Method of using pentoxifylline for treating inflammation

A combination product containing (A) on the one hand a xanthine derivative of the formula ##STR1## in which one of the radicals R.sup.1 and R.sup.3 represents a straight-chain alkyl, .omega.-1)-oxoalkyl or (.omega.-1)-hydroxyalkyl group having 3 to 8 carbon atoms, and the two other radicals R.sup.2 and R.sup.3, or R.sup.1 and R.sup.2 represent straight-chain or branched alkyl groups having 1 to 8 carbon atoms in the position of R.sup.1 and R.sup.3 and 1 to 4 carbon atoms in the position of R.sup.2, the maximum total of carbon atoms in these two alkyl substituents being 10, or of the formula ##STR2## in which R represents an alkyl radical having 1 to 4 carbon atoms, or prodrug forms of the oxoalkylxanthines of the formula I and II or of the hydroxylalkylxanthine of the formula I, or its metabolites, and PA0 (B) on the other hand O-acetylsalicylic acid or its pharmacologically tolerated salts, PA0 (C) with or without a pharamaceutical vehicle, for sequential administration in the treatment of diseases caused or characterized by impaired constituents of blood, in particular platelets or erythrocytes, but also leukocytes, in such a manner that component (A) is released first, and its use in human and veterinary medicine.

It is known that 1-(5-oxohexyl)-3,7-dimethylxanthine (pentoxifylline) is 
used as a pharmaceutical agent for the improvement of the flow properties 
of blood. The supposed cause of this is (Deutsche mediz, Wochenschrift 107 
(1982), 1674) that the viscous stress of the blood decreases because the 
deformability of the erythrocytes is improved by treatment with 
pentoxifylline. Moreover, the in vitro aggregation of platelets can be 
inhibited by pentoxifylline, but only at concentrations which are above 
those used in medicinal treatment (IRCS (Med. Sci.) 8 (1980) 293, 
Thrombos, Haemostas, 46 (1981) 272). 
In addition, it has been reported that, with pentoxifylline, the release of 
a substance having antiaggregatory activity from rat aortas ex vivo can be 
increased by treatment of the animals with pentoxifylline. It is likewise 
known that the release of the substance having antiaggregatory activity, 
presumably prostacyclin, thus stimulated can be suppressed by treatment of 
the rats with acetylasalicyclic acid (Vasa 10 (1981) 249). Our own 
continuing experiments have confirmed this (see below). 
O-Acetylsalicylic acid is known to be an inhibitor of the aggregation of 
human blood platelets (for example Br. J. clin. Pharmac. 7 (1979) 283), 
and it has been reported that it may sow valuable therapeutic effects in 
terms of the prevention of thromboses and strokes 1073. N. Engl. J. Med. 
299 (1978). The mechanism of action has been reported to be that 
acetylsalicylic acid inhibits the enzyme cyclooxygenase, which is 
localized in the blood platelets (J. Clin. Invest. 56 (1975) 624), and the 
biosynthesis of thromboxane A.sub.2, which promotes the aggregation, is 
inhibited. However, acetylsalicylic acid is also able to inhibit the 
cyclooxygenase located in the vessel wall and thus the synthesis of 
prostacyclin, which inhibits the aggregation. However, since the 
inhibition of vascular cyclooxygenase is found only at higher doses of 
acetylsalicylic acid (Pharmacol. Research Commun. 10 (1978) 759), 
consequently the recommendation is that an antithrombotic effect be 
achieved with low doses of acetylsalicylic acid (Lancet, iii (1979) 1213, 
Prostaglandins and Medicine 4 (1980) 439). However, there is also a report 
that the antithrombotic effect of acetylsalicylic acid increases with 
increasing doses, and that an optimal effect is achieved under conditions 
in which there is substantial inhibition of the biosynthesis of both 
prostacyclin and thromboxane (Prostaglandins, Leukotrienes and Medicine 12 
(1983) 235). 
The summation of the favorable effect of acetylsalicylic acid on the one 
hand, and that of the xanthine derivative 
7-(2-diethylaminoethyl)theophylline on the other hand, by preparation of 
the acid-base adduct of the two individual substances and its use in 
medicine has also already been disclosed (GB Laid-Open Application No. 2 
096 138). In addition, the effect of combined, simultaneous administration 
of pentoxifylline and acetylsalicylic acid on the survival time of 
platelets in patients with artificial heart valves has been disclosed 
(Singapore Med. Journal 20 Suppl. 1 (1979) 30). 
It has now been found that administration, successively with a time 
interval, of (A) xanthine derivatives or their active metabolites on the 
one hand, and (B) acetylsalicylic acid or its pharmacologically tolerated 
salts on the other hand, in a particular sequence, makes possible an 
extremely great improvement in the treatment of disorders which are caused 
or characterized by impaired constituents of blood, in particular 
platelets or erythrocytes, but also leukocytes. The sequential 
administration of the xanthine derivatives, in particular pentoxifylline, 
followed by the administration of acetylsalicyclic acid or of its salt, 
only after until 10 minutes to 4 hours have elapsed, leads to much greater 
effects than when there is simultaneous administration of the combination 
of the two individual substances, in which case there is in fact a 
reduction in this effect. This is all the more surprising since the 
simultaneous administration of xanthine derivatives, such as 
pentoxifylline, and acetylsalicylic acid leads only to such antithrombotic 
and antiaggregatory effects as would have been obtained on administration 
of acetylsalicylic acid alone (see below, Tables 1 and 2). 
Thus the invention relates to combination products containing (A) xanthine 
derivatives of the formula (I) or (II), (see Patent claim 1) or prodrugs 
of oxoalkyl- or hydroxyalkylxanthines, or their active metabolites, and 
(B) O-acetylsalicylic acid or its pharmacoolgically tolerated salts, with 
or without (C) a pharmaceutical vehicle, for sequential administration in 
the treatment of disorders caused or characterized by impaired 
constituents of blood, in particular platelets or erythrocytes, but also 
leukocytes, in such a manner that component (A) is released first. In 
other words, the agents according to the invention are suitable, because 
of their superadditive effects, for antithrombotic, bloodflow-promoting, 
antiinflammatory, analgesic, antiaggregatory and cytostatic treatment or 
prophylaxis. Thus the invention also relates to the use of (A) xanthine 
derivatives of the formula I or II, or of prodrug forms of the 
oxoalkylxanthines of the formulae I and II, or of the 
hydroxyalkylxanthines of the formula I, or of their metabolites, and (B) 
O-acetylsalicylic acid or its pharmacologically tolerated salts, (C) with 
or without pharmaceutical vehicles for the preparation of agents which 
bring about sequential release, in such a manner that component (A) is 
released first, for disorders which are caused by impaired constituents of 
blood. The invention furthermore relates to the preparation of 
pharmaceutical formulations as claimed in claim 3, and to the use of the 
agent in human and veterinary medicine. The combination products according 
to the invention make it possible for the xanthine derivative to be 
released, i.e. be bioavailable, even before the acetylsalicyclic acid. 
