Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-27
2003-06-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S383000, C514S252150, C514S275000, C514S221000, C514S649000
Reexamination Certificate
active
06579899
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a novel process for treating stress in a subject suffering from at least one symptom of stress. More specifically, the invention relates to the use of precursors or prodrugs that enhance serotonin-mediated neurotransmission, as well as intermediates in the biosynthesis of serotonin, for treating stress in such a subject.
BACKGROUND OF THE INVENTION
Individuals responding to stressful events can experience one, two or three of the following stages: (1) stage one, mobilization of energy; (2) stage two, exhaustion or consuming energy; and (3) stage three, draining energy stores.
In stage one, the mobilization of energy, the body responds to stress through a release of Adrenalin and a fight or flight response. Symptoms of this stage include increased heart rate and blood pressure, rapid breathing, sweating, decreased digestion rate and indigestion.
If there is no relief from stage one, the individual enters phase two, exhaustion or consuming energy. Here, the body will begin to release stored sugars and use up fats. Symptoms of this stage include feeling driven, feeling pressured, tiredness and fatigue, increased smoking, coffee drinking and/or alcohol consumption, anxiety, memory loss, and acute illnesses such as colds and flu.
If either the stressful situation is not resolved, or the individual's reaction to the situation is not changed, the individual enters phase three, draining energy sources. Here, the individual becomes chronically stressed, and the body's need for energy resources outpaces its ability to produce them. Symptoms of this stage include serious illnesses such as heart disease, ulcers, and mental illness, as well as insomnia, errors in judgment, and personality changes.
At present, patients suffering from stress related disorders are treated for the symptoms of stress by the use of pharmaceutical compositions containing drugs such as anxiolytics or sometimes with beta-blockers. Anxiolytics frequently used include drugs such as benzodiazepines, diazepam being a specific example. The beta-blocking drugs used for treatment of such patients include propranolol. The use of these classes of drugs for such treatments is discussed in
Goodman and Gilman's Pharmacological Basis of Therapeutics,
Seventh Edition, 1985, Alfred G. Gilman et al., editors, pages 192-201, the entirety of which is herein incorporated by reference.
The serotoninergic drug fenfluramine is known to be an effective drug for treating obesity. The racemic mixture, D,L-fenfluramine, is disclosed in U.S. Pat. No. 4,452,815 as being effective for inhibiting the abnormal craving for carbohydrates which afflicts some people and is associated with obesity. Dexfenfluramine is also indicated for use in treating patients who cannot control their eating habits or appetite. The use of dexfenfluramine for this purpose was disclosed in U.S. Pat. No. 4,309,445. In both of these patents, fenfluramines were used for treating a patient's appetite or craving for certain types of food. Nowhere in these patents is the use of fenfluramines taught or suggested for treatment of stress or stress symptoms.
Wurtman, et al., in Brain Serotonin, Carbohydrate-Craving, Obesity and Depression,
Obesity Research
, vol. 3, suppl. 4, Nov. 4, 1995, pages 477S-480S present a theoretical mechanism by which fenfluramines work for suppressing appetite for certain food types, the entirety of which is herein incorporated by reference. Dexfenfluramine is shown in this publication to be useful for treating obesity suffered by such people, but there is no teaching or suggestion that dexfenfluramine is useful for treating stress itself.
Wurtman et al. describes the serotoninergic fenfluramines as acting to facilitate weight loss in subjects in three ways:
“They accelerate the onset of satiety and enhance basal metabolic rate by about 100 calories per day. They also inhibit the ‘carbohydrate craving’ manifested by many people who are overweight or are becoming so, and there is reason to believe that this inappropriate eating behavior actually constitutes a ‘serotonin hunger’ by the brain, in which case giving the serotoninergic drug might constitute a specific therapy for the etiologic process causing the obesity.”
Further discussion of the known functioning of fenfluramines is found in Wurtman, et al., Brain Serotonin, Carbohydrate-Craving, Obesity and Depression,
Recent Advances in Tryptophan Research,
G. A. Filippini, et al. eds., Plenum Press, New York, 1996, pages 35-41 the entirety of which is herein incorporated by reference.
The use of dexfenfluramine for treating animals inflicted with periodic pain is discussed in Dexfenfluramine: Effects on Food Intake in Various Animal Models, Rowland, et al.,
Clinical Neuropharmacology,
vol. 11, suppl. 1, pp. S33-S50 the entirety of which is herein incorporated by reference. This article indicates in the abstract that: “. . . both stress-induced eating as well as a food-motivated response (running) are particularly sensitive to inhibition by dexfenfluramine.”
Rowland et al. discloses the administration of dexfenfluramine to rats exhibiting increased eating behavior in response to tail pinching. Dexfenfluramine (DF) was found to decrease the eating behavior of the tail pinched rats.
Rowland, et al., discusses the implications of their experiments with regard to stress-induced eating as follows on page S37, wherein DF refers to dexfenfluramine:
“Mild tail pressure induces eating and gnawing in rats, and this may be a model of stress-induced eating in humans. Garattini reported that DF potently inhibits tail pressure-induced eating, and that the DI
50
of 0.6 mg/kg is about one-half of the doses effective in the other paradigms reviewed so far. It was previously reported that racemic fenfluramine inhibits tail pressure-induced eating as well as concurrent behaviors such as gnawing, locomotion, and vocalization. In the study with DF, only the amount eaten was reported, rather than all oral behaviors. These data thus suggest that DF may be an especially potent inhibitor of stress-related eating. Further studies are needed to clarify the effect of DF on other oral behaviors, as well as whether it has ‘antistress’ effects along with its anorectic action.”
Rowland, et al., indicate only that fenfluramines inhibit tail pinching-induced eating and other behaviors stemming from the tail pinching protocol in rats. Rowland, et al. did not teach or suggest that fenfluramines can be used as a treatment for reducing stress itself. Thus, until the present invention, it was only known that dexfenfluramine inhibits eating in rats which have had their tails pinched. It was not previously known whether dexfenfluramine or d,1-fenfluramine in particular, or serotoninergic drugs in general, would be effective for treatment of stress. One skilled in the art would not have been led by the results of Rowland, et al. in rats, to treat humans suffering from stress with dexfenfluramine.
A need continues to exist for improved and alternative methods and compositions for treating stress and symptoms related thereto.
SUMMARY OF THE INVENTION
Briefly, the present invention is a novel treatment for stress and symptoms of stress in a subject. The applicants have discovered that administering precursors or prodrugs that enhance serotonin-mediated neurotransmission to a patient in need thereof can bring about a reduction in the stress felt by the patient and the symptoms of stress manifested by the patient. The treatment of stress and stress related symptoms of a patient with the compounds of the present invention has not been previously reported.
The present invention provides an appropriate treatment for stress in human patients, especially those suffering from stress-induced overeating. This invention is based on the discovery that prodrugs of serotonin, or intermediates in the biosynthesis of serotonin, such as tryptophan or 5-hydroxytryptophan, or their salts, can alleviate symptoms of stress in patients, when administered in effective amounts or at appropriat
Wurtman Judith J.
Wurtman Richard J.
Jagoe Donna
Katten Muchin Zavis & Rosenman
Krass Frederick
Massachusetts Institute of Technology
Sira Serge
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