Title:  Use of serotonin agonists to alleviate disordered breathing episodes in a mammal

United States Patent:  6,387,907

Assignee:  The Trustees of the University of Pennsylvania (Philadelphia, PA)

Filed:  November 12, 1999

The invention includes compositions for alleviating or preventing a disordered breathing episode. The composition of the invention comprises a serotonin re-uptake inhibitor, a TRH agonist and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.

SUMMARY OF THE INVENTION

The invention relates to a composition for alleviating or preventing a disordered breathing episode in a mammal. The composition comprises a serotonin re-uptake inhibitor and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.

In one embodiment of the composition of the invention, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.

In another embodiment of the composition of the invention, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan.

In yet another embodiment of the composition of the invention, the serotonin re-uptake inhibitor comprises trazadone, the serotonin precursor comprises L-tryptophan, and the ratio, by weight, of L-tryptophan to trazodone is between about 13.3 to 1 and about 13.5 to 1.

In still another embodiment of the composition of the invention, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.

In one aspect, the composition of the invention comprises both the serotonin precursor and the serotonin agonist. In another aspect, the composition further comprises a TRH agonist, such as one selected from the group consisting of TRH, montirelin, and CG-3703.

The invention also relates to a kit for alleviating or preventing a disordered breathing episode in a mammal. The kit comprises a serotonin re-uptake inhibitor and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.

In one embodiment of the kit of the invention, the agent is selected from the group consisting of L-tryptophan, L-5-hydroxytryptophan, serotonin, 5-CT, and DOI and is in a unit dosage form.

In another embodiment of the kit of the invention, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone and is in a unit dosage form.

In yet another embodiment of the kit of the invention, the unit dosage form of the agent is an oral unit dosage form and wherein the unit dosage form of the serotonin re-uptake inhibitor is an injectable solution.

In still another embodiment of the kit of the invention, the kit further comprises an instructional material describing administration of the serotonin re-uptake inhibitor and the agent for the purpose of alleviating or preventing a disordered breathing episode in a mammal.

The invention further relates to a method of alleviating a disordered breathing episode in a mammal. This method comprises administering a serotonin re-uptake inhibitor to the mammal and administering an agent to the mammal. The disordered breathing episode is thereby alleviated. The serotonin re-uptake inhibitor is administered in an amount effective to enhance or extend the hypoglossal motoneuron-stimulating effect of endogenous serotonin of the mammal. The agent is selected from the group consisting of a serotonin precursor and a serotonin agonist, and is administered in an amount effective to prevent tachyphylaxis associated with administration to the mammal of the serotonin re-uptake inhibitor.

In one embodiment of this method, the mammal is afflicted with a condition associated with a disordered breathing episode, such as one selected from the group consisting of hypersomnolence, snoring, hypopneas, apneas, obstructive sleep apnea, sleep hypopnea syndrome, upper airway resistance syndrome, and severe snoring conditions associated with arousal from sleep. Preferably the mammal is a human.

In another embodiment of this method, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.

In yet another embodiment of this method, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan,

In still another embodiment of this method, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.

In another embodiment of this method, both the serotonin precursor and the serotonin agonist are administered to the mammal.

In one aspect, this method further comprises administering a TRH agonist to the mammal. The TRH agonist may, for example, be one selected from the group consisting of TRH, montirelin, and CG-3703.

The invention still further relates to a method of preventing a disordered breathing episode in a mammal imminently anticipated to experience a disordered breathing episode. This method comprises administering a serotonin re-uptake inhibitor to the mammal and administering an agent to the mammal. The disordered breathing episode is thereby alleviated. The serotonin re-uptake inhibitor is administered in an amount effective to enhance or extend the hypoglossal motoneuron-stimulating effect of endogenous serotonin of the mammal. The agent is selected from the group consisting of a serotonin precursor and a serotonin agonist and is administered in an amount effective to prevent tachyphylaxis associated with administration to the mammal of the serotonin re-uptake inhibitor.

In one embodiment of this method, the mammal is afflicted with a condition associated with a disordered breathing episode, such as one selected from the group consisting of hypersomnolence, snoring, hypopneas, apneas, obstructive sleep apnea, sleep hypopnea syndrome, upper airway resistance syndrome, and severe snoring conditions associated with arousal from sleep. Preferably, the mammal is a human.

In another embodiment of this method, the serotonin re-uptake inhibitor is selected from the group consisting of trazadone, fluoxetine, and nefazodone.

In yet another embodiment of this method, the serotonin precursor is selected from the group consisting of L-tryptophan and L-5-hydroxytryptophan.

In still another embodiment of this method, the serotonin agonist is selected from the group consisting of serotonin, 5-CT, and DOI.

In another embodiment of this method, both the serotonin precursor and the serotonin agonist are administered to the mammal.

In aspect, this method further comprises administering a TRH agonist to the mammal, such as one selected from the group consisting of TRH, montirelin, and CG-3703.

Claim 1 of 12 Claims

What is claimed is:

1. A composition for alleviating or preventing a disordered breathing episode in a mammal, said composition comprising a serotonin re-uptake inhibitor, a TRH agonist, and an agent selected from the group consisting of a serotonin precursor and a serotonin agonist.

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