It is a particular advantage that, because of the superadditive effect on 
consecutive administration, the amounts of xanthine derivative and 
acetylsalicylic acid which are to be administered can be reduced to those 
amounts which, on administration alone, show only a minimal 
pharmacological effect so that, at the same time, side effects which are 
elicited by high doses of these medicaments can be diminished. This is of 
great importance because it is known that acetylsalicylic acid can, in the 
customary doses, elicit undesired side effects (for example British 
Journal of Clinical Pharmacology 1980, 10, Suppl. 2 and International 
Meeting on Side Effects of Antiinflammatory, Analgesic Drugs, Verona, 
Sept, 13-15, 1982, Abstracts), such as asthma, allergic urticaria, 
analgesic nephropathy and peptic ulcers. Moreover, the xanthine 
derivatives may show undesired side effects. By means of the combination 
product according to the invention it is now possible, surprisingly, to 
reduce drastically the dose of acetylsalicylic acid necessary for humans, 
as well as the amount of xanthine derivative, so that there is an even 
greater improvement in the general toxicological tolerability (see below).

Examples of suitable xanthine derivatives are 1,3,7-trisubstituted 
compounds of the formula I, in which one of the radicals R.sup.1 and 
R.sup.3 is a straight-chain alkyl, (.omega.-1)-oxoalkyl or 
(.omega.-1)-hydroxyalkyl group having 3 to 8 carbon atoms, and the two 
other radicals R.sup.2 and R.sup.3, or R.sup.1 and R.sup.2, are 
straight-chain or branched alkyl groups having 1 to 8 carbon atoms in the 
position of R.sup.1 and R.sup.3, and 1 to 4 carbon atoms in the position 
of R.sup.2, the total of the carbon atoms in these two alkyl substituents 
being a maximum of 10. 
In this context, xanthine compounds of the formula I which are preferred 
are those in which R.sup.1 or R.sup.3 denotes an alkyl, 
(.omega.-1)-oxalkyl or (.omega.-1)-hydroxyalkyl radical having 5 to 6 
carbon atoms, and the two alkyl substituents R.sup.2 and R.sup.3, or 
R.sup.1 and R.sup.2, together comprise 2 to 6 carbon atoms. 
Among these compounds, those which are in turn particularly preferred are 
those which carry a hexyl, 5-oxohexyl or 5-hydroxyhexyl group in the 
position of R.sup.1 or R.sup.3. These include, in particular, 
1-hexyl-3,7-dimethylxanthine, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine, 
1-(5-oxohexyl)-3,7-dimethylxanthine, 
1,3-dimethyl-7-(5-hydroxyhexyl)xanthine, 
1,3-dimethyl-7-(5-oxohexyl)xanthine, 
1-(5-hydroxyhexyl)-3-methyl-7-propylxanthine and 
1-(5-oxohexyl)-3-methyl-7-propylxanthine. 
Another suitable group of xanthines comprises the compounds of the formula 
II, in which R represents an alkyl radical having 1to 4 carbon atoms. 
It is not necessary for the oxoalkylxanthines of the formulae I and II and 
the hydroxyalkylxanthines of the formula I to be used per se, it is also 
possible to use them in the form of a prodrug from which the 
therapeutically active xanthine compounds having the substituents defined 
in the formulae I and II can be released only by biotransformation in the 
body. Examples of those suitable for this purpose are the acetalized 
oxoalkylxanthines in which the carbonyl group has been replaced by the 
structural element of the formula (III) (see patent claim 6), and the 
O-acylated hydroxylalkylxanthines having the structural element of the 
formula R.sup.6 --CO--O-- (IV) in place of the hydroxyl group, where 
R.sup.4 and R.sup.5 each represent an alkyl group having up to 4 carbon 
atoms, or together represent an ethylene, trimethylene or tetramethylene 
group, and R.sup.6 denotes an alkyl radical having up to 4 carbon atoms, 
phenyl, substituted phenyl, pyridyl or substituted pyridyl. 
Suitable pharmacologically tolerated salts of acetysalicylic acid are those 
with pharmacologically tolerated metal cations, ammonium, amine cations or 
quaternary ammonium cations. Those of the alkali metals, such as lithium, 
sodium and potassium, and of the alkaline earth metals, such as magnesium 
and calcium, are preferred, although it is also possible to use cationic 
forms of other metals, such as aluminum, zinc and iron. 
Pharmacologically tolerated amine cations are those of primary, secondary 
or tertiary amines, such as the alkylamines, for example methyl-, 
dimethyl-, trimethyl-, ethyl-, dibutyl-, triisopropyl-, N-methylhexyl-, 
benzyl-, .beta.-phenylethylamine, ethylenediamine, diethylenetriamine, 
piperidine, morpholine, piperazine, mono-, di- and tri-ethanolamine, 
ethyldiethanolamine, N-butylethanolamine and the like. Other suitable 
amine salts are the basic amine salts of lysine and of arginine. Examples 
of suitable pharmacologically tolerated quaternary ammonium cations are 
tetramethylammonium, tetraethylammonium and benzyltrimethylammonium. 
The xanthine derivatives on the one hand, and the acetylsalicylic acid 
component on the other hand, can also be administered simultaneously to 
achieve the superadditive effect, but administration in dosage units in a 
separate form is preferred, even though the components can also be 
administered in mixtures, in a suitable form, which permit administration 
consecutively in time. The dosage units can be in the form of solid drug 
forms, such as capsules (including microcapsules which, in general, do not 
contain a pharmaceutical vehicle), tablets (including coated tablets and 
pills), or suppositories, where, when capsules are used, the capsule 
material assumes the function of the vehicle, and the contents can be in 
the form of, for example, a powder, gel, emulsion, dispersion or solution. 
However, it is particularly advantageous and straight-forward to prepare 
oral and peroral formulations with the two active compounds, which contain 
the calculated amounts of the active compounds, together with each desired 
pharmaceutical vehicle, and which are of such a nature that the release of 
the active compounds takes place sequentially. It is also possible to use 
an appropriate formulation (suppository) for rectal treatment. Likewise, 
transdermal and parenteral (intraperitoneal), intravenous, subcutaneous or 
intramuscular) injection of solution, for example by means of suitable 
multichamber injection units, is possible. 
