the present invention is now based on the idea that intolerance of certain pharmaceuticals may possibly be caused by administration thereof being followed by release of such large amounts of tnf in the body that necroses or other side effects arising from overproduction of tnf occur . this idea has been confirmed by investigations with the antimycotic amphotericin b , which is known to result in 100 % lethality after parenteral administration in animal experiments if certain amounts of active substance are exceeded . however , if amphotericin b is administered together with a tnf inhibitor the amphotericin b , which is otherwise highly toxic , is tolerated without side effects . hence the invention relates to a pharmaceutical which , besides a substance releasing tumor necrosis factor ( tnf ), also contains a tnf inhibitor . xanthine derivatives have proven to be suitable tnf inhibitors . 1 ) compounds of the formula i ## str1 ## in which one of the radicals r 1 and r 3 represents a straight - chain alkyl , ( ω - 1 )- oxoalkyl or ( ω - 1 )- hydroxyalkyl group having 3 to 8 carbon atoms , and the two other radicals , r 2 and r 3 or r 1 and r 2 , represent straight - chain or branched alkyl groups having 1 to 8 carbon atoms in the position of r 1 and r 3 and 1 to 4 carbon atoms in the position of r 2 , where the total of carbon atoms in these two alkyl substituents does not exceed 10 , 2 ) compounds of the formula ii ## str2 ## in which r represents an alkyl radical having 1 to 4 carbon atoms , 3 ) compounds of the formula iii ## str3 ## in which at least one of the radicals r 4 and r 6 represents a tertiary hydroxyalkyl group of the formula ## str4 ## where r 7 denotes an alkyl group having up to 3 carbon atoms , and n denotes an integer from 2 to 5 , and -- if only one of the radicals r 4 or r 6 denotes such a tertiary hydroxyalkyl group of the formula iiia -- the other radical represents a hydrogen atom or an aliphatic hydrocarbon radical r 8 which has up to 6 carbon atoms and whose carbon chain can be interrupted by up to 2 oxygen atoms or substituted by an oxo group or up to two hydroxyl groups ( in which case an oxo or hydroxyl group present in the radical r 8 is preferably separated from the nitrogen by at least 2 carbon atoms ), and r 5 represents an alkyl group having 1 to 4 carbon atoms , 4 ) prodrug forms of the compounds of the formulae i to iii , and / or in turn , those among these compounds which are particularly preferred have the formula i with a hexyl , 5 - oxohexyl or 5 - hydroxyhexyl group in the position of r 1 or r 3 . these include , in particular , 1 - hexyl - 3 , 7 - dimethylxanthine , 1 -( 5 - hydroxyhexyl )- 3 , 7 - dimethylxanthine , 3 , 7 - dimethyl - 1 ( 5 - oxohexyl ) xanthine , 7 -( 5 - hydroxyhexyl )- 1 , 3 - dimethylxanthine , 1 , 3 - dimethyl - 7 -( 5 - oxohexyl ) xanthine , 1 -( 5 - hydroxyhexyl )- 3 - methyl - 7 - propylxanthine and 3 - methyl - 1 -( 5 - oxohexyl )- 7 - propylxanthine (= propentofylline ), especially 3 , 7 - dimethyl - 1 -( 5 - oxohexyl ) xanthine (= pentoxifylline ). particularly preferred compounds of the formula iii are those compounds in which r 5 represents a methyl or ethyl group . equally preferred are those compounds of the formula iii in which only one of the two radicals r 4 or r 6 represents the tertiary hydroxyalkyl group defined above . additionally preferred are those compounds in which r 7 represents a methyl group , and n denotes an integer from 3 to 5 , so that the tertiary hydroxyalkyl radical iiia represents either [(- 1 )- hydroxy -( ω - 1 )- methyl ]- pentyl , - hexyl or - heptyl , especially those in which r 5 denotes methyl or ethyl . in addition , worthy of particular emphasis are those compounds of the formula iii in which r 4 represents the tertiary hydroxyalkyl group , and r 6 represents alkyl , hydroxyalkyl or alkoxyalkyl , having 1 to 4 carbon atoms in each case , such as , for example , 7 - ethoxymethyl - 1 -( 5 - hydroxy - 5 - methylhexyl )- 3 - methylxanthine . another embodiment of the invention comprises using the oxoalkylxanthines of the formula i and ii , or the hydroxyalkylxanthines of the formula i and iii , not as such but in the form of a prodrug from which the therapeutically active xanthine compounds , having the substituents defined in formulae i , ii and iii , can be released only by bio - transformation in the body . suitable for this purpose are , for example , the acetalized oxoalkylxanthines in which the carbonyl groups are replaced by the structural element of the formula iv ## str5 ## and the o - acylated hydroxyalkylxanthines