Use of ergot alkaloids as an anthelmintic agent
Methods for preventing, inhibiting or treating parasitic flatworm infection in a vertebrate are provided that include administering an effective amount of a composition comprising one or more ergot alkaloids, one or more lysergic acid amides, or one or more dimethoxyisoquinoline derivatives.
1. A method of inhibiting or treating parasitic flatworm infection in a vertebrate, comprising:
administering an effective amount of a composition comprising one or more ergot alkaloids, one or more lysergic acid amides, or any combination thereof, wherein the ergot alkaloid is an agonist or partial agonist of Schistosoma serotonergic G-protein coupled receptor.
2. The method of claim 1 wherein the ergot alkaloid or the lysergic acid amide is an agonist or partial agonist of Schistosoma mansoni serotonergic G-protein coupled receptor (Sm.5HTR), Schistosoma japonicum serotonergic G-protein coupled receptor (Sj.5HTR) or Schistosoma haematobium serotonergic G-protein coupled receptor (Sh.5HTR), or any combination thereof.
3. The method of claim 1 wherein the ergot alkaloid comprises an ergopeptine.
4. The method of claim 1 wherein a combination of ergot alkaloids, a combination of lysergic acid amides, or a combination of at least one ergot alkaloid and at least one lysergic acid amide is administered.
5. The method of claim 1 wherein the vertebrate is a human or a non-human mammal.
6. The method of claim 1 wherein the amount inhibits contractility, viability, egg laying (number of eggs laid), or egg production by the flatworm or the amount is effective to reduce schistosomiasis, neurocystcicerosis or clonochiasis.
7. The method of claim 1 wherein the composition comprises a compound of formula (I):
wherein,
R 1 is hydrogen, trifluoromethyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, or alkylaryl;
R 2 is hydrogen, trifluoromethyl, halogen, cyano, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, alkylaryl, OR x , OCOR x , ONR x R y , SR x , NR x R y , NR x OR y , NR x NR x R y , NR x COR y , NR x CO 2 R y , NR x SO 2 R y , COR x , or CO 2 R x ;
R 3 is hydrogen, trifluoromethyl halogen, cyano, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, alkylaryl, OR x , OCOR x , ONR x R y , SR x , NR x R y , NR x OR y , NR x NR x R y , NR x COR y , NR x CO 2 R y , NR x SO 2 R y , COR x , or CO 2 R x ;
R 4 is hydrogen, trifluoromethyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl aryl, or alkylaryl;
R 5 is hydrogen, trifluoromethyl halogen, cyano, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, alkylaryl, OR x , OCOR x , ONR x R y , SR x , NR x R y , NR x OR y , NR x NR x R y , NR x COR y , NR x CO 2 R y , NR x SO 2 R y , COR x , or CO 2 R x ;
R x and R y are independently at each occurrence hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, or alkylaryl;
X—Y is a carbon-carbon single bond or a carbon-carbon double bond;
deuterated analogs thereof,
or pharmaceutically acceptable salts thereof.
8. The method of claim 1 wherein the composition comprises a compound of formula (II):
wherein,
R 6 is hydrogen, trifluoromethyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, or alkylaryl;
R 7 is hydrogen, trifluoromethyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl aryl, or alkylaryl;
R 8 is hydrogen, trifluoromethyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl C 3-10 cycloalkyl, aryl, or alkylaryl;
R 9 is hydrogen, trifluoromethyl, halogen, cyano, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, alkylaryl, OR x , OCOR x , ONR x R y , SR x , NR x R y , NR x OR y , NR x NR x R y , NR x COR y , NR x CO 2 R y , NR x SO 2 R y , COR x , or CO 2 R x ;
R x and R y are independently at each occurrence hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, aryl, or alkylaryl;
X—Y is a carbon-carbon single bond or a carbon-carbon double bond;
A is a bond or NR x ;
deuterated analogs thereof,
or pharmaceutically acceptable salts thereof.
9. The method of claim 1 wherein the compound is administered weekly.
10. The method of claim 1 wherein the vertebrate is further administered caffeine or praziquantel.
11. The method of claim 1 wherein the composition is orally, intramuscularly, rectally, intravenously or intranasally administered.
12. The method of claim 1 wherein composition is a tablet or animal feed.
13. The method of claim 1 wherein the vertebrate is a human and the parasitic worm or helminth selected from the group consisting of Roundworm, Whipworm, Hookworm, Ascaris, Pinworm, Strongyloides , Schistosome, and Trematodes.
14. The method of claim 1 wherein the worm is S. masoni, S. haemutobium, S. japanicum, S. mekongi or S. intercalatum.
15. The method of claim 1 wherein the worm or helminth is resistant to praziquantel.
16. The method of claim 1 wherein ergotamine, dihydroergotamine and lisuride are administered.
17. The method of claim 16 wherein ergotamine, dihydroergotamine and lisuride are concurrently administered.
18. The method of claim 1 wherein parasitic flatworm infection is inhibited or treated.
19. The method of claim 7 wherein R 3 is OH and R 4 is C 1-10 alkyl.
20. The method of claim 8 wherein R 8 is C 1-10 alkyl.