Combination products of this type can be prepared by customary processes. 
The sequential release according to the invention (bioavaiability) of the 
active compounds can be achieved by covering, in a customary manner, for 
example according to Sucker, Fuchs and Speiser, Pharmazeutische 
Technologie (pharmaceutical Technology), Stuttgart 1978, page 424, the 
tablets, pills or granules, which contain as the medicament 
acetylsalicylic acid or its medically tolerated salts, such as D,L-lysine 
monoacetylsalicylates, with a coating which contains as the active 
compound, for example, pentoxifylline, advantageously in combination with 
swelling agents (muciferous substances), resins, such as polystyrene, or 
other customary agents promoting tolerability. .The tablets, pills or 
granules which are used as the core can be prepared by customary processes 
and can contain vehicles and other customary auxiliaries, such as starch, 
for example potato, corn or wheat starch, cellulose or its derivatives, in 
particular microcrystalline cellulose, silica, various sugars, such as 
lactose, magnesium carbonate and/or calcium phosphates. The coating, which 
contains, for example, pentoxifylline, can be applied to the core by, for 
example, the processes customary in pharmaceutical technology, such as 
compression, immersion or fluidized bed processes, or by drum coating. The 
coating solution is usually composed of sugar and/or starch syrup, with 
the addition of gelatine, gum arabic, polyvinylpyrrolidone, synthetic 
cellulose esters, surface-active substances, plasticizers, pigments and 
similar additives according to the state of the art. 
The sequential release of the active compounds can also be achieved using 
layered tablets (this term also including eccentric-core tablets), which 
are likewise described in Sucker et al., Loc. cit., in which the layer 
which is absorbed more rapidly contains the xanthine, advantageously 
likewise combined with muciferous substances or other customary agents 
promoting tolerability. In this drug form, the release of the active 
compounds can be achieved by differences in the rates of release from the 
tablet layers owing to the use of suitable and customary auxiliaries, such 
as those, for example, detailed above. Gradated release of the two active 
compounds, for example pentoxifylline and acetylsalicylic acid, can also 
be achieved by the component which contains the acetylsalicylic acid also 
containing retarding agents, where appropriate also in the form of 
permeable membranes, such as those based on cellulose or polystyrene 
resin, or ion exchangers, or being used in the form of microcapsules which 
are resistant to gastric juice or make possible delayed release. However, 
the core containing the acetylsalicylic acid can also be provided with a 
coating, for example composed of polymethacrylic esters (Eudragit.RTM.) 
which makes possible delayed release. 
All of the customary flow-regulating agents, lubricating agent or 
lubricants, such as magnesium stearate, and mold-release agents can be 
used for the preparation of the drug forms. 
The ratio by weight of the acetylsalicylic acid to the xanthine 
derivatives, such as pentooxifylline, can vary within wide limits. The 
exact ratio which is to be used for a particular combination can readily 
be determined using the experimental procedures described below. In 
general, the proportion by weight of xanthine derivatives, for example 
pentoxifylline, related to one part by weight of acetylsalicylic acid, is 
between a minimum of about 0.1, preferably a minimum of about 0.3-0.5 and, 
in particular, a minimum of about 2, and a maximum of about 50, preferably 
a maximum of about 10. It is also possible by use of these experimental 
procedures to determine the optimal time interval between the 
administration of the xanthine derivative and of the acetylsalicylic acid, 
or the optimal rate of release from the pharmaceutical formulations. The 
xanthine derivative, for example pentoxifylline, is released first, and 
then, 15 minutes to 4 hours later, the acetylsalicylic acid component. A 
time interval of about 20 to 90 minutes, and especially between 30 and 60 
minutes, is particularly preferred. Of course, the dose which is to be 
administered depends on a variety of factors, such as the organism to be 
treated (i.e. human or animal, age, weight and general state of health), 
the severity of the symptoms, the disease which is to be treated, (where 
present) the nature of the concurrent treatment with other medicaments, 
the frequency of treatment etc. The doses are generally administered up to 
five times a day, and preferably once to three times a day. The ratio by 
weight of individual active compounds should lie within the range 
indicated above, and the amount of the constituents should lie within the 
range indicated above, and the amount of the constituents should lie 
within the effective dose range which is tolerated by the organism which 
is to be treated. 
For example, the preferred dose of acetylsalicylic acid is, when 
administered alone to humans, 500 to 2,000, in particular 1,000, mg two or 
three times a day. The preferred dose of pentoxifylline is, when 
administered alone to humans, 200 to 800, in particular 300 to 600, mg two 
or three times a day. It is possible to calculate exactly the relevant 
amounts from these ratios by weight for the ratio of acetylsalicylic acid 
to pentoxifylline. Thus, a suitable treatment comprises the administration 
of, for example, one, two or more, preferably 3 to 8, single doses of the 
combination products according to the invention, each containing 100 to 
600, preferably at least 200 and, in particular, up to 400 mg of the 
xanthine derivative, in particular of pentoxifyllin, and 10 to 2,000, for 
example up to 400, mg of acetylsalicylic acid or the equivalent amount of 
a salt, where the amount is, of course, dependent on the number of single 
doses as well as the disorder which is to be treated, and a single dose 
can comprise, for example, several tablets which are administered 
simultaneously. However, the invention also allows good results to be 
obtained in cases in which the administration of particularly small 
amounts of acetylsalicylic acid (for example 10-50 mg per day or less) is 
desired, the results being considerably better than when the same amount 
of acetylsalicylic acid is administered alone. 
The agents according to the invention can be used in the same manner as 
known antithrombotic agents and agents inhibiting blood platelet 
aggregation. In vivo uses comprise the administration to humans and 
animals in order to prevent the formation of arterial and venous blood 
clots, such as, for example, to prevent transient ischemic attacks, and 
for the long-term prophylaxis following myocardial infarctions and 
strokes, and for arteriosclerosis, as well as for treatment after surgery 
to prevent postoperative thrombosis and for the after-treatment of cancer 
to prevent or reduce the metastatic effect. Administration to patients who 
are connected to heart-lung machines and to kidney dialysis is also 
possible, likewise to patients with artificial heart valves, vessel 
prostheses etc. Of course, administration for the actual indications for 
the individual constituents, for example promotion of blood flow 
(intermittent claudication) and analgesic and antiinflammatory effects 
(including for chronic inflammation) is possible. In antiinflammatory 
preparations the ratio of the xanthine derivative to component B is in 
general between 0.1 and 1, while it is in other preparations in general 
between 0.5 and 50. 
