Method Of Therapeutic Administration of DHE To Enable Rapid Relief Of Migraine While Minimizing Side Effect Profile

Abstract

Pharmaceutical compositions containing dihydroergotamine (DHE) and methods in which DHE is administered to patients for treatment of migraine without side effects or adverse effects are disclosed. Methods for rapid treatment of migraine with DHE are disclosed comprising: dampening the peak plasma concentration (C max ) and slightly delaying the peak such as to avoid activating the dopaminergic and adrenergic receptors, while achieving sufficient active binding to the serotonin receptors to provide relief from migraine symptoms within a timeframe that permits rapid resolution of migraine symptoms. Inhaler devices suitable for the methods are disclosed. Kits for practicing the methods of invention are disclosed.

1 . A method for rapid treatment of migraine in an individual with DHE or salts, hydrates, polymorphs, prodrugs, ion pairs and metabolites thereof, while minimizing side effects, the method comprising:
 administering to the individual an amount of a DHE formulation at a rate sufficient for obtaining relief from a migraine symptom,   wherein the amount and rate of DHE administration causes a significant reduction in a side effect.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the side effect is selected from the group consisting of nausea, emesis, vasospasm, paraesthesia, hypertension, dizziness, anxiety, dyspnea, headache, flushing, diarrhea, rash, increased sweating, cardiac valvulopathy, pleural and retroperitoneal fibrosis, adverse cardiovascular effect, blood pressure instability and arterial constriction. 
     
     
         4 . The method of  claim 1 , wherein the side effect is selected from the group, consisting of nausea and emesis. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) is less than 15,000 pg/ml concentration in the circulating plasma in humans, and the time (T max ) following administration when the peak plasma concentration is attained, is less than 30 minutes after administration. 
     
     
         22 . The method of  claim 21 , wherein the C max  of DHE is less than 10,000 pg/mL in the circulating plasma. 
     
     
         23 . The method of  claim 21 , wherein the C max  of DHE is less than 7,500 pg/mL in the circulating plasma. 
     
     
         24 . The method of  claim 21 , wherein the DHE is administered at a rate such that the T max  of DHE is less than 20 minutes in the circulating plasma. 
     
     
         25 . The method of  claim 1 , wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) of DHE is at least 10-fold reduced from the C max  of DHE administered by direct intravenous delivery. 
     
     
         26 . The method of  claim 1 , wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) of DHE is at least at least 1 minute delayed from the T max  of DHE administered by direct intravenous delivery. 
     
     
         27 . The method of  claim 24 , wherein the administration of DHE to achieve the C max  and T max  levels results in at least partial relief from a migraine syndrome selected from the group consisting of pain, nausea, phonophobia and photophobia, wherein the relief is achieved in 30 minutes or less, and further wherein drug-induced nausea, cardiovascular side effects or other adverse effects are reduced. 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 1 , wherein an unit dose of less than 2.0 mg DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof is administered. 
     
     
         30 . The method of  claim 14 , wherein an unit dose of less than 2.0 mg DHE or salts, hydrates, polymorphs prodrugs, ion pairs and metabolites thereof is administered and an area the curve of the concentration of the drug in the systemic circulation versus time (AUC) of the drug delivered is within 75% of the comparable intravenous (IV) delivered dose. 
     
     
         31 . The method of  claim 1 , wherein the administration results in a peak plasma concentration of a primary active metabolite of DHE of less than 1,000 pg/ml at C max . 
     
     
         32 . The method of  claim 31 , wherein the primary active metabolite of DHE is 8-hydroxy-dihydroergotamine. 
     
     
         33 . The method of  claim 31 , wherein the of the primary metabolite is less than 500 pg/mL in the circulating plasma. 
     
     
         34 . The method of  claim 31 , wherein the C max  of the primary metabolites is less than 200 pg/mL in the circulating plasma. 
     
     
         35 . The method of  claim 31 , wherein the T max  of the primary metabolites is less than 90 minutes in the circulating plasma. 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 1 , wherein the DHE formulation is administered by a mode selected from the group consisting of: intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoresis, and transdermal administration. 
     
     
         39 . The method of  claim 38 , wherein the DHE formulation is administered by pulmonary inhalation comprising aerosols, dry powder inhalers, nebulizers, vaporizers or pressurized metered dose inhalers (pMDI). 
     
     
         40 . The method of  claim 38 , wherein the DHE formulation is administered by a breath activated metered dose inhaler. 
     
     
         41 . The method of  claim 1 , wherein the DHE formulation is administered by a mode selected from the group consisting of intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, sublingual, buccal, intranasal, oral inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, iontophoresis, and transdermal administration, and
 further wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) is less than 10,000 pg/ml concentration in the circulating plasma in humans, and the time (T max ) following administration when the peak plasma concentration is attained, is less than 30 minutes after administration.   
     
     
         42 . The method of  claim 41 , wherein the DHE formulation is administered by pulmonary inhalation comprising aerosols, dry powder inhalers, nebulizers, vaporizers or pressurized metered dose inhalers (pMDI). 
     
     
         43 . The method of  claim 42 , wherein the DHE formulation is administered by a breath activated metered dose inhaler. 
     
     
         44 . The method of  claim 43 , wherein the DHE formulation is administered without administering an anti-emetic to the individual. 
     
     
         45 . The method of  claim 1 , wherein the DHE formulation is administered to an individual by a breath activated metered dose inhaler,
 wherein the DHE is administered at a rate such that the peak plasma concentration (C max ) is less than 10,000 pg/ml concentration in the circulating plasma in humans, and the time (T max ) following administration when the peak plasma concentration is attained, is less than 20 minutes after administration, and   further wherein the DHE formulation is administered without administering an anti-emetic to the individual.   
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled)