MXPA00003355A - Application of tnf antagonists as medicaments for treating septic diseases - Google Patents

Abstract

The invention relates to the application of TNF antagonists in order to produce medicaments for treating septic diseases characterized by an increasing coarse of the interleukin-6 serum level during a measurement interval of at least thirty minutes.

Description

APPLICATION OF TNF ANTAGONISTS AS MEDICATIONS TO TREAT SEPTIC DISEASES The present invention relates to the use of TNF antagonists for the treatment of septic disorders. It is known that the term tumor necrosis factor (TNF) comprises two cytotoxic factors (TNF-α and TNF-β) that are produced mainly by lymphocytes and activated monocytes. EP 260 610 describes, for example, anti-TNF antibodies that are said to be usable to inactivate TNF in conditions associated with an increase in TNF in the blood, such as septic shock, transplant rejection, allergy, autoimmune diseases, shock of lung, disorders in coagulation or inflammatory alterations of bone. In medical texts, septic conditions are defined as a collective term for clinical conditions in which the agents causing inflammation, for example, bacteria, start from a focus and reach the bloodstream, which initiates a wide range of subjective pathological manifestations and objective. Furthermore, it was found that the clinical image can vary widely depending on the type of causal agent, the response of the body, the main focus and the different participation of the organs (Stur et al. "Grundbegriffe der Inneren Medizin", 13th edition, page 570, Gustav Fischer Verlag, Stuttgart, 1984). It has been suggested that different cytokines are involved in the complex pathophysiological process of sepsis. Based on data from animal experiments, TNF in particular is attributed (Beutler et al., Science 229, (1985), 869-871), an important activity in septic shock. This finally gave rise to clinical studies conducted on the treatment of patients with -sepsis with anti-TNF antibodies. However, it was found in a phase II study, in multiple hospitals, recently published on the treatment of severe sepsis with murine monoclonal anti-TNF antibody that the total group (80 patients) did not benefit in terms of survival rate from of the treatment with the antibody. Only patients with high levels of TNF in the circulation appeared to benefit in terms of the probability of survival from the administration of high doses of anti-TNF antibody (CJ Fisher et al., Critical Care Medicine, vol.21, No. 3, pages 318-327). There is also a reference in this study to a correlation between the plasma concentrations of TNF and IL-6.

The activity of the cytokine interleukin-6 (IL-6) in sepsis is unclear and contradictory. High concentrations of IL-6 have been found in the serum of some patients with sepsis (Hack et al., Blood 74, No. 5, (1989) 1704-1710). Waage describes a correlation between the concentrations of the cytokines IL-6 and IL-8 and the severity of the shock but they have no effect alone or in combination with TNF, in terms of mortality, on the development of a shock syndrome (Waage in " Tumor Necrosis Factors ", ed. B. Beutler, Raven Press, New York, 1992, pages 275-283). Some scientists have attributed a beneficial role for IL-6 in septic shock because IL-6 inhibits, in the form of inactive feedback control, the production of TNF induced by LPS (Libert et al., In "Tumor Necrosis Factor: Molecular and Cellular Biology and Clinical Relevance "ed. W. Fiers, Karger, Basle, 1993, pages 126-131). WO 95/00291 describes the TNF antagonists as medicaments for the treatment of sepsis in patients in whom serum interleukin-6 concentrations are 500 pg / ml. However, from clinical studies it emerged that the treatment described in WO 95/00291 is not always satisfactory.