In vivo investigations 
The combination of pentoxifylline and acetylsalicylic acid was assessed in 
vivo using a design of experiment in which an intravascular thrombosis was 
generated with a laser in the arterioles of the mesentery of a rat. This 
procedure is a suitable experimental model for the combination product 
according to the invention. The evaluation was carried out by analysis by 
vital microscopy (Nature, 218 (1968) 887 and Haemostasis 13 (1983) 61 and 
IRCS Med. Sci. 12 (1984)91). 
The test substances were administered in 0.9% sodium chloride solution 
(which contained 1% carboxymethylcellulose (Serva, Heidelberg)) either 
orally, intraperitoneally or intravenously. Control animals were treated 
in the corresponding manner but without the test substances. The 
experimental animals used were male or female Sprague-Dawley or Wistar 
rats. 
The investigation with pentoxifylline, other xanthine derivatives and 
acetylsalicylic acid in the laser-induced thrombosis model was carried out 
on female Sprague-Dawley rats of body weight about 200 g. The animals 
which were to be investigated underwent s.c. premedication with 0.1 mg of 
atropine sulfate in solution and were anesthetized with 100 mg of ketamine 
hydrochloride and 4 mg of xylazine per kg of body weight i.p. The 
investigation made use of arterioles and venules of the mesentery, which 
was coated with degassed liquid paraffin, having a diameter of about 13 
.mu.m. The beam of a 4W argon laser (supplied by Spectra Physics, 
Darmstadt) was introduced coaxially, by means of a beam adaptation and 
adjustment system (supplied by BTG, Munich), into the inverted optical 
path of a microscope (ICM 405, LD-Epipland 40/0.60; supplied by Zeiss, 
Oberkochen). The wavelength used was 514.5 nm, with an energy above the 
objective of 30.5 mW. The exposure time per single shot was 1/15 sec. All 
the measuring operations were recorded by video camera (Trinicon tube, 
Sony, Cologne) and stored in a recorder (Sony, U-matic 3/4"). The test 
substances were administered in various doses to the experimental animals, 
orally one hour, and on i.v. administration 10 min., before the start of 
the experiment, control animals receiving the same amount of placebo. The 
substances were administered as follows: 1) as a single dose, (2) together 
as a combination or (3) first acetylsalicylic acid and, after 1 h, 
pentoxifylline or another xanthine derivative, and (4) first 
pentoxifylline or another xanthine derivative and, after 1 h, 
acetylsalicylic acid (Table 1a). Table 1b shows the effect of various time 
intervals. Table 1c summarizes the effects of other xanthine derivatives. 
Evaluation 
The number of shots needed to induce a defined thrombus is counted. The 
shot frequency amounts to one lesion every 2 minutes, and all the thrombi 
with a minimum size of 1/4 of the vessel radius which were formed during 
the observation period were counted and measured. 
The results of the experiment were subjected to statistical analysis using 
the .sup.2 test (L. Cavalli-Storza, Biometrie (Biostatistics), Stuttgart, 
1969, pages 49 et seq.). 
Results 
The results are recorded in Tables 1a-c. The effects of the single oral 
doses of 5 mg/kg acetylsalicylic acid or pentoxifylline are not 
significant, but pentoxifylline does show 20% inhibition of thrombus 
formation. Both substance have a significant effect at an oral dose of 10 
mg/kg. Simultaneous administration of pentoxifylline and acetylsalicylic 
acid produced no effect in the laser model. This was also the case when 
acetylsalicylic acid was administered first and pentoxifylline was 
administered after 1 h. In contrast, administration of pentoxifylline 
first and acetylsalicylic acid after 1 h has a dose-dependent, significant 
effect in the model of laser-induced thrombosis in the arteriles and 
venules of the rat mesentery. The superadditive effect of this sequential 
administration compared with single doses is clearly evident from the 
percentage change compared with controls (Table 1a). 
The results listed in Table 1b show that there is a wide range for the 
timespan which can be selected between the two single doses, the optimum 
being between 15 and 180 minutes. The effects according to the invention 
can also be achieved with other xanthine derivatives (see patent claims) 
when they are administered with acetylsalicylic acid but displaced in 
time. The antithrombotic effects of a selection of these xanthine 
derivatives are recorded in Table 1c. 
The sequential administration can be carried out using a commercially 
available perfusion unit with two separately controllable chambers (for 
example that supplied by Braun, Melsungen; with motor-driven feed designed 
to be separate via a timeswitch). The two chambers of the perfusion unit 
were filled with pentoxifylline solution (corresponding to 10 mg of 
pentoxifylline/kg rat) and with acetylsalicylic acid solution 
(corresponding to 1 mg/kg respectively (for solvent, see above). The 
timeswitch controlled the injection of the acetylsalicylic acid solution 
20 min. after the injection of the pentoxifylline solution into the caudal 
vein. In a comparison experiment, both chambers were injected 
simultaneously. The results corresponded to the measurements obtained 
after oral administration, i.e. the effects obtained on sequential 
administration were far greater than those obtained on simultaneous 
administration. 
Ex vivo investigations 
Platelet aggregation was determined by procedures known per se. Male 
rabbits (own breed, BASK, SPF Wiga about 2.5 to 3.5 kg) were treated 
intravenously (ear vein) with pentoxifylline and/or DL-lysine 
monoacetylsalicylate dissolved in physiological saline. Then blood was 
taken from the ear vein, a 3.8% strength trisodium citrate solution was 
added in the ratio 9:1, and the mixture was incubated at room temperature 
for 45 minutes. It was subsequently centrifuged at 1,000 revolutions per 
minute for 10 minutes. The upper layer, which comprises the platelet rich 
plasma, was separated off, and the lower layer was centrifuged at 28,000 
revolutions per minute for 10 minutes. The upper layer now contained the 
platelet-poor plasma, which was likewise separated off. The platelet-rich 
plasma was diluted with the platelet-poor plasma to about 6 to 
7.times.10.sup.8 platelets/ml (Coulter counter, Coulter Electronics, 
Krefeld). Platelet aggregation was followed optically by measurement of 
the light transmission in a Born aggregometer (supplied by Labor GmbH, 
Hamburg). The volume of the test mixture was 0.25 ml, and the temperature 
was 37.degree. C. Aggregation was induced with 2.times.10.sup.-4 M 
arachidonic acid (Serva, Heidelberg) purified by preparative high-pressure 
liquid chromatography (HPLC reversed phase C-18 column under protective 
gas (argon). The increase in platelet aggregation was followed on the 
basis of the light transmission. The variable measured in this system is 
the maximum aggregation amplitude E. The results are recorded in Table 2. 
