Compositions and methods for treating respiratory depression with fenfluramine
5-HT receptor agonists are useful in the treatment of a variety of diseases. Provided herein are methods of treating and/or reducing the occurrence of respiratory depression caused by an opioid in a human patient or patient population using a 5-HT receptor agonist, such as, for example, a 5-HT4 agonist (e.g., fenfluramine). Methods of stimulating one or more 5-HT 4 receptors in the brain of a patient undergoing treatment with an opioid, wherein the patient is at risk of respiratory depression, by administering a 5-HT4 agonist (e.g., fenfluramine) to a subject in need thereof are provided. Pharmaceutical compositions for use in practicing the subject methods are also provided.
1. A method of reducing incidence of respiratory depression caused by a toxin in a selected human patient population, comprising:
selecting a population of human patients exposed to the toxin and thereby at risk of respiratory depression;
administering to the selected patient population a therapeutically effective dose of a 5-HT4 agonist; and
allowing the 5-HT 4 agonist to stimulate 5-HT 4 receptors in the selected patient population, thereby reducing incidence of respiratory depression caused by the toxin in the patient population.
2. The method of any of claim 1 wherein the respiratory depression is intensified by co-ingestion or co-administration of alcohol or other CNS depressants.
3. The method of any of claim 1 , wherein the 5-HT 4 agonist is selected from the group consisting of fenfluramine, BIMU-8, Cisapride, Mosapride, Prucalopride, Renzapride, RS-67506, Tegaserod, Zacopride, Metoclopramide, and Sulpiride, or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the 5-HT 4 agonist is fenfluramine, or a pharmaceutically acceptable salt thereof; and
wherein fenfluramine is administered in a therapeutically effective dose as an adjunctive therapeutic agent; and
wherein the therapeutically effective dose of fenfluramine is selected from the group consisting of 0.2 mg/kg/day to 0.08 mg/kg/day up to a 30 mg maximum daily dose.
5. The method of claim 4 , wherein the therapeutically effective dose of fenfluramine is administered in an oral liquid dosage form.
6. The method of claim 1 , wherein the 5-HT 4 agonist has a characteristic selected from the group consisting of:
(a) inactive at the 5-HT2B receptor;
(b) a neutral agonist of the 5-HT2B receptor; and
(c) an inverse agonist of the 5-HT2B receptor 5-HT2B receptor.
7. The method of claim 6 , wherein the patient exhibits a significantly higher responder rate compared with placebo, the method further comprising:
repeating the administering over a period of days until the patient exhibits a ≥40% reduction from baseline in occurrence of respiratory depression.
8. The method of claim 6 , wherein the patient exhibits at least a ≥50% reduction in occurrence of respiratory depression.
9. The method of claim 6 , wherein the patient exhibits at least a ≥75% reduction in occurrence of respiratory depression.
10. The method of claim 6 , wherein the patient exhibits at least a ≥90% reduction in occurrence of respiratory depression.
11. The method of claim 6 , wherein the patient completely free of an occurrence of respiratory depression.
12. The method of claim 1 , wherein the 5-HT 4 agonist is fenfluramine or a pharmaceutically acceptable salt thereof.
13. The method of claim 2 , wherein the 5-HT 4 agonist is fenfluramine or a pharmaceutically acceptable salt thereof.