BG99683A - Antiphlogistic combination having minimum side effect - Google Patents

Abstract

The anti-inflammatory combination finds application for treatment prevention of acute or chronic musculoskeletal inflammatory processes. It has been reduced gastric injuries while in use, while preserving or enhances the anti-inflammatory effect. It consists of 4- (4-bromophenyl) -2-methyl- 1,2,3,4-tetrahydroisoquinoline hydrochloride and non-steroidal anti-inflammatory drugs preparations which can be administered as separate pharmaceutical compositions or as a single composition.

Description

The invention relates to an improved anti-inflammatory combination with minimal side-ulcerogenic effect for the treatment of various inflammatory processes and consisting of non-steroidal anti-inflammatory drugs and 4- (4-bromophenyl) -2-methyl-1,2,3,4-tetrahydriisoquinoline hydrochloride.

It is known that the side-effect of non-steroidal anti-inflammatory drugs is damage to the gastric mucosa (1) C; Systematic use of anti-inflammatory drugs / leads to an increase in the development of gastric or duodenal ulcers in the oral administration of these drugs.These side effects can be further exacerbated by combining them with other factors such as stress or smoking.

It is known that the ulcerative side effect of anti-inflammatory drugs can be reduced by combination therapy with prostaglandins, which are protectors of gastric mucosa (2).

Some success in reducing the ulcerative effect of anti-inflammatory drugs has also been achieved through combination therapy with H 2 ' receptor antagonists such as ranitidine (3) or roxatidine acetate (4).

- 2 In our patent application EP 'Q4QQ319, we have described a method for the preparation of 4- (4-bromophenyl) -2-methyl-1,2,3,4 tetrahydroisoquinoline hydrochloride, and its protective effect against stress-induced gastric ulcers in rats. The protective effect of the isoquinoline derivative was found to be. manifests in minimal doses and is repeated. higher than that of the histamine Hg receptor antagonist Roxatage. / 5 /

It is an object of the invention to combine the use of non-steroidal anti-inflammatory drugs and 4- (4-bromophenyl) -2-methyl-1,2,3,4 bw · trachydroaioquinoline hydrochloride of formula 1

aa treatment and prevention of inflammatory processes, as well as for the prevention of gastric lesions caused by anti-inflammatory drugs.

We have found in rat experiments that coadministration of compound 1 with non-steroidal anti-inflammatory drugs prevents or diminishes the gastric damage caused by non-steroidal anti-inflammatory drugs, as demonstrated by the examples described in the description.

; Co-administration of compound 1 and non-steroidal anti-inflammatory drugs in a carrageenan-induced model of acute rat paw inflammation leads to the maintenance or enhancement of. the anti-inflammatory effect, which is illustrated by the examples described.

The combination therapy of the invention can be used to treat inflammatory processes, especially acute or 'chronic' musculoskeletal inflammatory processes, such as rheumatitis or osteoarthritis. caused by anti-inflammatory drugs. Such gastrointestinal lesions include duodenal or gastric ulcers, gastritis, damage to the gastric mucosa, or small intestine.

Non-steroidal anti-inflammatory drugs that may be used according to the invention are aspirin, indomethac, for brufen, piroxicam, ketoirofen, naproxen, diclofenac, tolmetin, phenylbutazone, etodolac, sulindac.

Preferred anti-inflammatory preparations according to the invention are aspirin, indomethacin, piroxicam. and diclofenas and particularly preferred aspirin and indomethacin.

Compound 1 of the invention may be co-administered with anti-inflammatory drugs in the form of separate pharmaceutical compositions; alternatively, compound 1 and anti-inflammatory drugs may be administered. administered according to the invention as a single pharmaceutical composition for oral administration is containing effective amounts of the active ingredients »

When compound. 1 and anti-inflammatory preparations are administered as separate pharmaceutical compositions, Compound 1. is administered in the form of tablets, the composition of which is described in one embodiment of the invention.