Female rats (Hoe Wiskf, about 180 g) were treated by oral administration of 
the following medicaments (in polyethylene glycol (PEG), NW 400, 
corresponding to 1 ml/kg): 
Experiment (1.) 30 mg/kg pentoxifylline, after 30 min 3 mg/kg 
acetylsalicylic acid. 
Experiment (2.) 30 mg/kg pentoxifylline, after 30 min. 10 mg/kg 
acetylsalicylic acid. 
Experiment (3.) 30 mg/kg acetylsalicylic acid, after 30 min. 30 mg/kg 
pentoxifylline. 
Experiment (4.) 10 mg/kg acetylsalicylic acid, after 30 min. 30 mg/kg 
pentoxifylline. 
Experiment (5.) 30 mg/kg pentoxifylline, after 30 min. only solvent. 
Control experiment (6.) ml/kg PEG 400 without medicaments. 
These procedures were repeated after 18 hours and, 1 hour after the last 
administration, the rats were sacrificed under ether anesthesia, and the 
thoracic aorta was removed. Segments of aorta were immediately incubated 
in 3 ml of buffered 0.09M NaCl solution, pH=7.5, at 24.degree. C. for 30 
min. Aliquots of the supernatants from the aortas were then used as 
inhibitors of the aggregation of human platelets induced with adenosine 
diphosphate, as follows: blood was taken, by careful cannulation of the 
antecubital vein, from apparently healthy male and female volunteers who 
had taken no medicaments in the preceding 10-day period, and was 
immediately stabilized with sodium citrate (ad 0.38%). Platelet-rich 
plasma (PRP) was obtained as the supernatant after centrifugation at 
140.times.g for 15 minutes, the platelet content in this being in the 
range 1.5-3.5.times.10.sup.8 /ml (Coulter counter). Platelet aggregation 
was followed optically by measurement of the light transmission in a Born 
aggregometer (supplied by Labor GmbH, Hamburg). The total volume of the 
test mixture was 0.25 ml. The plasma was pre-incubated with the aorta 
supernatants at 37.degree. C. for 5 min., and then aggregation was induced 
with 2.times.20.sup.-6 M adenosine diphosphate. Dose-effect curves as a 
function of the weight of the aorta were constructed from the maximum 
aggregation applitudes in each case, and the antiaggregatory activity in 
the supernatant from 0.1 mg of aorta was determined from these graphs. The 
weights of the aortas were determined by weighing of the aortas which had 
been dried at 60.degree. C. for 20 hours. The measurements of aggregation 
were carried out in the period 1-2 hours after the blood was taken. 
Toxicity test. Method 
Rats were treated orally as described above, but with increasing doses. One 
group received pentoxifylline, and a second group received pentoxifylline 
plus acetylsalicy-lic acid in the ratio by weight of 10:1. The lethal dose 
was calculated by the customary standard procedure (Litchfield and 
Wilcoxon, 1949) as the LD.sub.50 : LD.sub.50 (pentoxifylline)=1400 mg/kg 
LD.sub.50 (pentoxifylline/acetylsalicylic acid)=1400 mg/kg 
Results 
The toxicological tolerability was the same for both groups. This means 
that the ratio between the pharmaceutical dose and the lethal dose for the 
combination of pentoxifylline and acetylsalicylic acid according to the 
invention is much smaller, and thus is considerably more favorable, than 
on administration of pentoxifylline or acetylsalicylic acid alone. 
Test of gastric tolerance 
Method 
Fasted male Sprague-Dawley rats weighing 200-300 g were treated orally as 
described above with pentoxifylline and, after one hour, with 
acetylsalicylic acid, or only with acetylsalicylic acid. 24 hours after 
the last medication, the stomach was cut open along the lesser curvature, 
cleaned under running water, and inspected for mucosal lesions. All 
lesions visible on macroscopic inspection of the mucosa of the glandular 
stomach were regarded as ulcers. 
Result 
The gastric ulcerogenicity of acetylsalicylic acid is unaffected by 
pretreatment with pentoxifylline (Table 4). This means that the ratio of 
the pharmaceutical dose to the dose which is not tolerated by the stomach 
for the combination according to the invention (administration of 
pentoxifylline before acetylsalicylic acid) is considerably smaller and 
more favorable than that on administration of acetylsalicylic acid alone 
since, according to Table 1, considerably larger amounts of 
acetylsalicylic acid are necessary to achieve the same amtithrombotic 
effects. 
Investigation using a model of chronic inflammation 
The hemorheological, antithrombotic, antiaggregatory and antiinflammatory 
effects of the combinations according to the invention were investigated 
after oral administration for 21 days in the pathological model of 
adjuvant arthritis (induced with Mycobacterium butyricum) in the rat by 
the method of Clinical Hemorheology 3 (1983) 469-480, and were compared 
with those of the appropriate individual substances. Blood was taken from 
the thoracic aorta 1 hour after the last administration of substance. All 
the details of the determination of the hemorheological effect were as 
described in Clinical Hemorheology 4 (1984) 263-273. The erythrocyte 
deformability was quantitatively determined in a filtrometer (Myreene MF 
4, Roetgen, Germany) by evaluation of the initial gradient of the flow 
curve. Table 5a shows that the erythrocyte filterability, which is reduced 
in arthritic rats compared with healthy control rats, can be increased 
again by acetylsalicylic acid and pentoxifylline. Even combined 
administration of the two substances at the same time shows superadditive 
effects, but they are particularly promoted with consecutive 
administration (pentoxifylline 1 hour before acetylsalicylic acid). 
The antithrombotic effect was measured using the laser model as described 
above. Table 5b shows the results. Whereas an average of 2.173 (=100%) 
laser shots had to be used to achieve a throbus in healthy control 
animals, 0.99 (=46%) shots are sufficient for arthritic animals, i.e. the 
tendency to thrombosis is increased in diseased animals. Table 5b shows 
that the tendency to thrombosis is decreased by treatment with the 
medicaments and, in particular, by administration of the combination 
according to the invention there is approximation to the figures found for 
healthy animals. 
The measurements of platelet aggregation were carried out as described 
above in detail. However, instead of arachidonic acid 0.04 mg of collagen 
was used to induce platelet aggregation in 1 ml of platelet-rich plasma 
(PA II aggregometer from Myrenne, Roetgen). The aggregation amplitude 
(aggregation Tendency) is highest (=100%) for the untreated arthritic 
rats, while no aggregation occurs with 0.04 mg of collagen in healthy rats 
(Table 5c). The listed results show that the pathologically increased 
aggregation tendency in the arthritic rat can be reduced by the 
medicaments mentioned. Consecutive administration (pentoxifylline and, 1 
hour later, acetylsalicylic acid) again shows superadditive effects. 