having the structural element of the formula ( v ) in place of the hydroxyl group , where r 9 and r 10 each represents an alkyl group having up to 4 carbon atoms or together represent an ethylene , trimethylene or tetramethylene group , and r 11 denotes an alkyl radical having up to 4 carbon atoms or optionally substituted phenyl or pyridyl . the ratio by weight of the substance releasing tnf to the xanthine derivative in the combination products according to the invention can cover a wide range . a ratio by weight of about 1 : 100 to about 100 : 1 is to be preferred , particularly preferably from about 1 : 10 to about 10 : 1 . the combination products according to the invention can be administered in a variety of ways . for example , they can be administered intravenously , intramuscularly , intraperitoneally , subcutaneously or orally . the combination products according to the invention are prepared by converting the substance releasing tnf and at least one xanthine derivative , where appropriate with other additives and / or auxiliaries , into a suitable administration form . the additives or auxiliaries belong to the group of vehicles , preservatives and other customary auxiliaries . examples of auxiliaries which can be used for oral administration forms are starch , for example potato , corn or wheat starch , cellulose or derivatives thereof , especially microcrystalline cellulose , silica , various sugars such as lactose , magnesium carbonate and / or calcium phosphates . in addition , it is advantageous to add to the oral administration forms auxiliaries which improve the tolerability of the medicaments , such as , for example , mucilage - formers and resins . to improve the tolerability , the medicaments can also be administered in the form of enteric capsules . furthermore , it may be advantageous to add to the administration form , or to a component of the combination product , an agent to slow release , where appropriate in the form of permeable membranes , such as , for example , those based on cellulose or polystyrene resin , or ion exchangers . it is surprising that the said xanthine derivatives , although they are cleared from the body after only a few hours , nevertheless are able to suppress the undesireable side effects of substances releasing tnf , even when the latter are excreted from the body only over a very long period . thus , for example , amphotericin b is still detectable in the body after 12 hours , whereas a xanthine derivative such as pentoxifylline has been excreted from the body after only 3 to 4 hours . despite this the tnf - inhibiting effect of the xanthine derivative is sufficient . the tnf - inhibiting effect of xanthine derivatives has been detected experimentally in the following way : in the case of amphotericin b , it has been shown that the highly toxic side effects of the substance derive from the release of tnf . the release of tnf in mouse serum can be detected by a specific elisa method using murine monoclonal anti - tnf . intraperitoneal administration of amphotericin b in amounts of 100 mg / kg or more to mice is found to be followed by 100 % mortality . the experimental results compiled in the attached table show that the toxic effect of amphotericin b cannot be overcome even by dexamethasone . however , if amphotericin b is administered together with pentoxifylline , then all the mice which received 100 or 150 mg / kg amphotericin b survive when 100 mg / kg pentoxifylline is administered . not until an excessive dose of 200 mg / kg amphotericin b is administered is it no longer possible to neutralize the side effects by administration of 100 mg / kg pentoxifylline . __________________________________________________________________________ % mortality in albino mice after a single intraperitoneal administrationof the product ( group size : 5 mice ) ampho - pentoxi - tericin bdexamethasone fyllinemg / kgmg / kg mg / kg day 0 day 1 day 2 day 3 day 4 day 5 day 6 day 7__________________________________________________________________________100 0 0 0 40 100100 0 10 0 20 60 80 100100 0 50 0 20 40 60 60 60 60 60100 0 100 0 0 0 0 0 0 0 0100 100 0 0 0 0 20 40 40 40 40150 0 0 0 100150 0 10 0 40 100150 0 50 0 60 80 80 100150 0 100 0 0 0 0 0 0 0 0200 0 0 100200 0 10 80 100200 0 50 40 100200 0 100 0 20 100200 100 0 0 100__________________________________________________________________________
pharmaceuticals which contain a substance releasing tumor necrosis factor are better tolerated and can be given in higher doses when they contain a tnf inhibitor , especially a xanthine derivative .