Sepsis is a severe systemic infectious disease in which bacteria continuously or intermittently enter the blood from an infection focus, which is caused by diseases such as infectious diseases, cirrhosis, renal failure, diabetes and dystocia, or by therapies against injury or disease, such as indwelling catheter, transfusion device, dialysis or tracheostomy. In its broader sense, sepsis is not restricted to the invasion by a microorganism into a host, but is defined to include clinical conditions of infectious diseases, in which two or more of the following are met: (1) body temperature >38° C. or <36° C.; (2) heart rate >90 beats/min.; (3) frequency of respiration >20 breaths/min. or PaCO2<32 mmHg; (4) number of leukocytes >12,000/μl or <4000/μl, or ratio of stab neutrophil>10%. Recently, the pathological conditions exhibiting these symptoms are called systemic inflammatory response syndrome (SIRS) (Crit. Care Med., 20:864-874, 1992). Sepsis further includes organ dysfunction, severe sepsis complicated with hypoperfusion or hypotension, lactic acidosis, hypouresis and septic shock complicated with consciousness disorder (Chest,101:1644-1655,1992). Severe sepsis and septic shock induce disseminated intravascular coagulation syndrome (DIC), adult respiratory distress syndrome (ARDS) and multiple organ dysfunction (MODS).
The causative bacteria of sepsis are mainly staphylococci, streptococci, Escherichia coli, Pseudomonas aeruginosa, Klebsiella and Enterobacter. By the infection of these bacteria, high fever, chill, tachycardia and strong systemic symptoms are exhibited, and existence of the infective bacteria is often confirmed in the arterial blood, venous blood, spinal fluid and bone marrow fluid.
Recently, due to the development of various strong antibiotics, sepsis caused by these bacteria is decreasing. However, sepsis caused by new bacteria such as MRSA, which acquired a resistant gene is increasing. Reflecting the increase of treatments using indwelling catheter or transfusion device, dialysis, and invasive treatments and surgery such as tracheostomy, there is a tendency that the larger the scale of the hospital, the more the occurrence of sepsis. Further, frequency of sepsis is increasing among those having poor resistance to infections, such as newborns, elder people, patients suffering from hematopoietic organ tumors and patients whose immunities are decreased due to administration of adenocorticotropic hormones or anticancer agents. Thus, sepsis is continuously increasing in spite of the development of medicine.
A method for prevention or therapy of sepsis now employed is carried out by administering the best antibiotic against the causative bacterium after detecting the causative bacterium and determining the sensitivities thereof to antibiotics, and by simultaneously promoting the defending ability of the host by fluid replacement, replenishment of electrolytes, improvement of hypoproteinemia, replenishment of nutrients, administration of γ-globulin and the like (Masataka KATSU, Encyclopedia of medical sciences,37:263-265,1984). In cases where the shock unfortunately appears, treatments such as removal of lesion by surgery, improvement of circulatory dysfunction, administration of opsonin-activating substances, administration of adenocorticotropic hormones, administration of synthetic protease inhibitors, and the like are carried out. However, since the symptoms of the underlying basal disease and the symptoms of sepsis overlap, clear diagnosis is not easily carried out, which often gives difficulty in the prevention and therapy of sepsis. In cases where the septic shock occurs, the prevention and therapy are difficult. Thus, sepsis is a disease which gives a high death rate even at present.
The death rate of sepsis varies from 10%-20% s to 50% depending on the report. Forty percent of sepsis cases are complicated with septic shock, and the prognosis of the shock is bad. There is a report which shows the death rate of the shock is 77 to 90% (New Development of Sepsis, pp3-8, Medicine Journal Co., Ltd., 1998, Ann Intern Med 115: 457-469, 1991). Therefore, the primary object of the therapy is the prevention of the septic shock. If the changes which occurs in the initial stage of the shock are grasped and early diagnosis is attained, early treatment can be attained and improvement of prognosis is expected. However, although a number of anti-shock drugs and therapeutic methods have been studied, almost none of them were judged effective.