Anti-inflammatory drugs are administered in the form of known pharmaceutical compositions.

The doses at which compound 1 and anti-inflammatory drugs are administered to humans or animals depends on the route of administration of the anti-inflammatory drugs or the clinical condition of the patient.

The preferred doses for compound 1 are from 5 to 25 mg per unit dose, preferably from 10 to 20 mg. The single dose can be administered one to four times daily.

Non-sterile anti-inflammatory drugs may be administered in a fever that is contained within the normal dose range in which these preparations are therapeutically effective. For example, 10 to 10C mg · indomethacin, 50 mg to 1 g aspirin, 5 to 50 mg piroxicam, 25 to 10C mg dclofenac, for hedgehog. dose,

In cases where compound 1. and anti-inflammatory drugs are administered as a single pharmaceutical composition, the latter contains. in addition, the active ingredients and pharmaceutically acceptable excipients. Suitable excipients include: binders / worm or wheat starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose /, fillers / lactose, microcrystalline cellulose, basic calcium, phosphate /, lubricants / magnesium stearate, talc or silica, talc or silica sulfate /

The pharmaceutical compositions may be prepared by methods known in the pharmaceutical industry. For example, a compound and anti-inflammatory drugs may be mixed with appropriate excipients. The tablets may be prepared by direct compression or by dry granulation of the mixture. e, and will be stained by known methods using suitable pharmaceutically acceptable colorants.

The present invention also provides a method for the treatment of inflammatory conditions in humans and animals, comprising the co-administration of compound 1 and anti-inflammatory drugs.

In an alternative aspect, the present invention also relates to the prevention and treatment of gastric damage in humans and animals caused by anti-inflammatory preparations comprising administering compound 1 at effective doses.

The following examples illustrate the invention without limiting it:

EXAMPLE 1 Investigation of the interaction of Compound 1 and indomethacin in a carrageenan-induced model of acute paw inflammation in rats when co-administered with the drug preparation. (d)

78 Wistar white rat rats of both sexes weighing 180-20.0 were used. Compound 1 was administered as a 1% aqueous solution and indomethacin as a 1% Tween 8Θ suspension.

Animals were divided into 5 units in 4 test groups and a large control group of 10 animals. The test groups were orally treated as follows: I group-indomethacin 10 mg / kg, II group / indomethacin 10 mg / kg and compound 1 2 mg / kg, group III - indomethacin 20 mg / kg, group IV - indomethacin 20 mg / kg and compound 1 2 mg / kg. The control group was administered 1 ml / 100 g of distilled nozzle hourly after, the treatment of animals was injected subplantally into both hind paws of 0.10 ml of 1 $ suspension of carrageenan. Paw volume was measured plethysometrically over the following time periods: baseline, 1,2,3,4,5 and 24 hours of carrageenan injection. The percentage inhibition of carrageenan edema development by hours was calculated by the following formula :

paw swelling paw swelling = --- L ---- OSHNA-ERUYA ----- XW0 control group paw swelling

The results of. Attempts to study the interaction of Compound 1 with indomethacin in rat carrageenan edema mod are presented in Tables L and 2.0t in Table 1. It can be seen that itcomethacin c. a dose of 10 mg / kg has a pronounced, anti-inflammatory effect. compared to the control at 0.001 it is scored at 3.4 and 5th. hour after. treatment of animals with carotene. The anti-inflammatory activity of indomethacin 10 mg / kg increased in dynamics, at the 5th hour the rate of suppression of edema was 63.8 / tab 2. / In the combined administration of indomethacin 10 mg / kg and compound 1 2 mg / kg statistically significant difference from the control group at p <0.001 was reported at 3.4 and 5 hours and at 0.05 at 24 hours after carrageenin administration. Co-administration of indomethacin 10 mg / kg and compound 1 2 mg / kg leads to an increase in the anti-inflammatory activity of itcomethacin. Statistical significance reported at 0.05 for 5 hours against indomethacin / tab alone; The percentage of inhibition of naragenic edema in the treatment of animals concomitantly with indomethacin 10 mg / kg and compound 1. 2. mg / kg is 73.8 / tab. 2 /.