The antiinflammatory effect was quantitatively measured, as quoted above, 
using the volume of the edema of the paw and using the standard necrosis 
index. The formation of necrosis and edema decreases markedly on treatment 
with the medicaments. Table 6 shows the relative improvement in the 
symptoms of the treated animals compared with the untreated arthritic 
rats. The consecutive administration according to the invention 
(pentoxifylline and, 1 hour later, acetylsalicylic acid) again shows 
superadditive effects. 
Pharmaceutical formulations 
It was also possible, in place of the i.v. injection by a perfusion unit 
described above, to use suspensions and solid formulations, which are 
suitable for oral, peroral and rectal administration, to achieve 
superadditive effects. 
Examples of formulations of this type for administration to humans contain 
x mg of pentoxifylline or other xanthine derivatives (see Examples 1-17) 
as the pure substance and/or as a commercially available finished 
formulation (Trental.RTM., supplied by Albert Roussel Pharma GmbH, 
Wiesbaden or Rentylin.RTM., supplied by Dr. Rentschler Arzneimittel GmbH & 
Co., Laupheim (abbreviated to T and R respectively) or parts of these 
finished formulations, combined with y mg of acetylsalicylic acid which 
can also be bound to basic ion exchangers (Dowex.RTM. 1.times.8, and 
QAE-Sephadex.RTM. (Serva, Heidelberg)) or to an adsorber resin 
(Amberlite.RTM. XAD 2), or can be in the form of commercially available 
microcapsules (Colfarit.RTM., Bayer AG, Leverkusen (abbreviated to C)) or 
crystals (R 95D and M 80D supplied by Rohm Pharma GmbH, Weiterstadt, 
Germany). The pharmaceutical vehicles in these combinations are gels which 
have been solidified by heating: 
(a) 20 percent by weight of gelatine/1 percent by weight of glycerine in 
water, and 
(b) 1 percent by weight of agarose in water, and 
(c) 10 percent by weight of ethylcellulose 150 (Hercules GmbH, Hamburg) in 
acetone/water (80:20% by weight), in each case with or without 8 percent 
by weight of pentoxifylline, or another xanthine derivative, stirred in, 
or commercially available gelatine capsules (for administration to humans 
and large animals, size D (supplied by Kapsugel, Basle)). 
The pharmaceutical formulations (see Examples 1-17) are added to 10 ml of 
canine gastric juice or 10 ml of 0.1N HCL and are maintained at 37.degree. 
C. in vitro, stirring gently. Aliquots of the supernatant are taken at 
specified time intervals and are fractionated by high-pressure liquid 
chromatography (column: Rad Pak C18 (Waters GmbH, Eschborn, Germany) 
100.times.8 mm, 10 .mu.m, mobile phase: 300 ml of methanol/1 ml of acetic 
acid, 700 ml of water, flow rate: 1.5 ml/min) and the components are 
determined quantitatively by UV detection at 280 nm. The pharmaceutical 
formulations are inserted in duodenal fluid (dog) or sodium bicarbonate 
solution (pH=7.4) in an analogous manner. 
For administration to small animals (see Table 1, rats), the constituents 
of the formulations mentioned in Examples 1-17 are each reduced to 1/200 
of the weights, or capsules of sizes 4 and 5 are used. 
__________________________________________________________________________ 
released after ( . . . min) 
at 
pH = 1.8 
Example 
Pharmaceutical 
Content of acetyl- 
Content of xanthine 
% acetylsalicylic 
% xanthine 
No. vehicle salicylic acid 
derivative (total) 
acid derivative 
__________________________________________________________________________ 
1 Capsule 58 mg (M80D) 
350 mg 7-(2-Oxopro- 
0 (15) 77 (15) 
pyl)-1,3-di-n-butyl- 
0 (30) 99 (30) 
xanthine .sup. 2 (90) (x) 
2 Capsule 33 mg (M80D) 
100 mg 1-Hexyl-3,7-di- 
0 (15) 79 (15) 
methyl-xanthine 
.sup. 0 (30) 
98 (30) 
3 Capsule 45 mg (M80D) 
400 mg pentoxifylline 
0 (15) 79 (15) 
.sup. 0 (30) 
99 (30) 
4 Coating: gelatine 
500 mg (C) 205 mg 1-(5-Hydroxy- 
0 (5) 2,5 (5).sup. 
containing 205 mg hexyl)-3,7-dimethyl- 
0 (10) 15 (10) 
xanthine xanthine 2,6 (15) 28 (15) 
Core: C 
5 Coating: gelatine 
105 mg (R95D) 
195 mg 1-(5-Hydroxyhexyl)- 
0 (5) 6 (5) 
containing 195 mg 3,7-dimethylxanthine 
0 (10) 21 (10) 
xanthine 4 (15) 35 (15) 
Core: R 95 D 22 (60) 76 (60) 
6 1st Layer: 1 g 
408 mg (M80D) 
400 mg pentoxifylline 
0 (15) 10 (15) 
gelatine contain- 0 (30) 20 (30) 
ing M80D .sup. 0 (60) 
40 (60) 
2nd Layer: R 
7 1st Layer: agarose, 
85 mg (M80D) 
470 mg pentoxifylline 
.sup. 0 (60) 
30 (60) 
containing 70 mg 
xanthine plus M80D 
2nd Layer: R 
8 Coating: agarose, 
62 mg (Dowex 1 .times. 8) 
190 mg 1-(5-Hydroxy- 
0 (5) 4 (5) 
containing 190 mg hexyl)-3-Methyl-7- 
0 (10) 18 (10) 
xanthine propyl-xanthine 
3 (15) 31 (15) 
Core: Acetylsalicylic 
acid bound to Dowex 
9 Coating: gelatine 
30 mg 280 mg 1-(5-Oxohexyl)- 
0 (5) 3 (5) 
containing 280 mg 3-methyl-7-propyl- 
5 (10) 18 (10) 
xanthine xanthine 30 (15) 35 (15) 
Core: Acetylsalicylic 
acid 
10 Suspension of 1 ml 
530 mg (M80D) 
50 mg 1,3-Dimethyl-7- 
0 (5) 4 (5) 
xanthine solution (5-hydroxyhexyl)- 
0 (15) 20 (15) 
(50 mg/ml) and M80D xanthine 2 (20) 35 (20) 
11 Coating: gelatine 
95 mg (Amberlite) 
100 mg 1,3-Dimethyl-7- 
0 (5) 4 (5) 
containing 100 mg (5-oxohexyl)-xanthine 
0 (15) 20 (15) 
xanthine 2 (20) 35 (20) 
Core: Acetylsalicylic 
acid bound to Amberlite 
12 Capsule 390 mg (M80D) 
180 mg pentoxifylline 
0 (15) 10 (15) 
0 (30) 20 (30) 
0 (60) 38 (60) 
.sup. 0 (90) 
46 (90) 
13 Coating: gelatine 
108 mg (M80D) 
465 mg pentoxifylline 
.sup. 0 (60) 
18 (60) 
containing 65 mg 
pentoxifylline and 
100 mg M80D 
Core : pentoxifylline 
(T) 
14 Capsule 35 mg (M80D) 
200 mg pentoxifylline(T) 
0 (30) 28 (30) 
60 mg pentoxifylline 
.sup. 0 (60) 
39 (60) 
15 Capsule 62 mg (M80D) 
200 mg pentoxifylline(T) 
0 (30) 19 (30) 
0 (60) 29 (60) 
.sup. 0 (75) 
36 (75) 
16 1st Layer: pent- 
82 mg (M80D) 
400 mg pentoxifylline 
0 (30) 20 (30) 
oxifylline(R) .sup. 0 (60) 
38 (60) 
2nd Layer: 1 g 
Agarose,contain- 
ing M80D 
17 1st Layer: Pent- 
11 mg (M80D) 
590 mg pentoxifylline 
0 (30) 32 (30) 
oxifylline(R) .sup. 0 (60) 
39 (60) 
2nd Layer: Gela- 
tine, containing 
190 mg Pentoxi- 
fylline and M80D 
__________________________________________________________________________ 
(x)The M80D acetylsalicylic acid crystals which are insoluble in gastric 
acid are quantitatively dissolved at pH 7.4. 