It is thought that sepsis is caused by inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), interleukin 6 (IL-6) and interleukin 8 (IL-8), which are excessively produced by monocytes, macrophages, vascular endothelial cells and the like in response to the infectious stimuli (such as bacterial cells per se, endotoxins, cell wall components which are peptide glycan/teichoic acid complexes and exotoxins). By the excessively produced inflammatory cytokines, eicosanoid and lipid mediators of platelet-activating factor are released, and the cytokine net work is activated by the interaction thereof, so that the inflammatory reaction is amplified. During this process, complement system, coagulation system, kinin system and adrenocorticotropic hormone/endorphin system are also activated, and the systemic inflammatory reaction of which underlying symptom is vascular endothelial disorder is induced. For expression of circulatory disorders or histotoxic disorders, participation of elastase originated from granulocytes and active oxygen has been shown (New Development of Sepsis, pp3-8, Medicine Journal Co., Ltd., 1998).
Therefore, a number of clinical tests of the therapeutic methods which inhibit the inflammatory cytokines, represented by administration of substances that inhibit the inflammatory cytokines have been carried out. However, all of them were unsuccessful (Lancet,351:929-933,1998, JAMA,271:1836-1843,1994). Bone suggested that the reason for the failure of the tests may be the homeostasis in the body by which an action in the body necessarily accompanies a counteraction therefor so that they are balanced (Crit. Care Med., 24:1125-1128,1996). In fact, it is known that surgery or severe acute pancreatitis induces both the inflammatory cytokines and the anti-inflammatory cytokines or inflammatory cytokine-inhibiting substances (Intensive Care, 10;815-822,1998). If the induction of the anti-inflammatory cytokines is too strong, anergy is presented or the patient becomes easily infective. This anti-inflammatory cytokines-dominant state is called compensatory anti-inflammatory response syndrome (CARS), and participates in the onset of organ dysfunction in sepsis together with SIRS. That is, the pathological state of sepsis is double-faced, and it is important for the therapy to control both the inflammatory cytokine reactions and the anti-inflammatory cytokine reactions. Therefore, it is thought that therapeutic effects of the therapies in which only one of the reactions is inhibited by inhibition of inflammatory cytokines or the like were not exhibited.
Although intensive care developed during this 20 years, the death rate of sepsis is kept high and there are substantially no effective remedies. The reason therefor is that the pathological conditions of sepsis have not yet been completely understood (Nath. J. Med.,55:132-141,1999). It is also a reason therefor that therapeutic effects of drugs were studied by administering the test drugs before inducing the experimental sepsis in non-clinical animal tests.
Opioid drugs represented by morphine are widely used clinically as analgesics. It is thought that an opioid binds to an opioid receptor existing on the cell membrane and changes ion channels or enzymes through G protein, thereby exhibiting its pharmacological effectsThere are three types of opioid receptors called δ, κ and μ, and structures of these receptors were clarified by the cloning of the genes (Pharmacol. Rev.,48:567-592,1996). Most of the opioids clinically used are the drugs which act on μ receptor. Known agonists include morphine, codeine, oxycodone, pethidine and fentanyl, and known antagonists include naloxone and levallorphan. Other clinically used opioids include butorphanol, pentazocine and eptazocine, and they act on both μ receptor and κ receptors (Basis and Clinic of Opioids, pp9-15, MIX Co., Ltd., 2000). Known pharmacological actions of the compounds which act on μ receptor include actions causing analgesia, miosis, respiratory depression, emesis or nausea, constipation, euphoria and pruritus.
As for the compounds which selectively act on κ receptor, no drugs which can be clinically used have been obtained. However, a number of compounds which can be non-clinically used are known, and clinical tests of some of them are now being conducted (Exp. Opin. Invest. Drugs,6:1351-1368,1997). Known pharmacological actions of the compounds which act on κ receptor include actions causing analgesia, sedation, discomfort, diuresis, cell protection and antipruritus.
As for the actions of opioids on sepsis, the action of morphine which is a μ agonist, and the action of naloxone which is a μ antagonist, are reported. The former is reported to decrease survival rate of experimental sepsis models, and the latter, naloxone, is reported to suppresses fever of experimental sepsis models (J. Neuroimmuneol.,95:107-114,1999, Eur. J. Pharmacol.,401:161-165,2000). U.S. Pat. Nos. 4,267,182 (1981) and 4,434,168 (1984) describe narcotic antagonists for therapies of various shocks. However, compounds which selectively act on κ receptor are not described. It is not clear how a compound which acts on κ receptor behaves with respect to sepsis.
On the other hand, U.S. Pat. No. 5,482,930 (1996) discloses anti-inflammation actions of des-Tyr dynorphine which is one of the compounds that act on κ receptor and of analogues thereof.