Indomethacin at a dose of 20 mg / kg has anti-inflammatory activity with statistical significance compared to the control at 0.001. at 3,4,5 and 24 hours after administration of carotene / tab ·. 1. / .The percentage of inhibition of carrageenan edema at the 5th hour is 77, E / tai. Co-administration of icdomethacin 20 mg / kg and compound 1. 2 mg / kg showed an anti-inflammatory effect with statistical significance at the control at 0.001 at 3.4 and 5 hours and at p <0.05 at 24- The combined administration of indomethacin and compound 1 resulted in a statistically significant reduction in the anti-inflammatory effect of indomethacin 2C mg / kg at 0.001 per 5 hours / tab. 2 / .The percentage of inhibition of naragenic edema is 60% / Tab.2./.

EXAMPLE '2'. The definition of deer is the interaction of compound 1 and itcomethacin when co-administered with a model of irritant effect on the rat gastric mucosa. (6)

The 48 rats, divided into groups of 6, were tested for oral gastric mucosa not: itcodomethacin at doses of 10 and 20 mg / kg, concomitant administration of indomethacin 10 mg / kg and compound 1 at doses of 2 and 4 mg / kg and concomitant administration of indomethacin 20 mg / kg and compound 1 - 2,4,6 and 8 μγ / κι

- 6 hours after treatment, the animals were killed, their stomachs removed and macroscopic changes of the gastric mucosa on a 5-point scale were recorded:

Q- without. effect, 1- from 1 to 3 hemorrhages, 2 ~ over. 3 hemorrhages, etc. 3 small ulcers, 3 - over, 3 small ulcers and up to 3 large ulcers, 4 - over 3 large ulcers.

After determining the effects on the scale, the ulcerative index (U /) was calculated using the following formula:

UI sum of estimates X% of animals received the impaired number of experimental animals per group

It can be seen from Table 3 that indomethacin administered at a dose of 10 mg / kg causes an irritating effect on the rat mucosa in the expression of haemorrhage and up to 3 small and 3 large ulcers. Ulcerogenic index is 183, 3. .E ^ Premature administration of indomethacin 1.0 mg / kg with compound 1 at a dose of 2 mg / kg reduces gastric lesions etc. minor hemorrhages.Ulcerogenic index decreases to 11.1.Increase the dose of compound 1 to 4 mg / k in combination with indomethacin . 10 mg / kg, decreases to a greater extent the ulcerative index (2.07).

Indomethacin. 20 mg / kg causes severe gastric lesions, with the formation of large ulcers.The ulcerogenic index is 250 Simultaneous treatment of animals with indomethacin 20 mg / kg and compound. 1 at doses of Z and 4 mg / kg influence the ulcerative index, as from 250 it is reduced to 77.7 and 16.6. Accordingly, the dries 6 and 8 mg / kg of compound 1 in combination with indomethacin 20 mg / kg show no sweat gastric lesions caused by indomethacin ..

EXAMPLE 3 Investigation of the interaction of Compound 1 and aspirin in a rat model of acute paw inflammation with the co-administration of both drugs »

65 white Wistar rats were used from each of the two weighing between 180-200 g. »

Aspirin was administered at a dose of 40 mg / kg / 1% aqueous solution / oral. Compound 1 was administered as a 1% aqueous solution orally in freezing 1,2,4 and 8 mt / kg

The experiments were performed using the method of 14 / ί et al / ^ /

Animals were distributed in 5 units in 5 experimental groups and one control group of 10 animals. The experimental groups were treated

orally with the following substances and doses: group I - aspirin 40 mg / kg: group II - aspirin 40 mg / kg and compound 1 1 mg / kg, group III aspirin 40 mg / kg and compound 1-2 mg / Krf group - aspirin 40 mg / kg: and compound 1-4 mg / kg; Ϊ aspirin group 40 mg / kg and compound 18 mg / kg. The control group was administered 1 ml / 100 g distilled water.

