Method to increase systemic blood pressure in shock
Provided herein are methods of stabilizing blood pressure in severe sepsis/septic shock and other types of distributive shock using TRPV1 agonists. Also provided are pharmaceutical formulations for increasing blood pressure in septic shock the formulation including at least one TRPV1 agonist in a dosage form for parenteral administration, wherein the TRPV1 agonist is selected from capsaicin, daphnane TRPV1 agonists, vanillotoxin, N-oleoyl dopamine, N-arachidonyl dopamine, BrP-LPA, and derivatives and analogues thereof. Also provided are TRPV1 agonists co-lyophilized with adrenergic agonists and/or angiotensins in a dosage form for reconstitution and parenteral administration.
1 . A method of treatment of hypotension in a human patient in septic shock, the method comprising: co-administering at least two TRPV1 agonists to the patient in an amount sufficient to increase and/or maintain a systolic blood pressure of 65 mm Hg or greater in the patient, wherein the at least two TRPV1 agonists comprise BrP-LPA and a vanillotoxin.
2 . The method of claim 1 , wherein the at least two TRPV1 agonists further comprise one or more of a TRPV1 agonist selected from the group consisting of a capsaicin, a daphnane TRPV1 agonist, N-oleoyl dopamine, N-arachidonyl dopamine.
3 . The method of claim 2 , wherein the TRPV1 agonist is a capsaicin analogue selected from the group consisting of oleoylvanillamine, rinvanil, and phenylacetylrinvanil.
4 . The method of claim 2 , wherein the vanillotoxin is a double-knot spider toxin (DkTx).
5 . The method of claim 2 , wherein the TRPV1 agonist is a daphnane TRPV1 agonist selected from the group consisting of resiniferatoxin and tinyatoxin.
6 . The method of claim 1 , wherein the at least two TRPV1 agonists are co-administered with an adrenergic agonist selected from the group consisting of dopamine, phenylephrine, norepinephrine, and metaraminol.
7 . The method of claim 1 , wherein the at least two TRPV1 agonists are co-administered with an angiotensin.
8 . The method of claim 7 , wherein the angiotensin is selected from the group consisting of Angiotensin II (SEQ ID NO. 1), Angiotensin III (SEQ ID NO. 2) and Angiotensin IV (SEQ ID NO. 3).
9 . The method of claim 1 , wherein the at least two TRPV1 agonists are administered intravenously.
10 . The method of claim 1 , wherein the at least two TRPV1 agonists are administered by a topical patch.
11 . The method of claim 1 , wherein the at least two TRPV1 agonists are co-lyophilized prior to treatment.
12 . The method of claim 1 , wherein the vanillotoxin is a double-knot spider toxin (DkTx).
13 . The method of claim 1 , wherein the at least two TRPV1 agonists further comprise one or more of a TRPV1 agonist selected from the group consisting of capsaicin, oleoylvanillamine, rinvanil and phenylacetylrinvanil.
14 . A pharmaceutical formulation for increasing blood pressure in a human patient in septic shock, the formulation comprising at least two TRPV1 agonists in a dosage form for parental administration, wherein the at least two TRPV1 agonists comprise BrP-LPA and a vanillotoxin.
15 . The pharmaceutical formulation of claim 14 , wherein the at least two TRPV1 agonists further comprise one or more of a TRPV1 agonist selected from the group consisting of a capsaicin, a daphnane TRPV1 agonist, N-oleoyl dopamine, N-arachidonyl dopamine.
16 . The pharmaceutical formulation of claim 15 , wherein the formulation is lyophilized.
17 . The pharmaceutical formulation of claim 16 , further comprising a co-lyophilized adrenergic agonist selected from the group consisting of dopamine, phenylephrine, norepinephrine, and metaraminol.
18 . The pharmaceutical formulation of claim 16 , further comprising a co-lyophilized angiotensin selected from the group consisting of Angiotensin II (SEQ ID NO. 1), Angiotensin III (SEQ ID NO. 2) and Angiotensin IV (SEQ ID NO. 3).
19 . The pharmaceutical formulation of claim 14 , wherein the vanillotoxin is a double-knot spider toxin (DkTx).
20 . The pharmaceutical formulation of claim 14 , wherein the at least two TRPV1 agonists further comprise one or more of a TRPV1 agonist selected from the group consisting of capsaicin, oleoylvanillamine, rinvanil and phenylacetylrinvanil.