CN1163272C - Application of TNF antagonists as medicaments for treating septic diseases - Google Patents
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
- C07K16/241—Tumor Necrosis Factors
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Abstract
The invention relates to the application of TNF antagonists in order to produce medicaments for treating septic diseases in which an increasing coarse of the interleukin-6 serum level during a measurement interval of at least thirty minutes.
Description
The present invention relates to the purposes that the TNF antagonist is used for the treatment of septic diseases.
Known terms tumor necrosis factor (TNF) comprises two kinds of cytotoxic factor (TNF-α and TNF-β) that in most of the cases produced by activated lymphocyte and mononuclear cell.
For example, described among the EP 260 610 and it is said and anti-TNF antibody can be used for making the raise TNF inactivation of relevant disease with blood TNF, described disease such as septic shock, transplant rejection, anaphylaxis, autoimmune disease, shock lung, blood coagulation disorders or inflammation of bone disease.
In medical textbook, septic diseases is defined as the common terminology that begins and enter the clinical setting of blood flow from focus to by the factor that causes inflammation (for example antibacterial), it can cause a large amount of subjectivities and objective pathological manifestations.Further find the different complex situations that clinical setting can be comprised according to the type of pathogen, the reactivity of health, original focus and organ and significantly change (Sturm etc. " Grundbegriffe der Inneren Medizin ", the 13rd edition, 570 pages, GustavFishcher Verlag, Stuttgart, 1984).
The complex pathophysiological process of having pointed out a large amount of cytokines to relate to sepsis.Since from zooperal data be the basis (Beutler etc., Science, 229 (1985) 869-871), think that TNF especially plays an important role in septic shock.
This has finally produced the clinical research of carrying out with anti-TNF Antybody therapy sepsis patient the time.
Yet, in study in the multicenter II phase of recently announcing discovery with the serious sepsis of Mus monoclonal anti-TNF Antybody therapy the time with regard to survival rate whole groups (80 patients) all do not have benefited from therapeutic scheme with described antibody.Seem to have benefited from the administration (the 21st rolls up the 3rd phase 318-327 page or leaf for C.J.Fisher etc., Critical Care Medicine) of the anti-TNF antibody of high dose with regard to survival probability opinion only has the TNF concentration of rising in circulation patient.The dependency that in this research, also relates to Plasma TNF levels and IL-6 level.
The part of being explained by cytokine interleukin-6 (IL-6) in sepsis is unclear and is opposition.Have been found that the level rising (Hack etc., Blood, 74, the 5 phase (1989) 1704-1710) of IL-6 in some sepsis patient's serum.
Waage has described the concentration of cytokine IL-6 and IL-8 and the dependency between the shock order of severity, but with regard to mortality rate, they neither can or not work to the shock syndrome with TNF separately yet, and (Waage is described in " Tumor Necrosis Factors ", B.Beutler edits, Raven Press, New York, 1992, the 275-283 page or leaf).
Some scientist will be in septic shock beneficial effect owing to IL-6, because IL-6 can suppress the inductive TNF of LPS-and produces that (Libert etc. are described in " Tumor Necrosis Factors:Molecular and Cellular Biology andClinical Relevance " in the process that forms negative feedback control, W.Fiers, Karger, Basle edits, 1993, the 126-131 page or leaf).
Disclose the TNF antagonist among the WO 95/00291 and can be used as the medicine that is used for the treatment of the sepsis patient, in these patients, the serum levels of interleukin-6 is 500pg/ml or higher.
Yet, from clinical research, demonstrate success always of disclosed Therapeutic Method among the WO 95/00291.
Obviously exist available TNF antagonist successfully to treat the situation of sepsis, and unsuccessful and in fact be incompatible with the treatment of TNF antagonist in other situation.
The objective of the invention is to reliably and apace identify those patients that can successfully use the trouble sepsis of TNF antagonist for treating.
We have found that this purpose followingly is used for identifying that the feature that can successfully treat the patient who suffers from septic diseases realizes by utilizing:
The serum levels of interleukin-6 raises, promptly at least 30 minutes mensuration in the time limit interleukin-6 serum levels in slower timing be higher than the interleukin-6 serum levels of measuring first.