One hour later, all the animals were injected subplacerally into the two hind paws with 0.10 ml of 1% suspension of carrageenan. The paw volume was measured plethysometrically over the following time periods: baseline, 1,2,3 , 4,5 and 2 * 1 hour of carrageenan injection.

The results obtained were statistically processed (tab. ^).

The percentage inhibition of development of carrageenan edema by hours (tab. £) was calculated by the following formula:

paw swelling _ paw swelling in% suppression = contr. group experimental group x 100 paw swelling in contr. group

The results of a study of the interaction of aspirin with Compound 1 in a model of acute inflammation-carrageenin swelling in the rat paw are presented in Tables & Tables. 5 · Table b shows that aspirin at a dose of 40 mg / kg has an anti-inflammatory effect. A statistically significant difference from the control at /> 4 0.001 and ^ 40.05 was recorded at 1 and S hours, respectively. animals with carrageenin.

: Addition of compound 1 at various doses to aspirin 40 / mg / kg results in an increase in the anti-inflammatory effect of aspirin. For a dose of 1 mg / kg of compound 1, a statistically significant difference from control was reported at p <0.001 for all hours. A statistically significant difference from aspirin alone at ^ > 0.01 is reported at 3.4 and 5 hours post-carrageenan. A dose of 2 mg / kg of compound 1 administered concomitantly with aspirin 40 mg / kg is statistically significant control at /> / 0.001 for all hours of observation.According to the self-administration of aaspirin 40 mg / kg the statistical significance is at 0.05 at 2 and 5 hours and at pl 0.01 at the 3rd hour.Dose of 4 mg / kg of compound 1 administered concomitantly with aspirin 40 mg / kg showed statistical significance over controls at> 4 0.01 per 2 hours with and 0,001 for all other chasove.Statisticheska significance to samostoyatelns applications aspirin account of the first hour at pl 0,05, 0,01

J ϋ h

J? Ί ί-i ί

I £

at 4 and 5 hours and ^ 20,001 at the 3rd hour after carrageenin administration.

A dose of 8 mg / kg of compound 1 showed statistical significance compared to the control at 0.01 at the 2nd hour and at p £ 0.001 at 1, 3.4.5 and 24 hours. , 05 at 2 h, 0.01 at 5 h, and 0.001 at h and 4 h after carrageenan injection.

Table £ shows the percentages of inhibition of carrageenan? new edema with aspirin 40 mg / kg alone in acute inflammation with carrageenan. Aspirin exhibits an anti-inflammatory effect in the first hour after administration of carrageenan. The percentage inhibition of carrageenan edema is 46.8.In dynamics of the effect of aspirin alone 40 mg / kg decreases at 5 hours - 16.2 Co-administration of aspirin 40 mg / kg and compound 1 at a dose of 1 mg / kg at 1 hour after carrageenin administration does not change the rate of suppression of edema (46.8 ) .The dynamics of carrageenan edema suppression did not occur romenya substantially the 5th hour is 45.0.

Administration of compound 1 at a dose of 2 mg / kg and aspirin 40 mg / k leads to an increase in the effect of aspirin. In the 1st hour injection of carrageenan, the process of suppression of edema is 55.3.In dynamics slightly reduces the anti-inflammatory effect. 5 hours after administration of carrageenan, the percentage of edema suppression is 36. Compared to self-administered aspirin, an increase in the anti-inflammatory effect is observed. Compound 1 administration at a dose of 4 mg / kg in combination with 40 mg / kg aspirin significantly increases the anti-inflammatory effect. effect of aspirin.In the 1st hour with When administered with carrageenin, the percentage of edema suppression was 63.8. At '3 and 4 hours, the percentages were commensurate with that of aspirin in the 1st hour after administration of carrageenin (48.1 and 47.6). at a dose of 8 mg / kg and aspirin 40 mg / kg, leads to the manifestation of anti-inflammatory effect in the late hours - 3 and ⁴ - hour after injection of carrageenan. The percentages of swelling suppression are 41.8 and 44.0, respectively.