TABLE 1a 
__________________________________________________________________________ 
Effect of various sequences of administration of pentoxifylline and/or 
acetylsalicylic acid 
on Laser-induced thrombosis 
Dose mg/kg 
Number of Number 
Changes from 
rat weight 
animals 
Number of 
of shots 
controls 
Substance oral n lesions/animal 
- x 
SEM 
absolute 
% .chi..sup.2 
__________________________________________________________________________ 
test 
Control -- 12 48 2,17 
0,01 
-- -- -- 
Acetylsalicylic acid 
1 6 24 1,88 
0,35 
-0,35 -13 
Acetylsalicylic acid 
5 6 24 1,79 
0,20 
-0,38 -18 
Acetylsalicylic acid 
10 6 24 2,92 
0,20 
0,75 35 p &lt; 0,01 
Pentoxifylline 
5 6 24 2,63 
0,24 
0,46 21 
Pentoxifylline 
10 6 24 3,33 
0,36 
1,16 54 p &lt; 0,01 
Pentoxifylline + 
5 6 24 2,42 
0,26 
0,25 12 
Acetylsalicylic acid 
+5 
Pentoxifylline + 
10 6 23 2,52 
0,26 
0,35 16 
Acetylsalicylic acid 
+1 
Pentoxifylline + 
10 6 24 2,25 
0,26 
0,08 4 
Acetylsalicylic acid 
+ 10 
Acetylsalicylic acid 
5 6 24 1.96 
0,19 
-0,21 -10 
after 1 h pentoxifylline 
+5 
Acetylsalicylic acid 
1 7 28 2.36 
0,23 
0,19 9 
after 1 h pentoxifylline 
+10 
Acetylsalicylic acid 
10 6 24 2.17 
0,21 
0 0 
after 1 h pentoxifylline 
+10 
Pentoxifylline 
5 6 24 3,21 
0,21 
1,04 48 p &lt; 0,01 
after 1 h acetylsalicylic 
+5 
acid 
Pentoxifylline 
10 6 24 3,88 
0,33 
1,71 79 p &lt; 0,01 
after 1 h acetylsalicylic 
+1 
acid 
Pentoxifylline 
10 6 24 4,71 
0,35 
2,54 117 p &lt; 0,01 
after 1 h acetylsalicylic 
+10 
acid 
Pentoxifylline 
30 6 24 3,97 
0,34 
1,8 83 
Acetylisalicylic acid 
30 6 24 3,21 
0,2 
1,04 48 
Pentoxifylline 
30 6 24 4,86 
0,34 
2,69 124 p &lt; 0,01 
after 1 h acetylsalicylic 
+1 
acid 
Pentoxifylline 
30 6 24 4,83 
0,37 
2,66 123 p &lt; 0,01 
after 1 h acetylsalicylic 
+10 
acid 
Acetylsalicylic acid 
2 6 24 2,50 
0,27 
0,33 15 
(Sephadex .RTM.) 
Pentoxifylline + 
10 6 24 3,95 
0,32 
1,78 82 p &lt; 0,01 
after 1 h acetylsalicylic 
+2 
(Sephadex .RTM.) 
Formulation analogous 
10 6 24 2,79 
0,19 
0,62 29 
to Example 3, acid- 
insoluble microencapsulated 
acetylsalicylic acid (M80D) 
Pentoxifylline + 
10 6 24 4,28 
0,32 
2,11 97 p &lt; 0,01 
acid-insoluble micro- 
+10 
encapsulated acetyl- 
salicylic acid (M80D) 
Formulation analogous 
10 6 24 2,78 
0,20 
0,63 29 
to Example 16 
Acid-insoluble micro- 
encapsulated acetylsalicylic 
acid (M80D) 
Pentoxifylline + 
10 6 24 4,88 
0,35 
2,71 125 p &lt; 0,01 
acid-insoluble micro- 
30 
encapsulated acetyl- 
salicylic acid (M80D) 
__________________________________________________________________________ 
TABLE 1b 
__________________________________________________________________________ 
Effect of pentoxifylline and acetylsalicylic acid on laser-induced 
thrombosis. 
Effect of the time interval between the administrations of the 
substances. 
