provoke and exacerbate each other.
Patients with anxiety disorders who visit psychiatrists usually have somatic anxiety symptoms. This is probably because by the time a patient is referred to a psychiatrist, or is willing to see one, the disorder has become persistent and of substantial severity. Perhaps because of the somatic anxiety symptoms, improvements by patients with post-traumatic stress disorder (PTSD) on serotonin-enhancers alone is often incomplete and slow, and side-effects are often problematic. Serotonin-enhancers are better tolerated by and more effective in patients who do not have somatic anxiety symptoms.
The blockade of beta-adrenergic receptors decreases the effects of internal secretions of t
Gerber Eliot
Rose Shep K.
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