EXAMPLE 4.0Determining the interaction of Compound 1 and aspirin when co-administered with a model of irritant effect on the rat gastric mucosa. (B)

The effect of oral administration on the gastric mucosa of: aspirin 40 mg / kg and the interaction between aspirin 40 mg / kg g and compound 1 at 1,2,4 doses was tested on 30 white rats, divided into 6 groups. and 8 mg / kg when co-administered. Four hours after treatment, the animals were killed, their stomachs were removed and macroscopic changes of the gastric mucosa were reported on a 5-point scale: 0 - no effect, 1 - 1 to 3 hemorrhages, 2 - more than 3 hemorrhages and up to 3 small ulcers; 3 - over 3 small ulcers and up to 3 large ulcers; 4 - over 3 large ulcers;

After determining the effect on the scale, the street index (ίυ) was calculated using the following formula:

the sum of the estimates x% of the animals were damaged

U i number of test animals in group j Table 6 shows that aspirin at a dose of 40 mg / kg had an irritating effect on the rat gastric mucosa expressed in

With the formation of hemorrhages and small ulcers.The ulcerogenic index is

L 41,6.

Concomitant administration of aspirin 40 mg / kg and 1 mg / kg of compound 1 showed no irritant effect on the gastric mucosa. The ulcerogenic index was O. Simultaneous administration of compound 1 at doses of 2 and 4 mg / kg and aspirin 40 mg / kg causes no significant irritant effect on the gastric mucosa.Ulcerogenic indexes are 16.6 and 22.2, respectively. Increasing the dose of compound 1 to 8 mg / kg increases the irritant effect of aspirin at a dose of 40 mg / kg. The ulcerative index is 99.9.

EXAMPLE 5. A pharmaceutical composition comprising compound 1

Composition for one tablet in mg 1. Compound 1 5.0 mg 2. Lactose monohydrate 40,0 mg H. Wheat starch 70,0 mg 4. Microcrystalline cellulose 73,0 mg 5.Talk 5.5 mg B. Magnesium stearate 1.5 mg 7Lelatine 5.0 mg 8.Distilled water

Average weight 200.0 mg

The active ingredient, lactose, part of the wheat starch, part of the microcrystalline cellulose are mixed and the resulting mixture is granulated with an aqueous solution of gelatin. talc, then tablet.

EXAMPLE 6. A pharmaceutical composition comprising compound 1 and indomethacin.

Β $

I

And at $

Swallowing one tablet in mg 1. Compound 1 5 mg R. Indomethacin 25 mg H. Lactose monohydrate 64 mg F. Wheat starch 15 mg 5. Microcrystalline cellulose 15 mg 6.Talk 30 mg 7.Magnesium stearate 15 mg 8.Hydroxypropylmethylcellulose- vine E 15 15 mg 9.Ethyl alcohol 95% Average weight per tab. 130 mg

Compound 1, indomethacin, lactose monohydrate, wheat starch, microcrystalline cellulose, talc and magnesium stearate are mixed, and after homogenization of the mixture, granulate with the specified alcoholic solution of hydroxypropylmethyl cellulose to obtain a suitable tabletting mass.

. EXAMPLE 7. A pharmaceutical composition comprising compound 1 and aspirin.

Composition of one tablet in mg

1. Compound 1 1 mg 2. Aspirin 40 mg H. Wheat starch 94 mg 4. Stearic acid 2 mg 5. Microcrystalline cellulose 100 mg 6. Colloidal silicon two- • Oxide 3 mg 7.Talk 5 mg 8.Ethyl alcohol 95% Average weight for one tab . 245 mg

The active ingredients are mixed with a portion of wheat starch and microcrystalline cellulose, homogenized and the mixture granulated with an alcoholic stearic acid solution. and talc and settles.