The patient who suffers from sepsis and satisfy this standard is suitable for using the TNF antagonist for treating very much.
Preferred situation is that the patient that the serum levels of measuring time limit words spoken by an actor from offstage cytokine-6 is at least 500pg/ml is carried out this treatment.Yet it can and reach the scope of several mg/ml apparently higher than this level.
For whether the serum levels of determining interleukin-6 (IL-6) obtains raising, be necessary to carry out at least twice IL-6 and measure.
30 minutes to 48 hour time limit planted agents after IL-6 measures (measuring the time limit) first obtain for the second time slower measurement result.
Preferably measure the time limit at 2-24 hour, particularly 4-10 hour.
The patient who is treated can experience intensive treatment usually, and this treatment can not allow the strictness of institute's foundation to measure the restriction in time limit sometimes.
The degree that the IL-6 serum levels raises between twice mensuration is not very crucial for purposes of the present invention.
If the serum levels of IL-6 does not raise or measuring in the time limit even descending, do not recommend to use the therapeutic scheme of TNF antagonist so.
Can measure the serum-concentration of IL-6 by conventional sense method such as RIA or ELISA.The example of a most suitable detection system is the IL-6-EASIA that is provided by Medgenix.
Test, wherein for example measure the concentration that also can measure IL-6 in the C-activated protein a kind of active detection.
Because different assay methods or detection system produce different results to same mensuration sometimes, so reasonably be to use same assay method or detection system to measure the IL-6 level; If or use different systems, so they are calibrated mutually.
Suitable TNF antagonist is anti-TNF antibody, TNF receptor or its soluble fragments, TNF is conjugated protein or those still have the effect of TNF receptors bind and no longer have active those TNF derivants of any TNF.The TNF antagonist of these types has and is characterised in that they can catch the TNF that has produced and can't make it to reach the TNF receptor or be that they can fight for receptor with TNF.
Yet, prevent to form or the TNF antagonist that discharges TNF also is suitable for purposes of the present invention.This class material can suppress the expression of tnf gene for example or the TNF release from precursor forms.The example of suitable TNF antagonist is the inhibitor of TNF invertase.
For example, described TNF antagonism derivant, they are xanthine derivative, glucocorticoid, PGE2, Thalidomide, interleukin 4, interleukin 10, granulocyte stimulating factor (G-CSF), ciclosporin and alpha antitrypsin.Therefore, the chemical compound of these types also is suitable as the TNF antagonist.
For example, the TNF antagonist in the document of " DDT " July in 1997 the 2nd the 7th phase of volume and wherein citation, having described to be applicable to purposes of the present invention such as Mariott.
Anti-TNF antibody and fragment thereof are particularly preferred for purposes of the present invention.
The anti-TNF antibody that is applicable to purposes of the present invention is known (EP 260 610, and EP 351789, and EP 218 868).Can either use polyclonal antibody can use monoclonal antibody again.Suitable in addition is TNF binding antibody fragment such as Fab or F (ab ')
2Or strand Fv fragment.
Humanization or people's anti-TNF or its TNF binding fragment also are very suitable, because these molecules should not produce any anti-mouse-anti originality in the human patients body.
The mixture that also can use the mixture of various anti-TNF antibody or anti-TNF antibody and TNF receptor fragments is as active component.
The present invention includes pharmaceutical composition and be used to prepare these method for compositions, described pharmaceutical composition comprises suitable carriers on anti-TNF antibody and the atoxic inert medicine.
Prepare anti-TNF antibody with the usual manner that is used for production active component on the biotechnology, be generally liquid preparation or lyophilized products (referring to for example, Hagers Handbuch derpharmazeutischen Praxis, the 2nd volume the 5th edition, 1991,720 pages, ISBN 3-540-52459-2).By known method, according to a kind of usual manner for example by active component and the blended mode of carrier are come the production aforementioned pharmaceutical compositions.
