Abstract:
Levosimendan, or (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, which has been mentioned for the treatment of congestive heart failure, is useful in the treatment of septic shock.

Description:
This application is a national stage filing of PCT International Application No. PCT/FI01/00614, filed on Jun. 28, 2001. This application also claims the benefit of priority under 35 U.S.C. § 119(a) to Finnish patent application no. 20001542, filed on Jun. 29, 2000. 
     TECHNICAL FIELD 
     The present invention relates to a method for the treatment of septic shock by administering levosimendan, or (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile (I), or pharmaceutically acceptable salts thereof, to a patient in need of such treatment. 
     BACKGROUND OF THE INVENTION 
     Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for its preparation is described in EP 565546 B1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. Levosimendan is represented by the formula: 
     
       
                 
         
             
             
         
      
     
     The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066 and in Lilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69, 1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. The use of levosimendan in the treatment of pulmonary hypertension is described in WO 99/66912. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients. 
     Septic shock (also known as sepsis) is the leading cause of morbidity and mortality in the intensive care units. Despite increased knowledge about the pathophysiology underlying the clinical symptoms mortality remains high and has not decreased substantially over the last decades. 
     There are several causes of septic shock including bacterial, fungal and viral infections as well as non-invasive stimuli such as multiple trauma, severe burns, organ transplantations and pancreatitis. The fatal outcome of septic shock has recently been linked to the systemic release of substantial amounts of various cytokines in the body. 
     Septic shock requires prompt treatment since the patient&#39;s condition often deteriorates rapidly. Symptoms of septic shock include fever, hypothermia, falling blood pressure, rapid breathing, rapid heartbeat, skin lesions and leakage of plasma proteins into the tissues, metabolic acidosis and elevated plasma lactate. Septic shock is particularly characterised by maldistribution of blood flow and disturbances in tissue oxygen in various organs of the body. Distribution of blood flow may become heterogenous with subsequent under- and overperfusion of various tissues. These disturbances have been noted both at the macro- as well as at the microcirculatory level. Septic patient usually die as a result of poor tissue perfusion and injury followed by multiple organ failure. 
     One of the organs in which the disturbances in nutritive flow is especially important is the gut. The importance of preserved of splanchnic blood flow in various shock conditions, including septic shock, has been largely emphasized in the literature. Reductions in splanchnic blood flow have been a suggested contributor to the development of multiple organ failure as well as maintenance of sepsis by translocation of gut derived bacteria over a hyperpermeable gut wall. 
     Current therapeutic strategies in sepsis include antibiotics, in certain cases surgical intervention, blood volume replacement as well as inotropic support to the failing circulation. However, the current therapy has not proven to be successful. Insufficient response to intropic drugs in terms of cardiac output is not uncommon. Also the distribution of blood flow to various organs may become negatively affected. For example, splanchnic blood flow is not increased in spite of increased cardiac output. Thus, an improved method for treating septic shock would be of great value. 
     SUMMARY OF THE INVENTION 
     It has now been found that in the porcine model of endotoxin shock levosimendan unexpectedly counteracts endotoxin-induced splanchnic hyperperfusion as well as endotoxin-induced decreases in cardiac output. These favourable effects suggest that levosimendan is particularly beneficial in the treatment of septic shock. 
     Therefore, the present invention provides the use of (−)-[[4-(1,4,5,6-tetra-hydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment septic shock. 
     The present invention also provides a method for the treatment of septic shock in a patient, said method comprising administering to a patient in need thereof an effective amount of (−)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl]hydrazono]propanedinitrile or a pharmaceutically acceptable salt thereof. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows the effect of levosimendan on the cardiac index in a porcine model of endotoxin shock compared to control. 
         FIG. 2  shows the effect of levosimendan on the portal blood flow index in a porcine model of endotoxin shock compared to control. 
         FIG. 3  shows the effect of levosimendan on the pulmonary vascular resistance index in a porcine model of endotoxin shock compared to control. 
         FIG. 4  shows the effect of levosimendan on the portal venous blood flow lactate in a porcine model of endotoxin shock compared to control. 
     
