Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Patent
1998-07-28
1999-09-28
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
424456, 424464, 424436, 424422, 424434, 424489, 424449, 424497, A61K 920, A61K 900
Patent
active
059584297
DESCRIPTION:
BRIEF SUMMARY
The present invention belongs to the fields of pharmacology, medicine and medicinal chemistry, and provides methods and compositions for increasing the availability of serotonin, norepinephrine and dopamine in the brain of patients.
Over the past twenty years or more, the science of pharmacology has been particularly interested in the physiology of the neurons containing monoamines in the human brain. Discovery has followed discovery in the field and it has now been demonstrated that serotonin, norepinephrine and dopamine interact with a great number of receptors in the brain and control or affect processes which regulate many bodily organs and functions. Serotonin, particularly, has been found to be the key to a large number of processes which reveal themselves in both physiological and psychological functions.
Perhaps the most dramatic discovery in medicinal chemistry in the recent past is fluoxetine, a serotonin reuptake inhibitor, which is extremely effective in the treatment of depression. As a reuptake inhibitor, it increases the availability of serotonin in the synapse by reducing the uptake of serotonin by the serotonin uptake carrier. Excessive uptake results in depression, as well as other pathologies of the central nervous system. Not only is fluoxetine spectacularly effective in depression, it is also effective in treating numerous other conditions.
While the primary activity of fluoxetine and related drugs is the inhibition of the reuptake of serotonin, the cascade of monoamine processes in the brain connects serotonin with both norepinephrine and dopamine. Thus, the increase of availability of serotonin results in increased availability of norepinephrine and dopamine as well.
It has been recently discovered that blockade at the serotonin 1A receptor, particularly with antagonist activity, is also related to the availability of serotonin, and hence of norepinephrine and dopamine, in the brain. E.g., Artigas et al., Arch. Gen. Psychiatry 51, 248-251 (1994); Hjorth, J. Neurochem. 60, 776-779 (1993). Certain 5-HT.sub.1A antagonists are now in clinical trials as potentiators of serotonin reuptake inhibitors. The full benefit of providing compounds which effectively block the 5-HT.sub.1A receptor has not yet been explored, nor has the best method of exploiting the relationship between the 5-HT.sub.1A receptor and other serotonin processes been provided to the medical arts.
The present invention provides methods for increasing the availability of serotonin, norepinephrine and dopamine, even compared to the usual increased availability caused by treatment with fluoxetine and related drugs which have followed it.
The invention provides a method for potentiating the action of a first component chosen from the group consisting of fluoxetine, venlafaxine, citalopram, fluvoxamine, paroxetine, sertraline, milnacipran, and duloxetine in increasing the availability of serotonin, norepinephrine and dopamine in the brain, comprising administering a first component to a patient in need thereof in combination with a second component chosen from the group consisting of alprenolol, WAY 100135, WAY 100635, spiperone, pindolol, (S)-UH-301, penbutolol, propranolol, tertatolol, and a compound of the formula ##STR1## R.sub.1 is an optional methyl group substituted on one of the three connecting carbon atoms; (C.sub.1 -C.sub.4 alkyl)-O--, (C.sub.1 -C.sub.4 alkyl)--S(O).sub.p --, or halo; formula ##STR2## where a and c are independently 1-5, b is 0-5, and (a+c) is greater than 2; group; (C.sub.4 -C.sub.8 cycloalkyl) optionally substituted with C.sub.1 -C.sub.4 alkyl or phenyl; a bicycloalkyl group of the formula ##STR3## wherein a and c are independently 1-5, b is 0-5, and (a+c) is greater than 2; optionally phenyl substituted C.sub.2 -C.sub.10 alkyl where the phenyl group can be optionally substituted with R.sub.2 as previously defined; or (C.sub.1 -C.sub.4 alkylidene)-T--(C.sub.1 -C.sub.4 alkyl), where T is --O--, --S--, --SO--, or --SO.sub.2 --; or when taken together with the carbon atom to which they are attached fo
REFERENCES:
patent: 5532244 (1996-07-01), Wong et al.
patent: 5532250 (1996-07-01), Wong et al.
patent: 5532264 (1996-07-01), Wong et al.
patent: 5532268 (1996-07-01), Wong et al.
patent: 5538992 (1996-07-01), Wong et al.
patent: 5552429 (1996-09-01), Wong et al.
Sanders-Bush E. and S. Mayer, 5-Hydroxytryptamine (Serotonin) Receptor Agonists and Antagonists, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eds. Hardman and Limbird, 249-263, 1996.
Gartside S.E., Umbers V., Hajos J. and T. Sharp, Interaction between a Selective 5-HT1A Receptor Antagonist and an SSRI In Vivo: Effects on 5-HT Cell Firing and Extracellular 5-HT, 115:1064-1070, 1995.
Hjorth S., Serotonin 5-HT1A Autoreceptor Blockade Potentiates the Ability of the 5-HT Reuptake Inhibitor Citalopram to Increase Nerve Terminal Output of 5-HT In Vivo: A Microdialysis Study, J. Neurochemistry, 60(2):776-779, 1993.
Areval D., Afonso R., Castro R. and M. Rodriguez, Fetal Brain Serotonin Synthesis and Catabolism is under Control by Mother Intake of Tryptophan, Life Sciences, 49:53-66, 1991.
Schaechter J.D. and R.J. Wurtman, Tryptophan Availability Modulates Serotonin Release from Rat Hypothalamic Slices, J. Neurochemistry, 53(6):1925-1933, 1989.
Fernstrom J.D. and R.J. Wurtman, Brain Serotonin content: Physiological Dependence on Plasma Tryptophan Levels, Science 173:149-152, 1971.
Eli Lilly and Company
Page Thurman K.
Titus Robert D.
Ware T.
LandOfFree
Potentiation of serotonin response does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Potentiation of serotonin response, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Potentiation of serotonin response will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-700262