AU614607B2

AU614607B2 - Use of and agent for reducing side effects of tnf

Info

Publication number: AU614607B2
Application number: AU34064/89A
Authority: AU
Inventors: Hubert Heuer
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1988-05-11
Filing date: 1989-05-05
Publication date: 1991-09-05
Anticipated expiration: 2009-05-05
Also published as: EP0341558A2; ES2042864T3; GR3005387T3; EP0341558A3; IL90206A0; KR900017592A; DK220789A; ATE78695T1; HUT52381A; DK220789D0; DE58901920D1; ZA893259B; CA1336825C; JPH0276825A; AU3406489A; DE3816169A1; JP2709139B2; EP0341558B1

Abstract

Concomitant administration of TNFs with a PAF antagonist allows the unwanted side effects of the TNFs to be reduced and the therapeutic index of the TNFs to be increased.

Description

i -ri 1AUST8RA6) 1 e 0 7 Fcrm PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: ,Cormplete Spscificatzon Lodged: Accepted: Lapsed: Published: Priority: 9 r 1 Related Art: a TO BE CCOMPLEED BY APPLICAN SName of Applicant: Address of Applicant: Actual Inventors: Address for Service: Ccplete Specification SIDE EFFECTS OF TNF BOEHRINGER INGELBEIM INTERNATIONA GMBH D-6507 Ingelheim am Rhein, Federal Republic of Gexmany.

HUBERT HEUER CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia, for the invention entitled: USE OF AND AGENT FOR REDUCING The following statement is a full description of this invention, including the best method of performing it known to us 54156.03 Use of and agent for reducinq side effects of TNF The invention relates to PAF-antagonist agents for reducing undesirable side effects which occur during the therapeutic use of tumour necrosis factors (TNF) and the use thereof.

Tumour necrosis factors are proteins which are formed primarily by monocytes/macrophages (TNF-o.) or lymphocytes (TNF-3), as well as by other types of cell in the body after suitable stimulation. These proteins exhibit a cytostatic and cytotoxic effect on tumour 0* cells in vitro and a therapeutic effect in various in o 15 vivo tumour models in experimental animals. In addition, TNFs show an antiviral activity against Svarious types of virus, they activate the immune defences against parasites and act directly and/Qa indirectly as mediators in immune reactions, 20 inflammatory processes and other processes in the body, although the mechanisms of activity are as yet unexplained in many cases.

0 A series of observations have led to the conclusion that endogenically released TNFS play a part in various pathological conditions. Thus, TNF-a appears to be a *I 'mediator of cachexia, which may occur in chronically invasive diseases. TNF-a also appears to play a significant part in the pathogenesis of shock caused by gram-negative bacteria (endotoxin shock). Similarly, ,0 TNF has been postulated to have a function in the tissue damage which occurs in the course of inflammatory processes in the joints and other tissues.

These findings suggest that on the one hand, there are possible therapeut:ic applications of TNF in oncology, virology, parapitology and in bacterial infections, but on the other hand, the therapeutic use is likely to be limited by dosage-dependent side -2effects, particultarly the shock-inducing effect of TNFs.

As described above, the endogenic release of TNFs may also have undesirable effects.

According to one aspect of the invention, we have now found that by simultaneously administering one or 4 more PAF-antagonlists and a TNF, some of the undesirable side effects of TNFs, e.g. shock-like conditions, can be reduced and the shock-induced reduction in the gastrointestinal speed of passage can be inhibited.

For the PAF-antagonists, it is possible to use one or m.1ore compounds having such activity including for example those described in European Applications Nos.

176 927, 176 928, 176 929, 194 4116, 230 942, 240 899, 254 245 and 255 028. The PAF-a-ktagonists disclosed in to 440 15 the above applications are suitable for use accor< 4ng to the invention. Preferably the PAF antagonist selected from one or more of the following; 4-(2chilorophienyl) -9-mneth-yl-2 (4 -morpholinyl) -3 -propanondiazepine (WE~B 2086);, 6-(2-clorophienyl)-8,9-ditiydro-linethyl (4-morpholiniyl)cairboniyl]-411,7H-cyclopentaf4,]th ien o 2 -ffl, 2, 4 1tr iaz o Io 3 4 )d ia zep ine (WEB 2170) or 6-(2-chilorophienyl)-8,9-dihydro-l-methyl-8- 2i [dipropylaminocarboiyl]-411,711-aVclopentaf4 (3,2ffll,2,4]triazolof4 3-a)(1,4]diazepinie (WEB 2347) or Hia acid addition salts thereof as well as the compounds 4 emphasised or referred to as preferred in the aboveo mentioned European Patent applications.

In animal experiments, the motality of Mice induced by the administration of TI4F could be inhibited ,1n vivo using one or more PAF-ngoit Web 2347) according to thle inventiot, and similarly, thle priming of mice with TNF for an increased :sensitivijty to the administration of a second doso of TflNP coU18 also be inhibited inl yio r

T

ile phrase "simul taneous a011il-listration" indicates that rNFs.i and PAF-antagonist May be administered in a -7-IJ joint formulation or in separate formulations given at a specific time interval between the respective administrations. For example, the PAF-antagonist may be administered before the TNF, the time interval being determined inter alia by the duration of activity of the PAF-antagonist, i.e. the TNF is administered just as long as the PAF-antagonist is still providing a sufficient effect. Alternatively, the PAF--antagonist may be administered a short time after the TNF.

The administration of one or more PAF antagonist according to the invention provides a method of reducing the side-effects that occur during the therapeutic use of TNF.

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According to yet a further aspect of the invention, we provide a composition which comprises one or more PAF antagonists in association with a tumour necrosis factor.

The active substances may be administered in the form of conventional galenic preparations. Injectable solutions are primarily suitable for TNFs, which means that joint formulations with PAF-antagonists are generally in the form of injectable solutions. If the active substances are administereQ separately, the PAFantagonists may be in the form of conventional preparations known from the literature to be suitable.

The dosage is generally within the dosage proposed or described as suitable in the literature for the individual active substances. H.)wever, since the combined application increases the therapeutic range for TNFs, TNF may if desired also be administered in a higher dose than would be normally acceptable when it is used on its own.

Claims

1. A method of reducing side effects which occur in a subject during the therapeutic use of TNF by said subject which comprises the simultaneous administration (as defined herein) to the subject of one or more PAF- antagonists and a tumour necrosis factor (TNF).

2. A composition which comprises a PAF-antagonist in association with a tumour necrosis factor. 4004 o 0 5 o a 15 9 O 996 09 90 9 0 e 9<

3. A method or composition as claimed in claim 1 or claim 2 wherein the PAF-antagonist is WEB 2086, WEB 2170 or WEB 2347 (as defined herein), or an acid-addition salt thereof.

4. A composition as claimed in either of claims 2 or 3 which includes a pharmaceutically acceptable carrier, diluent or excipient. A composition as claimed in any of claims 2 to 4 in the form of an injectable solution, or a u.e as claimed in claim 1 wherein the medicament is in the form of- an injectable solution. I 0 9 0 Ce DATED t,hin 18Lh day of June 1991 BOiHR INGFR [NGETiEIM 1 NTERNAT [LONAI GMBI By Their Paltentb Abborneys: CAtLINAN [iAWRIE K) I i