Dose in each case 10 mg/kg pentoxifylline orally then, after the time 
indicated, 
1 mg/kg acetylsalicylic acid 
Number 
Number 
of of % change from 
Substance animals 
lesions 
- x 
SEM 
controls 
.chi..sup.2 -Test 
__________________________________________________________________________ 
Control (Placebo) 
8 32 2,19 
0,02 
-- -- 
Pentoxifylline without 
9 36 3,27 
0,32 
+49 p &lt; 0,05 
acetylsalicylic acid 
Acetylsalicylic acid 
9 36 1,90 
0,34 
-13 
without pentoxifylline 
0 min 9 36 2,18 
0,13 
0 -- 
15 min 5 20 3,42 
0,21 
+56 p &lt; 0,05 
30 min 5 20 3,59 
0,17 
+64 p &lt; 0,01 
45 min 5 20 3,68 
0,19 
+69 p &lt; 0,01 
60 min 7 28 3,71 
0,18 
+76 p &lt; 0,01 
90 min 4 16 3,33 
0,23 
+52 p &lt; 0,01 
120 min 4 16 2,91 
0,21 
+33 p &lt; 0,01 
180 min 8 32 2,63 
0,21 
+20 p &lt; 0,05 
300 min 8 32 2,25 
0,17 
+3 -- 
__________________________________________________________________________ 
TABLE 1c 
______________________________________ 
Antithrombotic effect of xanthine derivatives (in each 
case 10 mg/kg orally, n = 3) (column a) or consecutive 
administration according to the invention (10 mg/kg xanthine 
derivative and, 1 hour later, 1 mg/kg acetylsalicylic acid oral- 
ly , n = 3) (column b) in the laser model on the rat. The 
percentage improvement compared with the placebo controls 
is shown. Experimental details in the text. 
Substance a b 
______________________________________ 
Control (only acetylsalicylic acid) 
-- -10% 
1-(5-Oxohexyl)-3-methyl- 
42% 56% 
7-propylxanthine 
1-(5-Hydroxyhexyl)-3-methyl- 
40% 53% 
7-propylxanthine 
1-(5-Hydroxyhexyl)-3,7-dimethyl- 
52% 68% 
xanthine 
1-Propyl-3-methyl-7-(5-hydroxyhexyl-)- 
35% 42% 
xanthine 
1-Hexyl-3,7-dimethylxanthine 
39% 46% 
1-Ethyl-3-ethyl-7-(5-oxohexyl-)- 
41% 48% 
xanthine 
1-n-Butyl-3-n-butyl-7-(2-oxopropyl-)- 
33% 50% 
xanthine 
1-(5-Hydroxyhexyl)-3-methyl-7-(2-methyl- 
23% 34% 
propyl)-xanthine 
1-(2-Methylpropyl)-3-methyl-7- 
28% 39% 
(5-oxohexyl-)-xanthine 
1-(5-Oxohexyl)-3-methyl-7-(2-methyl- 
28% 39% 
propyl-)-xanthine 
1-(2-Methylpropyl)-3-methyl-7- 
29% 39% 
(5-hydroxyhexyl)-xanthine 
1-(Isopropyl)-3-methyl-7-(5-hydroxy- 
31% 36% 
hexyl-)-xanthine 
1-(3-Methylbutyl-3-methyl-7-(5-oxo- 
26% 35% 
hexyl)-xanthine 
1-(3-Methylbutyl)-3-methyl-7-(5- 
28% 37% 
hydroxyhexyl-)-xanthine 
1-(3-Oxobutyl)-3-methyl-7-propyl- 
40% 49% 
xanthine 
______________________________________ 
TABLE 2 
______________________________________ 
Time course of the effect of pentoxifylline 
and/or DL-lysine monoacetylsalicylate on 
platelet aggregation 
Aggregation 
Time course 
i.v. dose 
amplitude 
Substance (min) mg/kg E ex vivo 
______________________________________ 
I. without control 
0 -- 27,5 
DL-Lysine mono- 
15 1,5 
acetylsalicylate 
30 23,5 
DL-Lysine mono- 
35 0,5 
acetylsalicylate 
45 19,5 
Pentoxifylline 
90 20 
150 20 
II. without control 
0 -- 26 
Pentoxifylline 
15 20 
DL-Lysine mono- 
45 1,5 
acetylsalicylate 
110 0,5 
III. without control 
0 -- 23 
Pentoxifylline 
15 10 
45 22 
Pentoxifylline 
60 10 
120 20 
______________________________________ 
TABLE 3 
______________________________________ 
Exeriment 
1 2 3 4 5 6 
______________________________________ 
Aggregation 
0,15 0,6 0,15 0,6 0,15 
0,45 
amplitude E 
(.times. 10.sup.2) 
Difference 
-0,3 +0,15 -0,3 +0,15 -0,3 -- 
from the 
control 
experiment 
______________________________________ 
TABLE 4 
______________________________________ 
Ulcerogenic effect of medicaments 
Number 
of 
Number animals 
Acetylsalicylic acid 
of with 
mg/kg animals ulcers 
Substance oral n n 
______________________________________ 
Acetyl- 1,25 10 1 
salicylic 12,50 10 2 
acid 25 10 5 
50 10 7 
100 10 9 
Consecutive 
1,25 10 1 
administration, 
12,5 10 2 
i.e. in each 
25 10 5 
case 100 mg/kg 
50 10 7 
of pentoxyfyl- 
100 10 8 
line 1 h before 
acetyl- 
salicylic acid 
______________________________________ 
TABLE 5 
______________________________________ 
Effect of various medicaments on blood parameters of the 
arthritic rat (n = 8 per group) (for details, see text) 
tendency 
to throm- 
bosis induc. 
erythrocyte 
(number platelet 
Arthritic rat filterability 
of shots) 
aggregation 
______________________________________ 
untreated 59% 46% 100% 
10 mg Acetylsalicylic acid 
63% 47% 62% 
180 mg Acetylsalicylic acid 
68% 91% 35% 
30 mg Pentoxifylline 
79% 87% 94% 
30 mg Pentoxifylline- 
84% 57% 93% 
at the same time 
10 mg Acetylsalicylic acid 
30 mg Pentoxifylline- 
86% 91% 43% 
at the same time 
180 mg Acetylsalicylic acid 
30 mg Pentoxifylline, 
90% 109% 22% 
after 1 hour 
10 mg Acetylsalicylic acid 
30 mg Pentoxifylline, 
96% 104% 30,5% 
after 1 hour 
180 mg Acetylsalicylic acid 
(healthy control rats 
100% 100% 0%) 
______________________________________ 
TABLE 6 
______________________________________ 
Percentage improvement, compared with untreated arthritic 
rats, in the arthritic rats treated with various medica- 
ments (n = 8 per group) (for details, see text). 
Volume of 
paw edema 
left right Necrosis 
paw paw index 
______________________________________ 
10 mg Acetylsalicylic acid 
2 3 8 
180 mg Acetylsalicylic acid 
28 26 28 
30 mg Pentoxifylline 
3 0 7 
30 mg Pentoxifylline 
3 0 4 
10 mg Acetylsalicylic acid 
30 mg Pentoxifylline/ 
10 13 28 
180 mg Acetylsalicylic acid 
30 mg Pentoxifylline/ 
9 12 19 
after 1 hour 
10 mg Acetylsalicylic acid 
30 mg Pentoxifylline/ 
34 32 34 
after 1 hour 
180 mg Acetylsalicylic acid 
______________________________________