EXAMPLE 8. A pharmaceutical composition comprising compound 1 rin.

and aspis Composition of one tablet in mg

1. Compound 1 5 mg 2. Aspirin 200 mg 3. Wheat starch 100 mg 4. Stearic acid 5 mg 5. Microcrystalline cellulose 100 mg B.Colloidal silicon dioxide -KIS 5 mg 7.Talk 5 mg 8.Ethyl alcohol 95% Average weight of one tab · 420 mg

The preparation method is analogous to Example 7.

REFERENCES j I. Lanza F.L., Rayer G.L., Nelson R.S., Chen T.T., Seckman E.,.

I ί RackM.F .: Dig. Dis. Sci., 24, 823, 1979.

I l 2. Graham D. Y.: Gastroenterology, 96, 675 »1989.

j 3. Hecla 1., Ishii K., Shinozaki K., Aral H., Hatanaka M.: Chem.

ΐ Pharm. Bull., 38, 3035,. 1990.

4. Muller P., Jackisch P., Simmon B.: Arzneim-Forseh. (Drug

J C Res.), 44 (II), 10, 1994.

!

^: 5. Monieshka DM, Ivanova N., Ivanov Ch.B., Angelova IG:

EP 0400 31 9 AI / 20.04- 90.

ί 6 * Komatsu T., Saito Ch., Awata H., Sakai <1.,. Inukai T., Yammat § H.: Arzneim-ForsctL., 23 (12), 16 90, 1973.

i V · fi / ίL6 ^^ C, A. Xisfcy / 1/1 * 53 & al,? £ xp> τ№ · _z / ίγ7 _t 3 ^

I

Effect of indonetacin and concomitant administration of nondiietacin with compound 1 on paw volume in rat prenenican: carrageenin

dose £ ι OUTPUT. stand- paw volume D + d / k night 1 hr 2h Sc 4h hours 2 + h

0, S7 + 1 ~ · '. ··? <“· 1.63 ·; - 1 - 7ΰ + ·· ·; - “7 ·. .., control _n : j - 12 C ·. 13 . In

indometh. Q, 7 s

C: g Cull and _ Ί; ·? D: _ ·: · M, s: 9 “7 indone. 4: ί: lOug / kg P 99 - • ΐ _ "'' · C; ·. .:. '? · comp .1 ΰ, 11  '· 1 ·? U. 7'7 : f · ·.!

2ug / kg

··: · :::

· '·': At.

·?

INFLUENCE Ηό. INDOGUTACIN AND INDEXF ^ TcLcIN PRI.ΠΟ / ΗΗ ^ ϊ-ι UNION t BUT WITH

C * bG DIN ^ NIO j. Ei'bpXy ό.ό.ρο.Γ '^ ΗΗϊ-ίΟΘ ISLAND H ch JichHc *. y 'Γ7Π ~ οΧ dose

ΠΟ ι Ю К ^ KApeu E? Hi AND WHAT * Im. Oh and OK

Ei l t * -t 4

ΗΗμΟΓ'ί'τΤ rrrs / k

4> t. · <

im home ¹ mg /

ΗΗιμΌγΪΟΤ.

O ' ^- ' .......... .. · j .. ...

sod.1 ~ 2 .J

Tab.