It is evident that there are cases of sepsis that can be treated satisfactorily with TNF antagonists, while in other cases the treatment with TNF antagonists is not satisfactory and in fact is contraindicated. An object of the present invention is to identify, reliably and quickly, those patients suffering from sepsis who can be treated satisfactorily with TNF antagonists. We have found that this objective is achieved through the use of the following characteristics to identify patients with septic conditions who can be treated satisfactorily: The concentration of interleukin-6 in serum is increasing, that is, within a period of measurement of at least 30 minutes the concentration measured in the last time is greater than the concentration measured first. Patients who have sepsis and who meet this criterion are very suitable for treatment with TNF antagonists. The preferred treatment is performed in patients whose serum interleukin-6 concentration in the measurement period is at least 500 pg / ml. However, it may also be distinctly greater than this concentration and may be up to the order of some g / ml. To establish the concentration of interleukin-6 (IL-6) is increasing, it is necessary to perform at least two measurements of IL-6. The second and last measurement must be obtained within a period of 30 minutes to 48 hours after the first measurement of IL-6 (measurement period). The period of preference measurement is 2-24, in particular 4-10 hours. The patients who are going to be treated are, as a rule, undergoing intensive medical treatment that sometimes does not allow compliance with the limits in the strict measurement period. The measurement of the increase in serum IL-6 concentration between the two measurements is not as important for use according to the invention. If the concentration of IL-6 in serum does not increase or even fall during the measurement period, treatment with TNF antagonists is not recommended. The concentrations of IL-6 in serum can be determined by common detection methods such as RIA. or ELISA. An example of a very suitable detection system is IL-6-EASIA supplied by Medgenix. The concentration of IL-6 can also be determined in an activity study in which, for example, the C-reactive protein is assayed. Different measurement methods or test systems sometimes pro different results for the same measurement, It is advisable to use the same measurement method or test system to determine the concentrations of IL-6 or, if different systems are used, calibrate them to each other. Suitable TNF antagonists are anti-TNF antibodies, TNF receptors or soluble fragments thereof, TNF binding proteins or those TNF derivatives that still possess TNF receptor binding but no longer have TNF activity. TNF antagonists of these types have the characteristic that they trap TNF that has already been prod and do not allow TNF to reach the TNF receptor or to compete with TNF for the "receptor." However, the TNF antagonists that prevent The formation or release of TNF is also suitable for use according to the invention Substances of this type inhibit, for example, the expression of the TNF gene or the release of TNF from the precursor forms. Suitable TNF antagonists are inhibitors of TNF convertase TNF antagonist activities have been described, for example, for xanthine derivatives, glucocorticoids, prostaglandin E 2, thalidomide, interleukin-4, interleukin-10, granulocyte-stimulating factor (G) -CSF), cyclosporine and α-antitrypain Thus, compounds of these types are also suitable as TNF antagonists TNF antagonists suitable for use according to the invention they are described, for example, by Mariott et al., DDT, vol. 2, No. 7, July 1997 and in the literature mentioned in it. Anti-TNF antibodies and fragments thereof are particularly preferred for use according to the invention. Anti-TNF antibodies suitable for use according to the invention are known (EP 260 610, EP 351 789, EP 218 868). It is possible to use polyclonal and monoclonal antibodies. Also suitable are fragments of antibodies that bind to TNF, such as Fab or F (ab ') 2 fragments or Fv fragments of a single chain. Humanized or humanized anti-TNF antibodies or their fragments that bind to TNF are also very suitable because these molecules should not cause any anti-mouse antigenicity in human patients. It is also possible to use mixtures of different anti-TNF antibodies or anti-TNF antibodies and fragments of the TNF receptor as the active ingredient. The present invention includes pharmaceutical compositions which, in addition to the non-toxic, inert, and pharmaceutically suitable carriers, contain anti-TNF antibodies, and the processes for producing these compositions. The anti-TNF antibodies are formulated in a customary manner for active ingredients produced by biotechnological methods, usually as a liquid or lyophilized formulation (see, for example, Hagers Handbuch der pharmazeutischen Praxis, vol.2, 5th edition, 1991, page 720). ISBN 3-540-52459-2). The aforementioned pharmaceutical compositions are produced in a conventional manner by the known methods, for example, by mixing the active ingredient (s) with the carrier (s). In general, it has proven advantageous to administer the active ingredient (s) suitable for use according to the invention in total amounts of from about 0.1 to about 100, preferably 0.1 to 10 mg / kg of body weight. every 24 hours, when appropriate in the form of several individual doses or by continuous intravenous route and, when appropriate, during a treatment period of several days until obtaining the desired results. Administration can take place briefly intravenously from individual doses or long-term continuous intravenous administration of the daily dose for 24 hours. An individual dose preferably contains the active ingredient (s) in amounts of about 0.1 to about 10 mg / kg of body weight. However, it may be necessary to deviate from the established dose, in particular as a function of the age and size of the patient to be treated and the nature and severity of the condition, the nature of the composition and the administration of the drug, and the period over which the administration is carried out. The invention is further illustrated in the following example.

Employ Treatment of patients with sepsis with an anti-TNF antibody fragment of urine (F (ab ') 2), designated Mab 195F (INN: AFELIMOMAB). In total, 251 patients with severe sepsis who were treated with an anti-TNF antibody fragment (afelimomab) or as control patients were analyzed in a clinical study in multiple hospitals. Of the 251 patients, 47 had an increase and 178 had a decrease in serum IL-6 concentration. The figure shows that a decrease in mortality can be obtained by treatment in the group with increasing concentrations of IL-6 (mortality of 55.6% compared to 69% in controls). There is no evident success of treatment with Mab 195 F in the group where the concentration of IL-6 in serum was decreasing; On the contrary, in fact, an adverse effect of the treatment is evident (mortality 54.7% compared to 50.6% in the control group). The treatment group received, in addition to the normal treatment for sepsis, the product of the trial, afelimomab for a period of three days as a total of 9 brief intravenous injections lasting 15 minutes, each at 8-hour intervals, in a single dose of 1 mg / kg of body weight each time. The control group received in addition to the normal treatment of sepsis a pharmacologically inactive product (placebo) administered with the same regimen. The result of this clinical study clearly demonstrates that the treatment of severe sepsis with anti-TNF antibodies is particularly successful when sepsis patients who are treated have an increasing concentration of IL-6 in serum. Patients who have a declining serum IL-6 level, therefore, should not be treated with TNF antagonists.

Claims (1)

1. CLAIMS The use of TNF antagonists to produce drugs. for the treatment of those septic conditions where the concentration of interleukin-6 in serum increases in a measurement period of at least 30 minutes. The use as mentioned in claim 1, wherein the concentration of interleukin-6 in serum is 500 pg / ml and greater in the period of measurement. The use as mentioned in claim 1, wherein the measurement period is 4-10 hours. The use as claimed in claim 1, wherein a F (ab ') 2 fragment of the monoclonal anti-TNF antibody is used as a TNF antagonist, a commercial package containing a TNF antagonist together with instructions for the use of this antagonist of TNF for the treatment of septic diseases where the concentration of IL-6 in serum increases in a measurement period of at least 30 minutes. The commercial package as recited in claim 5, wherein a monoclonal anti-TNF antibody is used as a TNF antagonist. A method to establish if a patient suffering from sepsis can be treated with TNF antagonists, the method comprises the following steps: (a) determine the concentration of interleukin-6 in serum in the patient at a first time t ±. (b) the determination of the concentration of interleukin-6 in serum at a second time t2 which is at least 30 minutes after the first time ti, and the determination of the ratio: Conc IL- (t2) V Conc IL- (ti) (c) treatment with TNF antagonists in the case where V > 1.