    
    
     DETAILED DESCRIPTION 
     The method of the invention comprises a step of administering to a subject an amount of levosimendan effective to reduce, inhibit or prevent symptoms of septic shock in a patient. In particular the method comprises administering to a patient an amount of levosimendan effective to counteract endotoxin-induced harmful effects on the peripheral circulation of a patient. The term “treatment of septic shock” is intended to cover therapeutic and/or prophylactic treatments. The administration of levosimendan can be enteral, e.g. oral or rectal, or parenteral, e.g. intravenous or transdermal. 
     The effective amount of levosimendan to be administered to a subject depends upon the condition to be treated, the route of administration, age, weight and the condition of the patient. In general levosimendan is administered orally to man in daily dose from about 0.1 to 20 mg, preferably from 0.2 to 15 mg, more preferably from 0.5 to 10 mg, given once a day or divided into several doses a day, depending on the age, body weight and condition of the patient. Levosimendan can be administered by intravenous infusion using the infusion rate typically from about 0.01 to 10 μg/kg/min, more typically from about 0.02 to 5 μg/kg/min. For the intravenous treatment of septic shock an intravenous bolus of 10-200 μg/kg followed by infusion of 0.2-3 μg/kg/min may be needed. 
     Levosimendan is formulated into dosage forms suitable for the treatment of septic shock using the principles known in the art. It is given to a patient as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions whereby the contents of the active compound in the formulation is from about 0.5 to 100% per weight. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art. It is evident that suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients, antioxidants, colours, sweeteners, wetting compounds, release controlling components and other ingredients normally used in this field of technology may be also used. 
     For oral administration in tablet form, suitable carriers and excipients include e.g. lactose, corn starch, magnesium stearate, calcium phosphate and talc. For oral administration in capsule form, useful carriers and excipients include e.g. lactose, corn starch, magnesium stearate and talc. For controlled release oral compositions release controlling components can be used. Typical release controlling components include hydrophilic gel forming polymers such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethyl celluloses, alginic acid or a mixture thereof; vegetable fats and oils including vegetable solid oils such as hydrogenated soybean oil, hardened castor oil or castor seed oil (sold under trade name Cutina HR), cotton seed oil (sold under the trade names Sterotex or Lubritab) or a mixture thereof; fatty acid esters such as triglycerides of saturated fatty acids or their mixtures e.g. glyceryl tristearates, glyceryl tripalmitates, glyceryl trimyristates, glyceryl tribehenates (sold under the trade name Compritol) and glyceryl palmitostearic acid ester. 
     Tablets can be prepared by mixing the active ingredient with the carriers and excipients and compressing the powdery mixture into tablets. Capsules can be prepared by mixing the active ingredient with the carriers and excipients and placing the powdery mixture in capsules, e.g. hard gelatin capsules. Typically a tablet or a capsule comprises from about 0.1 to 10 mg, more typically 0.2 to 5 mg, of levosimendan. 
     Formulations suitable for intravenous administration such as injection or infusion formulation, comprise sterile isotonic solutions of levosimendan and vehicle, preferably aqueous solutions. Typically an intravenous infusion solution comprises from about 0.01 to 0.1 mg/ml of levosimendan. 
     Salts of levosimendan may be prepared by known methods. Pharmaceutically acceptable salts are useful as active medicaments, however, preferred salts are the salts with alkali or alkaline earth metals. 
     EXAMPLES 
     Pharmaceutical Example 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Hard gelatin capsule size 3 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Levosimendan 
                  2.0 mg 
               
               
                   
                 Lactose 
                  198 mg 
               
               
                   
                   
               
             
          
         
       
     
     The pharmaceutical preparation in the form of a capsule was prepared by mixing levosimendan with lactose and placing the powdery mixture in hard gelatin capsule. 
     Experiments 
     20 kg landrace pigs were anesthetized and catheterized. After baseline measurements 8 pigs received 200 μg/kg levosimendan as a 10 minute bolus followed by an infusion of 200 μg/kg/hour. 9 animals served as controls. 
     In the second phase of the experiment the animals were given an infusion of endotoxin (from  E. Coli  bacteria) 30 minutes after the start of the bolus dose of levosimendan. The endotoxin infusion was maintained for 3 hours and the levosimendan infusion was maintained throughout the experiment until 5 hours after onset of endoxemia. Comparison between the two groups was made with ANOVA. 
     The changes in the cardiac index, splanchnic (portal) blood flow index, portal venous blood lactate and pulmonary vascular resistance are shown in  FIGS. 1-4 . In the Figures, (−0.5 h) means the start of levosimendan bolus and (0 h) the start of endotoxin infusion. The results show that levosimendan can significantly counteract endotoxin-induced circulatory disorders. All levosimendan treated animals survived whereas one animal in the control group died.