Test of irritant effect on groan, mucous membrane of rats by oral administration of indomethacin and indonetacin with compound 1

Θ-ΘΟ / Annoying act yours on the gastric mucosa dose in ~ without effect up to 3 blood- pouring to 3 ulcers sticks up to 3 lemma ulcers over 3 shaved ulcers NOW IS ^ ent ι; T. 0 1 4 10 -:.; / Kg 0 / β INDOI & T. • 1. ·· L ' 2 '£ 1 1 :: ..- 2., 2 10nrs / kg _{4 /:} indomethacin. comp. 1 -2: ;; '- ·; / k ύ 2 1 1. ': : in / ::. g ........ indometh. comp. 1 -4yy; d / k P · /? : J - ·. . .. .... 20: ;; gk kg 0 / lb indometh. 1 / £ 1 ! · '··' ⁴ , ·· .. 20: ^: · k- ....... . ·. · ·. indometh. 2 / £ :. / B • i. ·. · .: ...., . ....

Shedd. x tuur ^ ·· '(·

20ro _S / ::: o ... _: . _{/ e} . indometh. .1 --4.:,:in/ kg / £ P. 2o _m,; / kg:., _{/ £} ι /.- ::  . ·· f: ··. ·. ··. ' indometh. .:. · ... · · _ · · .. '; t · - · ll-Sog / ky w, ___________ _r ____________________ (iKogpn /: / d _{D [} ..,. indomet. 1, ό <y 2 k · I £ ·: 2 1 C -: i- A G-> j.- ..... \ -Ex.? X b. .-

Tab. 'ί

Effect of aspirin and concomitant administration of aspirin ate compound 1 on paw edema in rat carrageenin a.

and ί

ί і

dose OUTPUT. paw volume ♦ SD in UU / 4 is STOI - night 1h 2h 4h 5h 84-

control 4- 0. 3 7- a. ι _ ···. ··? · » 4L- .1. • ί * ···  7 and · - · 1 .1. ... with. 13 and.O- · - · , 15 a, ίο 3, 18 - , 15 0, 11 + 1- aspirin U, 84 · - 1, 18 1 , 40 - 1, 80 ·· A. , 51 - 4.0 / 9 // _g w, 0, 03 11 .. 08 p le 0, 1 3 The scoreboard is now 0-1. .1. L 4 . - l Aspirin 40.? is k H 0, ...: ·. 1 ·. 1 G '1 , ότ - L: ·! ·: Y. L L L L ::: L · :! ·: L '\ j: <; _Mr compd. 1 1yy / 4 <y 3.08 0 - 08 0 .. 15 0, .12 3, L · 510 0, 1 4 aspirin 40 uchL y ·?.:: · ¹ .: L ........ L L *::! ·: L: ·: 9. L L in: . 07 ^; - ϊ - * - ··:; ... 1 · '? 2. ; ·· -. compd. 1 ί? . ··. . ». ··. ! ···. ·; ·. hL ' ..  . 2tU / h e. ·. L. 7 - * · · ·

aspirin 0.87- ·· . = .. l l l 1.03 ~. . l:: ·? ·: .1 - <9 / ' . ·., L L 7 - - f 1.31- · 2 : ::: L l L 1.40 ·· ... .. 40 ·. ··; ·: -. ·· 0,0 3 0.08 ·· Εη 0, 38 : X Cu · _ · ·. · ·,. · Ο

compound 1 gp / ku aspirin

COifiy / k hr. 1 '

:!: L L L Λ. 4 _ _ .... 1,24-, · · · - L: 5: L L. - ι .:. D ·. G-Q G: 9. '* ~ ·' 0. 0 2 0; 0 7 '' : Ί. Π - ' ⁸ ~'' > - ·?

Data are presented as means + standard deviation (21L

C 0 Ι ·. with straight reference values.

Ca> statistical significance

Of statistical significance statistical significance at p < 3 &gt; C with respect to aspirin 4G, ₅ g /; ~ at p <C, 01 relative to aspirin 4G; .. L ;, h at 1-13,301 to aspirin 40 t cO.'f. · _. ·.