The general verified favourable administration total amount that is applicable to the active component of purposes of the present invention is about the about 100mg/kg body weight of 0.1-/24 hours, preferred 0.1-10mg/kg body weight/24 hours, if suitable, could be would to divide the form administration or the continuous infusion administration of dosage several times; And if suitable, in several days treatment phase, can reach required result.Can in 24 hours, carry out administration by of short duration venoclysis single dose or by the mode of long-term continuous infusion dosage every day.The active component that preferably contains the about 10mg/kg body weight of the 0.1-that has an appointment in the single dose.Yet, be necessary to deviate from described dosage, particularly depend on character and seriousness, the character of described compositions and the character of the medicine that gives and the time limit of carrying out administration as treatment patient's age and stature and original disease.
In the following example, further explain the present invention.
Embodiment
With the mouse-anti that is called MAK 195F-TNF antibody fragment (F (ab ')
2) (INN:AFELIMOMAB) treatment sepsis patient.
In a word, in a kind of multiple center clinical study, analyze 251 patients or patient in contrast with the serious sepsis of trouble of anti-TNF antibody fragment (afelimomab) treatment.
In 251 patients, there is the serum levels of 47 patients' IL-6 to raise, and has 178 patients' IL-6 serum levels to reduce.
Accompanying drawing show by the decline that in the treatment group that the IL-6 level raises, has realized mortality rate (with 69% of matched group be 55.6% than mortality rate).
In the group that the IL-6 serum levels descends, there is not significant success with MAK 195F treatment; On the contrary, in fact Zhi Liao untoward reaction obviously (compare with 50.6% mortality rate in the matched group, mortality rate is 54.7%).
Except that the standard care of sepsis, the patient of treatment group in 3 days time limit, also to accept to amount to 9 times, continue the treatment of 15 minutes of short duration infusion test products afelimomab at every turn, each 8 hours at interval, single dose be the 1mg/kg body weight/time.Except that the standard care of sepsis, the matched group patient also will accept the false product (placebo) of non-activity on the administered agents in the same manner.
This clinical research result clearly proves: when the sepsis patient who is treated has the IL-6 serum levels of rising, be successful especially with the serious sepsis of anti-TNF Antybody therapy.Therefore patient with IL-6 serum levels of decline does not use the TNF antagonist for treating.
Claims (6)
1.TNF antagonist is used for the treatment of those in the purposes aspect the medicine of the septic diseases of the serum levels rising of the mensuration time limit of 30 minutes to 48 hours interval words spoken by an actor from offstage cytokine-6 in preparation.
2. the purposes described in claim 1, wherein said is 500pg/ml and at this more than value at the serum levels of measuring time limit words spoken by an actor from offstage cytokine-6.
3. the purposes described in claim 1, wherein said test period is limited to 4-10 hour.
4. the purposes described in claim 1 is wherein with the F of monoclonal anti-TNF antibody (ab ')
2Fragment is as the TNF antagonist.
5. one kind comprises that TNF antagonist and this TNF antagonist are used for the treatment of the commodity medicated bag of the operation instruction of the septic diseases that the serum levels at mensuration IL-6 in the time limit of 30 minutes to 48 hours interval raises.
