Patent Publication Number: US-4225605-A

Title: Ergolene or ergoline compounds for treating congestive heart failure

Description:
The present invention relates to a new use of a compound chosen from ergolenes and ergolines possessing activity as dopaminergic stimulants, particularly peripheral dopaminergic stimulants as indicated by significant activity, e.g. a decrease in blood pressure and a selective vasodilation in mesenteric and renal blood vessels, in the anaesthetised dog (chloralose-urethane) on administration of from 5 to 25 μg/kg of the compound. 
     Alternatively such peripheral dopaminergic activity is indicated by central dopaminergic activity in standard tests e.g. those described in DOS No. 2,509,471. 
     The compound is, for example: 
     (a) 2-Bromo-α-ergocryptine (which is the preferred compound), 
     (b) 6-Methylergolin-8α-acetonitrile, 
     (c) 6-Methylergolin-8β-acetonitrile, 
     (d) 6-Methyl-2-chloro-ergoline-8β-acetonitrile, 
     (e) 6-Methyl-8α and β-(2-pyridylthiomethyl)ergolenes and ergolines, such as 6-methyl-8β-(2-pyridylthiomethyl)ergolene, 
     (f) 6-Methyl-8β-carbamoylmethylergoline, 
     (g) 6-Methyl-8α-(dimethylsulphamoylamino)ergoline, 
     (h) 6-Methyl-8α-(diethylsulphamoylamino)ergoline, 
     (i) 1,6-Dimethyl-8α-(dimethylsulphamoylamino)ergoline, or 
     (j) 6-methyl-8α-diethylcarbamoylamino-ergoline. 
     It has been found that the compounds are useful for the treatment of congestive heart failure, as indicated by standard trials. In one trial, four male patients, mean age 61 years, suffering from hypertension and arteriosclerotic cardiac insufficiency were studied. No diuretic or digitalis drugs had been administered for 15 days before the trial. 
     During the trial, the ratio PEP/LVET (PEP=pre-ejection period ; LVET=left-ventricular ejection time) before and 30, 60 and 90 minutes after administration of 2.5 to 5 mg of the compound was measured, and found to decrease significantly over the trial. Examples of the results obtained with 2-bromo-α-ergocryptine are as follows: 
     
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Ratio PEP/LVET                                                            
           Post-medication (minutes)                                      
Pre-medication                                                            
             30        60        90                                       
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0.46         0.46      0.44      0.43                                     
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     The cardiac frequency also remained stable. 
     For the abovementioned use, the dosage will, of course, vary depending on the mode of administration and therapy desired. However, in general, satisfactory results are obtained with a daily dosage of from about 0.01 to about 10 mg per kg animal body weight, conveniently given in divided doses 2 to 4 times a day or in sustained release form. For the larger mammal, the total daily dosage is in the range from about 2.5 to 40 mg, e.g. up to 10 mg, and dosage forms suitable for oral administration comprise from about 0.5 to about 20 mg of the compound admixed with a solid or liquid carrier or diluent. 
     The compound may be administered in pharmaceutically acceptable acid addition salt form. Such forms are known and have in general the same activity as the corresponding free base form. Examples of suitable acids for salt formation include methane-sulphonic acid, fumaric acid, tartaric acid and hydrochloric acid. 
     The compounds may be administered on their own or as a pharmaceutical composition. Such compositions are known and may be formulated in conventional manner to be, for example, tablets, powders, granules, capsules, suspensions, solutions, sirups and elixirs for enteral administration or injectable solutions and suspensions for parenteral administration. 
    
    
     The following Examples illustrate compositions suitable for use in the invention. 
     EXAMPLE 1: 2-Bromo-α-ergocryptine tablets 
     Tablets suitable for enteral administration and containing the following ingredients, may be produced in known manner. 
     
         ______________________________________                                    
Ingredients        Weight                                                 
______________________________________                                    
2-Bromo-α-ergocryptine methane-                                     
                   2.87 mg  (corresponding                                
sulphonate                  to 2.5 mg of base)                            
Lactose            96.18 mg                                               
Maize starch       14.00 mg                                               
Polyvinylpyrrolidone                                                      
                   5.00 mg                                                
Magnesium stearate 0.70 mg                                                
Talc               1.20 mg                                                
Colouring substances                                                      
                   0.05 mg                                                
                   120 mg                                                 
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     EXAMPLE 2: 2-Bromo-α-ergocryptine capsules 
     Hard gelatine capsules suitable for enteral administration and containing the following ingredients, may be produced in known manner. 
     
         ______________________________________                                    
Ingredients     Weight.sup.(1)                                            
                             Weight.sup.(2)                               
______________________________________                                    
2-Bromo-α-ergocryptine                                              
                3.00 mg      11.47 mg                                     
methanesulphonate                                                         
Lactose         105.00 mg    160.03 mg                                    
Maize starch    20.00 mg     120.00 mg                                    
Talc            4.50 mg      --                                           
Aerosil® 200 (Degussa)                                                
[colloidal silica]                                                        
                1.00 mg      1.5 mg                                       
Magnesium stearate                                                        
                1.50 mg      3.0 mg                                       
Maleic acid     --           4.0 mg                                       
Optionally colouring                                                      
substances      q.s.         q.s.                                         
                135 mg       300 mg                                       
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 .sup.(1) Corresponding to 2.61 mg of base                                
 .sup.(2) Corresponding to 10 mg of base                                  
 
    
     EXAMPLES 3 and 4: Sterile suspension for injection and oral liquid suspension 
     The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses. The injectable suspension is suitable for administration once a day, whereas the oral liquid suspension is suitably administered 2 to 4 times per day for this purpose. 
     
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                 Weight       Weight                                      
                 Sterile injectable                                       
                              Oral liquid                                 
Ingredient       suspension   suspension                                  
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2-bromo-α-ergocryptine                                              
                 7 mg         7 mg                                        
Sodium carboxy methyl                                                     
cellulose, U.S.P.                                                         
                 1.25 mg      12.5 mg                                     
Methyl cellulose  0.4 mg      --                                          
Polyvinylpyrrolidone                                                      
                 5 mg         --                                          
Lecithin         3 mg         --                                          
Benzyl alcohol    0.01 mg     --                                          
Magnesium aluminum silicate                                               
                 --           47.5 mg                                     
Flavor           --           q.s.                                        
Color            --           q.s.                                        
Methyl paraben, U.S.P.                                                    
                 --           4.5 mg                                      
Propyl paraben, U.S.P.                                                    
                 --           1.0 mg                                      
Polysorbate 80 (e.g. Tween 80)                                            
U.S.P.           --           5 mg                                        
Sorbitol solution, 70% U.S.P.                                             
                 --           2.500 mg                                    
Buffer agent to adjust pH for                                             
desired stability                                                         
                 q.s.         q.s.                                        
Water            .sup.(1)     .sup.(2)                                    
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 .sup.(1) for injection, q.s. to 1 ml.                                    
 .sup.(2) q.s. to 5 ml.