Effect of aspirin and aspirin with compound 1 on cwhcthgtg it ·:

IN LOGHPHY ORHU CO.R. PUNINOSIS ISLAND OF LOIA IN RATH

DOSE And suppress.NN ' р -.-313 И ι И У ТО But rso.pO.1 * '* * OH Θ ......... ·;. "" ' about »- H U Ή Ο .. Cw -1 aspirin And '' · /g.·.-: D - “-! 'Mr- ν>, ο 1 ;, .1. 1 * ". ·" Γ

o.C P I r I I ;;; <? / ku co ^ d .1 -Ztlu / ku

OS 11Irin

ex PIRIN

40pc

YUD .x “wily / ί ·: y

TEST DRO.ZN ^ WHAT! ABOUT ι SH6- "-Z-pX"? 'O j ON - "IGc6" IC0. Ηό t · П7> Х «.» · **?

PRI 11 «? Roro.71NO or rILOF / ZINE NO. OOiiHpHH AND «SnIRIN

WITH. Oh Er? Smoke? H * b · - “l

a-so WELL 3 WHAT / DVIS IS YOUR YELLOW With t Οί · ί8шОЛИ .1 dBriijo. dose is _ ...... ..., ... without TO о КРО-ЗО ~ DO О ^ία ^ ΚΗ TO ο ΓΟ · ”Ηομ -> ι Ο Ltd. ofoHT from l ΙΗοά. NUTS .ΠΟ (ΊΗ PUTS PLEASE? PERSONALS r \ I .L f._ »ο -ΐ- 40g; r = //: =! 1/6 2/6 3 / 6 0 6 ό -t'l. ό i aspirin 4O.L - / ': S.: ... ... O. ·· C · Pirin '- · ^{: J :} ··· .-. ; -. comp. 1 -1 yy; ~ / k 5 ^ rx · - PRI me R 6 'J ^: · - ' : 6 /. j comp. 1 ~ 2G. : / 40gp //: with 4/6 ΰ 2 / .ς ι ”: / _. 1 aspirin comp. 1 -4yy; d / k 401;: · = // o .,. ... . · .- ··. - - .- n aspirin i J 4 comp. 1 -Sn; c / k ·

'5

Claims (8)

An anti-inflammatory combination for the treatment of acute or chronic musculoskeletal inflammatory processes (arthritis or osteoarthritis) characterized in that it contains 4- (4-bromophenyl) -2-methyl-1,2,3,4 tetrahydroisoquinoline hydrochloride and non-steroidal anti-inflammatory drugs . 2. The anti-inflammatory combination according to claim 1, characterized in that the anti-inflammatory preparation is aspirin, indomethacin, ibobrufen, piroxicam, ketoprofen, n8proxen, diclofenav, tolmetin, phenylbutazone, etodolac, sulindac. An anti-inflammatory combination according to claim 1, characterized in that it consists of 4- (4-bromophenyl) -2-methyl) -1, 2,3,4 tetrahydroisoquinoline hydrochloride and indomethacin. An anti-inflammatory combination according to claim 1, characterized in that it consists of 4- (4-bromophenyl) -2-methyl-1,2, 3,4 tetrahydroisoquinoline hydrochloride and aspirin. 5. The anti-inflammatory combination according to claim 1, characterized in that N @ n consists of 4- (4-bromophenyl) -2-methyl-1,2, 3,4 tetrahydroisoquinoline hydrochloride and diclofenac. 6. Administration of 4- (4-bromophenyl) -2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride and anti-inflammatory preparations according to claim 1.1 simultaneously: sequentially in the form of separate pharmaceutical compositions. A pharmaceutical composition for oral administration comprising 4- (4-bromophenyl) -2-methyl-1,2,3,4 tetrahydroisoquinoline hydrochloride and non-steroidal anti-inflammatory drugs together with pharmaceutical excipients. Use of 4- (4-bromophenyl) -2-methyl -%, 2,3,4 - tetrahydroisoquinoline hydrochloride for the preparation of medicaments for the prevention of gastrointestinal lesions caused by non-steroidal anti-inflammatory drugs.