6. the commodity medicated bag described in claim 5 wherein is used as the TNF antagonist with monoclonal anti-TNF antibody.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19746868.3 | 1997-10-23 | ||
| DE19746868A DE19746868A1 (en) | 1997-10-23 | 1997-10-23 | Use of tumour necrosis factor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1277556A CN1277556A (en) | 2000-12-20 |
| CN1163272C true CN1163272C (en) | 2004-08-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988105144A Expired - Fee Related CN1163272C (en) | 1997-10-23 | 1998-10-15 | Application of TNF antagonists as medicaments for treating septic diseases |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1024831A2 (en) |
| JP (1) | JP2001521009A (en) |
| KR (1) | KR20010024549A (en) |
| CN (1) | CN1163272C (en) |
| AU (1) | AU756167B2 (en) |
| BR (1) | BR9813114A (en) |
| CA (1) | CA2306790A1 (en) |
| DE (1) | DE19746868A1 (en) |
| HU (1) | HUP0100105A3 (en) |
| IL (1) | IL135083A0 (en) |
| NO (1) | NO20001894L (en) |
| WO (1) | WO1999021582A2 (en) |
| ZA (1) | ZA989615B (en) |
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| RU2181297C2 (en) | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Method of treatment of pathological syndrome and medicinal agent |
| UA76639C2 (en) | 2002-08-02 | 2006-08-15 | Олєг Ільіч Епштєйн | Homeopathic medication and method for treating erectile dysfunctions |
| UA76640C2 (en) * | 2002-08-02 | 2006-08-15 | Олєг Ільіч Епштєйн | Method for correcting pathological immune responses and homeopathic medicinal agent |
| RU2309732C1 (en) | 2006-03-13 | 2007-11-10 | Олег Ильич Эпштейн | Pressed solid oral formulation of medicinal preparation and method for preparing solid oral formulation of medicinal preparation |
| SG187035A1 (en) | 2010-07-15 | 2013-02-28 | Oleg Iliich Epshtein | Combination pharmaceutical composition and methods of treating functional diseases or conditions of gastrointestinal tract |
| FR2962656A1 (en) | 2010-07-15 | 2012-01-20 | Oleg Iliich Epshtein | METHOD FOR INCREASING THE EFFECT OF AN ACTIVATED-POTENTIALIZED FORM OF ANTIBODY |
| EP2415461B1 (en) * | 2010-07-24 | 2012-10-31 | Roche Diagnostics GmbH | Stabilization of interleukin 6 in serum based solutions |
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|---|---|---|---|---|
| AU626572B2 (en) * | 1988-07-18 | 1992-08-06 | Chiron Corporation | Monoclonal antibodies reactive with cachectin |
| GB9109645D0 (en) * | 1991-05-03 | 1991-06-26 | Celltech Ltd | Recombinant antibodies |
| NZ278607A (en) * | 1994-02-07 | 1999-05-28 | Knoll Ag | Use of tnf antagonists for treating disorders involving elevated serum levels of il-6 wherein the serum levels are 500pg/ml or above |
-
1997
- 1997-10-23 DE DE19746868A patent/DE19746868A1/en not_active Withdrawn
-
1998
- 1998-10-15 WO PCT/EP1998/006545 patent/WO1999021582A2/en not_active Application Discontinuation
- 1998-10-15 AU AU12284/99A patent/AU756167B2/en not_active Withdrawn - After Issue
- 1998-10-15 EP EP98955459A patent/EP1024831A2/en not_active Withdrawn
- 1998-10-15 KR KR1020007004361A patent/KR20010024549A/en not_active Application Discontinuation
- 1998-10-15 CN CNB988105144A patent/CN1163272C/en not_active Expired - Fee Related
- 1998-10-15 BR BR9813114-1A patent/BR9813114A/en not_active IP Right Cessation
- 1998-10-15 JP JP2000517740A patent/JP2001521009A/en active Pending
- 1998-10-15 IL IL13508398A patent/IL135083A0/en unknown
- 1998-10-15 HU HU0100105A patent/HUP0100105A3/en unknown
- 1998-10-15 CA CA002306790A patent/CA2306790A1/en not_active Abandoned
- 1998-10-22 ZA ZA9809615A patent/ZA989615B/en unknown
-
2000
- 2000-04-12 NO NO20001894A patent/NO20001894L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2306790A1 (en) | 1999-05-06 |
| CN1277556A (en) | 2000-12-20 |
| IL135083A0 (en) | 2001-05-20 |
| AU1228499A (en) | 1999-05-17 |
| EP1024831A2 (en) | 2000-08-09 |
| BR9813114A (en) | 2000-08-15 |
| AU756167B2 (en) | 2003-01-09 |
| NO20001894D0 (en) | 2000-04-12 |
| JP2001521009A (en) | 2001-11-06 |
| DE19746868A1 (en) | 1999-04-29 |
| WO1999021582A3 (en) | 1999-07-15 |
| KR20010024549A (en) | 2001-03-26 |
| WO1999021582A2 (en) | 1999-05-06 |
| NO20001894L (en) | 2000-04-12 |
| HUP0100105A3 (en) | 2003-08-28 |
| HUP0100105A2 (en) | 2001-05-28 |
| ZA989615B (en) | 2000-04-20 |
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